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eP021: Case report of a Mexican family with alpha mannosidosis and a novel probably pathogenic variant in the MAN2B1 gene

      Background

      Alpha-mannosidosis (AM: OMIM #248500) is an ultra rare autosomal recessive lysosomal storage disorder characterized by a low enzymatic activity of α-Mannosidase.
      The disorder is characterized by a range of progressive clinical phenotypes, mainly, intellectual disability (ID), psychiatric symptoms, hearing impairment, coarse facial features, skeletal changes, recurrent otolaryngological and pulmonary infections (immunodeficiency), and asthma. AM has been classified in 3 types in order to describe its clinical presentation. Type 1 is the mildest form, with onset after age 10 years, without skeletal abnormalities and very slow progression. Type 2 is a moderate form, with onset before age 10 years, presence of skeletal abnormalities and slow progression with development of ataxia by age 20 to 30 years. Type 3 is the severe form, with onset in early infancy, skeletal abnormalities, and obvious progression leading to early death from primary central nervous system involvement or myopathy. Most patients correspond to clinical type 2. Despite the clinical heterogeneity of the disorder, there are no apparent genotype/phenotype correlations.
      The MAN2B1 gene is located to chromosome 19p13.13, spans 21.5 kbp, and consists of 24 exons. 130 pathogenic or probably pathogenic MAN2B1 variants spread along the gene have been identified in AM patients; the variants include insertions, deletions, duplications, and nonsense, splice site and missense variants. Most of these variants are private, just one missense variant (c.2248C>T, p.Arg750Trp) has been found in 18 patients from eight different countries.
      Our aim is to describe a familial case of AM from a clinical, biochemical and molecular point of view in a Mexican family with two affected cases.

      Case presentation

      Patient 1
      The proband is an 11-year-old girl, second child of healthy non-consanguineous parents of Mexican-Mestizo origin (Northern Mexico). She has a family history of a younger brother similarly affected. She was born at 39 weeks of gestation following a normal pregnancy; birth weight was 3,710 g (>90th centile), and height of 57 cm (>90th centile). She began crawling at 12 months, walking at 24 months and said her first word at 5 years. Bilateral moderate hearing loss was diagnosed at 9 years old following a history of recurrent otitis in infancy. The physical examination showed height of 138 cm (5th centile), weight of 3,680 g (25th centile), and head circumference of 50.5 cm (<3th centile), language delay, coarse flat facies, broad forehead with prominent metopic suture, thick eyebrows, oblique upward palpebral fissures, telecanthus, and blue nevus on sclerae, anteverted nostrils, dental anomalies, hypertrichosis, lubar blue spots, prominent abdomen, hepatomegaly and skeletal anomalies.
      Patient 2
      This is a 6-year-old boy, brother of patient 1, who was born at 35 weeks of gestation following an uncomplicated pregnancy. At birth he presented respiratory distress, the weight was 2,800 g (50th centile) and length was 52 cm (>90th centile). He began walking at 25 months and at present days he is not able to talk. He has history of bilateral inguinal hernia, recurrent otitis, hypoacusia and tonsillectomy. The physical examination showed somatometry in normal percentiles, language delay, coarse facies, dolichocephaly, broad forehead with frontal protuberances, blue nevus on sclerae, flat nasal tip, telecanthus, mid-facial retrution, hypertrichosis, blue dorso-lumbar spots, prominent abdomen, hepatomegaly and skeletal anomalies.
      According to the clinical features, AM type 2 was suspected; therefore, an enzymatic determination of leukocyte alpha-mannosidase (E.C. 3.2.1.24) was performed in the patient and his sister. The residual enzyme activity was found to be decreased (6%: 3.57 nMol/mg prot/h; ref: 56.53 - 200.42 nMol/mg prot/h). MAN2B1 gene was analyzed using the massive sequencing technique based on amplicon sequencing. The amplicons cover both the coding region and the highly conserved exon-intron junctions. The minimum coverage for each amplicon is >20x. The reference sequence is: MAN2B1: NM_000528.3.
      A homozygous duplication of a cytosine at position 89 (c.89dup, p.Pro31Thrfs*43) was identified in both patients, which causes a change in the reading frame from codon 31 and a termination codon 42 positions forward.

      Conclusion

      The worldwide prevalence of AM is estimated in 1/500,000–1/1,000,000 live births. Most of the patients have been reported in Germany, United States, United Kingdom, Turkey and Poland. This disease is widely underdiagnosed, particularly in Latin American countries. The prevalence of AM in Mexico is unknown. The present familial case is the first reported in our country.
      Alpha-mannosidose deficiency was confirmed in this case by gold standard study and by molecular study. The MAN2B1: c.89dupC variant does not have a clinical designation in public databases, however, based on established guidelines it can be classified as a probably pathogenic as it is a loss-of-function variant that has not been reported in any population.
      The differential diagnosis includes other lysosomal storage diseases such as mucopolysaccharidoses (MPS) and Gaucher’s disease; it is therefore advisable to include a α-mannosidase testing for all patients suspicious to MPS but with a negative MPS test result.
      AM although rare, should be considered in the approach to a child with hearing loss, dysmorphism, ID, skeletal deformities, and visceromegaly.
      The early detection of the disease, allows, besides accurate genetic counselling, better therapeutic management, since it is currently treatable with enzyme replacement therapy (velmanase alfa). Access to early treatment brings great benefits to patients relieving some severe manifestations, improving the quality of life.