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Pyridoxine-Dependent Epilepsy.


Gospe SM Jr1.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2001 Dec 7 [updated 2017 Apr 13].

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Herman and Faye Sarkowsky Endowed Chair of Child Neurology, Professor, Neurology and Pediatrics, University of Washington School of Medicine, Seattle, Washington



Pyridoxine-dependent epilepsy is characterized by intractable seizures within the first weeks to months of life that are not controlled with antiepileptic drugs but respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). Multiple types of clinical seizures have been reported in individuals with pyridoxine-dependent epilepsy. Dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical; recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Infants with the classic neonatal presentation begin to experience seizures soon after birth. Atypical features include: late-onset seizures (seizures that begin from late infancy up until age 3 years); seizures that initially respond to antiepileptic drugs and then become intractable; seizures during early life that do not respond to pyridoxine but are then controlled with pyridoxine several months later; and prolonged seizure-free intervals (≤5.5 months) that occur after discontinuation of pyridoxine. Intellectual disability is common. Elevated concentration of α-aminoadipic semialdehyde (α-AASA) in urine and plasma is a strong biomarker of the disorder; pipecolic acid may also be elevated in plasma and cerebrospinal fluid.


The diagnosis of pyridoxine-dependent epilepsy is established in a proband: (a) showing a clinical response to pyridoxine administration followed by biochemical testing showing the presence of biomarkers; and/or (b) by the identification of biallelic pathogenic variants in ALDH7A1. Clinical diagnosis may be made in individuals experiencing status epilepticus or repetitive clinical seizures that are not controlled with antiepileptic drugs by concurrently administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation, and vital signs. In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over several minutes. If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. A corresponding change should be observed in the EEG, although it may be delayed by several hours. Alternatively, in children who experience frequent antiepileptic drug-resistant self-limited seizures, oral pyridoxine at a dose of 30 mg/kg/day may be initiated. Children who are pyridoxine dependent should have a resolution of their clinical seizures within three to seven days.


Treatment of manifestations: Pyridoxine-dependent epilepsy is initially controlled with the addition of daily supplements of pyridoxine; subsequently, in the majority of affected individuals all antiepileptic drugs can be withdrawn and seizure control continued with daily pyridoxine monotherapy in pharmacologic doses. To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled for several days. Special education programs are offered to affected individuals. Prevention of secondary complications: Overuse of pyridoxine can cause a reversible sensory neuropathy. Surveillance: Monitoring for development of clinical signs of a sensory neuropathy and regular assessments of intellectual function. Evaluation of relatives at risk: If the pathogenic variants in the family are known, molecular genetic testing of at-risk newborn sibs of a proband for early diagnosis and treatment to reduce morbidity and mortality. If the pathogenic variants in the family are not known and the at-risk sib is experiencing clinical seizures or encephalopathy, administration of pyridoxine acutely (under EEG monitoring) for diagnostic and therapeutic purposes. Pregnancy management: Supplemental maternal pyridoxine at a dose of 50-100 mg per day throughout the last half of pregnancy and after birth may be considered if the fetus is known to be affected or, if diagnostic prenatal testing is not pursued, in an at-risk fetus and neonate, until the diagnosis has been ruled out.


Pyridoxine-dependent epilepsy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants in a family are known.

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