Early-Onset Polymorphic Seizures and Hydrocephalus: A Clue to an Underlying Pyridoxine-Dependent Epilepsy

Abstract

Pyridoxine-dependent epilepsy (PDE) is a rare epileptic encephalopathy characterized by early-onset, drug-resistant seizures. It is predominantly caused by mutations in the ALDH7A1 gene, which leads to accumulation of α-aminoadipic semialdehyde (α-AASA) and piperidine-6-carboxylate (P6C) that inactivate pyridoxal 5′-phosphate, an essential cofactor in neurotransmitter metabolism. Seizures are typically unresponsive to standard antiseizure medications but show marked reduction with pyridoxine therapy.

We report a 6-month-old boy, born to parents with third-degree consanguinity, who developed drug-resistant seizures of varying semiology from day 2 of life, which showed complete cessation after addition of pyridoxine. Magnetic resonance imaging revealed hydrocephalus. Genetic testing confirmed a pathogenic ALDH7A1 variant. He remains seizure-free on pyridoxine, arginine, and a lysine-restricted diet.

This case highlights the importance of early trial of pyridoxine in neonates with resistant seizures. Hydrocephalus is an important clue toward the diagnosis. Genetic confirmation and lifelong pyridoxine therapy, along with a lysine-restricted diet and parental counselling, can prevent recurrent seizures and neurological deterioration. Prompt recognition of PDE, especially in high-risk settings like consanguinity or atypical imaging, enables targeted treatment and improved neurodevelopmental outcomes.

 

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Keywords

ALDH7A1 mutations - hydrocephalus - neonatal seizures - pyridoxine-dependent epilepsy

Introduction

Pyridoxine-dependent epilepsy (PDE; OMIM: 266100) is a rare autosomal recessive disorder caused by mutations in the ALDH7A1 gene, which encodes α-aminoadipic semialdehyde dehydrogenase enzyme, also known as antiquitin. The accumulation of α-aminoadipic semialdehyde (α-AASA) and piperidine-6 carboxylate (P6C) results in chemical inactivation of pyridoxal phosphate, a crucial cofactor in neurotransmitter synthesis. Classically, PDE presents as intractable neonatal seizures that respond dramatically to the pharmacological doses of pyridoxine. However, despite effective seizure control, a significant proportion of patients exhibit neurodevelopmental delay, with or without hydrocephalus. Diagnostic markers such as AASA, P6C, and pipecolic acid in blood, urine, and/or cerebrospinal fluid (CSF), suggestive electroclinical patterns, and typical clinical seizures help in diagnosing PDE at the bedside, followed by genetic confirmation of the underlying pathogenic variation in the ALDH7A1 gene.[1] Recent management guidelines focus on combining pyridoxine supplementation with lysine-reduction strategies to enhance long-term outcomes.[2]

 

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Case

A 6-month-old boy, born to a third-degree consanguineous couple, presented with recurrent seizures since day 2 of life. He was born at term via an uncomplicated vaginal delivery. On the second day of life, the baby exhibited feeding difficulties, relentless high-pitched crying, and inability to sleep. Subsequently, he developed clinical seizures of variable semiology ([Video 1]): multifocal erratic myoclonus occurring 6 to 7 times a day, bilateral tonic seizures lasting 4 to 5 seconds occurring multiple times a day, and flexor epileptic spasms in clusters of 3 to 4 spasms. With age, he also developed persistent downgaze, characteristic of the sunsetting sign. Multiple antiseizure medications (ASMs)—phenobarbitone, levetiracetam, and phenytoin, were added sequentially from day 4 of life, but the baby developed status epilepticus, requiring mechanical ventilation and midazolam infusion. Electroencephalography (EEG) revealed diffuse 3 to 4 Hz delta waves intermixed with low-voltage β activity, with infrequent spike-and-wave discharges in the right temporal region. He was treated with intravenous antibiotics for 21 days for suspected bacterial meningitis, given the early-onset seizures and irritability, although CSF cytology and biochemistry were normal. He was given a trial of oral pyridoxine, resulting in complete cessation of seizures. However, due to noncompliance, the baby continued to have multiple seizure episodes, including status epilepticus requiring multiple admissions over the next 2 months. At 3 months of age, he presented to our center, where pyridoxine was reinitiated considering the initial dramatic therapeutic response, polymorphic seizure semiology, and high index of suspicion for PDE, along with family counselling. He became seizure-free and EEG was unremarkable. Examination showed normal head circumference, poor head control, sun-setting sign, and central hypotonia. Magnetic resonance imaging of the brain showed mild hypoplasia of bilateral cerebral subcortical white matter, communicating hydrocephalus, and prominent cisterna magna ([Fig. 1A, B]), for which he underwent ventriculoperitoneal shunt. Whole-exome sequencing showed a homozygous, missense variant c.530C > A in exon 6 of the ALDH7A1 gene, which results in the amino acid substitution p.Ala177Glu. The in-silico predictions of this variant were damaging and it was classified as “pathogenic” as per ACMG (American College of Medical Genetics and Genomics) guidelines. Currently, at 9 months of age, he is seizure-free on pyridoxine (25 mg/kg/d), arginine (400 mg/kg/d) and a lysine-restricted diet.

