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Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

      Abstract

      Purpose

      To develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease.

      Methods

      Review of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases.

      Results

      Although clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI.

      Conclusion

      These guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic indivduals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network. Genet Med 2011:13(5):457– 484.

      Keywords

      Background

      The lysosomal storage diseases (LSDs) comprise a heterogeneous group of almost 50 disorders that are caused by genetic defects in a lysosomal acid hydrolase, receptor, activator protein, membrane protein, or transporter, causing lysosomal accumulation of substrates that are specific to each disorder. The accumulation is progressive, ultimately causing deterioration of cellular and tissue function. Many disorders affect the central nervous system (CNS) and most patients have a decreased lifespan and significant morbidity. The LSDs are often categorized according to the type of substrate stored (i.e., mucopolysaccharidoses, oligosaccharidoses, sphingolipidoses, gangliosidoses, etc.).
      • Wilcox W.R.
      Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care.
      Most lysosomal proteins are the products of housekeeping genes expressed throughout the body, but storage occurs only in those cells with an available substrate (e.g., GM2 ganglioside is present predominantly in the CNS and deficiency of hexosaminidase A, which acts on the GM2 ganglioside and can be measured in the blood, causes Tay Sachs disease, a CNS condition). In all cases, the diagnosis must be established by specific enzyme assays and by mutational analysis. Urinary mucopolysaccharides and oligosaccharides, although useful for screening, can be normal and increased nonspecifically in healthy neonates.
      • Piraud M.
      • Boyer S.
      • Mathieu M.
      • Maire I.
      Diagnosis of mucopolysaccharidoses in a clinically selected population by urinary glycosaminoglycan analysis: a study of 2,000 urine samples.
      Although each disorder is rare, LSDs as a group have a frequency of one in 7000–8000 live births.
      • Meikle P.J.
      • Hopwood J.J.
      • Clague A.E.
      • Carey W.F.
      Prevalence of lysosomal storage disorders.
      ,
      • Poorthuis B.J.
      • Wevers R.A.
      • Kleijer W.J.
      The frequency of lysosomal storage diseases in The Netherlands.
      The frequency estimate may be low as more individuals with mild disease and/or adult-onset forms of the diseases are being identified.
      All LSDs are inherited in an autosomal recessive fashion, except for Fabry, Hunter (mucopolysaccharidosis type II [MPS II]) and Danon diseases, which are X-linked. Some disorders are more prevalent in certain geographic areas or among particular population groups (e.g., Gaucher, Tay-Sachs, Niemann-Pick type A, and mucolipidosis IV are more common in Ashkenazi Jews), largely as a result of ancestral founder mutations.
      • Mistry P.K.
      Gaucher's disease: a model for modern management of a genetic disease.
      • Natowicz M.R.
      • Prence E.M.
      Heterozygote screening for Tay-Sachs disease: past successes and future challenges.
      • Schuchman E.H.
      • Miranda S.R.
      Niemann-Pick disease: mutation update, genotype/phenotype correlations, and prospects for genetic testing.
      For many diseases, such as Fabry, most kindreds have private mutations.
      Highly effective preconception carrier screening programs for populations at risk for Tay-Sachs disease have been in place since 1971,
      • Natowicz M.R.
      • Prence E.M.
      Heterozygote screening for Tay-Sachs disease: past successes and future challenges.
      ,
      • Becker M.H.
      • Kaback M.M.
      • Rosenstock I.M.
      • Ruth M.V.
      Some influences on public participation in a genetic screening program.
      leading to a great reduction in the number of affected children born. Carrier screening of Ashkenazi Jews has been expanded to include several other hereditary disorders found at higher frequency in this group.
      • Zinberg R.E.
      • Kornreich R.
      • Edelmann L.
      • Desnick R.J.
      Prenatal genetic screening in the Ashkenazi Jewish population.
      A single clinically defined disorder may be caused by more than one enzymatic defect, such as Sanfilippo disease (MPS III), that can be caused by a deficiency in any one of four hydrolases. Conversely, a disorder caused by a single enzyme deficiency usually gives rise to a spectrum of manifestations depending on the amount of residual enzyme activity and currently unknown modifiers. The age of onset, severity of symptoms, organ systems affected, and CNS manifestations can vary markedly, sometimes even within families. Although specific mutations or types of mutations can be associated with certain outcomes, genotype-phenotype correlations are typically not strong as with Gaucher disease (GD) patients with the same mutations who may present in childhood or be asymptomatic throughout adult life.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      For women with X-linked lysosomal storage disorders such as Fabry disease, the severity and extent of disease manifestations may be determined primarily by the degree of X-chromosomal inactivation,
      • Desnick R.J.
      • Ioannou Y.A.
      • Eng C.M.
      Alpha-galactosidase A deficiency: Fabry disease.
      although evidence of random inactivation has been shown.
      • Maier E.M.
      • Osterrieder S.
      • Whybra C.
      Disease manifestations and X inactivation in heterozygous females with Fabry disease.

      Diagnosis and ascertainment

      Probands are typically ascertained because of clinical signs and symptoms, often after the disease is advanced and interventions less efficacious. Presymptomatic individuals, the subject of this article, may be ascertained through screening of family members of the proband, carrier screening, prenatal testing, populations at risk for a genetic disorder, or newborn screening (NBS). As will be discussed for each disorder, diagnosis depends on enzymatic or molecular definition of mutations, or both.

      Treatment of LSDs

      Because of their wide-ranging medical and psychosocial ramifications, LSDs require an ongoing multidisciplinary, team approach to treatment. Comprehensive management generally combines disease-specific therapy (if available) with symptom-specific measures. The team leader should be someone (generally a biochemical geneticist) who is experienced in treating LSDs, is aware of disease-specific complications and nuances of therapy, and keeps up to date with recent advances. Each patient's team should include other relevant medical specialists familiar with LSDs. Once a diagnosis is established, genetic counseling is essential to provide patients and their families with an understanding of mode of inheritance, identify at-risk family members, and discuss recurrence risks. Patient and parent support groups are invaluable sources of emotional support and practical advice.
      Hematopoietic stem cell transplantation (HSCT) has been used successfully in the management of some LSDs. The rationale behind HSCT is that a reconstituted hematopoietic system from a healthy, matched donor will contain stem cells that can produce the missing enzyme. The small amounts of secreted enzyme are available to be taken up by mannose-6-phosphate receptors on other cells, endocytosed, and delivered to the lysosome. The major drawback to HSCT is its high morbidity and mortality, although both have improved over time, particularly with the use of refined conditioning regimens and cord blood as a stem cell source. Graft failure is more common in HSCT for some of the LSDs. The advantage of HSCT is that cells can integrate into many tissues, including the CNS. The disadvantages include the low level of correction and the time required for integration of the cells into other tissues, factors that currently preclude HSCT from being curative.
      Specific treatments for LSDs are evolving rapidly with the involvement of an expanding number of biotechnology companies. Most widely used is enzyme replacement therapy (ERT), which supplies the missing enzyme exogenously through repeated intravenous infusions. With ERT, larger doses of enzyme can be administered than are attainable through HSCT; however, the blood-brain barrier (BBB) cannot be crossed, precluding the use of ERT for CNS disease. Even in patients with significant CNS involvement, ERT may be useful for reducing the morbidity associated with the somatic manifestations. The usefulness of ERT in the pre- and peri-HSCT period is being studied, and intrathecal ERT is being tested for MPS I and II. ERT is currently commercially available for Gaucher, Fabry, MPS I, II, VI, and Pompe diseases (PDs) and is undergoing clinical trials for MPS IVA and Niemann-Pick type B.
      ERT is not without its challenges. Many patients do not produce native enzyme (and are cross-reacting immunologic material [CRIM]-negative) or make native enzyme that differs significantly from administered enzyme, and consequently make antibodies to the exogenous enzyme, which may reduce efficacy and often causes adverse infusion reactions. Fortunately, the infusion reactions are usually easy to treat, many patients develop tolerance over time, and allergic reactions are rare.
      Oral therapies are available for two LSDs and more are being tested. Cysteamine is used successfully to preserve renal function in cystinosis.
      • Gahl W.A.
      • Thoene J.G.
      • Schneider J.A.
      • O'Regan S.
      • Kaiser-Kupfer M.I.
      • Kuwabara T.
      NIH conference. Cystinosis: progress in a prototypic disease.
      • Schneider J.A.
      • Clark K.F.
      • Greene A.A.
      Recent advances in the treatment of cystinosis.
      • Gahl W.A.
      • Balog J.Z.
      • Kleta R.
      Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy.
      Substrate reduction therapy (SRT) with N-butyldeoxynojirimycin (OGT-918, miglustat, Zavesca; Actelion, Basel, Switzerland) reduces production of glycosphingolipids by inhibiting glucosylceramide synthase, the first step of their biosynthesis. SRT is approved for use in GD, although side effects preclude its more widespread use,
      • Cox T.
      • Lachmann R.
      • Hollak C.
      Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.
      ,
      • Elstein D.
      • Hollak C.
      • Aerts J.M.
      Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease.
      and Niemann-Pick type C in Europe. A new-generation agent (Genz-11638; Genzyme Corporation, Cambridge, MA) is being tested that may have fewer side effects. For SRT to reduce lysosomal storage, there must be residual enzyme activity, which is always the case in GD but not in other disorders. Unfortunately, SRT does not reduce substrate turnover, resulting in cellular depletion of these evolutionarily conserved (and presumably important) glycolipids, a fact that may ultimately limit the utility of this therapeutic approach.
      Oral small molecule chaperones are compounds that improve the folding and trafficking of lysosomal proteins with specific missense mutations. Clinical trials for Fabry disease are underway (Amicus Therapeutics, Camden, NJ). PTC124 (Ataluren®, PTC Therapeutics, South Plainfield, NJ) causes the ribosome to read-through nonsense codons and yet allows the ribosome to end translation normally at the correct stop codon. This drug, currently in testing for other conditions, could be useful for some patients with LSDs caused by nonsense mutations.
      Gene therapy holds the promise of a cure for LSDs. However, many hurdles must be overcome before gene therapy can be applied to the LSDs including delivery to the correct cells, random integration, sustained expression, and immune reactions.
      There is currently great variability in clinical practice for LSD treatment both within and among countries. Specific areas of controversy include when (and even if) to start specific therapies, what dose to use, how to monitor patients, when to stop treatments, and what adjunctive therapies should be used. Some of the variability is based on legitimate financial concerns given the expense of many specific therapies, but much has to do with the lack of long-term longitudinal studies with sufficient numbers of patients. Many available data comes from case reports, case series, clinical trials involving small numbers of patients, and voluntary patient registries as part of industry's postmarketing commitments to the drug regulatory agencies.
      For many countries, expense is a large consideration in the treatment of LSDs. Insurance plans may have a lifetime cap for drug expenses that can be rapidly exhausted with most of the available therapies. Some health systems demand that each new therapy be demonstrated to be cost-effective, a difficult challenge for these rare disorders. Some have designed special funding programs for rare disease treatments. Less affluent countries are unable to afford the drugs or routinely use a low dose. Some help is provided to many patients without resources by assistance programs from the drug companies; however, most individuals worldwide receive supportive and palliative care, at best.
      Caring for presymptomatic individuals, however, diagnosed highlights the current limitations in our diagnostic evaluations and decision making. In part, the difficulty is due to the often poor correlations of residual enzyme activity and genotype with the clinical phenotype. HSCT is a consideration for some disorders that may have CNS involvement. To be effective, HSCT has to be performed well before evidence of CNS involvement. Because phenotype-genotype correlations are imperfect, it will always be uncertain whether a particular newborn will need HSCT or not. Because HSCT has significant associated mortality and long-term morbidity, deciding if and when to transplant will be a major area of clinical difficulty, as discussed in the context of the individual disorders. Other areas of difficulty include the often variable clinical response to therapy, the long time required for improvement or stabilization to be evident for those who become affected, and the general lack of large natural history studies for comparison. Most disorders lack useful and accepted biomarkers for therapeutic decision making.

      Newborn screening

      Early detection of LSDs can be important for patients and their families and constitutes a major rationale for instituting NBS. For several disorders, it is clear that earlier initiation of therapy can make a substantial difference in outcome. The LSDs are sufficiently rare that most practitioners are unaware of their signs and symptoms, leading to diagnostic odysseys and delayed diagnoses. By the time patients are diagnosed, they may have suffered irreversible damage, limiting the effectiveness of treatment. Many patients remain undiagnosed. A second affected child is often born before the first is diagnosed. There is much to be learned about what can be realistically achieved with earlier detection (e.g., the response of skeletal disease in MPS VI) as well as the true incidence and extent of each disease.
      Testing from dried blood spots (DBSs) is now possible for several LSDs using the same blood spot sample and high-throughput platforms, making population screening technically feasible (Table 1).
      Table 1Comparison of two newborn screening assays for specific LSDs that can be determined from the same newborn screening sample
      However, only few data are available that address sensitivity and specificity of these assays. Nevertheless, the Centers for Disease Control and Prevention has already produced freely available quality control DBS material for several LSDs,
      • DeJesus V.R.
      • Zhang X.K.
      • Keutzer J.
      Development and evaluation of quality control dried blood spot materials in newborn screening for lysosomal storage disorders.
      making high-throughput screening programs feasible. NBS for some LSDs has or will begin shortly as pilot programs (Pompe and Fabry diseases in Taiwan and Fabry disease in Washington State) or as additions to established NBS programs (Krabbe disease [KD] in New York State and Krabbe, Fabry, Pompe, Niemann-Pick, and Gaucher diseases in the States of Illinois and Missouri; Austria has piloted two studies on Fabry and Pompe diseases, respectively). At the same time, Pompe and Krabbe diseases were nominated to the US Advisory Committee on Heritable Disorders of Newborns and Children for inclusion in NBS. The Advisory Committee on Heritable Disorders of Newborns and Children did not consider the evidence to be sufficient to be able to recommend their inclusion at the current time.
      As with any screening program, there are many ethical considerations in screening for LSDs. Variants of uncertain significance will certainly be identified. Adult-onset variants will be identified, perhaps in greater numbers than the early infantile forms of these diseases, and some patients with these may never develop symptoms or require therapy. Identification of both novel and adult-onset variants can lead to problems with insurability, labeling someone as vulnerable from birth, excluding from military service, etc. Consumers vary in their desire to detect late-onset disorders in the neonatal period and the acceptance of anxiety that some will face during a diagnostic evaluation for a positive screen. However, experience suggests that parents of patients and older patients with delayed diagnoses are almost universal in their support for early detection. Legislative changes will be needed to protect identified individuals from discrimination and ongoing counseling and support for patients and families will be required to minimize the psychosocial effects of early detection for adult onset LSDs. In this regard, in the United States, the Genetic Information Nondiscrimination Act provides legal protection against discrimination for health insurance or employment for individuals with a presymptomatic genetic condition.
      • Erwin C.
      Legal update: living with the Genetic Information Nondiscrimination Act.
      ,
      • Rothstein M.A.
      Putting the Genetic Information Nondiscrimination Act in context.
      Any NBS system requires an organized network of centers for definitive diagnostic tests, genetic counseling, and treatment. Generally, care of LSD patients is coordinated by biochemical geneticists or metabolic disease specialists at centers equipped to handle the complex, multidisciplinary needs of LSD patients. Such trained individuals and centers are currently in short supply. Large geographic regions are entirely lacking in the necessary expertise. Even within centers, caring for LSD patients is time consuming, often requires expertise and facilities for the treatment of children and adults, and involves a significant amount of unreimbursed time from physicians and their staff. Many private payers will not authorize follow-up visits at LSD centers, under the erroneous belief that any physician is capable and willing to deal with complex therapies and their side effects, coordinating multidisciplinary care and dealing with anxious families. Even if the patient can be seen by the appropriate specialist, they may only make recommendations for testing and treatment that is then up to the primary care physician to arrange, something many are ill-equipped or unwilling to do. Many patients must travel great distances to receive weekly or biweekly drug infusions, even if a local infusion center is available and long after home therapy could be appropriate.
      Another essential component of a LSD screening program is an experienced laboratory for rapid and accurate enzymatic and molecular testing. The laboratory must incorporate appropriate quality assurance and proficiency testing programs including sample sharing between laboratories. There are currently only a few laboratories around the world with the required expertise and experience.
      A final important part of a NBS program is a well-designed, monitored, longitudinal follow-up program. This will allow definition of natural history and response to therapies, providing answers to the many outstanding questions not addressed by small pilot programs, case series, and industry-sponsored registries. Such a follow-up network should have a biological repository of samples to serve as a resource for identification and validation of biomarkers and modifier genes. These are precisely the charges of the new American College of Medical Genetics (ACMG)/National Institutes of Health (NIH) Newborn Screening Translational Research Network.

