Keywords
Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.
Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Where individual authors are listed, the views expressed may not reflect those of authors’ employers or affiliated institutions.
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Introduction
Methylmalonic acidemia (MMA; OMIM 251000, OMIM 251100, OMIM 251110, OMIM 277410, OMIM 277400) and propionic acidemia (PA; OMIM 606054) are inborn errors of metabolism of the propionate pathway characterized by accumulation of methylmalonic acid and propionic acid, respectively, leading to acute presentations related to metabolic acidosis and hyperammonemia, as well as chronic heterogenous complications.
Isolated MMA is caused by deficiency of the enzyme methylmalonyl-CoA mutase or defects in transport or metabolism of its cofactor, adenosyl-cobalamin. The disorder is genetically heterogenous and can be caused by biallelic pathogenic variants in 1 of the 5 genes, MMUT, MMAA, MMAB, MCEE, and MMADHC. MMA can be classified into subtypes based on responsiveness to cobalamin. In general, patients who are cobalamin responsive are thought to have less severe phenotypes, although there are reports of renal failure and subsequent need for renal transplant in this population.
1
MMA can also be classified according to the amount of residual enzyme activity, namely mut0 subtype for complete enzyme deficiency or mut– subtype for partial enzyme deficiency. In natural history and large cohort publications, clinical severity of the condition is gauged by age of first symptoms; frequency of metabolic crises; neurodevelopmental delay; progressive end organ involvement, including renal involvement, metabolic strokes, hearing loss, and eye involvement; and serum levels of methylmalonic acid.2
,3
PA is caused by deficiency of the enzyme propionyl-CoA carboxylase due to biallelic pathogenic variants in either the PCCA or PCCB genes. Similar to MMA, clinical severity has been classified based on age of presentation, neurologic outcomes (with metabolic strokes), end-organ complications (ie, cardiac arrhythmias, cardiomyopathies, optic atrophy, hearing loss), and frequency of metabolic crises.
4
,5
With current therapy, survival has improved as evidenced by a study focusing on the mut0 subtype demonstrating improved patient survival over successive decades (0% in 1970-1979, 50% in 1980-1989, 78.9% in 1990-1997).
3
However, despite the improved observed survival, medical management can be inadequate in preventing long-term mortality and morbidity in individuals with MMA and PA. The treatment of PA with liver transplantation (LT) and of MMA with LT or kidney transplantation (KT) or combined liver and kidney transplantation (LKT) in patients with severe metabolic phenotype and/or end organ failure has been available in some locations for almost 2 decades.6
The aim of this points to consider statement is to (1) review current practice related to organ transplantation, (2) provide general guidance in decision-making and management of patients being considered for or with completed transplants, (3) help design a framework for shared decision-making, and (4) outline known deficits in knowledge. However, many questions about long-term outcomes, single organ vs combined organ transplantation, as well as post-transplant medical and dietary management remain. Given these goals, the following points to consider are targeted to the medical genetics community and other disciplines that manage these patients regarding indications for transplantation, expected post-transplant outcomes, surveillance of potential complications, and post-transplant disease progression, as well as peri- and post-transplant nutritional management.Methods
A literature search of PubMed was done with the range of January 1960 through March 2021 using the following Boolean search terms: (“propionic acidemia” OR “propionic aciduria” OR “methylmalonic aciduria” OR “methylmalonic acidemia”) AND (“transplant” OR “liver transplant” OR “renal transplant”). Review of the search results by at least 2 of the authors identified 94 publications as applicable and formed the literature basis for the generation of this document (see Supplemental Table 1 for a full list of references).
Points to consider include the following:
- 1.The most common indication for transplantation in individuals with MMA and PA is severe early-onset disease with frequent episodes of metabolic decompensation. The decision to transplant and type of transplant indicated should be made after a thorough pretransplant evaluation by a multidisciplinary team consisting of biochemical geneticists, pediatric neurologists, transplant nephrologists, transplant gastroenterologists, transplant surgeons, dietitians, and social workers.
