Disorders of Pyridoxine Metabolism

Disorders of pyridoxine metabolism include pyridoxine-dependent epilepsy (PDE), pyridoxal-5′-phosphate- responsive epileptic encephalopathy, and tissue nonspecific isoenzyme of alkaline phosphatase deficiency. This chapter focuses on antiquitin (ATQ) deficiency, which is the main cause of autosomal recessive PDE and is characterized by early-onset epileptic encephalopathy resistant to antiepileptic medications but responsive to pharmacologic dosages of pyridoxine, which is a life-long requirement.ATQ, an aldehyde dehydrogenase in the lysine degradation pathway, is encoded by the ALDH7A1 gene. ATQ deficiency results in accumulation of α-aminoadipic semialdehyde (αAASA), piperideine-6-carboxylate, and pipecolic acid, which serve as diagnostic markers in urine, plasma, and cerebrospinal fluid (CSF). Elevated αAASA and at least one mutation in the ALDH7A1 gene are required for diagnostic confirmation.Ongoing research focuses on the effects of dietary lysine restriction in the management of ATQ deficiency, the delineation of the clinical spectrum of the disease (including neuroimaging findings), correlations between genotype and clinical and biochemical phenotypes, and molecular biology, as well as better understanding of the pathophysiology of this metabolic epilepsy. An international PDE Consortium has been established, employing collaborative data-sharing, digital media and novel trial methodologies, to attain these goals.