      Purpose

      This guideline is intended as an educational resource. It highlights current practices and therapeutic approaches to the diagnosis and management of individuals who may have a LSD that is identified by NBS, family screening through a proband, or because of carrier testing in at-risk populations and subsequent prenatal or postnatal testing. Rather than discussing all LSDs, this guideline focuses on select LSDs for which a NBS test and some specific treatment are available or may become available in the near future. The goal is to provide some guidance for confirmatory testing and subsequent management as well as to define a research agenda for longitudinal studies, such as the Newborn Screening Translational Research Network being initiated by the ACMG with funding from NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development.

      Target audience

      This guideline is directed at a wide range of providers, although care is commonly provided by metabolic disease specialists/biochemical geneticists and neuromuscular experts.

      Materials And Methods

      Consensus development panel

      An international group of experts in the (a) clinical and laboratory diagnosis, (b) treatment and management (cardiac, respiratory, gastrointestinal/dietary, musculoskeletal, neurologic, psychosocial, general medical, and supportive and rehabilitative), (c) NBS, and (d) genetic aspects of LSDs was assembled to review the evidence base and develop a guideline on the diagnosis and management of the presymptomatic LSD patient.
      Following a meeting during which published material and personal experience were reviewed by the panel, experts in the various areas reviewed the literature (predominantly English language identifiable with a PubMed search) in these areas and drafted their appropriate guideline sections. All members of the panel reviewed and approved the final guidelines. Consensus was defined as agreement among all members of the panel. For the most part, the recommendations must be considered as expert opinion because additional levels of evidence were not available in the literature. Where available, evidence from clinical trials is used to guide recommendations. The guideline was reviewed by the ACMG Board and approved on August 23, 2010.

      Results: Guidelines For Specific LSDs

      Pompe disease or glycogen storage disease type II (OMIM# 232300)

      Synonyms

      Acid maltase deficiency, acid α-glucosidase (GAA) deficiency.

      Background

      PD is due to intralysosomal accumulation of glycogen secondary to deficiency of GAA (EC 3.2.1.20). The resulting clinical phenotypic spectrum ranges from infantile to adult-onset. PD was first recognized by Dr. Pompe in a 7-month-old infant
      • Pompe J.C.
      Over idiopatische hypertrofie van het hart.
      and later named as PD.
      • Cori G.T.
      Glycogen structure and enzyme deficiencies in glycogen storage disease.
      PD was the first inborn error of metabolism to be recognized as a LSD.
      • Hers H.G.
      Alpha-glucosidase deficiency in generalized glycogen storage disease (Pompe's disease).
      The overall prevalence of PD is estimated to be approximately 1:40,000 in the Netherlands and in New York City.
      • Ausem M.G.
      • Verbiest J.
      • Hermans M.P.
      Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling.
      • Ausems M.G.
      • ten Berg K.
      • Kroos M.A.
      Glycogen storage disease type II: birth prevalence agrees with predicted genotype frequency.
      • Martiniuk F.
      • Chen A.
      • Mack A.
      Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease.
      The prevalence of infantile-onset PD is estimated to be 1:138,000 births in the Netherlands, 1:33,000 in Taiwan based on NBS, and it seems to be more frequent overall in the Chinese and Afro-American populations.
      • Ausem M.G.
      • Verbiest J.
      • Hermans M.P.
      Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling.
      ,
      • Ausems M.G.
      • ten Berg K.
      • Kroos M.A.
      Glycogen storage disease type II: birth prevalence agrees with predicted genotype frequency.
      ,
      • Hirschhorn R.
      • Reuser A.J.J.
      Glycogen storage disease type II: acid alpha glucosidase (acid maltase) deficiency.
      ,
      • Chien Y.H.
      • Lee C.
      • Thurberg B.L.
      Pompe disease in infants: improving the prognosis by newborn screening and early treatment.

      Clinical phenotype

      All patients with PD have variable but progressive, intralysosomal glycogen storage in skeletal, heart, and smooth muscles with resulting organ damage and ultimate organ failure. The rate of glycogen accumulation depends on residual enzyme activity, environmental factors (nutrition), muscle fiber type, physical activity, and as yet unknown genetic modifiers.
      • Fukuda T.
      • Ahearn M.
      • Roberts A.
      Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease.
      Patients with the same haplotypes around the mutant gene may in fact exhibit different clinical phenotypes.
      • Kroos M.A.
      • Pomponio R.J.
      • Hagemans M.L.
      Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype.
      Although PD is often classified into two separate categories—infantile-onset and late-onset—based on age of onset of symptoms, PD is a clinical disease spectrum.
      • Winkel L.P.
      • Hagemans M.L.
      • Van Doorn P.A.
      The natural course of non-classic Pompe's disease; a review of 225 published cases.
      • Kishnani P.S.
      • Steiner R.D.
      • Bali D.
      Pompe disease diagnosis and management guideline.
      • Kishnani P.S.
      • Corzo D.
      • Nicolino M.
      Recombinant human acid α-glucosidase: major clinical benefits in infantile-onset Pompe disease.
      • Hirschhorn R.
      • Reuser A.J.J.
      Glycogen storage disease type II: acid a-glucosidase (acid maltase) deficiency.
      Patients with infantile (classic) PD present with progressive left ventricular hypertrophy and generalized muscular hypotonia (floppy infant) and typically die within the first year of life because of cardiorespiratory failure.
      • van den Hout H.M.
      • Hop W.
      • van Diggelen O.P.
      The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature.
      • Howell R.R.
      • Byrne B.
      • Darras B.T.
      • Kishnani P.
      • Nicolino M.
      • van der Ploeg A.
      Diagnostic challenges for Pompe disease: an under-recognized cause of floppy baby syndrome.
      • Infantile-Onset Pompe Disease Natural History Study Group
      A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease.
      • Di Rocco M.
      • Buzzi D.
      • Tarò M.
      Glycogen storage disease type II: clinical overview.
      Significant cardiomyopathy may already be present in utero and readily detected by prenatal ultrasound. In addition, the electrocardiogram (ECG) may show conduction abnormalities including a short PR interval, characteristic tall QRS complexes, and Wolf-Parkinson-White syndrome in some patients.
      • Winkel L.P.
      • Hagemans M.L.
      • Van Doorn P.A.
      The natural course of non-classic Pompe's disease; a review of 225 published cases.
      ,
      • Hirschhorn R.
      • Reuser A.J.J.
      Glycogen storage disease type II: acid a-glucosidase (acid maltase) deficiency.
      ,
      • Infantile-Onset Pompe Disease Natural History Study Group
      A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease.
      ,
      • Cook A.L.
      • Kishnani P.S.
      • Carboni M.P.
      Ambulatory electrocardiogram analysis in infants treated with recombinant human acid alpha-glucosidase enzyme replacement therapy for Pompe disease.
      Additional symptoms include macroglossia, hepatosplenomegaly, and feeding difficulties.
      • Winkel L.P.
      • Hagemans M.L.
      • Van Doorn P.A.
      The natural course of non-classic Pompe's disease; a review of 225 published cases.
      ,
      • Kishnani P.S.
      • Steiner R.D.
      • Bali D.
      Pompe disease diagnosis and management guideline.
      ,
      • Van den Hout H.M.
      • Hop W.
      • Van Diggelen O.P.
      The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature.
      Patients usually present with disease symptoms at approximately 3 months of age and death occurs at a median age of 6.0–8.7 months.
      • Infantile-Onset Pompe Disease Natural History Study Group
      A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease.
      ,
      • Van den Hout H.M.
      • Hop W.
      • Van Diggelen O.P.
      The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature.
      The leading clinical symptom in patients with late-onset PD (“nonclassic” childhood, juvenile, or adult-onset) is progressive muscle weakness due to initial involvement of the muscles of the proximal lower limbs and the paraspinal muscles. There is a significant early involvement of the diaphragm and accessory respiratory muscles, which leads to respiratory failure necessitating assisted ventilation, in some instances, even when patients are still ambulatory.
      • Di Rocco M.
      • Buzzi D.
      • Tarò M.
      Glycogen storage disease type II: clinical overview.
      Occasionally, respiratory failure may be the presenting clinical symptom associated with frequent upper airway infections, orthopnea, sleep apnea, and morning headaches.
      • Hirschhorn R.
      • Reuser A.J.J.
      Glycogen storage disease type II: acid a-glucosidase (acid maltase) deficiency.
      ,
      • Di Rocco M.
      • Buzzi D.
      • Tarò M.
      Glycogen storage disease type II: clinical overview.
      Cardiac involvement is typically not observed in late-onset PD although some patients do have rhythm abnormalities due to underlying Wolf-Parkinson-White syndrome and cardiac hypertrophy can be noted in some.
      • Müller-Felber W.
      • Horvath R.
      • Gempel K.
      Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients.
      • van der Beek N.A.
      • Soliman O.I.
      • van Capelle C.I.
      Cardiac evaluation in children and adults with Pompe disease sharing the common c.-32-13T>G genotype rarely reveals abnormalities.
      • Soliman O.I.
      • Van der Beek N.A.
      • Van Doorn P.A.
      Cardiac involvement in adults with Pompe disease.
      Vascular involvement of large intracranial blood vessels due to glycogen storage in smooth muscle cells leading to cerebral aneurysms has been reported.
      • Hirschhorn R.
      • Reuser A.J.J.
      Glycogen storage disease type II: acid a-glucosidase (acid maltase) deficiency.
      ,
      • Laforêt P.
      • Petiot P.
      • Nicolino M.
      Dilative arteriopathy and basilar artery dolichoectasia complicating late-onset Pompe disease.
      ,
      • Refai D.
      • Lev R.
      • Cross D.T.
      • Shimony J.S.
      • Leonard J.R.
      Thrombotic complications of a basilar artery aneurysm in a young adult with Pompe disease.

      Current diagnostics

      The use of acarbose to inhibit activity of the isoenzyme maltase glucoamylase made it possible for the first time to measure GAA activity reliably in leukocytes and DBSs.
      • Chamoles N.A.
      • Niizawa G.
      • Blanco M.
      • Gaggioli D.
      • Casentini C.
      Glycogen storage disease type II: enzymatic screening in dried blood spots on filter paper.
      • Zhang H.
      • Kallwass H.
      • Young S.P.
      Comparison of maltose and acarbose as inhibitors of maltase-glucoamylase activity in assaying acid alpha-glucosidase activity in dried blood spots for the diagnosis of infantile Pompe disease.
      • Zhang X.K.
      • Elbin C.S.
      • Chuang W.L.
      Multiplex enzyme assay screening of dried blood spots for lysosomal storage disorders by using tandem mass spectrometry.
      GAA activity can be either measured using fluorometry or tandem mass spectrometry (MS/MS).
      • Chamoles N.A.
      • Niizawa G.
      • Blanco M.
      • Gaggioli D.
      • Casentini C.
      Glycogen storage disease type II: enzymatic screening in dried blood spots on filter paper.
      ,
      • Zhang H.
      • Kallwass H.
      • Young S.P.
      Comparison of maltose and acarbose as inhibitors of maltase-glucoamylase activity in assaying acid alpha-glucosidase activity in dried blood spots for the diagnosis of infantile Pompe disease.
      ,
      • Dajnoki A.
      • Mühl A.
      • Fekete G.
      Newborn screening for Pompe disease by measuring acid alpha-glucosidase activity using tandem mass spectrometry.
      ,
      • Li Y.
      • Scott C.R.
      • Chamoles N.A.
      Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening.
      Although there is a correlation between GAA activity in fibroblasts and clinical phenotype, the clinical phenotype may not be readily predicted through enzyme analysis in different tissues.
      • Pompe Disease Diagnostic Working Group
      Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting.
      Serum creatine kinase, transaminases, and lactate dehydrogenase are increased in most patients with PD but may occasionally be within normal limits in those with adult-onset PD.
      • Winkel L.P.
      • Hagemans M.L.
      • Van Doorn P.A.
      The natural course of non-classic Pompe's disease; a review of 225 published cases.
      Muscle biopsies for primary diagnostic purposes are obsolete as the false-negative diagnostic rate may be significant.
      • Winkel L.P.
      • Hagemans M.L.
      • Van Doorn P.A.
      The natural course of non-classic Pompe's disease; a review of 225 published cases.
      ,
      • Di Rocco M.
      • Buzzi D.
      • Tarò M.
      Glycogen storage disease type II: clinical overview.
      Urinary hex 4 is a breakdown product of glycogen and is typically increased in the majority of patients with PD. Levels of excretion are higher in infants and those with significant disease burden. Levels have correlated with muscle biopsy glycogen content. It is useful for monitoring the clinical response to treatment.
      • An Y.
      • Young S.P.
      • Kishnani P.S.
      Glucose tetrasaccharide as a biomarker for monitoring the therapeutic response to enzyme replacement therapy for Pompe disease.
      ,
      • Young S.P.
      • Zhang H.
      • Corzo D.
      Long-term monitoring of patients with infantile-onset Pompe disease on enzyme replacement therapy using a urinary glucose tetrasaccharide biomarker.
      Two hundred eighty-nine different pathogenic mutations in GAA are known including nonsense, missense, small deletions, insertions, and nonpathogenic mutations. Details on mutations and associated phenotypes can be found at http://www.pompecenter.nl/?Moleculaire_Aspecten.
      • Kroos M.
      • Pomponio R.J.
      • Van Vliet L.
      Update of the Pompe Disease mutation database with 107 sequence variants and a format for severity rating.
      A new tool that estimates the severity of a particular GAA sequence variant has been introduced. The severity of a given GAA sequence variant is reflected in the quantity and quality of GAA precursor (110 kD) and modified precursor molecules (95 kD, 76 kD, and <20 kD) following transfection of COS cells.
      • Kroos M.
      • Pomponio R.J.
      • Van Vliet L.
      Update of the Pompe Disease mutation database with 107 sequence variants and a format for severity rating.
      ,
      • Moreland R.J.
      • Jin X.
      • Zhang X.K.
      Lysosomal acid alpha-glucosidase consists of four different peptides processed from a single chain precursor.
      Molecular testing is the preferred technique for prenatal diagnosis, provided the genotype of the index patient is known. Alternatively, enzyme analysis in chorionic villi may be used.
      • Di Rocco M.
      • Buzzi D.
      • Tarò M.
      Glycogen storage disease type II: clinical overview.