- 2.Transplantation leads to improvement or resolution in episodes of metabolic crises and stabilization of other end-organ complications, such as cardiomyopathy and renal dysfunction. There have been rare reports of decompensation and metabolic strokes in relation to surgery or several years after the procedure. Some degree of liberalization of protein restriction appears to be tolerated after transplantation, but it remains unclear if a completely unrestricted diet should be recommended.
- 3.Energy demands and catabolism are increased during the transplant procedure and in the early post-transplant period. Therefore, administration of sufficient caloric support is essential to prevent metabolic decompensation and promote a successful recovery.
- 4.Complications can be seen in relation to the graft, surgery (acute or chronic rejection, vessel thrombosis, infection, bleeding), use of immunosuppressants (infection, cancer, posterior reversible encephalopathy syndrome, and post-transplant lymphoproliferative disorder), or related to the disease itself.
- 5.Patients who have undergone a transplant should be followed up closely and receive periodic surveillance (as detailed in the discussion) pertaining to graft survival and use of immunosuppressants as well as for metabolic status and end-organ complications of the disease.
Discussion
Transplant-related considerations
Pretransplant evaluation
Decision-making for transplantation in PA and MMA should be made after consultation with a multidisciplinary team, including biochemical geneticists, pediatric neurologists, transplant nephrologists, transplant gastroenterologists, metabolic dietitians, surgeons, and social workers, to help inform benefit-risk assessment, timing for evaluation, and organ type selection. Reviews of up-to-date literature with families particularly in relation to survival, metabolic crisis, neurodevelopmental outcomes, and risks of immunosuppressive medications in the short and long term are a crucial part of pretransplant evaluation. Literature from the Urea Cycle Disorders Consortium has identified myriad perspectives, including clinical, social, and local health care systems, that should be integrated in the decision-making process.
7
For some patients, limited access to a metabolic center increases the risk for delayed interventions and worse outcomes. Access to care can drive decision-making with long-term, post-transplant care in some cases being more consistent and available than lifelong metabolic care, especially across the transition from pediatric to adult care.Indications and organ type selection
The severity of the phenotype in PA and MMA ranges from severe neonatal forms to apparently asymptomatic cases with no clinical signs of the disease. The European registry and network for Intoxication type Metabolic Diseases (E-IMD) identified 22% (33 out of 149) of patients with MMA and 18.8% (19 out of 101) of patients with PA as asymptomatic (ie, never having an identified metabolic decompensation), with the remainder being symptomatic (experienced at least 1 metabolic crisis).
5
Although newborn screening (NBS) can impact mortality, neonatal onset and severe forms of PA and MMA often present before return of screen results.2
Because of this, NBS appears to have little impact on intellectual disability and other morbidities. The differences in complications seen between early and late onset (diagnosis <30 days or >30 days of life) as a measure of severity show that the most severe cases have worse symptoms, which implies that reducing or preventing metabolic crises may improve outcomes.2
,3
LT and LKT (and to some extent, KT) appear to markedly reduce but not necessarily eliminate the risk for metabolic decompensation and are associated with excellent short- to intermediate-term patient and graft survival.
8
, 9
, 10
, 11
, 12
There are multiple reports describing patients with PA and cardiomyopathy (including those who had severe cardiomyopathy, requiring left ventricular assist devices and extra corporeal membrane oxygenation) with heart function stabilizing after LT.12
, 13
, 14
, 15
, 16
Chronic kidney disease and renal failure are known complications of MMA and have increasingly been identified in individuals with PA.17
In these cases, LKT and KT have been used successfully to improve renal function and eliminate the need for dialysis.1
,18
, 19
, - Jiang Y.Z.
- Zhou G.P.
- Wu S.S.
- Kong Y.Y.
- Zhu Z.J.
- Sun L.Y.
Safety and efficacy of liver transplantation for methylmalonic acidemia: a systematic review and meta-analysis.
