Epileptic encephalopathies in inborn errors of metabolism in young children: focus on pyridoxine-dependent epilepsy

Abstract

Inborn errors of metabolism (IEM) represent one of the most clinically significant yet underdiagnosed causes of epileptic encephalopathies in young children. The team of the Department of Pediatric Neurology at the State Institution "Ukrainian Center of Maternity and Childhood of the NAMS of Ukraine" has been investigating this problem for over 25 years, which served as the foundation for the preparation of this publication. Particular attention is warranted by pyridoxine-dependent epilepsy (PDE) — a rare autosomal recessive disorder caused by pathogenic variants in the ALDH7A1 gene — as a classical example of a treatable metabolic epileptic encephalopathy.

Aim - to systematize current evidence on epileptic encephalopathies in inborn errors of metabolism in young children, and to elucidate the underlying pathogenetic mechanisms, clinical features, and approaches to diagnosis and treatment.

A systematic review of the scientific literature was conducted using PubMed/MEDLINE and OMIM databases, with a focus on publications from the past 10 years.

A clinical case of a 3-month-old girl with neonatal epilepsy refractory to standard therapy is presented. The diagnostic workup included prolonged video-EEG monitoring, brain MRI, biochemical investigations, and next-generation sequencing (NGS) using the CarrierSeq panel (420 genes). Epileptic seizures associated with IEM are characteristically resistant to standard antiseizure medications and may present as status epilepticus at onset. Age of manifestation serves as a key diagnostic indicator: the neonatal period is most typical for pyridoxine-dependent epilepsy, urea cycle defects, and nonketotic hyperglycinemia, while infancy is more characteristic of GLUT1 deficiency, biotinidase deficiency, and peroxisomal disorders. The diagnostic algorithm encompasses three tiers: a basic biochemical panel (glucose, lactate, pyruvate, ammonia, blood gas analysis, plasma amino acids, urine organic acids, acylcarnitine profile), specialized metabolic tests (α-aminoadipic semialdehyde, pipecolic acid, cerebrospinal fluid pyridoxal phosphate level), and molecular genetic analysis. An empirical therapeutic trial with pyridoxine (30 mg/kg/day for 3 days) is indicated in all neonates with seizures of unknown etiology refractory to conventional therapy. In the presented case, two pathogenic variants in compound heterozygous state were identified in the ALDH7A1 gene, confirming the diagnosis of PDE. Targeted therapy comprising pyridoxine, arginine, folinic acid, and a lysine-restricted diet resulted in sustained seizure remission and normalization of psychomotor development.

Conclusions. Early identification and verification of a metabolic defect enables pathogenetically targeted treatment with the potential to fundamentally alter the disease prognosis. Nutritional and vitamin-micronutrient therapy represents an effective therapeutic approach for treatable forms of metabolic epilepsy, particularly in pyridoxine-dependent epilepsies.

The authors declare no conflict of interest.