      Ascertainment

      A PD NBS pilot program in Taiwan used acarbose and 4-methylumbelliferyl-b-d-glucuronide (4-MUG) to measure GAA activity in DBS.
      • Chien Y.H.
      • Chiang S.C.
      • Zhang X.K.
      Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program.
      The screening program covers approximately 45% of the Taiwanese population, and the same laboratory provides Pompe diagnostic services for all of Taiwan. Between October 2005 and March 2007, more than 130,000 newborn infants were screened, and PD was diagnosed in four infants during their first month of life. In contrast, three infants were diagnosed during the same time period based on clinical symptoms alone between the age of 3 and 6 months. All infants except one in the screening group had infantile-onset PD and were started on ERT.
      • Chien Y.H.
      • Chiang S.C.
      • Zhang X.K.
      Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program.
      The recall rate for repeat blood tests was 0.82% and for clinical recall 0.091%.
      • Chien Y.H.
      • Chiang S.C.
      • Zhang X.K.
      Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program.
      ,
      • Kemper A.R.
      • Hwu W.L.
      • Lloyd-Puryear M.
      • Kishnani P.S.
      Newborn screening for Pompe disease: synthesis of the evidence and development of screening recommendations.
      The use of MS/MS for enzyme analysis in DBS for the diagnosis of Fabry, Gaucher, Krabbe, Niemann-Pick, and Pompe diseases, respectively, has been evaluated.
      • Zhang X.K.
      • Elbin C.S.
      • Chuang W.L.
      Multiplex enzyme assay screening of dried blood spots for lysosomal storage disorders by using tandem mass spectrometry.
      • Dajnoki A.
      • Mühl A.
      • Fekete G.
      Newborn screening for Pompe disease by measuring acid alpha-glucosidase activity using tandem mass spectrometry.
      • Li Y.
      • Scott C.R.
      • Chamoles N.A.
      Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening.
      The MS/MS technique for GAA analysis in DBS was further evaluated and validated on more than 10,000 anonymous newborn infants in Austria and 29 known patients with PD.
      • Dajnoki A.
      • Mühl A.
      • Fekete G.
      Newborn screening for Pompe disease by measuring acid alpha-glucosidase activity using tandem mass spectrometry.
      The recall rate in this study was 0.03%.
      • Dajnoki A.
      • Mühl A.
      • Fekete G.
      Newborn screening for Pompe disease by measuring acid alpha-glucosidase activity using tandem mass spectrometry.
      Antibodies against epitopes of lysosomal proteins including GAA have also been used for detection in neonatal screening samples, although a formal validation on a larger number of samples has not been done.
      • Amalfitano A.
      • Bengur A.R.
      • Morse R.P.
      Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.
      Patients with PD and structurally intact epitopes may not be readily detected by this method.

      Therapy

      Alglucosidase alfa (recombinant GAA [rhGAA], Myozyme®/Lumizyme®; Genzyme Corporation) has been shown to be effective in the treatment of patients with early- and late-onset PD.
      • Meikle P.J.
      • Grasby D.J.
      • Dean C.J.
      Newborn screening for lysosomal storage disorders.
      ,
      • Kishnani P.S.
      • Steiner R.D.
      • Bali D.
      Pompe disease diagnosis and management guideline.
      ,
      • Kishnani P.S.
      • Corzo D.
      • Nicolino M.
      Recombinant human acid α-glucosidase: major clinical benefits in infantile-onset Pompe disease.
      ,
      • Geel T.M.
      • McLaughlin P.M.
      • de Leij L.F.
      • Ruiters M.H.
      • Niezen-Koning K.E.
      Pompe disease: current state of treatment modalities and animal models.
      • Kishnani P.S.
      • Nicolino M.
      • Voit T.
      Chinese hamster ovary cell-derived recombinant human acid α-glucosidase in infantile-onset Pompe disease.
      • Van den Hout H.
      • Reuser A.J.
      • Vulto A.G.
      • Loonen M.C.
      • Cromme-Dijkhuis A.
      • van der Ploeg A.T.
      Recombinant human alpha-glucosidase from rabbit milk in Pompe patients.
      • van der Ploeg A.T.
      • Clemens P.R.
      • Corzo D.
      A randomized study of alglucosidase alfa in late-onset Pompe's disease.
      The individual response to ERT may vary due to development of rhGAA specific antibodies, age of presentation, rate of progression of disease, muscle fiber type, defective autophagy, and underlying genotype.
      • Fukuda T.
      • Ahearn M.
      • Roberts A.
      Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease.
      ,
      • Kishnani P.S.
      • Steiner R.D.
      • Bali D.
      Pompe disease diagnosis and management guideline.
      The development of rhGAA antibodies may be more frequent in patients with absent GAA protein (CRIM-negative) and have an impact on the prognosis of patients with infantile-onset PD.
      • Fukuda T.
      • Ahearn M.
      • Roberts A.
      Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease.
      Induction of immune tolerance to reduce rhGAA antibody formation has been evaluated in GAA knockout mice.
      • Joseph A.
      • Munroe K.
      • Housman M.
      • Garman R.
      • Richards S.
      Immune tolerance induction to enzyme replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model.
      ,
      • Sun B.
      • Bird A.
      • Young S.P.
      • Kishnani P.S.
      • Chen Y.T.
      • Koeberl D.D.
      Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance.
      Success with a tolerance-inducing regimen including treatment with anti-CD20 monoclonal antibody (rituximab) plus methotrexate and intravenous gamma globulin has been reported in a CRIM-negative infant.
      • Mendelsohn N.J.
      • Messinger Y.H.
      • Rosenberg A.S.
      • Kishnani P.S.
      Elimination of antibodies to recombinant enzyme in Pompe's disease.
      Clinical trials are ongoing in infants.
      Neurological symptoms in infantile-onset PD were not readily observed due to early death within the first year. The advent of ERT and the increased survival rate in infants treated early have uncovered neurological manifestions of PD related to cochlear dysfunction and delayed myelination, and bulbar involvement.
      • Chien Y.H.
      • Lee N.C.
      • Peng S.F.
      • Hwu W.L.
      Brain development in infantile-onset Pompe disease treated by enzyme replacement therapy.
      • Kamphoven J.H.
      • de Ruiter N.M.
      • Winkel L.P.
      Hearing loss in infantile Pompe's disease and determination of underlying pathology in the knockout mouse.
      • Jones H.N.
      • Muller C.W.
      • Lin M.
      Oropharyngeal dysphagia in infants and children with infantile Pompe disease.
      The long-term outcome of surviving infants on ERT is unfolding.

      Recommended follow-up procedures

      A suggested diagnostic algorithm is presented in Figure 1.
      Fig. 1
      Fig. 1Diagnostic algorithm for Pompe disease. NBS, newborn screening; GAA, acid α-glucosidase; CRIM, cross-reactive immunologic material; ERT, enzyme replacement therapy.
      • 1.
        Confirm the diagnosis by demonstrating GAA deficiency in a blood-based assay (DBS, leukocytes, and lymphocytes) or fibroblasts. Enzyme analysis in a blood-based assay is preferred due to the faster turnaround, lower costs, and reduced invasiveness.
      • 2.
        Assess CRIM status by Western blot/mutation analysis for patients with infantile presentation (cardiac involvement in infancy).
      • 3.
        Mutation analysis of the GAA gene.

      Clinical follow-up and intervention

      • 1.
        Laboratory tests including serum creatine kinase, transaminases, lactate dehydrogenase, and urinary hex4.
      • 2.
        Chest radiograph, ECG, and 2D echocardiogram
      • 3.
        Clinical evaluation including swallow, pulmonary, and neurological examination.
      • 4.
        Prompt initiation of ERT in patients with infantile PD.
      • 5.
        Evaluations every 6–12 months in the remaining patients.
      It is important to identify patients with infantile PD as early as possible because ERT needs to be initiated as early as possible. The management of patients with infantile PD should be done at specialized centers with the appropriate expertise and back-up facilities. Under no circumstances should ERT be given at home or in peripheral potentially understaffed hospitals. Infantile patients are an anesthesia risk for infusion port placement and could develop airway problems should an infusion-related reaction occur. Close cardiology follow-up is required as cardiac remodeling occurs with ERT. A frank discussion with the parents is warranted regarding poor outcomes in CRIM-negative patients who typically do poorly on ERT alone.
      • Kishnani P.S.
      • Goldenberg P.C.
      • DeArmey S.L.
      Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants.
      The role of immune modulation in tolerance induction is emerging and data look promising.
      • Mendelsohn N.J.
      • Messinger Y.H.
      • Rosenberg A.S.
      • Kishnani P.S.
      Elimination of antibodies to recombinant enzyme in Pompe's disease.
      Long-term issues should also be discussed.

      Fabry disease (OMIM# 301500)

      Synonyms

      Anderson-Fabry Disease, angiokeratoma corporis diffusum, α-galactosidase A (α-gal A) deficiency.

      Background

      Fabry disease is a X-linked inherited lysosomal storage disorder caused by deficiency of the enzyme α-gal A (E.C. 3.2.1.22).
      • Brady R.O.
      Inherited metabolic diseases of the nervous system.
      Affected patients have insufficient ability to degrade the membrane glycosphingolipid ceramide trihexoside (GL-3). The subsequent deposition of GL-3 in body tissues leads to the symptoms of the disease. No ethnic predilection exists for Fabry disease, which occurs in approximately 1:40,000 male births.
      • Meikle P.J.
      • Hopwood J.J.
      • Clague A.E.
      • Carey W.F.
      Prevalence of lysosomal storage disorders.
      However, studies from select populations have shown a Fabry disease prevalence of 1:100–1:1000 male dialysis patients, 1:20–1:30 of “idiopathic” hypertrophic cardiomyopathy cases, and 1:20 male (1:40 female) patients with cryptogenic strokes.
      • Nakao S.
      • Kodama C.
      • Takenaka T.
      Fabry disease: detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype.
      • Kotanko P.
      • Kramar R.
      • Devrnja D.
      Results of a nationwide screening for Anderson-Fabry disease among dialysis patients.
      • Tanaka M.
      • Ohashi T.
      • Kobayashi M.
      Identification of Fabry's disease by the screening of alpha-galactosidase A activity in male and female hemodialysis patients.
      • Nakao S.
      • Takenaka T.
      • Maeda M.
      An atypical variant of Fabry's disease in men with left ventricular hypertrophy.
      • Sachdev B.
      • Takenaka T.
      • Teraguchi H.
      Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.
      • Rolfs A.
      • Böttcher T.
      • Zschiesche M.
      Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study.

      Clinical phenotype

      Fabry disease causes significant morbidity and mortality in both hemizygous males and heterozygous females. The mean age of presentation for affected boys is 6–8 years; the typical presenting symptom is acute, episodic pain crises followed by chronic acroparesthesias.
      • Ramaswami U.
      • Whybra C.
      • Parini R.
      Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey.
      • Ries M.
      • Mengel E.
      • Kutschke G.
      Use of gabapentin to reduce chronic neuropathic pain in Fabry disease.
      • Hopkin R.J.
      • Bissler J.
      • Banikazemi M.
      Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry.
      GL-3 accumulation in the vascular endothelium and other cells leads to hearing loss, myocardial microvascular ischemia, dysrhythmias, hypertrophic cardiomyopathy, valvular insufficiency, gastrointestinal symptoms, hypohidrosis, temperature and exercise intolerance, dysregulation of vascular tone and autonomic functions, obstructive lung disease, progressive renal insufficiency leading to kidney failure, and increases the risk of cerebrovascular accidents and myocardial infarctions.
      • Rosenberg D.M.
      • Ferrans V.J.
      • Fulmer J.D.
      Chronic airflow obstruction in Fabry's disease.
      • Brown L.K.
      • Miller A.
      • Bhuptani A.
      Pulmonary involvement in Fabry disease.
      • Branton M.H.
      • Schiffmann R.
      • Sabnis S.G.
      Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course.
      • Eng C.M.
      • Germain D.P.
      • Banikazemi M.
      Fabry disease: guidelines for the evaluation and management of multi-organ system involvement.
      • Kampmann C.
      • Wiethoff C.M.
      • Martin C.
      Electrocardiographic signs of hypertrophy in fabry disease-associated hypertrophic cardiomyopathy.
      • Schiffmann R.
      • Scott L.J.
      Pathophysiology and assessment of neuropathic pain in Fabry disease.
      • Stemper B.
      • Hilz M.J.
      Postischemic cutaneous hyperperfusion in the presence of forearm hypoperfusion suggests sympathetic vasomotor dysfunction in Fabry disease.
      • Bierer G.
      • Kamangar N.
      • Balfe D.
      • Wilcox W.R.
      • Mosenifar Z.
      Cardiopulmonary exercise testing in Fabry disease.
      • Hughes D.A.
      • Mehta A.B.
      Vascular complications of Fabry disease: enzyme replacement and other therapies.
      • FOS Investigators
      Natural history of the cerebrovascular complications of Fabry disease.
      • Shah A.J.
      • Kapoor N.
      • Crooks G.M.
      Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B.
      Early death in hemizygotes occurs typically in the late fifth to early sixth decade from kidney failure, strokes, and cardiac events.
      • Waldek S.
      • Patel M.R.
      • Banikazemi M.
      • Lemay R.
      • Lee P.
      Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry.
      • MacDermot K.D.
      • Holmes A.
      • Miners A.H.
      Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females.
      Heterozygous females, previously thought to be asymptomatic “carriers,” can have significant symptomatology, generally at a later age than hemizygous men.
      • Gupta S.
      • Ries M.
      • Kotsopoulos S.
      • Schiffmann R.
      The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women.
      • Wang R.Y.
      • Lelis A.
      • Mirocha J.
      • Wilcox W.R.
      Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life.
      • Wilcox W.R.
      • Oliveira J.P.
      • Hopkin R.J.
      Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry.
      There is a “cardiac variant” of attenuated Fabry disease with hypertrophic cardiomyopathy as the predominant symptom, although these patients may develop milder symptoms in other organ systems.
      • Elleder M.
      • Poupetová H.
      • Kozich V.
      [Fetal pathology in Fabry's disease and mucopolysaccharidosis type I].