Transplant Rev (Orlando). 2021; 35100592https://doi.org/10.1016/j.trre.2020.100592
20
, 21
Genotype−phenotype correlations are limited, and there is currently insufficient data to determine whether a milder metabolic phenotype would benefit from early transplantation to prevent long-term complications (such as renal dysfunction or cardiomyopathy). Mut-, MMAA-related, and MMAB-related cases of MMA are generally less likely to have severe decompensations and thus might result in a different risk-benefit analysis for transplantation.KT alone has been performed in older patients with MMA who have renal failure (especially those with MMAA and MMAB genotypes).
22
These patients have few or no metabolic decompensations; therefore, renal dysfunction was the major deciding factor for KT, which is a lower risk procedure than LKT.1
,18
,20
In contrast, there have also been reports of adult patients with PA who underwent successful KT or heart transplantation for acute renal failure23
or dilated cardiomyopathy,24
respectively. However, there is currently insufficient data to establish long-term efficacy in these situations and long-term longitudinal data are required. Renal transplantation in this patient population appears to stabilize biochemistry, but graft survival may be less favorable when compared with transplants done for other causes of renal failure. However, despite more frequent surgical complications of the LKT procedure, recent data suggest that LKT should be considered in individuals with chronic renal failure given improved metabolic outcomes, as well as the ability to liberalize protein restriction to some degree.25
Current data on KT vs LKT in patients with MMA are limited to short follow-up. Thus, long-term studies comparing outcomes in individuals who have had KT vs LKT will be important for determining the risk-benefit analysis in the subset of patients with MMA and primarily renal complications. LT alone for PA increases metabolic stability but can be associated with nephrotoxicity from immunosuppressive medications. LT alone for MMA is being performed at early ages, before the onset of renal dysfunction, with a goal of preventing metabolic decompensations. Evidence on whether this approach can prevent renal failure later in life is still being gathered. LKT is predominately done for individuals with MMA who have some renal dysfunction and significant frequency of metabolic crises, because the risk of the procedure is considered less than the mortality and morbidity resulting from severe and frequent decompensations.Perioperative dietary and fluid management
Optimal perioperative and postoperative dietary and fluid management are especially crucial for individuals with MMA and PA who undergo organ transplantation. Proper nutritional support in the perioperative period plays an integral role in successful organ transplantation in all organ recipients. In addition, optimal nutrition before and during LT improves patient and graft survival, helps to protect from infections, and decreases the risk of vascular complications, bile leak, and intestinal perforation.
26
Energy demand and catabolism are increased in solid organ recipients because of anesthesia and surgical stress during the transplant procedure. The nutritional goals in the perioperative period center around prevention of catabolism to avoid metabolic decompensation.
27
Sufficient delivery of calories is also essential to promote wound healing and avoid infections.26
During the perioperative fasting period, an infusion of 10% dextrose is typically started at a rate of 1.5 times the normal maintenance rate (by weight to approximate a glucose infusion rate of 8 mg/kg/min) while monitoring blood glucose levels and acid-base balance.27
, 28
, 29
, 30
Patients with indications of metabolic decompensation should not undergo surgery. Poor metabolic status during LT carries a high risk for mortality and severe postoperative metabolic complication.27
In the early post-transplant period, energy demand and catabolism remain increased because of surgical stress during transplantation.
26
During this period, caloric support of 120% of basal energy expenditure is recommended.31
It is essential to supply sufficient calories and minimize catabolism to prevent metabolic decompensations, but it can be challenging in the setting of early liver dysfunction and risk of developing lactic acidosis.32
Parenteral nutritional support in the early postsurgery period is required, with the goal to transition to enteral nutritional support as soon as possible.26
,31
Typically, total parenteral nutrition with 5% to 20% dextrose should be initiated shortly after the transplant, providing 0.5 gm protein/kg/day and can be gradually increased with the goal to transition to enteral feeding as early as possible.28
,32
To provide additional calories, additional lipid emulsion can be used as tolerated. Resuming enteral nutrition within 12 hours of transplant has been shown to reduce postoperative viral infections and produce better nitrogen retention.33
In the first 2 post-transplant months (acute phase), there is an increased need for nutrients and protein to promote healing and deter infection.34
However, there is a lack of specific nutrition guidance during the perioperative phase in individuals with MMA and PA. Moreover, the optimal specific target for protein intake remains unclear.Given the use of steroids in the acute post-transplant period, hyperglycemia may be noted. If hyperglycemia is present, patients need insulin to control glucose levels in the postoperative period, which may also help to promote anabolism.