Fig. 1 (A, B) T1 (A) and T2 (B) images showing dilatation of both temporal horns (left > right) and the third ventricle. The fourth ventricle is also dilated. There is also mild hypoplasia of bilateral subcortical white matter.

Video 1 Video displaying varying seizure types in the patient: tonic, multifocal myoclonus, epileptic spasms, and tonic seizure with paroxysmal downgaze.

 

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Discussion

Early-onset PDE is characterized by a combination of various seizure types, usually occurring in the first hours of life, unresponsive to standard ASMs, and responding only to immediate administration of pyridoxine hydrochloride. The pyridoxine dependence is lifelong, and the interruption of daily pyridoxine supplementation leads to the recurrence of seizures. The electroclinical presentation of PDE is quite heterogeneous. Our patient exhibited multiple seizure types, including multifocal myoclonus, tonic seizures, epileptic spasms in clusters, and tonic seizures with paroxysmal downgaze. This seizure variability, with initial nonspecific EEG findings, often leads to misdiagnosis of sepsis in neonates. EEG findings in PDE may range from normal background to burst suppression, hypsarrhythmia, or multifocal epileptiform discharges, depending on disease stage and severity.[3]

Although pyridoxine is the cornerstone of treatment, delayed initiation and poor adherence can result in ongoing seizure activity, status epilepticus, and secondary brain injury. Our patient initially responded well to pyridoxine, but noncompliance led to breakthrough seizures and repeated intensive care unit admissions. Reinitiation of pyridoxine, coupled with parental education and metabolic support, resulted in sustained seizure control, reinforcing the importance of early diagnosis, long-term compliance, and family counselling. Structural brain abnormalities, including cerebral atrophy, delayed myelination, corpus callosum hypoplasia, ventriculomegaly, or communicating hydrocephalus requiring shunting of CSF have been reported in PDE. The occurrence of hydrocephalus is relatively rare, being reported in nearly 8% of patients with ALDH7A1 mutations.[4] The pathophysiology of hydrocephalus in PDE is not fully understood, but it may arise from chronic metabolic injury, altered CSF circulation, or secondary gliosis in the aqueduct.[5]

Our case underscores the complex clinical course and poor awareness of vitamin-responsive metabolic epilepsies. Early-onset, drug-refractory polymorphic seizures, development of hydrocephalus, presence of consanguinity, and epileptic encephalopathy on EEG are early clues. Empirical pyridoxine trial in neonates with drug-resistant seizures remains a low-risk, high-benefit intervention that may prevent long-term neurological sequelae.

 

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Conflict of Interest

None declared.

• References

• 1 Sharawat IK, Suthar R, Saini AG, Sankhyan N. Pyridoxine trial in early infantile epileptic encephalopathy: never forget!. Ann Indian Acad Neurol 2020; 23 (05) 727-729
• 2 Coughlin II CR, Tseng LA, Abdenur JE. et al. Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 2021; 44 (01) 178-192
• 3 van Karnebeek CDM, Tiebout SA, Niermeijer J. et al. Pyridoxine-dependent epilepsy: an expanding clinical spectrum. Pediatr Neurol 2016; 59: 6-12
• 4 Toldo I, Bonardi CM, Bettella E. et al. Brain malformations associated to Aldh7a1 gene mutations: Report of a novel homozygous mutation and literature review. Eur J Paediatr Neurol 2018; 22 (06) 1042-1053
• 5 Kesavan S, Singanamalla B, Krishna Sahitya DS, Saini AG, Vyas S. Epilepsy and hydrocephalus: should pyridoxine-dependent epilepsy cross our minds?. Ann Indian Acad Neurol 2020; 23 (02) 239-241

Publication History

Article published online:
17 October 2025