Mutations in the ALDH7A1 gene cause pyridoxine-dependent seizures.

To The ediTor Recently, Lin and colleagues have reported a case of pyridoxine-dependent seizures in this journal 1. The diagnosis was based upon the clinical criteria as formulated by Baxter 2. In discussing the case the authors state that the underlying pathophysiology of the disorder is unknown and that no biochemical aids are available in establishing the diagnosis. Indeed, for 50 years pyridoxine dependent epilepsy has been a clinical diagnosis based on the clinical effect of pyridoxine and confirmation of the diagnosis by a trial of pyridoxine withdrawal. However, in 2006 mutations in the ALDH7A1 gene have been found in patients with pyr-idoxine-dependent seizures 3. Since then, mutations within this gene have been shown to be present in the majority of patients with a clinical diagnosis of pyridoxine-dependent seizures 3-6. These mutations cause a deficiency in α-aminoadipic semialdehyde (α-AASA) dehydroge-nase, indirectly leading to a secondary deficiency in pyri-doxal-5-phosphate (P5P), which causes seizures. Administration of pyridoxine restores the P5P pool, thus controlling seizure activity 3. Another consequence of α-AASA dehydrogenase deficiency is an accumulation of α-AASA within the body, leading to increased plasma and cerebrospinal fluid levels 3. α-AASA is excreted in the urine, thus leading to highly increased urinary levels in pyridoxine dependent patients with ALDH7A1 mutations. We and others have shown that urinary α-AASA should be used as the biomarker for pyri-doxine dependent seizures 3-5,7. In conclusion, in contrast to what Lin and co-authors have stated, the underlying pathophysiology and genetic mutations can be determined in the vast majority of patients with pyridoxine-dependent seizures. The diagnosis is no longer merely dependent on clinical criteria, but can be confirmed at the metabolite level by measuring α-AASA in the urine of suspected patients. Ideally, urinary α-AASA quantification and, if the biomarker is increased, subsequent DNA analysis should be performed in any child with suspected pyridoxine-dependent seizures. A trial of withdrawal in these patients should be omitted 7. references 1.