28
Certain patients, especially the subset with cardiac complications, may require fluid restriction and in such situations, a higher dextrose content in the fluids will be required to achieve caloric goals. Those requiring insulin and high glucose infusion should be monitored for increases of lactic acid because of a potential interference with Krebs-cycle entry and inhibition of pyruvate dehydrogenase by toxic metabolites.35
In the setting of lactic acidosis (plasma lactate >5 mmol/L), the use of insulin should be reconsidered.Outcomes following transplantation
Outcomes related to graft survival and related complications
Outcomes from the United Network for Organ Sharing demonstrate that from 2002 to 2012, liver graft survival was 92% at 30 days, 89% at 1 year, and 83% at 5 years in organic acidemias and urea cycle disorder (UCD) groups.
36
These numbers are similar to the number of children who received LT for biliary atresia (91%, 88%, and 83%) and better than those with cholestatic disorders (95%, 86%, and 75%). The literature pertaining to KT for patients with MMA demonstrates 100% survival at 1 year and 83% survival at 5 years (Table 1).1
,37
,38
Table 1Summary of literature describing outcomes in LT and KT for MMA and PA
| Authors/Reference | PA cases | Patient survival | Transplant graft survival | Postoperative outcomes | Notes |
|---|---|---|---|---|---|
| Yorifuji et al 11 | N = 3 | 100% | 100% | Improvement in protein intake from 0.7 g/kg/day to 1.7 g/kg/day, one episode of acidosis with EPS resolved with support | Living related transplant from heterozygous parents |
| Charbit-Henrion et al 13 | N = 12 (17 LTs) | 42% patient survival at 1 y | 60% at 5 y | No metabolic decompensation among survivors with significantly relaxed protein restriction | Study period 1991-2013 CM resolved in 3 patients with pretransplant CM 3 patients with normal cardiac function developed CM and died post-transplant |
| Critelli et al 32 | N = 3 | 100% patient survival | 100% graft survival | >1.2 mg/kg/day post-transplant protein intake | Significantly lower serum glycine levels post-transplant |
| Yap et al 6 | N = 204 (193 LTs, 2 KTs) | Post-transplant survival 86% | 9 retransplants | CM reversed in 50% of cases in collective series of 38 manuscripts | |
| Zhou et al 12 | N = 70 | 95% patient survival | 91% graft survival | Pooled estimates for rejection, HAT, viral infection = 20%, 8%, 14%, respectively, 66% with liberalization of protein intake | Pooled estimates model |
| Pillai et al 10 | N = 8 | 100% patient survival at 5 y | 90.9% graft survival | No CM pre or post transplant |
The papers included in this table are intended to be representational of the literature and not comprehensive. In addition, examples of both single studies and metanalyses are included.
CM, cardiomyopathy; EPS, extrapyramidal symptoms; HAT, hepatic artery thrombosis; KT, kidney transplant; LT, liver transplant; MMA, methylmalonic acidemia; PA, propionic acidemia.
Complications from transplantation include perioperative issues, such as bleeding, vessel thrombosis, postoperative infection, and acute and chronic rejection. Monitoring of organ specific markers (Table 2) and acid-base status is recommended to assess recovery from acute graft injury. It is important to note that more surgical complications are seen in patients who are transplanted at younger ages or have lower weights.