      Current diagnostics

      Reduced leukocyte α-gal A enzyme levels will be found in hemizygotes. As GL-3 storage begins prenatally, boys will have increased GL-3 levels in plasma and urinary sediment. LysoGL-3 may be a useful biomarker for the monitoring of treatment efficacy.
      • Aerts J.M.
      • Groener J.E.
      • Kuiper S.
      Elevated globotriaosylsphingosine is a hallmark of Fabry disease.
      Heterozygote leukocyte enzyme activity and tissue GL-3 levels vary, are often in the “normal” range, and do not correlate with presence or severity of Fabry symptoms.
      • Wilcox W.R.
      • Oliveira J.P.
      • Hopkin R.J.
      Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry.
      ,

      Wang RY, Abe JT, Cohen AH, Wilcox WR. Enzyme replacement therapy stabilizes obstructive pulmonary Fabry disease associated with respiratory globotriaosylceramide storage [published online ahead of print October 21,2008. J Inherit Metab Dis doi: 10.1007/s10545-008-0930-x.

      Most pathogenic GLA mutations are “private” and nonrecurrent; more than 300 mutations have been described. In general, mutations that result in prematurely truncated α-gal A, which are approximately 45% of those reported, will result in a classical Fabry phenotype in a hemizygote.
      • Stenson P.D.
      • Ball E.V.
      • Mort M.
      Human Gene Mutation Database (HGMD): 2003 update.
      Missense mutations that result in very low leukocyte α-gal A levels will also result in a classical phenotype. Because Fabry disease shows marked intrafamilial variability, predicting symptom severity, age of onset, and rate of progression is quite difficult even for a hemizygote with a mutation known to cause a classical phenotype. Mutations with residual α-gal A enzyme activity thought to consistently produce an attenuated phenotype (e.g., N215S)
      • Topaloglu A.K.
      • Ashley G.A.
      • Tong B.
      Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.
      ,
      • Eng C.M.
      • Niehaus D.J.
      • Enriquez A.L.
      • Burgert T.S.
      • Ludman M.D.
      • Desnick R.J.
      Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the alpha-galactosidase A gene.
      have been reported in patients with classical disease.
      • Bekri S.
      • Enica A.
      • Ghafari T.
      Fabry disease in patients with end-stage renal failure: the potential benefits of screening.
      For heterozygotes, intrafamilial variability, lack of correlation between biochemical markers and phenotype, and lyonization make presymptomatic prediction of phenotypic severity impossible. One pseudodeficiency allele, D313Y, has been described with low plasma α-gal A activity and slightly reduced leukocyte enzyme activity.
      • Froissart R.
      • Guffon N.
      • Vanier M.T.
      • Desnick R.J.
      • Maire I.
      Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma.
      One study estimated the frequency of the D313Y allele to be 1 in 220 X-chromosomes, implying a 1 in 660 frequency in males.
      • Yasuda M.
      • Shabbeer J.
      • Benson S.D.
      • Maire I.
      • Burnett R.M.
      • Desnick R.J.
      Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele.

      Ascertainment

      Variant forms of Fabry disease with significant residual enzyme activity, including those who may not develop any symptoms, may be particularly common in NBS, up to 1:3,100–1:4600 male births, in one study.
      • Spada M.
      • Pagliardini S.
      • Yasuda M.
      High incidence of later-onset fabry disease revealed by newborn screening.
      Taiwan has also established a NBS program for Fabry disease and identified 42 male and 3 female infants with α-galactosidase mutations of 110,027 screened for a prevalence of 1:2400 live births and 1:1600 male births.
      • Lin H.Y.
      • Chong K.W.
      • Hsu J.H.
      High incidence of the cardiac variant of Fabry disease revealed by newborn screening in the Taiwan Chinese population.
      No data have been published regarding the sensitivity, specificity, false-positive rate, and positive predictive value of NBS for Fabry disease.

      Therapy

      Two versions of recombinant human α-galactosidase A (rhαGAL): alfa (Replagal®; Shire, Cambridge, MA) and beta (Fabrazyme®; Genzyme Corporation) have been developed. Results for clinical trials conducted on both versions have been published; in the United States, only rhαGAL beta was approved for treatment of Fabry disease, whereas, both forms are available in Europe, Australia, and Canada.
      • Schiffmann R.
      • Murray G.J.
      • Treco D.
      Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.
      • Eng C.M.
      • Guffon N.
      • Wilcox W.R.
      Safety and efficacy of recombinant human alpha-galactosidase A—replacement therapy in Fabry's disease.
      • Eng C.M.
      • Banikazemi M.
      • Gordon R.E.
      A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.
      • Schiffmann R.
      • Kopp J.B.
      • Austin III, H.A.
      Enzyme replacement therapy in Fabry disease: a randomized controlled trial.
      ERT with rhαGAL is the standard of care for symptomatic patients with Fabry disease.
      • Eng C.M.
      • Germain D.P.
      • Banikazemi M.
      Fabry disease: guidelines for the evaluation and management of multi-organ system involvement.
      ,
      • Desnick R.J.
      • Brady R.
      • Barranger J.
      Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy.
      ERT with rhαGAL significantly reduces plasma GL-3 and tissue GL-3 storage in myocardium, kidney, and skin. Those treated with rhαGAL also demonstrated significant reduction in pain scores.
      • FOS European Investigators
      Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy—a retrospective analysis from the Fabry Outcome Survey.
      Subsequent studies have indicated that ERT also stabilizes renal function if initiated in patients with urinary protein excretion <1 g/24 hours. ERT also slows progression of renal insufficiency in those with significant proteinuria, improves pulmonary and gastrointestinal symptoms, and reduces renal, cardiac, and CNS events.
      • De Schoenmakere G.
      • Chauveau D.
      • Grünfeld J.P.
      Enzyme replacement therapy in Anderson-Fabry's disease: beneficial clinical effect on vital organ function.
      • Germain D.P.
      • Waldek S.
      • Banikazemi M.
      Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease.
      • Bierer G.
      • Balfe D.
      • Wilcox W.R.
      • Mosenifar Z.
      Improvement in serial cardiopulmonary exercise testing following enzyme replacement therapy in Fabry disease.
      • Dehout F.
      • Roland D.
      • Treille de Granseigne S.
      • Guillaume B.
      • Van Maldergem L.
      Relief of gastrointestinal symptoms under enzyme replacement therapy [corrected] in patients with Fabry disease.
      • Waldek S.
      PR interval and the response to enzyme-replacement therapy for Fabry's disease.
      • Weidemann F.
      • Breunig F.
      • Beer M.
      Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study.
      • Banikazemi M.
      • Bultas J.
      • Waldek S.
      Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.
      Women treated with ERT demonstrated reduced left ventricular hypertrophy as well as plasma and urinary GL-3
      • Baehner F.
      • Kampmann C.
      • Whybra C.
      • Miebach E.
      • Wiethoff C.M.
      • Beck M.
      Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study.
      . ERT in children also reduced plasma and urinary GL-3 levels.
      • Ries M.
      • Clarke J.T.
      • Whybra C.
      Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease.
      However, ERT cannot completely mitigate valvular disease, acroparesthesias, and risk for cerebrovascular accidents.
      Adjunctive therapies such as statins and aspirin for reduction of thromboembolic risk factors, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers for treatment of proteinuria and hypertension, and various antiepileptic medications for the treatment of neuropathic pain are recommended as part of the comprehensive care of a patient with Fabry disease.
      • Eng C.M.
      • Germain D.P.
      • Banikazemi M.
      Fabry disease: guidelines for the evaluation and management of multi-organ system involvement.
      Clinical trials are being conducted in selected patients with missense GLA mutations using a competitive inhibitor of the α-gal A enzyme. In low concentrations, this inhibitor stabilizes misfolded (but functional) α-gal A as the enzyme is synthesized in the endoplasmic reticulum of the cell, allowing for transport into the lysosome where it can properly degrade GL-3.

      Recommended follow-up procedures

      A suggested diagnostic algorithm is presented in Figure 2.
      Fig. 2
      Fig. 2Diagnostic algorithm for Fabry disease. NBS, newborn screening; α-gal-A, α- galactosidase A; ERT, enzyme replacement therapy.
      • 1.
        NBS will detect primarily hemizygotes; because of the variability in α-gal A enzyme activity in heterozygotes, it will likely fail to detect a substantial percentage (40–60%) of female infants with Fabry disease.
        • Wilcox W.R.
        • Oliveira J.P.
        • Hopkin R.J.
        Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry.
        ,
        • Dajnoki A.
        • Fekete G.
        • Keutzer J.
        Newborn screening for Fabry disease by measuring GLA activity using tandem mass spectrometry.
        • a.
          Because of this variability, any females identified by NBS will need molecular testing for confirmation.
        • b.
          A male infant who screens positive for Fabry disease should have confirmatory testing performed by analyzing leukocyte α-gal A enzyme activity.
      • 2.
        If the enzyme activity is low (in males) or a GLA mutation is found (in females), the infant should be referred for evaluation and genetic counseling at a metabolic center.
      • 3.
        Confirmatory GLA sequencing should be performed in any male infant with low α-gal A enzyme activity, given the predicted high frequency of the D313Y pseudodeficiency allele.
        • a.
          A detailed pedigree should be constructed to determine at-risk family members and testing offered, because most mutations are familial. If a mutation is not identified, pedigree analysis, measurement of biomarkers such as urinary GL-3, and molecular examination for deletions may clarify the patient's status.

      Clinical follow-up and intervention

      Management recommendations for ERT initiation and multidisciplinary follow-up have been published for both pediatric and adult Fabry patient.
      • Eng C.M.
      • Germain D.P.
      • Banikazemi M.
      Fabry disease: guidelines for the evaluation and management of multi-organ system involvement.
      ,
      • Desnick R.J.
      Enzyme replacement therapy for Fabry disease: lessons from two alpha-galactosidase A orphan products and one FDA approval.
      Once the diagnosis of Fabry disease has been confirmed:
      • 1.
        Baseline diagnostic studies (ECG, echocardiogram, ophthalmologic examination, renal function tests, plasma and/or urine GL-3) should be obtained. Affected members identified as a result of screening should also undergo identical evaluations; adults should also undergo additional testing as recommended.
        • Eng C.M.
        • Germain D.P.
        • Banikazemi M.
        Fabry disease: guidelines for the evaluation and management of multi-organ system involvement.
      • 2.
        In global practice, there is wide variability in the usage of ERT even for hemizygotes, with some starting therapy at a young age even without symptoms and others waiting until end organ damage is evident. The decision to initiate ERT should be made according to the clinical judgment of the managing metabolic physician in conjunction with the family of the patient.
      • 3.
        The infant should be seen by the metabolic specialist at 6-month intervals and monitored for onset of Fabry symptoms.

      Gaucher disease

      Synonyms

      GD type 1, Nonneuronopathic GD (OMIM# 230800); GD type 2, acute neuronopathic GD (OMIM# 230900); GD type 3, chronic or subacute neuronopathic GD (OMIM# 231000); acid-β-glucosidase deficiency.

      Background

      GD is the most common lysosomal storage disorder, characterized by lysosomal accumulation of undegraded glucosylceramide because of deficiency or insufficient activity of the enzyme acid-β-glucosidase (glucocerebrosidase, glucosylceramidase, EC 4.2.1.25).
      • Grabowski G.A.
      Phenotype, diagnosis, and treatment of Gaucher's disease.
      GD is a pan-ethnic disorder. Estimates concerning disease prevalence in the general population vary between 1:40,000
      • Meikle P.J.
      • Hopwood J.J.
      • Clague A.E.
      • Carey W.F.
      Prevalence of lysosomal storage disorders.
      and 1:60,000.
      • Grabowski G.A.
      • Andria G.
      • Baldellou A.
      Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment. Consensus statements.
      In the Ashkenazi Jewish population, particularly, a high number of patients are observed with a calculated disease prevalence of approximately 1:800.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      As a very rare variant, GD can also be caused by a deficiency of the nonenzymatic sphingolipid activator protein SAP C (or saposin C).
      • Christomanou H.
      • Aignesberger A.
      • Linke R.P.
      Immunochemical characterization of two activator proteins stimulating enzymic sphingomyelin degradation in vitro. Absence of one of them in a human Gaucher disease variant.
      • Ho M.W.
      • O'Brien J.S.
      Gaucher's disease: deficiency of ‘acid’ -glucosidase and reconstitution of enzyme activity in vitro.
      • Tylki-Szymańska A.
      • Czartoryska B.
      • Vanier M.T.
      Non-neuronopathic Gaucher disease due to saposin C deficiency.
      • Velayati A.
      • Yu W.H.
      • Sidransky E.
      The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders.

      Clinical phenotype

      Based on characteristic patterns of clinical signs and age of onset, GD is subdivided into three main disease variants: type 1 (nonneuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic).
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      Although this categorization facilitates clinical management to a certain degree, it is important to realize that GD, like other lysosomal storage disorders, consists of a continuous spectrum of disease variants with “asymptomatic” and less severely affected type 1 patients at one end and severely affected type 2 and lethal in utero forms at the severe end of the clinical scale.
      • Wilcox W.R.
      Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care.
      ,
      • Meikle P.J.
      • Hopwood J.J.
      • Clague A.E.
      • Carey W.F.
      Prevalence of lysosomal storage disorders.
      A detailed list of subtype- and system-specific disease manifestations of GD is given in Table 2.
      Table 2Symptoms of Gaucher disease subtypes
      In general, the type 1 patients who present in childhood tend to have more pronounced visceral and bony disease manifestations than those that present in adulthood.
      • Grabowski G.A.
      Phenotype, diagnosis, and treatment of Gaucher's disease.
      Type 1 patients can experience growth retardation, delayed puberty, leukopenia, impairment of pulmonary gas exchange, and destruction of vertebral bodies with secondary neurologic complications.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      There is an increased risk for multiple myeloma
      • Christomanou H.
      • Chaba′s A.
      • Pa′mpols T.
      • Guardiola A.
      Activator protein deficient Gaucher's disease. A second patient with the newly identified lipid storage disorder.
      and Parkinson disease.
      • Rosenbloom B.E.
      • Weinreb N.J.
      • Zimran A.
      • Kacena K.A.
      • Charrow J.
      • Ward E.
      Gaucher disease and cancer incidence: a study from the Gaucher Registry.
      Some authors have proposed a subdivision of type 3 GD into three variants, depending on the most prominent disease symptoms. Variant 3a is characterized by rapidly progressive neurological manifestations (oculomotor apraxia, cerebellar ataxia, spasticity, refractory myoclonic seizures, and dementia) with variable visceral symptoms, whereas the 3b variant shows more pronounced visceral and bony symptoms with less severe, slowly progressive CNS involvement. A “3c” variant has been reported primarily in patients of Druze descent, with mild visceral disease, slowly progressive neurological manifestations, and unique to this subtype, cardiac valvular calcifications and corneal opacities.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      ,
      • Grabowski G.A.
      Phenotype, diagnosis, and treatment of Gaucher's disease.

