Genetic heterogeneity for autosomal recessive pyridoxine-dependent seizures

Abstract

Pyridoxine-dependent seizure (PDS) is a rare autosomal recessive intractable seizure disorder only controlled by a daily supplementation of pharmacological doses of pyridoxine (Vitamin B6). Although glutamate decarboxylase utilizes pyridoxal phosphate as a cofactor during conversion of the excitatory amino acid, glutamate, to the inhibitory neurotransmitter, gamma-amino butyric acid (GABA), several studies have failed to demonstrate a linkage to either of the glutamate-decarboxylase-encoding genes (GAD1 and GAD2) and PDS excluding involvement of this functional candidate. However, in 2000, a locus for PDS was mapped to a 5 cM interval at chromosome 5q31 in four consanguineous and one multisib pedigree (Z(max)=8.43 at theta=0 for marker D5S2017) [Cormier-Daire et al. in Am J Hum Genet 67(4):991-993 2000]. We undertook molecular genetic studies of six nonconsanguineous North American families, using up to ten microsatellite markers to perform haplotype segregation analysis of the 5q31 locus. Assignment to the chromosome 5q PDS locus was excluded in one of the six North American PDS pedigrees, as chromosome 5q31 haplotypes were incompatible with linkage to this locus. The remaining five PDS pedigrees showed haplotype segregation consistent with linkage to 5q31, generating a maximum combined lod score of 1.87 (theta=0) at marker D5S2011. In this study, we establish genetic heterogeneity for PDS, catalog 21 genes within the originally defined PDS interval, and identify additional recombinations that indicate a higher priority interval, containing just 11 genes.

Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene

“…Though genetic heterogeneity for neonatal onset pyridoxinedependent seizures has been reported recently, the majority of patients seem to map to the antiquitin locus on chromosome 5q31 [Bennett et al, 2005].…”

Diagnosis and treatment of neurotransmitter disorders

“…A gene locus was mapped to chromosome 5q31 in four consanguineous families and one multiply affected family [8]. Further studies established genetic heterogeneity for pyridoxine dependency, yet linkage in some affected families to 5q31 [9]. Elevation of pipecolic acid was reported in plasma and CSF in pyridoxine-dependent epilepsy [10].…”

New treatment paradigms in neonatal metabolic epilepsies

“…3). Linkage to markers at chromosome 5q31, which is the antiquitin site, had already been recognized (Cormier-Dare et al 2000), but not all kindreds show linkage and genetic heterogeneity is evident (Bennett et al 2005;Gospe 2006). Elevated urinary AASA appears to be a reliable biomarker for the diagnosis of antiquitin deficiency and, hence, pyridoxine-dependent seizures (Bok et al 2007).…”

“…A dosage of 50 mg/kg per day of pyridoxine has been recommended for patients who weigh 30 kg or less (Gospe 2002). A maximal maintenance dose of 500 mg is sometimes recommended, as the sensory neuropathy has not been demonstrated to develop in adults who received this dose daily for 2 years (Bendich and Cohen 1990).…”