36
Graft survival rate was 78% for children younger than 2 years of age and 88% for children older than 2 years. Higher weight at transplant was protective, but the risk was not significantly different between those weighing ≥5 to 10 kg and those weighing ≥10 to 20 kg.36
Risk for surgical complications must be weighed against the risk of metabolic decompensation and consequential morbidities. Among the 17 patients with MMA who received LKT, there was liver graft loss in 1 patient due to hepatic artery thrombosis and retransplant was required within 15 days, which was successful.36
Also inherent to any transplantation surgery, there is the risk of organ rejection, both early and late, which can be life-threatening.13
However, more recent immunosuppressive regimens have decreased the risk of rejection, and this is evident when comparing the rejection rates and subsequent mortality in each decade since 1990. Although acute rejection occurs in about 40% of patients, chronic rejection is rare in LT, and current 10-year outcomes denote 85% survival.39
Table 2Evaluations to consider pre- and post-organ transplantation
| Pretransplant evaluation | Post-transplant surveillance | ||
|---|---|---|---|
| Laboratory | Laboratory | ||
| Immune | Immune | ||
| CD4 | CD4 | ||
| Immunoglobulin G | Immunoglobulin G | ||
| Donor-specific antibodies | Donor-specific antibodies | ||
| Lymphocyte subsets | Plexiummune | ||
| Vaccine titers (native) | Lymphocyte subsets | ||
| Vaccine titers (native) | |||
| Metabolic | Metabolic | ||
| Ammonia | Ammonia (once after transplant then as needed) | ||
| Total/free carnitine | Total/free carnitine (every 3 mo for first year, then every 6-12 mo) | ||
| Plasma methylmalonic acid | Plasma methylmalonic acid (every 6-12 mo) | ||
| Acylcarnitine (every 3-6 mo) Plasma amino acids (every 3-6 mo) Lactate (every 3-6 mo) | |||
| Nutrition | |||
| 25-hydroxyvitamin D (annually) | |||
| Fasting lipid panel (every 3 mo first year, then every 6-12 mo) | |||
| Iron studies (every 3 mo first year, then every 6-12 mo) | |||
| Prealbumin (every 3 mo first year, then every 6 mo) Micronutrients (every 3 mo first year, then every 6-12 mo) | |||
| Other | Other | ||
| Thyroid tests (eg, TSH, free T4) Iron studies Fasting lipid panel Parathyroid level Cystatin C level Urine protein/creatinine ratio AST ALT GGTP Bilirubin | CBC with differential (every 3-6 mo) Thyroid tests (eg, TSH, free T4) (every 3 mo first year, then every 6-12 mo) Parathyroid level (every 3 mo first year, then every 6-12 mo) Cystatin C level (every 3 mo first year, then every 6-12 mo) Urine protein/creatinine ratio (every 3 mo first year, then every 6-12 mo) AST (every 3 mo first year, then every 6-12 mo) ALT (every 3 mo first year, then every 6-12 mo) GGTP (every 3 mo first year, then every 6-12 mo) Bilirubin (every 3 mo first year, then every 6-12 mo) | ||
| Imaging | Echocardiogram EKG CTA/CT (or MRI/MRA) abdomen and pelvis | Imaging | Echocardiogram (at least annually) EKG (at least annually) Dual-energy x-ray absorptiometry scan (usually first at 5-10 y, then every 5-10 y according to local standard of care) Brain MRI (as needed) |
| Screening | Eye exam (ophthalmology) Hearing evaluation Developmental evaluation (neuropsychology evaluation) (age appropriate) | Screening | Eye exam (ophthalmology) (annually) Hearing evaluation (annually) Developmental evaluation (neuropsychology evaluation) (age appropriate) |
CBC, complete blood count; CT, computed tomography; CTA, computed tomography angiography; EKG, electrocardiogram; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; TSH, thyroid-stimulating hormone.
a Home transplant team may differ according to their local practices.
b Depending on diet adequacy, growth trajectory, and clinical signs; micronutrients to consider include vitamins B12 and B6, erythrocyte folate, zinc, selenium, and essential fatty acids.
Immunosuppressive medications can result in a unique set of risks including infection, posterior reversible encephalopathy syndrome (PRES), and nephrotoxicity.