      Current diagnostics

      Biochemical markers

      GD is most commonly diagnosed by demonstrating insufficient acid-β-glucosidase enzyme activity in peripheral blood leukocytes or DBSs on filter paper. Alternatively, cultured skin fibroblasts or, in the case of prenatal diagnosis, amniotic fluid cells and chorionic villi can be used as tissue source.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      The measurement of β-glucosidase cannot reliably predict the disease phenotype or identify heterozygotes for GD.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      ,
      • Grabowski G.A.
      Phenotype, diagnosis, and treatment of Gaucher's disease.
      In addition, patients with saposin C deficiency will be missed by determination of β-glucosidase enzymatic activity.
      • Christomanou H.
      • Aignesberger A.
      • Linke R.P.
      Immunochemical characterization of two activator proteins stimulating enzymic sphingomyelin degradation in vitro. Absence of one of them in a human Gaucher disease variant.
      ,
      • Tylki-Szymańska A.
      • Czartoryska B.
      • Vanier M.T.
      Non-neuronopathic Gaucher disease due to saposin C deficiency.
      ,
      • Pámpols T.
      • Pineda M.
      • Girós M.L.
      Neuronopathic juvenile glucosylceramidosis due to sap-C deficiency: clinical course, neuropathology and brain lipid composition in this Gaucher disease variant.
      Abnormally low enzymatic test results can be further corroborated by the demonstration of increased glucosylceramide levels.
      • Groener J.E.
      • Poorthuis B.J.
      • Kuiper S.
      • Hollak C.E.
      • Aerts J.M.
      Plasma glucosylceramide and ceramide in type 1 Gaucher disease patients: correlations with disease severity and response to therapeutic intervention.
      Reflecting the high levels of macrophage activation in GD patients, chitotriosidase
      • Hollak C.E.
      • van Weely S.
      • van Oers M.H.
      • Aerts J.M.
      Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease.
      and CCL18/PARC/MIP-418
      • Boot R.G.
      • Verhoek M.
      • de Fost M.
      Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention.
      show moderate to massive elevations in almost all patients. Although these biomarkers are not specific for GD and cannot be used to predict the subtype, their increase is usually far more pronounced than in other disorders with macrophage involvement. Apart from their role as supportive diagnostic tool, they can be used to monitor the efficacy of specific therapies (see below), although the correlation between the level of each biomarker and severity of active disease is limited or at least a matter of debate.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      However, 5–6% of all GD patients are homozygous for a common 24-bp deletion in exon 10 of the chitotriosidase gene, which renders the enzyme inactive.
      • Boot R.G.
      • Renkema G.H.
      • Verhoek M.
      The human chitotriosidase gene. Nature of inherited enzyme deficiency.
      Alternative ancillary biomarkers comprise increased activities/concentrations of tartrate-resistant acid phosphatase, angiotensin converting enzyme, and plasma ferritin.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      ,
      • Grabowski G.A.
      • Andria G.
      • Baldellou A.
      Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment. Consensus statements.
      Sequencing of the GBA gene is the definitive method to diagnose GD. Within the Ashkenazi Jewish population, four common mutations (p.N370S, p.L444P, c.84insG, and c.IVS2 + 1) account for 90% of the disease-causing alleles; these same mutations account for 50–60% of disease causing alleles in non-Jewish patients.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      The p.L444P mutation accounts for nearly all disease-causing alleles in the Norrbottnian Swedish population, and the p.D409H mutation is responsible for the GD type 3c found in Druze kindreds. Recombinant (Rec) alleles contain several point mutations (including p.L444P) that arise as a result of gene rearrangements between GBA and a nonfunctional GBA pseudogene. Therefore, targeted mutation analysis of the p.L444P mutation cannot distinguish between isolated p.L444P mutations and Rec alleles, potentially leading to errors in genotype designation. A more detailed list of genotype-phenotype associations is given in Table 3. There are no known pseudodeficiency alleles for acid β-glucosidase.
      Table 3Phenotype-genotype correlations in Gaucher disease (GD)

      Ascertainment

      NBS programs for GD are expected to begin this year in at least two states in the United States. Given the high carrier frequency in Ashkenazi Jews, population-based prenatal carrier screening and testing of at-risk individuals in GD pedigrees have identified children and even identified older, currently “asymptomatic” GD type 1 individuals.

      Therapy

      GD type 1

      To date, two options are available for the specific therapy of patients with GD type 1. The reference treatment is ERT and it was GD that served as model disease to establish the efficacy of this therapeutic approach.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      The proof of concept studies date back to the early 1990s and used a modified human placental enzyme (alglucerase) to restore GBA activity in patients with GD.
      • Barton N.W.
      • Furbish F.S.
      • Murray G.J.
      • Garfield M.
      • Brady R.O.
      Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease.
      • Barton N.W.
      • Brady R.O.
      • Dambrosia J.M.
      Replacement therapy for inherited enzyme deficiency—macrophage-targeted glucocerebrosidase for Gaucher's disease.
      • Beutler E.
      • Kay A.
      • Saven A.
      Enzyme replacement therapy for Gaucher disease.
      In 1993, the recombinant successor enzyme (imiglucerase; recombinant human GBA; Cerezyme®, Genzyme Corporation) was introduced and numerous studies document safety and efficacy concerning major peripheral symptoms within the first year of treatment, whereas the response to bone abnormalities is less effective and may take at least several years.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      ,
      • Grabowski G.A.
      • Barton N.W.
      • Pastores G.
      Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources.
      • Pastores G.M.
      • Elstein D.
      • Hrebícek M.
      • Zimran A.
      Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies.
      • Sims K.B.
      • Pastores G.M.
      • Weinreb N.J.
      Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study.
      Approximately 15% of treated patients develop IgG antibodies against the recombinant enzyme and approximately half of these patients show mild to moderate allergic adverse events, particularly during the first year of treatment.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      In the majority of patients, antibodies disappear when ERT is continued with the same dosage,
      • Desnick R.J.
      Enzyme replacement therapy for Fabry disease: lessons from two alpha-galactosidase A orphan products and one FDA approval.
      ,
      • Rosenberg M.
      • Kingma W.
      • Fitzpatrick M.A.
      • Richards S.M.
      Immunosurveillance of alglucerase enzyme therapy for Gaucher patients: induction of humoral tolerance in seroconverted patients after repeat administration.
      ,
      • Zhao H.
      • Bailey L.A.
      • Grabowski G.A.
      Enzyme therapy of Gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies.
      and only a few patients develop therapy-limiting inhibitory antibodies.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      A second form of ERT for Gaucher was recently approved for use (velaglucerase alfa, VPRIV®; Shire, Wayne, PA).
      • Zimran A.
      • Altarescu G.
      • Phillips M.
      Phase I/II and extension study of velaglucerasealfa (Gene-ActivatedTM human glucocerebrosidase) replacement therapy in adults with type 1 Gaucher disease: 48-month experience.
      Finally, a third ERT product is being studied (taliglucerase alfa, UPLYSO®; Protalix Biotherapeutics, Carmiel, Israel).
      • Aviezer D.
      • Brill-Almon E.
      • Shaaltiel Y.
      A plant-derived recombinant human glucocerebrosidase enzyme—a preclinical and phase I investigation.
      An alternative to ERT is SRT with N-butyl-deoxynojirimycin (Miglustat; Zavesca®; Actelion Pharmaceuticals, Basel, Switzerland).
      • Cox T.
      • Lachmann R.
      • Hollak C.
      Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.
      ,
      • Elstein D.
      • Hollak C.
      • Aerts J.M.
      Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease.
      SRT was shown to be effective concerning hepatosplenomegaly, anemia, and thrombocytopenia; by contrast, improvements of bone disease were delayed and limited.
      • Pastores G.M.
      • Elstein D.
      • Hrebícek M.
      • Zimran A.
      Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies.
      ,
      • Mikosch P.
      • Reed M.
      • Baker R.
      • Holloway B.
      • Berger L.
      • Mehta A.B.
      • Hughes D.A.
      Changes of bone metabolism in seven patients with Gaucher disease treated consecutively with imiglucerase and miglustat.
      Comparison of independent dose finding studies of both drugs suggest that SRT is similarly effective as a low-dose treatment with ERT, but less effective than standard- or high-dose enzyme replacement.
      • Grabowski G.A.
      Phenotype, diagnosis, and treatment of Gaucher's disease.
      Therefore, SRT is currently only recommended as second-line therapy for adult patients with GD type 1, which either show severe side effects on ERT or refuse to receive ERT at all and have mild to moderate disease.
      • Grabowski G.A.
      Phenotype, diagnosis, and treatment of Gaucher's disease.
      The profile of adverse effects on SRT comprises mild to moderate diarrhea (85–90% of patients), which usually resolves within the first year of treatment and is amenable to dietary changes and drug treatment, an initial weight loss of 6–7% (60% of patients), (sensory) peripheral neuropathy, transient tremor (30%), and possibly cognitive impairment.
      Because of its rapid clinical progression, there is no specific therapy available for patients presenting with a GD type 2 phenotype. For patients with GD type 3, several therapeutic approaches have been tested in the past. In the pre-ERT era, a number of patients underwent HSCT, but long-term results have been poor.
      • Beutler E.
      • Grabowski G.A.
      Gaucher disease.
      ,
      • Ringden O.
      • Groth C.G.
      • Erikson A.
      • Granqvist S.
      • Månsson J.E.
      • Sparrelid E.
      Ten years' experience of bone marrow transplantation for Gaucher disease.
      In conjunction with the significant mortality risk associated with this treatment, HSCT is no longer recommended or performed for type 3 GD.
      When ERT was established, studies with standard and high-dose treatment were performed despite the fact that only trace amounts of the currently used enzyme preparation cross the intact BBB, if at all.
      • Xu Y.H.
      • Ponce E.
      • Sun Y.
      Turnover and distribution of intravenously administered mannose-terminated human acid beta-glucosidase in murine and human tissues.
      The results were heterogeneous: some authors observed beneficial effects and an overall deceleration of mental and neurological deterioration,
      • Capablo J.L.
      • Franco R.
      • de Cabezon A.S.
      • Alfonso P.
      • Pocovi M.
      • Giraldo P.
      Neurologic improvement in a type 3 Gaucher disease patient treated with imiglucerase/miglustat combination.
      whereas others could not demonstrate any significant therapeutic influence on the natural course of the neurological symptoms.
      • Davies E.H.
      • Erikson A.
      • Collin-Histed T.
      • Mengel E.
      • Tylki-Szymanska A.
      • Vellodi A.
      Outcome of type III Gaucher disease on enzyme replacement therapy: review of 55 cases.
      ,
      • Goker-Alpan O.
      • Wiggs E.A.
      • Eblan M.J.
      Cognitive outcome in treated patients with chronic neuronopathic Gaucher disease.
      Notably, no study showed any advantage of high-dose regimens when compared with the standard treatment.
      • Davies E.H.
      • Erikson A.
      • Collin-Histed T.
      • Mengel E.
      • Tylki-Szymanska A.
      • Vellodi A.
      Outcome of type III Gaucher disease on enzyme replacement therapy: review of 55 cases.
      ,
      • Zimran A.
      • Elstein D.
      No justification for very high-dose enzyme therapy for patients with type III Gaucher disease.
      Finally, studies combining ERT and SRT were initiated, based on the rationale that miglustat passes the BBB.
      • Lachmann R.H.
      • te Vruchte D.
      • Lloyd-Evans E.
      Treatment with miglustat reverses the lipid-trafficking defect in Niemann-Pick disease type C.
      Again, the results were ambivalent. Two case studies revealed stabilization
      • Cox-Brinkman J.
      • van Breemen M.J.
      • van Maldegem B.T.
      Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III.
      or even improvement
      • Capablo J.L.
      • Franco R.
      • de Cabezon A.S.
      • Alfonso P.
      • Pocovi M.
      • Giraldo P.
      Neurologic improvement in a type 3 Gaucher disease patient treated with imiglucerase/miglustat combination.
      of neurological signs in symptomatic patients with GD type 3 and, over a 3-year observation period, demonstrated prevention of further neurological manifestations in a young child whose only initial manifestation was disturbed saccadic eye movements.
      • Cox-Brinkman J.
      • van Breemen M.J.
      • van Maldegem B.T.
      Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III.
      By contrast, a multicenter study investigating the efficacy of a combination treatment in a bigger patient cohort was recently terminated ahead of schedule as a result of disappointing intermediate results.

      Future therapeutic approaches

      Phase II clinical trials of a small molecule chaperone for acid β-glucosidase (Amicus Therapeutics, Camden, NJ) were recently completed, with disappointing results. A phase II clinical trial with another SRT (Genz-112638; Genzyme Corporation) aims to reduce the profile of side effects and has recently completed its primary endpoint. Further studies are ongoing.

      Recommended follow-up procedures

      A suggested diagnostic algorithm is presented in Figure 3.
      Fig. 3
      Fig. 3Diagnostic algorithm for Gaucher disease. NBS, newborn screening; GBA, Acid-β-glucosidase; ERT, enzyme replacement therapy.

      Clinical follow-up and intervention

      Guidelines for the treatment of pediatric, adult, and female pregnant patients with GD type 1, and patients with GD type 2 have been published
      • >Brazilian Study Group on Gaucher Disease and other Lysosomal Storage Diseases
      Recommendations on diagnosis, treatment, and monitoring for Gaucher disease.
      • European Working Group on Gaucher Disease
      Management of neuronopathic Gaucher disease: revised recommendations.
      • Cox T.M.
      • Aerts J.M.
      • Belmatoug N.
      Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring.
      • Hughes D.
      • Cappellini M.D.
      • Berger M.
      Recommendations for the management of the haematological and onco-haematological aspects of Gaucher disease.
      • International Collaborative Gaucher Group (ICGG)
      Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients.
      (https://www.lsdregistry.net/gaucherregistry/). After confirmation of, and genetic counseling regarding the GD diagnosis:
      • 1.
        Evaluations for anemia/thrombocytopenia, hepatosplenomegaly, and bony involvement should be performed.
      • 2.
        For patients predicted to have neuronopathic GD, or for patients whose genotype cannot accurately predict phenotype, the degree of neurological impairment should also be assessed.
      • 3.
        Gaucher biomarker and anti-GBA antibody levels should be measured before initiation of ERT.
        • a.
          Type 3 GD patients should be started on treatment immediately;
        • b.
          Treatment in type 1 GD patients should begin if two or more manifestations listed in the Table 2 are present.
          • >Brazilian Study Group on Gaucher Disease and other Lysosomal Storage Diseases
          Recommendations on diagnosis, treatment, and monitoring for Gaucher disease.
        • c.
          Because of the lack of currently effective treatment for type 2 GD, only supportive care is recommended at this time.
      • 4.
        Infants should be monitored at regular intervals (at least quarterly) to assess response to treatment and for development of additional Gaucher manifestations that may require additional interventions.

      Krabbe disease (OMIM# 24520)

      Synonyms

      Globoid cell leukodystrophy.

