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The prevalence of Pyridoxine-dependent epilepsy (PDE) has been estimated to range from 1/20,000 to 1/783,000 live births. More than 200 cases have been reported in the literature to date.

Onset is classically fetal/neonatal but a later onset (>2 months) has also been reported. Patients present with epileptic encephalopathy manifesting with intractable seizures along with irritability, crying, poor feeding, gastrointestinal symptoms (emesis, abdominal distention), sleeplessness, facial grimacing and abnormal eye movements. Although prolonged seizures and recurrent episodes of status epilepticus are most common, recurrent self-limiting partial, generalized or atonic seizures, myoclonic events and infantile spasms can also occur. Intellectual disability/developmental delay ranges from mild to severe (particularly affecting the expressive language domain). With treatment, most patients achieve complete seizure control, but 75-80% have some degree of intellectual disability. Atypical features include seizures that initially respond to AEDs and later become intractable, seizures initially unresponsive to pyridoxine but that respond several months later and prolonged seizure-free intervals after the discontinuation of pyridoxine treatment.

PDE is caused by mutations in the ALDH7A1 gene (5q31) that encodes alpha-aminoadipic semialdehyde dehydrogenase (antiquitin), a multifunctional enzyme which, among other functions, is involved in the catabolism of cerebral lysine.

Diagnosis is suspected in patients with early onset epilepsy with a poor response to AEDs. Laboratory testing reveals elevated urinary and plasma concentrations of alpha-aminoadipic semialdehyde and sometimes elevated pipecolic acid in the plasma and cerebrospinal fluid. Electroencephalography findings are non-specific but thinning of the corpus callosum, particularly of the isthmus, is always seen on brain MRI. Molecular genetic testing, identifying homozygous or compound heterozygous ALDH7A1 mutations, confirms diagnosis.

Differential diagnoses include other causes of neonatal epileptic encephalopathy such as inborn errors of metabolism (e.g. glucose transporter type I deficiency, 4-hydroxybutyric aciduria and molybdenum cofactor deficiency), single gene defects and fetal or neonatal brain injury. Pyridoxal phosphate-responsive seizures, hyperprolinemia type 2 and infantile hypophosphatasia (see these terms) should also be excluded.

Prenatal diagnosis is possible in families with a known disease-causing mutation in order to start prophylactic prenatal/postnatal treatment.

PDE is inherited in an autosomal recessive manner. Genetic counseling is possible in families with a known mutation.

Standard treatment involves lifelong oral pyridoxine supplementation (15-30mg/kg/day, divided into 3 doses in infants; up to 200mg/day in neonates and 500mg/day in adults) to control seizures, as well as regular clinical follow-up. Initial interruption of status epilepticus requires up to five 100mg doses of pyridoxine administered intravenously while closely monitoring patients for signs of cardio-respiratory arrest. Dietary lysine restriction is also recommended as an adjunct to pyridoxine therapy. In at-risk pregnancies, mothers may take supplemental pyridoxine (100mg/day) during the last half of gestation and newborns should received prophylactic pyridoxine until diagnostic tests are finalized.

Prognosis is variable and depends, in part, on genotype, associated abnormalities in brain development, and response to pyridoxine treatment. A delay in diagnosis and initiation of treatment generally confers a poorer prognosis associated with more significant neurodevelopmental disabilities.