Epilepsy due to 20q13.33 subtelomere deletion masquerading as pyridoxine-dependent epilepsy
Heather C Mefford1, Joseph Cook, Sidney M Gospe
1Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington 98105, USA.
Insights
Pyridoxine-dependent epilepsy (PDE) is a genetic disorder. A patient initially diagnosed with PDE was found to have a chromosome 20 deletion, suggesting a new genetic cause for infantile seizures.
Area of Science:
- Genetics
- Neurology
- Biochemistry
Background:
- Pyridoxine-dependent epilepsy (PDE) is an organic aciduria caused by ALDH7A1 gene mutations, leading to antiquitin deficiency and medication-resistant seizures in infants.
- While the genetic basis of PDE is known, some patients present with similar phenotypes but lack antiquitin dysfunction, suggesting other underlying causes.
Observation:
- A patient with a 7-year history of clinical PDE diagnosis showed normal ALDH7A1 sequencing and PDE biomarkers.
- Array comparative genomic hybridization (CGH) revealed a 1.5-Mb terminal deletion on chromosome 20, encompassing KCNQ2 and CHRNA4 genes.
Findings:
- The identified deletion on chromosome 20, including KCNQ2 and CHRNA4, is proposed as the cause of the patient's neonatal epilepsy and neurodevelopmental disabilities.
- The patient's positive response to pyridoxine treatment was deemed coincidental, not indicative of PDE.
Implications:
- This case highlights the importance of array CGH in diagnosing epilepsy of unknown etiology, especially when typical PDE markers are absent.
- The findings expand the genetic landscape of early-onset epilepsy and underscore the need for comprehensive genetic testing beyond known PDE mutations.
Abstract:
A cause of antiepileptic medication resistant seizures presenting in neonates and young infants is pyridoxine-dependent epilepsy (PDE), an organic aciduria, which is due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin. Since the discovery of molecular basis of this disorder, a few patients have been reported with a similar clinical phenotype but without evidence of antiqutin dysfunction. We report on a patient who had carried a clinical diagnosis of PDE for 7 years, but who was than shown to have normal ALDH7A1 sequencing and the absence of biomarkers characteristic of this familial epilepsy. Array comparative genomic hybridization (CGH) demonstrated a 1.5-Mb terminal deletion of the long arm of chromosome 20, which included deletion of the KCNQ2 and CHRNA4 genes, both of which have been associated with specific epilepsy syndromes. We suggest that this boy's neonatal epilepsy and neurodevelopmental disabilities are secondary to this deletion and that his clinical response to pyridoxine was coincidental. This patient's history emphasizes the utility of array CGH in the evaluation of children with epilepsy of unknown etiology.
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