      Background

      KD is caused by the deficiency of galactocerebrosidase (GALC; EC 3.2.1.46), a lysosomal β-galactosidase that is responsible for cleavage of galactosyl moieties from a variety of substrates including galactosylceramide, monogalactosyldiglyceride, and psychosine.
      • Wenger D.A.
      • Suzuki K.
      • Suzuki Y.
      • Suzuki K.
      Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease).
      The name “globoid cell leukodystrophy” derives from the storage of myelin fragments and galactosylceramide in multinucleated macrophages (globoid cells) around blood vessels of affected white matter. KD is inherited as an autosomal recessive trait and more than 70 mutations, including missense, nonsense mutations, and small deletions in the GALC gene have been identified to date.
      • Wenger D.A.
      • Suzuki K.
      • Suzuki Y.
      • Suzuki K.
      Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease).
      ,
      • Wenger D.A.
      • Rafi M.A.
      • Luzi P.
      Molecular genetics of Krabbe Disease (globoid cell leukodystrophy): diagnostic and clinical implications.
      The resulting clinical phenotype is due to progressive damage of the white matter of the peripheral and CNSs and comprises a spectrum from early infantile KD (EIKD) to late-onset KD (LOKD).
      • Wenger D.A.
      • Rafi M.A.
      • Luzi P.
      • Datto J.
      • Costantino-Ceccarini E.
      Krabbe disease: genetic aspects and progress toward therapy.
      The incidence of KD in Europe and the United States is estimated to be 1:100,000 newborns.
      • Wenger D.A.
      • Rafi M.A.
      • Luzi P.
      • Datto J.
      • Costantino-Ceccarini E.
      Krabbe disease: genetic aspects and progress toward therapy.
      ,

      Wenger DA. Krabbe disease online NIH Gene review. Funded by the NIH developed at the University of Washington Seatlle, 2008; Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=krabbe. Accessed December 2, 2010.

      Based on these data before the onset of NBS for KD in New York, it was estimated that close to 90% of patients with KD may have the infantile form of disease. However, based on the data from the New York State NBS Program, the overall incidence of KD is approximately 0.91:100.000 and 0.26: 100,000 for EIKD based on the New York State case definition criteria (personal communication,
      • Orsini J.J.
      • Morrissey M.A.
      • Salvin L.N.
      Implementation of newborn screening for Krabbe disease: population study and cutoff determination.
      ).
      • Duffner P.K.
      • Caviness Jr, V.S.
      • Erbe R.W.
      The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York.

      Clinical phenotype

      Early infantile-onset KD

      Infants with EIKD typically present within the first months of life with progressive irritability, spasms upon noise stimulation, recurrent episodes of unexplained fever, blindness, and deafness.
      • Wenger D.A.
      • Rafi M.A.
      • Luzi P.
      • Datto J.
      • Costantino-Ceccarini E.
      Krabbe disease: genetic aspects and progress toward therapy.
      ,
      • Siddiqi Z.A.
      • Sanders D.B.
      • Massey J.M.
      Peripheral neuropathy in Krabbe disease: electrodiagnostic findings.
      The disease course is rapidly progressive, leading to frequent seizures, hyperpyrexia, hypersalivation, complete loss of social contact, and loss of bulbar functions. Death typically occurs within the first 2 years of age because of respiratory complications.
      • Wenger D.A.
      • Rafi M.A.
      • Luzi P.
      • Datto J.
      • Costantino-Ceccarini E.
      Krabbe disease: genetic aspects and progress toward therapy.
      Peripheral neuropathy is always present in EIKD but may not be observed in LOKD. A detailed description of the natural history of KD from the Hunter's Hope Krabbe Family Database has been recently reported.
      • Duffner P.K.
      • Jalal K.
      • Carter R.L.
      The Hunter's Hope Krabbe family database.
      Visual impairment, ataxia, and irritability, respectively, may be the first presenting symptoms in LOKD although age of onset may be highly variable.
      • Lyon G.
      • Hagberg B.
      • Evrard P.
      • Allaire C.
      • Pavone L.
      • Vanier M.
      Symptomatology of late onset Krabbe's leukodystrophy: the European experience.
      All patients with EIKD show abnormal nerve conduction studies (NCSs), whereas approximately 90% of patients with EIKD have abnormal brainstem auditory evoked responses (BAER), 65% have an abnormal electroencephalogram, and 53% have abnormal flash visual evoked potentials (VER).
      • Siddiqi Z.A.
      • Sanders D.B.
      • Massey J.M.
      Peripheral neuropathy in Krabbe disease: electrodiagnostic findings.
      ,
      • Husain A.M.
      • Altuwaijri M.
      • Aldosari M.
      Krabbe disease: neurophysiologic studies and MRI correlations.
      In contrast, only a small percentage of patients with LOKD show abnormal neurophysiologic studies.
      • Husain A.M.
      • Altuwaijri M.
      • Aldosari M.
      Krabbe disease: neurophysiologic studies and MRI correlations.
      Cranial magnetic resonance imaging (MRI) may show demyelination of white matter without any sign of peripheral nerve involvement.
      • Verdru P.
      • Lammens M.
      • Dom R.
      • Van Elsen A.
      • Carton H.
      Globoid cell leukodystrophy: a family with both late-infantile and adult type.
      Diffusion tensor imaging studies may help to identify early involvement of motor tracts in asymptomatic neonates with KD.
      • Escolar M.L.
      • Poe M.D.
      • Smith J.K.
      Diffusion tensor imaging detects abnormalities in the corticospinal tracts of neonates with infantile Krabbe disease.

      Current diagnostics

      Diagnosis of KD is made by demonstration of low GALC activity in leukocytes or DBSs.
      • Wenger D.A.
      • Suzuki K.
      • Suzuki Y.
      • Suzuki K.
      Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease).
      Confirmation of the diagnosis can be made by molecular analysis of the GALC gene.
      • Wenger D.A.
      • Suzuki K.
      • Suzuki Y.
      • Suzuki K.
      Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease).
      ,
      • Wenger D.A.
      • Rafi M.A.
      • Luzi P.
      Molecular genetics of Krabbe Disease (globoid cell leukodystrophy): diagnostic and clinical implications.
      Genotype-phenotype correlation is limited and may only be possible if the clinical impact of a particular genotype is known in a larger set of patients with KD.
      • Wenger D.A.
      • Rafi M.A.
      • Luzi P.
      Molecular genetics of Krabbe Disease (globoid cell leukodystrophy): diagnostic and clinical implications.
      ,
      • Xu C.
      • Sakai N.
      • Taniike M.
      • Inui K.
      • Ozono K.
      Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype-phenotype correlation.
      In principle, homozygosity for the 30-kb deletion may predict EIKD.
      • Wenger D.A.
      • Rafi M.A.
      • Luzi P.
      • Datto J.
      • Costantino-Ceccarini E.
      Krabbe disease: genetic aspects and progress toward therapy.
      Occasionally, patients with LOKD carry two severe mutations that abolish enzyme activity completely.
      • De Gasperi R.
      • Sosa M.A.
      • Sartorato E.L.
      Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy.
      There is variability in presentation even with the same genotype.

      Wenger DA. Krabbe disease online NIH Gene review. Funded by the NIH developed at the University of Washington Seatlle, 2008; Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=krabbe. Accessed December 2, 2010.

      Ascertainment

      New York State Laboratories, Wadsworth Center Albany, New York, started NBS for KD using MS/MS technology in August 2006. Through June 2009, 769,853 newborn infants were screened (personal Communication,
      • Orsini J.J.
      • Morrissey M.A.
      • Salvin L.N.
      Implementation of newborn screening for Krabbe disease: population study and cutoff determination.
      ).
      • Zhang X.K.
      • Elbin C.S.
      • Chuang W.L.
      Multiplex enzyme assay screening of dried blood spots for lysosomal storage disorders by using tandem mass spectrometry.
      ,
      • Orsini J.J.
      • Morrissey M.A.
      • Salvin L.N.
      Implementation of newborn screening for Krabbe disease: population study and cutoff determination.
      ,
      • Duffner P.K.
      • Caggana M.
      • Orsini J.J.
      Newborn screening for Krabbe disease: the New York state model.
      Out of a total of 140 recalls (recall rate 0.018%), two infants were identified to have EIKD and were transplanted; one died of transplant complications. Five additional infants were confirmed to have low enzyme activity but were not transplanted and are currently followed up very closely. An additional 13 and 36 infants were found to have moderately low or borderline low enzyme activity, respectively. All infants identified with low enzyme activity are being followed up by the Krabbe Disease Consortium in New York State.
      • Duffner P.K.
      • Caggana M.
      • Orsini J.J.
      Newborn screening for Krabbe disease: the New York state model.

      Therapy

      The only therapy at present is early allogeneic hematopoietic stem cells (HSCs) or cord blood transplantation.
      • Krivit W.
      • Shapiro E.G.
      • Peters C.
      Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy.
      ,
      • Escolar M.L.
      • Poe M.D.
      • Provenzale J.M.
      Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease.
      Escolar et al.
      • Escolar M.L.
      • Poe M.D.
      • Provenzale J.M.
      Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease.
      reported on the use of cord blood transplantation after myeloablative chemotherapy in 11 asymptomatic newborns and 14 symptomatic infants with EIKD. Presymptomatic infants before transplantation continued to show psychomotor development and gain of milestones. Symptomatic infants only showed minimal neurologic improvement after transplantation.
      • Escolar M.L.
      • Poe M.D.
      • Provenzale J.M.
      Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease.
      A review of 25 cases of presymptomatic infants transplanted for EIKD from different transplant centers from the United States and Canada demonstrated an overall mortality rate of 15%.
      • Duffner P.K.
      • Caviness Jr, V.S.
      • Erbe R.W.
      The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York.
      Despite successful engraftment, most transplanted infants developed signs of neurological disease related to KD.
      • Duffner P.K.
      • Caviness Jr, V.S.
      • Erbe R.W.
      The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York.

      Recommended follow-up procedures

      The diagnosis should be confirmed by demonstrating (1) GALC deficiency in leukocytes and (2) mutation analysis of the GALC gene.
      • 1.
        Early (preferably younger than 30 days of age) bone marrow/stem cell transplantation from cord blood should be considered in any case predicted to have EIKD (e.g., homozygosity for the 30-kb deletion, compound heterozygosity for the 30-Kb deletion, and another severe mutation with very low GALC activity). In most cases, the genotype cannot predict phenoytype.
      • 2.
        Other individuals requires follow-up at regular, 6–12 monthly intervals.
      • 3.
        Although there are no data on the appropriate follow-up studies, they could reasonably include the following: (a) neurologic examination, (b) cranial MRI, (c) neurophysiologic studies (BAER, VER, electroencephalogram, and NCS), (d) lumbar puncture (for cerebrospinal fluid protein), if subtle neurological signs are present, and (e) diffusion tensor imaging studies that may help to identify early involvement of motor tracts in asymptomatic neonates with KD.
        • Escolar M.L.
        • Poe M.D.
        • Smith J.K.
        Diffusion tensor imaging detects abnormalities in the corticospinal tracts of neonates with infantile Krabbe disease.

      Metachromatic leukodystrophy (OMIM# 250100)

      Synonyms

      Arylsulfatase A (ARSA) deficiency.

      Background

      Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by insufficient enzymatic activity of ARSA (E.C. 3.1.6.8). This enzymatic defect results in moderate to massive accumulation of sulfated glycolipids, in particular, galactosylceramide-3-O-sulfate (sulfatide), in the brain, peripheral nervous system, and kidneys.
      • Biffi A.
      • Lucchini G.
      • Rovelli A.
      • Sessa M.
      Metachromatic leukodystrophy: an overview of current and prospective treatments.
      ,

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      Although the age of onset and dynamics of disease progression vary, MLD is primarily characterized by progressive neurodegeneration of the central and peripheral nervous systems.
      MLD is a panethnic disorder; depending on the population studied, incidents estimates for the most common subtype, late infantile MLD, vary considerably between 1:40,000 (Sweden, Washington State) and 1:170,000 live births (Germany).
      • von Figura K.
      • Gieselmann V.
      • Jaeken J.
      Metachromatic leukodystrophy.
      Of note, certain ethnic populations show significantly higher incidence rates such as the Habbanite Jewish population (1:75), Alaskan Eskimos (1:2500), and Navajo Indians (1:6400).
      • von Figura K.
      • Gieselmann V.
      • Jaeken J.
      Metachromatic leukodystrophy.
      Two other biochemical defects have been identified that result in a MLD or MLD-like phenotype. Several patients described with a MLD phenotype were found to have a deficiency of the nonenzymatic sphingolipids activator protein saposin B (OMIM# 249900).
      • Deconinck N.
      • Messaaoui A.
      • Ziereisen F.
      Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency.
      • Shapiro L.J.
      • Aleck K.A.
      • Kaback M.M.
      Metachromatic leukodystrophy without arylsulfatase A deficiency.
      • Stevens R.L.
      • Fluharty A.L.
      • Kihara H.
      Cerebroside sulfatase activator deficiency induced metachromatic leukodystrophy.
      Multiple sulfatase deficiency (MSD), caused by mutations in the sulfatase activator enzyme sulfatase modifying factor 1 (SUMF1) (OMIM# 272200), not only results in progressive demyelination of the central and peripheral nervous systems but is also accompanied by ichthyosis and features of MPS.

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      ,
      • von Figura K.
      • Gieselmann V.
      • Jaeken J.
      Metachromatic leukodystrophy.

      Clinical phenotype

      Based on age of disease onset, MLD has been divided into three main subtypes: late infantile, juvenile, and adult MLD. As in other lysosomal storage disorders, this classification facilitates clinical management but ignores the fact that MLD comprises a phenotypic continuum. The phenotypes and natural histories of each subtype are summarized in Table 4. Although disease progression in late infantile MLD is more uniform in both presentation and dynamics, the juvenile and adult forms are considerably more variable. Patients with the latter two types may manifest with primarily neurologic symptoms of clumsiness, gait disturbance, worsening of coordination, and fine motor skills, or with primarily psychiatric symptoms of bizarre behaviors, emotional lability, personality changes, or even psychotic episodes. Although disease progression toward complete loss of all cognitive skills and function is observed in most patients, some experience periods of disease stability punctuated by episodic deterioration.

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      Table 4Natural history of metachromatic leukodystrophy (MLD) subtypes
      Sulfatide deposition occurs in the gallbladder, leading to papillomatous transformation that can be noted on abdominal ultrasound. Cerebrospinal fluid protein levels are generally increased, exceeding 50 mg/dL, in most MLD cases except the adult onset type. BAER and VER testing demonstrate impairment of hearing and vision. NCS velocities are slowed, reflecting peripheral demyelination and neuropathy. Demyelination of the CNS is evident on brain MRI initially as symmetric, nonenhancing periventricular and subcortical T2 white matter prolongation. With disease progression, cortical atrophy and ventriculomegaly become apparent. A scoring system for MRI has been developed for MLD.
      • Eichler F.
      • Grodd W.
      • Grant E.
      Metachromatic leukodystrophy: a scoring system for brain MR imaging observations.

      Current diagnostics

      Biochemical markers

      Deficient or insufficient residual activity of ARSA in peripheral blood leukocytes or cultured fibroblasts are a necessary, but not sufficient, condition for the diagnosis of MLD. ARSA “pseudodeficiency” is a relatively common variant that is found in 1–2% of the European and Euro-American individuals who have 5–15% of normal ARSA enzymatic activity but no sulfatide excretion or evidence of pathologic storage. These individuals never develop any disease-related clinical symptoms throughout their lives.
      • Dubois G.
      • Turpin J.C.
      • Baumann N.
      Absence of ASA activity in healthy father of a patient with metachromatic leukodystrophy.
      ,
      • Kihara H.
      • Ho C.K.
      • Fluharty A.L.
      • Tsay K.K.
      • Hartlage P.L.
      Prenatal diagnosis of metachromatic leukodystrophy in a family with pseudo arylsulfatase A deficiency by the cerebroside sulfate loading test.
      Because of the high prevalence of ARSA “pseudodeficiency,” any positive biochemical test result must obligatorily be corroborated by a second analytical test system, such as ARSA sequencing or measurement of urinary sulfatides (or molecular analysis), because patients with all types of MLD excrete increased levels of these compounds.

