ALDH6A1 – methylmalonate semialdehyde dehydrogenase deficiency

ALDH6A1 encodes methylmalonate semialdehyde dehydrogenase (MMSDH), a mitochondrial enzyme catalyzing the oxidation of methylmalonate semialdehyde in valine and pyrimidine catabolism. Deficiency of MMSDH leads to accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as β-alanine, manifesting as a variable metabolic and neurologic phenotype (PMID:23835272). The gene–disease relationship is inherited in an autosomal recessive pattern.

Biallelic pathogenic variants in ALDH6A1 have been identified in five unrelated probands across four families (PMID:23835272; PMID:32151545). Reported variants include homozygous missense changes and compound heterozygosity, exemplified by c.514T>C (p.Tyr172His) and c.1603C>T (p.Arg535Cys). Segregation consistent with affected individuals inheriting variants from each parent has been observed, although no extended multi-generational segregation data are reported.

Clinical presentations range from severe developmental delay with dysmyelination on brain MRI to failure to thrive and gastroesophageal reflux. Case 1 demonstrated transient elevations of lactate and organic acids, severe dysmyelination, and compound heterozygosity for c.514T>C (p.Tyr172His) and c.1603C>T (p.Arg535Cys) (PMID:23835272). Case 5 presented with failure to thrive, reflux, and a homozygous c.1261C>T (p.Pro421Ser) variant, improving under valine-restricted diet (PMID:32151545).

Functional assays corroborate pathogenicity: MMSDH activity in patient fibroblasts was reduced by >2.5 SD compared to controls, demonstrating loss of enzymatic function (PMID:23835272). In the fifth case, Western blotting showed marked reduction of MMSDH protein and patient cells exhibited increased superoxide production, decreased oxygen consumption, and reduced ATP generation, confirming mitochondrial dysfunction (PMID:32151545).

No alternative genetic causes have been reported, and the biochemical phenotype is specific to ALDH6A1 deficiency. Together, genetic and experimental data fulfill ClinGen criteria for a moderate level of clinical validity.

Key Take-home: ALDH6A1 mutations cause autosomal recessive methylmalonate semialdehyde dehydrogenase deficiency with variable metabolic and neurologic manifestations; enzymatic assays and exome sequencing are essential for diagnosis and management.

References

• Orphanet Journal of Rare Diseases • 2013 • Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria. PMID:23835272
• Molecular Genetics and Metabolism • 2020 • Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case. PMID:32151545

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