Pyridoxine-dependent epilepsy: report on three families with neuropathology

Abstract

Pyridoxine-dependent epilepsy (PDE) is a pharmacoresistant epileptogenic encephalopathy controlled by pyridoxine supplementation at pharmacological doses. Despite supplementation, the long-term outcome is often poor possibly because of recurrent seizures and developmental structural brain abnormalities. We report on five patients with PDE from three unrelated families. The diagnosis was confirmed by ALDH7A1 sequencing, which allowed for the characterization of two homozygous variations [NM_001182.3:c.1279G > C - p.(Glu427Gln) and c.834G > A - p.(Val278Val)]. Brain autopsy was conducted for one untreated patient with molecularly confirmed antiquitin deficiency. Macroscopic and histological examination revealed a combination of lesions resulting from recurrent seizures and consisting of extensive areas of cortical necrosis, gliosis, and hippocampic sclerosis. The examination also revealed developmental abnormalities including corpus callosum dysgenesis and corticospinal pathfinding anomalies. This case is the second to be reported in the literature, and our findings show evidence that antiquitin is required for normal brain development and functioning. Despite prophylactic prenatal pyridoxine supplementation during the last trimester of pregnancy in one of the three families and sustained pyridoxine treatment in three living patients, the clinical outcome remained poor with delayed acquisition of neurocognitive skills. Combined therapy (pyridoxine/arginine supplementation and lysine-restricted diet) should be considered early in the course of the disease for a better long-term outcome. Enhanced knowledge of PDE features is required to improve treatment strategies.

Consensus guidelines for the diagnosis and management of pyridoxine‐dependent epilepsy due to α‐aminoadipic semialdehyde dehydrogenase deficiency

“…9 Descriptive studies have reported patients with PDE-ALDH7A1 who died before pyridoxine was provided. 34,59,60 Furthermore, the withdrawal of pyridoxine has been associated with recurrence of seizures, [61][62][63][64][65] underscoring the necessity of pyridoxine in the treatment of PDE-ALDH7A1. The association between lysine reduction therapies and neurologic outcomes has been reported in a total of 10 observational studies describing 27 individual patients with PDE-ALDH7A1.…”

Neuroimaging Spectrum of Inherited Neurotransmitter Disorders

“…28,29 The pathogenesis of obstructive hydrocephalus remains unclear but may be related to subependymal gliosis with resultant acquired aqueductal stenosis. 30 Antiquitin is also expressed in the choroid plexus and ependyma and its dysfunction may result in deranged formation, absorption, or circulation of cerebrospinal fluid. 31,32 Patients with PDE have a high incidence of structural brain abnormalities, including callosal anomalies (►Fig.…”

Corpus Callosum Agenesis: An Insight into the Etiology and Spectrum of Symptoms

“…Although seizures can be controlled with pyridoxine, the metabolite levels do not change throughout therapy [47]. Antiquitin is also present in the radial glia and plays a role in the early development of the CNS, which is also associated with structural brain lesions in EPD patients, the most common being hypoplasia, partial agenesis, or dysplasia of CC (34% of patients in the study population of 44 subjects) [48].…”