13
These complications have been mostly associated with tacrolimus; however, studies exploring the risks and safety profile of alternate immunosuppressive medications, such as sirolimus and mycophenolate mofetil, are limited. Moreover, there is an increased risk for cancers (such as hepatoblastoma) and post-transplant lymphoproliferative disease (PTLD).13
,40
The use of viral monitoring and empiric antiviral prophylaxis has significantly reduced the risk of Epstein-Barr virus driven PTLD in the recent era.41
The most comprehensive approach is to take into consideration both allograft and nonallograft complications to achieve an ideal outcome metric with optimal graft function and low toxicity from immunosuppression.42
In a patient population such as PA and MMA, surgery and anesthesia present singular risks because they can trigger metabolic crisis. Risks for complications vary from center to center based on providers’ experience with common perioperative challenges.6
,13
PRES is a known complication of calcineurin-inhibitors and has been reported in individuals with PA and MMA after transplant.43
,44
PRES can present similarly to a metabolic stroke and imaging findings are crucial to recognize the entity. This complication usually responds to decreasing doses of antirejection medications.Outcomes related to metabolic crisis and dietary restriction
Episodes of metabolic decompensation typically are significantly reduced or eliminated after transplantation except for a few reports that describe rare episodes of acidosis (most commonly in those with living related donors) and/or metabolic strokes after transplantation.
10
,29
,45
, 46
, 47
, 48
, 49
In most of these cases, the metabolic crises resolved and were attributed to be a complication of the surgery entirely.45
,46
,49
However, these patients can occasionally present later with decompensations with mildly elevated ammonia and acidosis (without ketones).10
Some degree of liberalization of dietary protein restriction appears to be tolerated after LT.
6
,10
,11
,29
,30
,32
,49
, 50
, 51
, 52
However, it remains unclear whether a completely unrestricted diet is advisable, and some patients who are prescribed a liberalized diet independently continue to pursue a mild protein restriction or vegetarian diet, confounding conclusions regarding the safety of completely unrestricted diets.29
,48
,49
Although there is insufficient data to determine whether diet might be a contributing factor, there are several examples of metabolic stroke in individuals on an unrestricted diet,29
,45
,49
but there is also at least 1 report of metabolic stroke post-transplantation in an individual on a restricted diet.48
Particularly in MMA, the degree of underlying renal disease in patients without KT may also contribute to decision-making regarding protein restriction in individuals after LT. Moreover, there is little guidance in the literature regarding the appropriate ratio of natural protein to medical foods after LT in either disorder. Thus, further studies investigating the impact of an unrestricted diet vs restricted diet post-transplantation are needed in this setting.Despite some degree of protein restriction in many cases after LT, several reports indicate an improvement in height after transplantation.
10
,50
,53
However, in some cases, these improvements may not become apparent for at least 2 years after transplantation given the confounding effect of corticosteroids,10
,53
and the data from 1 study suggest that these gains in height may be more apparent in individuals transplanted before 1 year of age.53
Moreover, regardless of the protein prescription, in some cases, enteral tube feedings have been deemed no longer necessary post-LT because oral intake may improve in some individuals.29
,50
,54
,55
Neurologic outcomes: Strokes and developmental assessment
Most of the large cohort studies and case series exploring long and short-term neurologic outcomes after LT suggest that most patients have no new strokes or developmental regression post-transplant; however, neuroimaging findings in some patients who had repeat scans showed volume loss, gliosis, etc.
10
,46
Data also suggest that seizures and tremors might be common in the perioperative period.56
There are some reports of patients having strokes years after transplant with or without a clear trigger. For instance, 1 patient with MMA has been reported who received LT at 9 months and remained relatively stable until 5 years of age when she had a metabolic stroke in the basal ganglia in the setting of a febrile illness.45
A child with PA has been reported who presented with a fatal metabolic stroke 11 years post-LT without any evidence of biochemical decompensation.48
The etiology of these exceptional cases with sudden decompensation remains unclear and further functional studies are required to fully understand the risks. A magnetic resonance spectroscopy study in patients with neonatal-onset PA showed a significant decrease in basal ganglia glutamate plus glutamine and an increase in lactate during encephalopathic episodes. However, metabolite data from 2 children who had received LT were not significantly different from the comparator group.57
The literature suggests that methylmalonic acid levels are elevated in the cerebrospinal fluid even after transplant, and it can lead to ongoing injury to the basal ganglia, which are areas in the central nervous system with high energy requirements.46
,56
Studies evaluating long-term neurodevelopmental outcomes in patients with MMA or PA after transplantation are limited. Existing literature suggests that most patients maintained neurodevelopmental abilities or even made slight gains in motor and cognitive skills; however, a subset continued to be at risk for mild developmental delay, attention deficit hyperactivity disorder, and autism spectrum disorder.
