Glial localization of antiquitin: Implications for pyridoxine‐dependent epilepsy

Abstract

Objective A high incidence of structural brain abnormalities has been reported in individuals with pyridoxine-dependent epilepsy (PDE). PDE is caused by mutations in ALDH7A1, also known as antiquitin. How antiquitin dysfunction leads to cerebral dysgenesis is unknown. In this study, we analyzed tissue from a child with PDE as well as control human and murine brain to determine the normal distribution of antiquitin, its distribution in PDE, and associated brain malformations. Methods Formalin-fixed human brain sections were subjected to histopathology and fluorescence immunohistochemistry studies. Frozen brain tissue was utilized for measurement of PDE-associated metabolites and Western blot analysis. Comparative studies of antiquitin distribution were performed in developing mouse brain sections. Results Histologic analysis of PDE cortex revealed areas of abnormal radial neuronal organization consistent with type Ia focal cortical dysplasia. Heterotopic neurons were identified in subcortical white matter, as was cortical astrogliosis, hippocampal sclerosis, and status marmoratus of the basal ganglia. Highly elevated levels of lysine metabolites were present in postmortem PDE cortex. In control human and developing mouse brain, antiquitin immunofluorescence was identified in radial glia, mature astrocytes, ependyma, and choroid plexus epithelium, but not in neurons. In PDE cortex, antiquitin immunofluorescence was greatly attenuated with evidence of perinuclear accumulation in astrocytes. Interpretation Antiquitin is expressed within glial cells in the brain, and its dysfunction in PDE is associated with neuronal migration abnormalities and other structural brain defects. These malformations persist despite postnatal pyridoxine supplementation and likely contribute to neurodevelopmental impairments.

Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome

“…Past studies have identified possible structural brain defects in individuals with PDE [11,41]. In addition, several subjects in our study showed radiological evidence of brain injury likely caused by the seizures, and possibly the metabolic disturbances such as hypoglycemia, prior to diagnosis.…”

“…Subjects 2 and 5 had mesial temporal sclerosis with hippocampal injury, and both subjects had memory and concentration impairments [42,43]. Hippocampal sclerosis is most commonly associated with chronic epilepsy and has been associated with temporal lobe epilepsy and a history of febrile seizures [44,45], although it has been infrequently reported in subjects with PDE [41]. These observations link persisting neurologic dysfunction to brain damage occurring prior to the initiation of triple therapy, either the acute neurologic findings in subject 1 or the mesial sclerosis in subjects 2 and 5.…”

Refractory seizures in a term neonate due to pyridoxine dependent epilepsy

“…In three studies with a total of 44 patients with PDE, normal MRIs were seen in 20-31%. There have been two postmortem neuropathological studies of confirmed PDE [14,15]. Jansen et al reported severe dyslamination of the cortex with microcolumnar focal cortical dysplasia in resected tissue following right occipital and posterior parietal lobectomy at 15 months.…”

Lysine-Restricted Diet as Adjunct Therapy for Pyridoxine-Dependent Epilepsy: The PDE Consortium Consensus Recommendations

“…The Consortium recognizes that, aside from potential neurotoxic damage, the ID seen in PDE could be explained by the role of ATQ in neuronal migration (Jansen et al 2013), as well as the increased rate of fetal distress leading to premature birth and/or associated pathology (Mills et al 2010). Additionally, an association between delay in diagnosis and poor development has been reported (Bok et al 2012).…”