Pyridoxine-dependent Epilepsy With Elevated Urinary α-Amino Adipic Semialdehyde in Molybdenum Cofactor Deficiency

Abstract

α-Amino adipic semialdehyde (α-AASA) accumulates in body fluids from patients with pyridoxine-dependent epilepsy because of mutations in antiquitin (ALDH7A1) and serves as the biomarker for this condition. We have recently found that the urinary excretion of α-AASA was also increased in molybdenum cofactor and sulfite oxidase deficiencies. The seizures in pyridoxine-dependent epilepsy are caused by lowered cerebral levels of pyridoxal-5-phosphate (PLP), the bioactive form of pyridoxine (vitamin B(6)), which can be corrected by the supplementation of pyridoxine. The nonenzymatic trapping of PLP by the cyclic form of α-AASA is causative for the lowered cerebral PLP levels. We describe 2 siblings with clinically evident pyridoxine-responsive seizures associated with increased urinary excretion of α-AASA. Subsequent metabolic investigations revealed several metabolic abnormities, all indicative for molybdenum cofactor deficiency. Molecular investigations indeed revealed a known homozygous mutation in the MOCS2 gene. Based upon the clinically evident pyridoxine-responsive seizures in these 2 siblings, we recommend considering pyridoxine supplementation to patients affected with molybdenum cofactor or sulfite oxidase deficiencies.

Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients

“…26,27 The fact that patients with MoCD develop lens dislocation late at the age of approximately 8 years may be the reason for the lack of this finding in our cohort as all our patients are well below this average age. 28 …”

Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome

“…Despite the recognized limitations, plasma and urinary biomarkers are often used as surrogates for cerebral concentrations of the putative neurotoxic metabolites. α-Aminoadipic semialdehyde exists in vivo in a reversible equilibrium with the cyclic Shiff base, P6C; these compounds are useful biomarkers for both pyridoxine-dependent seizures, and potentially sulfite oxidase or molybdenum cofactor defects [36]. Measurement in vitro involves protein precipitation with acetonitrile, and treatment with borate buffer (pH 8.5) and fluorenylmethoxycarbonyl chloride (FMOC-chloride) to make FMOC derivatives, followed by analysis by LC-MS/MS [37].…”

Disorders affecting vitamin B6 metabolism

“…An elevated urinary AASA/creatinine ratio is a more reliable biomarker for this disorder than pipecolic acid although it is also elevated in some patients with molybdenum cofactor (MIM #252150) and sulfite oxidase deficiency (MIM #272300) . Simultaneous determination of sulfocysteine is therefore recommended to avoid diagnostic pitfalls . Recently 6‐oxo‐pipecolate has been reported as a novel biomarker for this disorder .…”