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      ,
      • Molzer B.
      • Sundt-Heller R.
      • Kainz-Korschinsky M.
      • Zobel M.
      Elevated sulfatide excretion in heterozygotes of metachromatic leukodystrophy: dependence on reduction of arylsulfatase A activity.
      ,
      • Whitfield P.D.
      • Sharp P.C.
      • Johnson D.W.
      • Nelson P.
      • Meikle P.J.
      Characterization of urinary sulfatides in metachromatic leukodystrophy using electrospray ionization-tandem mass spectrometry.
      Enzymatic assays using artificial substrates are inappropriate to predict possible disease phenotypes.
      • von Figura K.
      • Gieselmann V.
      • Jaeken J.
      Metachromatic leukodystrophy.
      Although MLD can usually be distinguished from MSD based on phenotype alone, the measurement of a second sulfatase enzyme activity should be considered. In contrast to other lysosomal storage disorders, no other biomarkers are currently available for MLD.
      The diagnosis of MLD can also be confirmed by molecular genetic analysis of the ARSA gene. To date, more than 140 disease relevant mutations have been identified (for details, see the Human Genome Mutation Database http://www.hgmd.cf.ac.uk/ac/gene.php?gene = ARSA). Several recurrent mutations have been observed that account for up to 60% of disease-relevant alleles in certain populations.

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      ,
      • von Figura K.
      • Gieselmann V.
      • Jaeken J.
      Metachromatic leukodystrophy.
      ,
      • Gieselmann V.
      Metachromatic leukodystrophy: genetics, pathogenesis and therapeutic options.
      ARSA mutations characterized in more detail have been divided into two groups: (1) “null alleles” such as c.459 + 1g>a (25% of disease alleles) and c.1204 + 1g>a that result in complete loss of enzymatic activity and (2) “R alleles” such as p.P426L (25% of disease alleles) and p.I179S (12.5% of disease alleles) that allow the synthesis of ARSA enzyme with residual catalytic activity of up to 5% of normal.

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      ,
      • Sevin C.
      • Aubourg P.
      • Cartier N.
      Enzyme, cell and gene-based therapies for metachromatic leukodystrophy.
      Based on this classification, genotype-phenotype correlations have been proposed
      • Polten A.
      • Fluharty A.L.
      • Fluharty C.B.
      • Kappler J.
      • von Figura K.
      • Gieselmann V.
      Molecular basis of different forms of metachromatic leukodystrophy.
      and further corroborated
      • Gieselmann V.
      Metachromatic leukodystrophy: genetics, pathogenesis and therapeutic options.
      ,
      • Rauschka H.
      • Colsch B.
      • Baumann N.
      Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype.
      ,
      • Biffi A.
      • Cesani M.
      • Fumagalli F.
      Metachromatic leukodystrophy—mutation analysis provides further evidence of genotype-phenotype correlation.
      to predict, in limited fashion, the clinical presentation and natural history (see Table 5). Although the predictive value of this correlation is excellent for patients homozygous for two null alleles, patients with one and two R alleles show considerable phenotypic variability, implicating other genetic and/or environmental factors that contribute to the disease course.

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      ,
      • von Figura K.
      • Gieselmann V.
      • Jaeken J.
      Metachromatic leukodystrophy.
      ,
      • Gieselmann V.
      Metachromatic leukodystrophy: genetics, pathogenesis and therapeutic options.
      Consequently, reliable prognostication in these cases is not possible.
      Table 5Genotype-phenotype correlations in metachromatic leukodystrophy (MLD)
      To date, two pseudodeficiency-related sequence variations have been identified that can occur independently or together in cis. One, c.*96A>G, destroys the polyadenylation signal 95 bp downstream of the translation termination codon
      • Gieselmann V.
      • Polten A.
      • Kreysing J.
      • von Figura K.
      Arylsulfatase A pseudodeficiency: loss of a polyadenylation signal and N-glycosylation site.
      ,
      • Harvey J.S.
      • Carey W.F.
      • Morris C.P.
      Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype.
      and results in a markedly decreased synthesis of a catalytically normal enzyme. The other, p.N350S, abolishes the N-glycosylation site of the ARSA enzyme and causes aberrant targeting of the protein away from the lysosome.
      • Harvey J.S.
      • Carey W.F.
      • Morris C.P.
      Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype.

      Ascertainment

      To date, one high-throughput screening system for the reliable detection of ARSA deficiency in DBS has been proposed, but no NBS programs have actually begun to screen for MLD.
      • Tan Tan M.A.
      • Dean C.J.
      • Hopwood J.J.
      • Meikle P.J.
      Diagnosis of metachromatic leukodystrophy by immune quantification of arylsulphatase A protein and activity in dried blood spots.
      A high false-positive rate is anticipated as a result of the high prevalence of pseudodeficiency alleles in many populations and will be problematic for any MLD NBS program. Given the high frequency of pseudodeficiency alleles, a homozygous pseudodeficient genotype is approximately 400 times, and a MLD/pseudodeficient genotype 30–50 times more common than a true MLD/MLD genotype.

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      Therapy

      Therapeutic options are at present very limited in MLD. For late infantile MLD, no approved specific therapy exists at all and treatment efforts are restricted to palliative and/or supportive measures including the prevention or delay of secondary complications.
      • Biffi A.
      • Lucchini G.
      • Rovelli A.
      • Sessa M.
      Metachromatic leukodystrophy: an overview of current and prospective treatments.
      ,
      • von Figura K.
      • Gieselmann V.
      • Jaeken J.
      Metachromatic leukodystrophy.
      ,
      • Sevin C.
      • Aubourg P.
      • Cartier N.
      Enzyme, cell and gene-based therapies for metachromatic leukodystrophy.
      Early HSCT at a presymptomatic stage is completely ineffective and is not recommended.
      • Sevin C.
      • Aubourg P.
      • Cartier N.
      Enzyme, cell and gene-based therapies for metachromatic leukodystrophy.
      ,
      • Bredius R.G.
      • Laan L.A.
      • Lankester A.C.
      Early marrow transplantation in a pre-symptomatic neonate with late infantile metachromatic leukodystrophy does not halt disease progression.
      Because of the less rapid disease progression, HSCT has been established for several years as the only specific therapeutic option for juvenile and adult forms of MLD.
      • Biffi A.
      • Lucchini G.
      • Rovelli A.
      • Sessa M.
      Metachromatic leukodystrophy: an overview of current and prospective treatments.
      ,
      • Krivit W.
      Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases.
      ,
      • Malatack J.J.
      • Consolini D.M.
      • Bayever E.
      The status of hematopoietic stem cell transplantation in lysosomal storage disease.
      Notably, HSCT harbors substantial risks and its real long-term effects are still unknown

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      ,
      • von Figura K.
      • Gieselmann V.
      • Jaeken J.
      Metachromatic leukodystrophy.
      . According to the current experience, when performed before onset of clinical symptoms, HSCT is able to stabilize cerebral demyelination and arrests or slows, disease progression in later-onset forms of MLD.

      Fluharty AL. Arylsulfatase A deficiency: GeneReviews, 2008;( last update). Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mld. Accessed December 2, 2010.

      ,
      • Krivit W.
      Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases.
      ,
      • Malatack J.J.
      • Consolini D.M.
      • Bayever E.
      The status of hematopoietic stem cell transplantation in lysosomal storage disease.
      On the other hand, HSCT does not arrest or ameliorate disease progression in the peripheral nervous system,
      • Krivit W.
      Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases.
      ,
      • Malatack J.J.
      • Consolini D.M.
      • Bayever E.
      The status of hematopoietic stem cell transplantation in lysosomal storage disease.
      and patients with successful HSCT have developed severe, peripheral neuropathy-related motor deficits several years after transplantation.
      • Sevin C.
      • Aubourg P.
      • Cartier N.
      Enzyme, cell and gene-based therapies for metachromatic leukodystrophy.

      Future therapeutic approaches

      A number of alternative therapeutic concepts are currently being developed and investigated. Phase I studies of intrathecal recombinant human ARSA have been completed, and phase II studies are recruiting patients at the time of this writing. Other modalities include cotransplantation of HSC and mesenchymal stem cells,
      • Koc O.N.
      • Day J.
      • Nieder M.
      • Gerson S.L.
      • Lazarus H.M.
      • Krivit W.
      Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).
      ,
      • Meuleman N.
      • Vanhaelen G.
      • Tondreau T.
      Reduced intensity conditioning haematopoietic stem cell transplantation with mesenchymal stromal cells infusion for the treatment of metachromatic leukodystrophy: a case report.
      umbilical cord blood transplantation,
      • Pierson T.M.
      • Bonnemann C.G.
      • Finkel R.S.
      • Bunin N.
      • Tennekoon G.I.
      Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy.
      ,
      • Tokimasa S.
      • Ohta H.
      • Takizawa S.
      Umbilical cord-blood transplantations from unrelated donors in patients with inherited metabolic diseases: single-institute experience.
      ex vivo HSC gene therapy, in vivo and cell-based gene therapies, and coexpression strategies with recombinant ARSA and the formylglycine-generating enzyme.
      • Biffi A.
      • Lucchini G.
      • Rovelli A.
      • Sessa M.
      Metachromatic leukodystrophy: an overview of current and prospective treatments.
      ,
      • Sevin C.
      • Aubourg P.
      • Cartier N.
      Enzyme, cell and gene-based therapies for metachromatic leukodystrophy.

      Recommended follow-up procedures

      The high frequency of pseudodeficiency alleles must be kept in mind when counseling a family whose newborn has been screened positive for MLD or an individual detected because of a prior affected family member/carrier screening in high-risk populations. Consequently, confirmation of the diagnosis must include (1) analysis of urinary sulfatides and (2) ARSA gene sequencing.
      • 1.
        Presymptomatically identified MLD patients should be followed at regular intervals by both a neurologist and a metabolic physician.
      • 2.
        Those predicted to have juvenile and late-onset MLD should be referred for a HSCT evaluation, recognizing that even early HSCT is ineffective for peripheral demyelination.
      • 3.
        Periodic brain MRI imaging to monitor the status of CNS demyelination should be performed to allow for scoring and monitoring of response to therapy.
      Care of late infantile MLD patients is currently limited only to palliative and supportive measures. Given the frequency of null alleles and the lack of treatment for the potentially high percentage of newborns to be identified with the late infantile type, it is questionable whether NBS should be considered for this disorder at the present time.

      Niemann-Pick disease, types A (OMIM# 257200) and B (OMIM# 607616)

      Synonyms

      Lysosomal acid sphingomyelinase deficiency, sphingomyelin lipidosis.

      Background

      Deficiency of lysosomal acid sphingomyelinase (ASM; E.C. 3.1.4.12), encoded by the sphingomyelin phosphodiesterase-1 (SMPD1) gene, results in types A and B Niemann-Pick disease (NPA and NPB, respectively). Undegradeable sphingomyelin accumulates primarily in CNS neurons and reticuloendothelial cells. Collectively, both types occur in approximately 1 in 250,000 live births; NPA is seen more frequently and NPB less so in the Ashkenazi Jewish population with an incidence of 1:40,000 live births, whereas NPB is more common in individuals of Northern African descent.
      • Simonaro C.M.
      • Desnick R.J.
      • McGovern M.M.
      • Wasserstein M.P.
      • Schuchman E.H.
      The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.

      Clinical phenotype

      Full details regarding symptomatology of NPA and NPB are given in Table 6. In general, NPA is characterized by neonatal-onset disease, neurodegeneration, and early death.
      • McGovern M.M.
      • Aron A.
      • Brodie S.E.
      • Desnick R.J.
      • Wasserstein M.P.
      Natural history of type A Niemann-Pick disease: possible endpoints for therapeutic trials.
      NPB has a more variable presentation, but age of onset is typically in later childhood or adulthood. Primary symptoms are related to hepatosplenomegaly and impaired pulmonary function due to accumulation of sphingomyelin in reticuloendothelial and pulmonary tissues.
      • McGovern M.M.
      • Aron A.
      • Brodie S.E.
      • Desnick R.J.
      • Wasserstein M.P.
      Natural history of type A Niemann-Pick disease: possible endpoints for therapeutic trials.
      ,
      • McGovern M.M.
      • Wasserstein M.P.
      • Giugliani R.
      A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B.
      With a few rare exceptions, cognition is spared.
      • Wasserstein M.P.
      • Aron A.
      • Brodie S.E.
      • Simonaro C.
      • Desnick R.J.
      • McGovern M.M.
      Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease.
      Table 6Symptoms of Niemann-Pick Types A (NPA) and B (NPB)

      Current diagnostics

      ASM activity assayed from fibroblasts or leukocytes is <5% of normal controls in NPA patients and between 2% and 10% of normal in those with NPB.
      • Gal A.E.
      • Brady R.O.
      • Hibbert S.R.
      • Pentchev P.G.
      A practical chromogenic procedure for the detection of homozygotes and heterozygous carriers of Niemann-Pick disease.
      Because of the overlap in enzymatic activity between NPA and NPB, enzyme assay alone is unreliable in predicting phenotype. For similar reasons, enzyme activity cannot differentiate carriers from normal individuals. Postmortem studies in brains of patients with Niemann-Pick disease demonstrate markedly increased sphingomyelin levels in NPA and normal sphingomyelin in NPB.
      • Rodriguez-Lafrasse C.
      • Vanier M.T.
      Sphingosylphosphorylcholine in Niemann-Pick disease brain: accumulation in type A but not in type B.
      Affected patients may have increased serum transaminases, reduced fasting levels of high-density lipoprotein cholesterol, and increased low-density lipoprotein. Patients also demonstrate progressive anemia and thrombocytopenia. The characteristic finding in biopsy specimens from liver, lung, or bone marrow is the “foam cell,” a large cell of histiocytic origin that is swollen with stored lysosomal lipid. Infiltration and accumulation of foam cells into body tissues leads to the visceromegaly, pulmonary compromise, and marrow dysfunction seen in both forms of the disorder.
      Sequencing of the SMPD1 gene is the most reliable method to confirm a diagnosis of NP. In the Ashkenazi Jewish population, three founder mutations p.R496L, p.L302P, and fsP330 account for more than 95% of mutant alleles and are associated with the NPA phenotype.
      • Simonaro C.M.
      • Desnick R.J.
      • McGovern M.M.
      • Wasserstein M.P.
      • Schuchman E.H.
      The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.
      Non-Jewish NPA patients generally have “private” SMPD1 mutations. NPB occurs in all ethnic backgrounds but is rarer in Ashkenazi Jews and more frequent in Northern Africans. The p.[Delta]R608 mutation predicts a NPB phenotype, even when found in trans with a NPA mutation,
      • Wasserstein M.P.
      • Desnick R.J.
      • Schuchman E.H.
      The natural history of type B Niemann-Pick disease: results from a10-year longitudinal study.
      and is thought to be protective against cognitive impairment. A few other mutations are also thought to be neuroprotective.
      • Wasserstein M.P.
      • Aron A.
      • Brodie S.E.
      • Simonaro C.
      • Desnick R.J.
      • McGovern M.M.
      Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease.
      Individuals with at least one p.Q292K mutation had later-onset neurologic abnormalities such as mental retardation, expressive language delay, areflexia, and abnormal retinal findings.
      • Wasserstein M.P.
      • Aron A.
      • Brodie S.E.
      • Simonaro C.
      • Desnick R.J.
      • McGovern M.M.
      Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease.
      This mutation seems to be more prevalent in the Czech and Slovak populations.
      • Pavlu-Pereira H.
      • Asfaw B.
      • Poupetova H.
      Acid sphinogomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study.

