Case study
Novel mutations in pyridoxine-dependent epilepsy

https://doi.org/10.1016/j.ejpn.2010.03.011Get rights and content

Abstract

Purpose

Pyridoxine-Dependent Epilepsy (PDE) is a rare autosomal recessive disease with neonatal seizures resistant to conventional anti-epileptic drugs. This metabolic disease has to be diagnosed early and treated to improve outcome. We report on two new mutations that open new prenatal prospects and suggest a new diagnostic procedure.

Case report

We describe PDE in a neonate carrying two novel mutations in the ALDH7A1 gene: c.[852_856delCTTAG] + [1230C > A]; p.[(Phe410Leu)] + p.[(Leu285CysfsX26)]. This case also illustrates that diagnosis could have been made without any pyridoxine withdrawal, thanks to the measurement of biomarkers. The patient was successfully treated with pyridoxine supplementation and currently shows normal neurological development.

Introduction

PDE is a rare autosomal recessive disease which was first described in 1954 by Hunt et al.1 The prevalence is about 1/700,000 in UK and Ireland2 and 1/400,000 in the Netherlands.3 It presents with neonatal intractable seizures, which are usually resistant to all anti-epileptic drugs (AED) but respond clinically and electrographically to pyridoxine supplementation. Conventionally, four clinical criteria are required for the diagnosis: seizures resistant to AED, good response to pyridoxine, complete seizure control on pyridoxine monotherapy, and seizure recurrence after pyridoxine withdrawal.4 The underlying defect is located at the level of alpha-aminoadipic semialdehyde dehydrogenase (α-AASA dehydrogenase) in the cerebral lysine degradation pathway. Patients with PDE have elevated α-AASA in all body fluids, and elevated pipecolic acid (PA) in plasma and cerebrospinal fluid (CSF). The accumulating compound α-AASA is in equilibrium with delta-1 piperideine-6-carboxylate (P6C). P6C inactivates pyridoxal phosphate (PLP) by a Knoevenagel condensation. PLP is the active form of pyridoxine, necessary for the action of glutamic acid decarboxylase, which leads to the synthesis of the inhibitory neurotransmitter GABA.5, 6 The antiquitin gene (ALDH7A1) encoding α-AASA dehydrogenase is located on chromosome 5q31.6, 7 Several mutations in the antiquitin gene have been described since the unravelling of PDE. We report on a patient who is compound heterozygous for two novel ALDH7A1 mutations.

Section snippets

Case report

The mother of this boy was a 24-year-old primigravida. The parents were not consanguineous and no family history of epilepsy was reported. Systematic ultrasound scans of the child during pregnancy were normal and no abnormal foetal movements were reported. At term delivery was uncomplicated with normal cardiotocographic rhythm and without trauma. The Apgar score was 10, 10 and 10 after 1, 5 and 10 min, birth weight was 3060 g (50th centile) without sign of infection or anoxic-ischemic

Discussion

We report on the clinical course of a neonate with pyridoxine-dependent seizures.

This patient had an early diagnosis of PDE and received appropriate pyridoxine therapy. His development is normal. Early diagnosis and adequate treatment are important to prevent specific impairment of higher brain function in PDE children7 In this patient, the elevated level of pipecolic acid in blood plasma, the elevated urinary α-AASA, and the identification of two novel mutations confirmed the clinical

Conclusions

Knowledge of specific biomarkers in biofluids and of the DNA mutations that can lead to PDE is essential for making a diagnosis of the disease without the pyridoxine withdrawal test and opens perspectives for prenatal diagnosis.

Acknowledgements

We are grateful to the patient and his family for participating in this study. The experiments performed are in accordance with current legislation in France. We thank Dr Alison Foote for editing the manuscript.

References (15)

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