Methylmalonate Semialdehyde Dehydrogenase Deficiency via the ALDH6A1 Gene

Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is an inborn error of valine and thymine metabolism (Chambliss et al. 2000; Marcadier et al. 2013). To date, only four patients with molecular diagnoses have been reported in the literature, so a complete clinical picture of this disorder is not known. Thus far, the clinical phenotype and biochemical hallmarks of the disorder seem to be extremely variable (Sass et al. 2012). Patients have ranged from essentially asymptomatic with only biochemical signs of the disorder (Chambliss et al. 2000) to quite severely affected. Those with a clinical phenotype may present with vomiting and diarrhea, life-threatening ketoacidosis, severe developmental delay, post-natal microcephaly, congenital brain dysgenesis with intracerebral calcifications, and dysmorphic facial features. Biochemically, all patients have been found to have elevated 3-hydroxyisobutric acid. Other biochemical signs seem to be more variable, but may include elevated 3-aminoisobutyric acid, β-alanine and 3-hydroxypropionic acid. In addition, some patients have been found to have elevated levels of methylmalonic acid and lactic acid (Chambliss et al. 2000; Sass et al. 2012; Marcadier et al. 2013).

Dietary control has been reported to help one patient catch up developmentally to his chronological age (Sass et al. 2012).

Pathogenic variants in ALDH6A1 on chromosome 14 at 14q24.3 are responsible for autosomal recessive MMSDH deficiency. To date, fewer than 10 pathogenic variants have been reported in the ALDH6A1 gene, all of which have been missense variants (Chambliss et al. 2000; Sass et al. 2012; Marcadier et al. 2013). No variants have been reported in more than one family.

The methylmalonate semialdehyde dehydrogenase protein is involved in the catabolism of valine and thymine. More specifically, the MMSDH protein catalyzes the oxidative decarboxylation of the intermediate methylmalonic semialdehyde to propionyl-CoA (Marcadier et al. 2013).

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature. Analytical sensitivity may be high as the few reported causative variants should be detectable by sequencing (Chambliss et al. 2000; Sass et al. 2012; Marcadier et al. 2013).

This test provides full coverage of all coding exons of the ALDH6A1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).