ALDH7A1 – Pyridoxine-Dependent Epilepsy

Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive neurometabolic disorder caused by biallelic mutations in the ALDH7A1 gene, encoding α-aminoadipic semialdehyde dehydrogenase (antiquitin). Affected infants present with early-onset, pharmacoresistant seizures that respond exclusively to high-dose pyridoxine and often adjunct folinic acid, highlighting the enzyme’s role in lysine catabolism and vitamin B6 homeostasis ([PMID:22529283]).

Genetic analyses in a cohort of 18 unrelated patients confirmed PDE in all individuals by elevated pipecolic acid and α-aminoadipic semialdehyde (AASA) biomarkers, with identification of 10 novel ALDH7A1 mutations across 36 alleles. The recurrent p.Glu399Gln variant accounted for 33% of alleles, demonstrating both allelic heterogeneity and founder effects in diverse populations ([PMID:17068770]).

Inheritance is autosomal recessive, supported by consanguineous pedigrees and compound heterozygosity. Segregation analysis in multiple families revealed at least 18 probands and 2 additional affected relatives carrying homozygous or compound heterozygous ALDH7A1 pathogenic variants, consistent with complete penetrance of loss-of-function alleles ([PMID:21397171]).

The variant spectrum includes missense, nonsense, splice-site, frameshift, and exon-deletion alleles. A representative pathogenic allele, c.1192G>C (p.Gly398Arg), was identified in homozygosity in a child with neonatal lactic acidosis and refractory seizures; prompt pyridoxine therapy achieved seizure freedom and normoglycemia ([PMID:22529283]).

Functional studies of recombinant ALDH7A1 missense mutants demonstrated complete loss of enzymatic activity in 12 disease-associated variants, confirming haploinsufficiency as the pathogenic mechanism. Enzyme assays using E. coli–expressed protein and natural substrate α-aminoadipic semialdehyde showed absent catalytic turnover for all tested mutants ([PMID:22784480]).

Structural and biophysical analyses of oligomerization-interface mutants (e.g., p.Arg162Ser, p.Arg469Cys) revealed impaired tetramer formation and disrupted NAD⁺ binding, corroborating the loss-of-function effect and elucidating mutation-specific molecular defects ([PMID:28087462]).

Early molecular diagnosis enables immediate pyridoxine administration, preventing irreversible neurodevelopmental injury. Adjunctive lysine-restricted diet and arginine supplementation further improve cognitive outcomes, underscoring the clinical utility of comprehensive metabolic and genetic screening for PDE.

Key Take-home: ALDH7A1 deficiency is a definitively established autosomal recessive cause of pyridoxine-dependent epilepsy; early genetic and biochemical testing is critical for prompt treatment and favorable long-term neurodevelopment.

References

• Human Mutation • 2007 • Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. PMID:17068770
• Pediatrics • 2012 • Profound neonatal hypoglycemia and lactic acidosis caused by pyridoxine-dependent epilepsy. PMID:22529283
• Pediatric Neurology • 2011 • Biomarkers aiding diagnosis of atypical presentation of pyridoxine-dependent epilepsy. PMID:21397171
• Molecular Genetics and Metabolism • 2012 • Overexpression of human antiquitin in E. coli: enzymatic characterization of twelve ALDH7A1 missense mutations associated with pyridoxine-dependent epilepsy. PMID:22784480
• Chemico-Biological Interactions • 2017 • Impact of disease-Linked mutations targeting the oligomerization interfaces of aldehyde dehydrogenase 7A1. PMID:28087462

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