      Ascertainment

      Early ascertainment is currently only through prenatal carrier or family-based testing. No pilot NBS programs have been established for NPA/NPB.

      Therapy

      Allogeneic or cord blood stem cell transplantation is ineffective at preventing neurocognitive regression in NPA, despite full donor engraftment.
      • Bayever E.
      • Kamani N.
      • Ferreira P.
      Bone marrow transplantation for Niemann-Picktype IA disease.
      ,
      • Morel C.F.
      • Gassas A.
      • Doyle J.
      • Clarke J.T.
      Unsuccessful treatment attempt: cord blood stem cell transplantation in a patient with Niemann-Pick disease type A.
      Allogeneic stem cell transplantation was reported in three NPB patients.
      • Shah A.J.
      • Kapoor N.
      • Crooks G.M.
      Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B.
      ,
      • Victor S.
      • Coulter J.B.
      • Besley G.T.
      Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant.
      • Schneiderman J.
      • Thormann K.
      • Charrow J.
      • Kletzel M.
      Correction of enzyme levels with allogeneic hematopoeitic progenitor cell transplantation in Niemann-Picktype B.
      • Nelson J.
      • Crowhurst J.
      • Carey B.
      • Greed L.
      Incidence of the mucopolysaccharidoses in Western Australia.
      Significant transplant-related complications were reported in all patients: poor linear growth, inadequate weight gain, and chronic graft-versus-host disease requiring immunosuppressive therapy. One patient experienced hepatic veno-occlusive disease with her first HSCT, developed graft failure, and required a second HSCT.
      • Shah A.J.
      • Kapoor N.
      • Crooks G.M.
      Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B.
      Although all three patients had normalization of leukocyte ASM enzyme activity, another patient experienced stagnation and regression of developmental milestones. At the time of the report, she was 18 years old, wheelchair bound, gastrostomy feeding dependent, with no verbal communication.
      • Victor S.
      • Coulter J.B.
      • Besley G.T.
      Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant.
      All three showed resolution of pulmonary involvement and hematopoietic abnormalities and incomplete improvement in visceromegaly.
      Clinical trials are in progress to determine the efficacy of ERT with recombinant human acid sphingomyelinase in patients with NPB (Clinical trials identification number NCT00410566).

      Recommended follow-up procedures

      A suggested diagnostic algorithm is presented in Figure 4. An infant with a positive newborn screen for NP should first have leukocyte ASM activity, transaminases, bilirubin levels, and lipid profile assayed. The infant and family should then be referred for evaluation and genetic counseling at a metabolic center. If the ASM activity is low, then SMPD1 gene sequencing should be obtained to determine the causative mutations. Mutations with clear phenotypic correlations will allow for prediction of type A or B disease. SMPD1 targeted gene sequencing should be recommended for any identified at-risk family members.
      Fig. 4
      Fig. 4Diagnostic algorithm for Niemann-Pick A (NPA) and B (NPB). NBS, newborn screening; ASM, lysosomal acid sphingomyelinase.

      Clinical follow-up and Intervention

      Once NP has been confirmed, the infant should be evaluated by an ophthalmologist with a dilated funduscopic examination. Plain radiographs of the chest and abdominal ultrasound should be performed at regular intervals to document the extent of pulmonary involvement and hepatosplenomegaly. The metabolic physician should evaluate the infant on a monthly basis, documenting weight gain, linear growth, pulse oximetry, and developmental progression. Eventually, the infant will need evaluation and regular follow-up by neurology and pulmonology as the disorder progresses. Because no curative treatment currently exists, only symptomatic and supportive care can be provided. Lipid lowering drugs (e.g., statins) are ineffective.

      MPS type I

      Synonyms

      MPS I-H, Hurler syndrome, severe MPS I (OMIM# 607014); MPS I-HS, Hurler-Scheie syndrome, intermediate MPS I (OMIM# 607015); MPS I-S, Scheie syndrome, attenuated MPS I (OMIM# 607016).

      Background

      MPS I is caused by a deficiency of α-l-iduronidase (EC 3.2.1.76), encoded by the IDUA gene. α-l-iduronidase participates in the degradation of heparan and dermatan sulfate, two glycosaminoglycans (GAGs) found in nearly all body tissues. Consequently, α-l-iduronidase deficiency results in a disease that involves multiple organ systems resulting from the accumulation of undegradable GAG material throughout the body. The population frequency of MPS I is estimated to be approximately 1 in 100,000 births, with MPS I-H the most common and MPS I-S the rarest of the subtypes.
      • Baehner F.
      • Schmiedeskamp C.
      • Krummenauer F.
      Cumulative incidence rates of the mucopolysaccharidoses in Germany.
      ,
      • Murphy A.
      • Flanagan O.
      • Dunne K.
      • Lynch S.
      High incidence of Cohen syndrome among Irish travelers.
      MPS I-H is especially common in the Irish Traveler population, with an incidence of 1 in 371 live births.
      • Murphy A.
      • Flanagan O.
      • Dunne K.
      • Lynch S.
      High incidence of Cohen syndrome among Irish travelers.

      Clinical phenotype

      Disease manifestations of MPS I span a continuum of severity and age of onset, with Hurler syndrome representing the most severe end of the clinical spectrum with the earliest onset and presence of neurocognitive regression, Scheie syndrome the attenuated end of the clinical spectrum with later age of onset, and Hurler-Scheie syndrome used to describe patients with intermediate disease severity and symptom onset. A detailed list of subtype- and system-specific disease manifestations of MPS I is given in Table 7. Emphasis must be made on the nonuniform nature of symptom severity; in other words, a patient with “intermediate” MPS I based on lack of cognitive involvement may have severe orthopedic disease and cardiac valvular dysplasia, for example.
      Table 7Symptoms of mucopolysaccharidosis I (MPS I)

      Current diagnostics

      α-l-iduronidase activity in MPS I is markedly reduced compared with normal controls. As a general rule, patients with MPS I-H have undetectable α-l-iduronidase activity whereas patients with MPS I-HS and MPS I-S have residual α-l-iduronidase activity. Evidently, as little as 0.4% of normal enzyme activity is sufficient to produce a mild phenotype.
      • Bunge S.
      • Clements P.R.
      • Byers S.
      • Kleijer W.J.
      • Brooks D.A.
      • Hopwood J.J.
      Genotype-phenotype correlations in mucopolysaccharidosis type I using enzyme kinetics, immunoquantification and in vitro turnover studies.
      Enzymatic activity alone is unreliable for prediction of phenotype because some MPS I-H patient fibroblasts had more enzyme activity than those from MPS I-HS patients; similarly, there were MPS I-HS cell lines with more activity than MPS I-S cells.
      • Bunge S.
      • Clements P.R.
      • Byers S.
      • Kleijer W.J.
      • Brooks D.A.
      • Hopwood J.J.
      Genotype-phenotype correlations in mucopolysaccharidosis type I using enzyme kinetics, immunoquantification and in vitro turnover studies.
      ,
      • Ashton L.J.
      • Brooks D.A.
      • McCourt P.A.
      • Muller V.J.
      • Clements P.R.
      • Hopwood J.J.
      Immunoquantification and enzyme kinetics of alpha-L-iduronidase in cultured fibroblasts from normal controls and mucopolysaccharidosis type I patients.
      Enzymatic analysis is also insufficient for carrier testing because of overlap in activity between normal individuals and heterozygotes.
      • Blanchard S.
      • Sadilek M.
      • Scott C.R.
      • Turecek F.
      • Gelb M.H.
      Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: application to screening newborns for mucopolysaccharidosis I.
      Certain IDUA mutations allow for prediction of the phenotype. Homozygosity or compound heterozygosity for the p.Q70X and p.W402X nonsense mutations predict a MPS I-H phenotype. p.Q70X and p.W402X are also the two most common mutations in Caucasian MPS I patients, accounting for 60–70% of mutant alleles in those populations.
      • Terlato N.J.
      • Cox G.F.
      Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.
      The presence of two nonsense mutations is predictive of a MPS I-H,
      • Terlato N.J.
      • Cox G.F.
      Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.
      although one 20-year-old homozygous p.W402X patient was described as having MPS I-S without further description of her phenotype.
      • Pereira V.G.
      • Martins A.M.
      • Micheletti C.
      • D'Almeida V.
      Mutational and oxidative stress analysis in patients with mucopolysaccharidosis type I undergoing enzyme replacement therapy.
      The p.R89Q missense and the c.678-7g>a (IVS5-7g>a) splice site mutations predict a mild phenotype.
      • Moskowitz S.M.
      • Tieu P.T.
      • Neufeld E.F.
      Mutation in Scheie syndrome (MPS IS): a G–>A transition creates new splice site in intron 5 of one IDUA allele.
      • Scott H.S.
      • Litjens T.
      • Nelson P.V.
      Identification of mutations in the alpha-L-iduronidase gene (IDUA) that cause Hurler and Scheie syndromes.
      • Yamagishi A.
      • Tomatsu S.
      • Fukuda S.
      Mucopolysaccharidosis type I: identification of common mutations that cause Hurler and Scheie syndromes in Japanese populations.
      • Gatti R.
      • DiNatale P.
      • Villani G.R.
      Mutations among Italian mucopolysaccharidosis type I patients.
      • Matte U.
      • Yogalingam G.
      • Brooks D.
      Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients.
      All three subtypes of MPS I have been reported in patients with the homozygous p.P533R mutation; both MPS I-H and MPS I-HS have been reported with p.P533R compound heterozygotes with other “severe” mutations.
      • Terlato N.J.
      • Cox G.F.
      Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.
      A rare p.A300T pseudodeficiency allele has been reported in one family.
      • Aronovich E.L.
      • Pan D.
      • Whitley C.B.
      Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency.

      Ascertainment

      Early ascertainment is currently only accomplished through family-based testing. As of yet, no NBS programs for MPS I have been established.

      Therapy

      Results for clinical trials with recombinant human α-l-iduronidase (laronidase) (rhIDU, Aldurazyme®; Genzyme Corporation) have been published.
      • Kakkis E.D.
      • Muenzer J.
      • Tiller G.E.
      Enzyme-replacement therapy in mucopolysaccharidosis I.
      ,
      • Wraith J.E.
      • Clarke L.A.
      • Beck M.
      Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase).
      Weekly ERT with 0.58 mg/kg/dose of rhIDU improved forced vital capacity and reduced symptoms of airway obstruction, apnea/hypopnea index, and duration of nighttime desaturation episodes. Exercise tolerance was increased, as patients receiving laronidase had significant improvement in the distance traveled during the 6-minute walk test compared with placebo. Liver and spleen volumes were reduced to near normal levels. Patients also demonstrated improvement in weight gain and linear growth velocity. Some improvement was also seen in restriction of joint mobility.
      • Kakkis E.D.
      • Muenzer J.
      • Tiller G.E.
      Enzyme-replacement therapy in mucopolysaccharidosis I.
      A similar efficacy profile was noted in MPS I-H patients receiving ERT.
      • Wraith J.E.
      • Clarke L.A.
      • Beck M.
      Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase).
      Urinary GAG excretion was reduced by 55–60% to levels at or below the upper limit of normal.
      • Wraith J.E.
      • Clarke L.A.
      • Beck M.
      Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase).
      ,
      • Wraith J.E.
      • Beck M.
      • Lane R.
      Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase).
      ERT does not seem to adequately treat the orthopedic manifestations of MPS I, especially with regard to spinal cord compression and vertebral dysplasia. Clinical trials are underway to determine whether intrathecal rhIDU infusion is effective for these manifestations (Clinical Trials identification number NCT00215527).
      Nearly all patients developed IgG antibodies to laronidase. Development of antibody was not associated with changes in urinary GAG levels, and titer levels decreased with continued infusions. Adverse effects of laronidase infusion were usually infusion reactions (flushing, fever, and headache) or anaphylactoid reactions (urticaria, rash, nausea, abdominal pain, and edema) and were managed by temporary reduction in infusion rate and administration of antihistamine and antipyretic medication.
      Multiple studies documenting neurodevelopmental and somatic disease outcomes after HSCT for MPS I-H have been reported.
      • Peters C.
      • Balthazor M.
      • Shapiro E.G.
      Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome.
      • Vellodi A.
      • Young E.P.
      • Cooper A.
      Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres.
      • Peters C.
      • Shapiro E.G.
      • Anderson J.
      Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group.
      • Souillet G.
      • Guffon N.
      • Maire I.
      Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources.
      • Staba S.L.
      • Escolar M.L.
      • Poe M.
      Cord-blood transplants from unrelated donors in patients with Hurler's syndrome.
      • Grewal S.S.
      • Wynn R.
      • Abdenur J.E.
      Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome.
      • Cox-Brinkman J.
      • Boelens J.J.
      • Wraith J.E.
      Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome.
      • Boelens J.J.
      • Wynn R.F.
      • O'Meara A.
      Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure.
      • Tolar J.
      • Grewal S.S.
      • Bjoraker K.J.
      Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome.
      Although HSCT creates significant morbidity stemming from postconditioning immunocompromise, pneumonitis, graft-versus-host disease, and hepatic veno-occlusive disease, and is subject to graft failure or chimerism, it is currently the only known treatment modality that prevents mental retardation. Survival and engraftment rates have steadily improved to 85–90% in recent series.
      • Souillet G.
      • Guffon N.
      • Maire I.
      Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources.
      • Staba S.L.
      • Escolar M.L.
      • Poe M.
      Cord-blood transplants from unrelated donors in patients with Hurler's syndrome.
      • Grewal S.S.
      • Wynn R.
      • Abdenur J.E.
      Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome.
      • Cox-Brinkman J.
      • Boelens J.J.
      • Wraith J.E.
      Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome.
      • Boelens J.J.
      • Wynn R.F.
      • O'Meara A.
      Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure.
      • Tolar J.
      • Grewal S.S.
      • Bjoraker K.J.
      Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome.
      One series saw no effect of pre-HSCT ERT on survival or engraftment,
      • Boelens J.J.
      • Wynn R.F.
      • O'Meara A.
      Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure.
      whereas another noted a reduction in pulmonary complications and successful engraftment and survival of all seven patients treated with combined therapy.
      • Tolar J.
      • Grewal S.S.
      • Bjoraker K.J.
      Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome.
      Other groups eschew ERT before transplant unless the patient has significant cardiopulmonary disease, citing the possibility of anti-α-iduronidase antibodies interfering with successful engraftment.
      HSCT performed before 24 months of age and the onset of significant developmental delay (developmental quotient < 70) has the highest probability of rescuing neurocognitive outcome; engrafted survivors may experience speech delay and learning disability.
      • Vellodi A.
      • Young E.P.
      • Cooper A.
      Bone marrow transplantation for mucopolysaccharidosis type I: expe