genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1

Pyridoxine-dependent epilepsy is a disorder associated with severe seizures that may be caused by deficient activity of α-aminoadipic semialdehyde dehydrogenase, encoded by the ALDH7A1 gene, with accumulation of α-aminoadipic semialdehyde and piperideine-6-carboxylic acid. The latter reacts with pyr...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of inherited metabolic disease 2010-10, Vol.33 (5), p.571-581
Main Authors:	Scharer, Gunter, Brocker, Chad, Vasiliou, Vasilis, Creadon-Swindell, Geralyn, Gallagher, Renata C, Spector, Elaine, Van Hove, Johan L. K
Format:	Article
Language:	eng
Subjects:	Adolescent Adult Aldehyde Dehydrogenase - chemistry Aldehyde Dehydrogenase - genetics Aldehyde Dehydrogenase - metabolism Anticonvulsants - therapeutic use Biochemistry Biological and medical sciences Child Child, Preschool Colorado Developmental Disabilities - genetics DNA Mutational Analysis Epilepsy - drug therapy Epilepsy - enzymology Epilepsy - genetics Female Gene Frequency Genetic Association Studies Genetic Predisposition to Disease Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Human Genetics Humans Infant Internal Medicine Male Medical genetics Medical sciences Medicine Medicine & Public Health Metabolic Diseases Models, Molecular Mutation Nervous system (semeiology, syndromes) Neurology Pediatrics Phenotype Protein Conformation Pyridoxine - therapeutic use Rapid Communication Structure-Activity Relationship Treatment Outcome Young Adult
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Pyridoxine-dependent epilepsy is a disorder associated with severe seizures that may be caused by deficient activity of α-aminoadipic semialdehyde dehydrogenase, encoded by the ALDH7A1 gene, with accumulation of α-aminoadipic semialdehyde and piperideine-6-carboxylic acid. The latter reacts with pyridoxal-phosphate, explaining the effective treatment with pyridoxine. We report the clinical phenotype of three patients, their mutations and those of 12 additional patients identified in our clinical molecular laboratory. There were six missense, one nonsense, and five splice-site mutations, and two small deletions. Mutations c.1217_1218delAT, I431F, IVS-1(+2)T > G, IVS-2(+1)G > A, and IVS-12(+1)G > A are novel. Some disease alleles were recurring: E399Q (eight times), G477R (six times), R82X (two times), and c.1217_1218delAT (two times). A systematic review of mutations from the literature indicates that missense mutations cluster around exons 14, 15, and 16. Nine mutations represent 61% of alleles. Molecular modeling of missense mutations allows classification into three groups: those that affect NAD+ binding or catalysis, those that affect the substrate binding site, and those that affect multimerization. There are three clinical phenotypes: patients with complete seizure control with pyridoxine and normal developmental outcome (group 1) including our first patient; patients with complete seizure control with pyridoxine but with developmental delay (group 2), including our other two patients; and patients with persistent seizures despite pyridoxine treatment and with developmental delay (group 3). There is preliminary evidence for a genotype-phenotype correlation with patients from group 1 having mutations with residual activity. There is evidence from patients with similar genotypes for nongenetic factors contributing to the phenotypic spectrum.
ISSN:	0141-8955 1573-2665