Case studyNovel mutations in pyridoxine-dependent epilepsy
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)
- et al.
A gene for pyridoxine-dependent epilepsy maps to chromosome 5q31
Am J Hum Genet
(2000) Allelic and non allelic heterogeneities in pyridoxine-dependent seizure revealed by ALDH7A1 mutational analysis
Mol Genet Metab
(2007)- et al.
Alpha-aminoadipic semialdehyde is the biomarker for pyridoxine dependent epilepsy caused by alpha-aminoadipic semialdehyde dehydrogenase deficiency
Mol Genet Metab
(2007 Aug) - et al.
Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine
Pediatrics
(1954) Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK
Arch Dis Child
(1999)- et al.
Epidemiology of pyridoxine dependent seizures in the Netherlands
Arch Dis Child
(2005) Pyridoxine-dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment
Curr Opin Neurol
(2006)
Cited by (22)
Disorders of pyridoxine metabolism
2020, Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 1Novel homozygous missense mutation in ALDH7A1 causes neonatal pyridoxine dependent epilepsy
2017, Molecular and Cellular ProbesCitation Excerpt :Post-natal epilepsy responsive to pyridoxine (PDE) is a very rare neonatal epilepsy form (OMIM 266100) with an estimated prevalence of 1:100.000 [1–4].
Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum
2016, Pediatric NeurologyCitation Excerpt :To overcome the limitations of our PubMed search and subsequent potential “reporting bias” (i.e., that only a selection of pyridoxine-dependent epilepsy patients is published as a case report), we also asked clinicians (all nine coauthors) with expertise and experience in ATQ deficiency to review and edit the clinical spectrum generated by the literature review, i.e., whether any symptoms were missing or unjustified and provide illustrative case vignettes. Of the 246 articles generated by the PubMed search, 49 met the outlined criteria, including 266 descriptions of patients with confirmed ATQ deficiency.5,7,8,11-55 Figure 2 provides a comprehensive visual overview of the presenting clinical and biochemical features of patients reported in the literature.
Disorders of Pyridoxine Metabolism
2014, Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease: Fifth EditionOverexpression of recombinant human antiquitin in E. coli: Partial enzyme activity in selected ALDH7A1 missense mutations associated with pyridoxine-dependent epilepsy
2014, Molecular Genetics and MetabolismCitation Excerpt :All four are heterozygous with other ALDH7A1 mutations in the patients in whom they were identified. Both p.F410L and p.Q425R were heterozygous with frameshift mutant alleles [12,13] that would not be expected to produce any functional protein. The p.V367G mutation was heterozygous with a second missense mutation p.G174V, a residue in the substrate binding region.