Disorders of pyridoxine metabolism
Disorders of pyridoxine (vitamin B6) metabolism affecting the function of the central nervous system include pyridoxine-dependent epilepsy (PDE) due to α-aminoadipic semialdehyde dehydrogenase (antiquitin) deficiency associated with pathogenic variants in ALDH7A1 (PDE-ALDH7A1), PDE due to abnormalities in pyridoxal 5′-phosphate (PLP) homeostasis protein (PLPHP deficiency) associated with pathogenic variants in PLPBP (PDE-PLPBP), a PLP-responsive epileptic encephalopathy due to a deficiency of pyridox(am)ine 5′-phosphate oxidase (PNPO deficiency), tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) deficiency, and pyridoxal kinase deficiency associated with a peripheral neuropathy with optic atrophy. This chapter focuses primarily on PDE-ALDH7A1, which is the most studied cause of autosomal recessive PDE. PDE-ALDH7A1 is characterized by early-onset epileptic encephalopathy resistant to antiseizure drugs but typically responsive to pharmacologic dosages of pyridoxine, which is a life-long requirement. Most patients have neurodevelopmental disability, and many have abnormalities in brain development. Antiquitin, an aldehyde dehydrogenase in the lysine degradation pathway, is encoded by ALDH7A1. Deficiency of this enzyme results in accumulation of α-aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C), and pipecolic acid, as well as other biomarkers in urine, plasma, and cerebrospinal fluid. Elevated AASA/P6C and at least one pathogenic variant in ALDH7A1 are required for diagnostic confirmation. In addition to treatment with pyridoxine, lysine reduction therapies (particularly if initiated within the first 6 months of life) should be considered for patients with PDE-ALDH7A1.