10
,18
,25
,29
,58
, 59
, 60
, 61
One study compared the IQ and adaptative behavior in patients with UCD, maple syrup urine disease, and organic acidemias who received LT. Of these patients, 6 (46%) had intellectual disability, 5 (39%) had autism spectrum disorder, and 1 out of 13 (8%) had cerebral palsy, compared with 1 out of 26 (4%), 0, 0, and 0% of matched patients with LT but not inborn errors of metabolism, respectively. The neurocognitive and functional outcomes remained poor even after LT in patients with metabolic disorders, particularly in the UCD group.62
Outcomes of MMA and PA cases from Taiwan showed that the IQ of the patients was improved after LT from 50 to 60.1 (P = .07) and the anxiety level of the caregiver was significantly reduced.55
Another large study including 77 patients with MMA and 37 with PA reported that most patients who were tested had no change in their IQ after transplantation (76/94, 81%).9
Therefore, counseling regarding developmental outcomes is crucial before transplantation to set appropriate parental expectations.Outcomes related to end-organ complications
There are multiple reports of cardiomyopathy stabilizing or improving after orthotopic LT in patients with MMA or PA.
10
,13
, 14
, 15
, 16
,63
Although many reports suggest resolution of cardiomyopathy after LT,13
other reports suggest that cardiomyopathy can recur or develop after transplantation.64
There have also been documented cases of prolonged QTc interval in patients with PA after LT, which implies that this disease-specific complication is not necessarily eliminated by transplant.62
Also, LT is contraindicated in some patients because of severe heart disease. Regarding renal complications, reports indicate that kidney function and neurologic status improve after LKT, but some patients have exhibited worsening renal function after LT.51
,65
,66
Sakamoto et al53
reported a patient who had pre-existing renal dysfunction before LT and developed renal failure from contrast used for endoscopic retrograde cholangiopancreatography. In addition, immunosuppressive medications may exert a toxic effect on the kidneys. It is important to consider that most patients with MMA have low muscle mass and therefore the serum creatinine and calculated estimated glomerular filtration rate cannot accurately reflect true renal function. However, a study showed that cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function.67
Data regarding optic complications post-transplantation are also limited. There is 1 report of a patient who developed acute exacerbation of chronic bilateral optic neuropathy shortly after LT; however, it subsequently improved and remained stable.- Manoli I.
- Sysol J.R.
- Epping M.W.
- et al.
FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia.
JCI Insight. 2018; 3e124351https://doi.org/10.1172/jci.insight.124351
56
Surveillance after transplantation
Surveillance related to graft and immunosuppressive medications
All patients who receive LT, LKT, and KT are expected to require some level of immunosuppressive medications for their lifetime. As discussed previously, immunosuppression increases risks for infections, PTLD, and other cancers.
6
,13
,40
,68
Routine post-transplant screening should include at least annual liver function tests (eg, AST, ALT, alkaline phosphatase, GGTP, bilirubin, and prealbumin), immunologic panel (donor-specific HLA antigens, Immunoplex, lymphocyte subsets, and IgG), kidney function tests (cystatin and urine protein and cells), parathyroid hormone level, and thyroid function tests (thyroid-stimulating hormone and free T4). The comprehensive metabolic panel should be monitored monthly for the first year and then every 3 months. In addition, neurocognitive assessment and neuroimaging (brain magnetic resonance imaging and magnetic resonance spectroscopy) should be obtained. Finally, the remainder of the interval testing is determined by center practice, which typically measures biochemical lab and immunosuppression medication levels every 2 to 3 months and may include protocol biopsies (Table 2).Surveillance related to disease specific complications
There is an improvement in biochemical markers of the disease (propionylcarnitine, methylmalonic acid, and 2-methylcitrate) after LT, LKT, or KT, but these do not completely normalize.
32
,37
,52
,56
,69
, 70
, 71
, - Noone D.
- Riedl M.
- Atkison P.
- et al.
Kidney disease and organ transplantation in methylmalonic acidaemia.
Pediatr Transplant. 2019; 23e13407https://doi.org/10.1111/petr.13407
72
When decompensation occurs post-transplantation, there is usually no signs of hyperammonemia, acidosis, or ketones and episodes are rather restricted to neurologic sequalae. Metabolic or neurologic decompensations are typically seen in patients with living-related, partial, or auxiliary grafts.6
,11
,53
,59
,73
,74
At first, third, and sixth month after transplantation and every 6 months thereafter, the following biochemical tests can be considered: plasma amino acids, lactate, plasma methylmalonic acid levels, acylcarnitine profile, and total/free carnitine levels. Also, to screen for progression of other long-term disease sequelae, patients should receive an annual echocardiogram, hearing screen, and eye examination consistent with current clinical recommendations.64
,75
Surveillance related to nutritional status
Follow-up with a dietitian or nutritionist is critical for all patients after LT regardless of the reason for transplantation.
26
Thus, nutritional assessment is an important component of the post-transplantation monitoring in individuals with MMA and PA even in patients who pursue minimal or no protein restriction or in whom tube feeds are deemed no longer necessary. Immunosuppressive medications used after LT can impact various micronutrients (eg, potassium, magnesium, calcium, and phosphorus). Likewise, regardless of the indication for LT, bone health can be impacted after transplantation as a result of corticosteroid use, deconditioning, and other factors. Vitamin D deficiency is highly prevalent in pediatric patients post-transplantation; therefore, vitamin D levels should also be monitored. Although there are no specific recommendations for bone density scans, these can be considered in high-risk individuals.26
Finally, given the prevalence of obesity and obesity-related disorders in individuals after LT, monitoring of body weight, body-mass index, and blood pressure has been recommended at each follow-up visit with annual evaluations of blood parameters to assess for hypertriglyceridemia, hypercholesterolemia, and insulin resistance.26
,76
Conclusion and Future Directions
The use of LT in patients with PA and KT or LKT in patients with MMA who exhibit a severe metabolic phenotype and/or end-organ dysfunction has been established as a practice over the past 2 decades. Although there is some movement toward the implementation of organ transplantation for most patients with PA or MMA after diagnosis, a comprehensive risk-benefit analysis should be applied as an integral part of the decision-making process. An existing clinical challenge is the prediction of disease severity in neonates identified through NBS to determine which individuals would possibly most benefit from earlier transplantation to reduce episodes of metabolic decompensation associated with increased morbidity and mortality. In addition, existing questions that require future study include whether isolated LT in patients with MMA delay progression of renal dysfunction ultimately requiring KT. Also, does the timing of LT impact the incidence of cardiomyopathy post-transplant? Another question to answer is whether there is a level of pre-existing neurologic dysfunction for which transplantation will not provide tangible benefits? Importantly, systematic longitudinal studies, including neurodevelopmental assessments, functional neuroimaging, and other end-organ functional assessments in patients with PA or MMA post-transplant, are currently lacking. Further implementation of multicenter longitudinal studies in these populations are essential to provide valuable data to address outstanding questions.
Conflict of Interest
The authors declare no conflicts of interest.
Additional Information
- Supplemental Table 1
References
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Article info
Publication history
Published online: December 19, 2022
Accepted:
November 7,
2022
Received:
November 3,
2022
Footnotes
The Board of Directors of the American College of Medical Genetics and Genomics approved this statement on October 24, 2022.
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Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
