Familial autosomal dominant reflex epilepsy triggered by hot water maps to 4q24-q28

Hot water epilepsy is a reflex or sensory epilepsy in which seizures are triggered by the stimulus of bathing in hot water. Although there is evidence of a genetic basis to its etiology, no gene associated with this disorder has so far been found. In order to identify the genetic locus involved in the pathophysiology of hot water epilepsy, we performed a genome-wide linkage analysis in a four-generation family manifesting the disorder in an autosomal dominant manner. Significant linkage was detected on chromosome 4q24-q28, with the highest two-point LOD score of 3.50 at recombination value (θ) of 0 for the marker D4S402. Centromere-proximal and centromere-distal boundaries of this locus were defined by the markers D4S1572 and D4S2277, respectively. The critical genetic interval spans 22.5 cM and corresponds to about 24 megabases of DNA. The genes NEUROG2, ANK2, UGT8 and CAMK2D, which are known to be expressed in human brain, are strong positional candidates and we propose to examine these and other genes in the locus to identify the causative gene for this intriguing form of epilepsy

A locus for autosomal dominant reflex epilepsy precipitated by hot water maps at chromosome 10q21.3-q22.3

Hot water epilepsy (HWE) is a form of reflex or sensory epilepsy wherein seizures are precipitated by an unusual stimulus, the contact of hot water over the head and body. Genome-wide linkage analysis of a large family with ten affected members, provided evidence of linkage (Zmax = 3.17 at θ = 0 for D10S412) to chromosome 10q21. Analysis of five additional HWE families, for markers on chromosome 10, further strengthened the evidence of linkage to the same chromosomal region with three out of five families showing concordance for the disease haplotype and providing a two-point LOD score of 4.86 at θ = 0 and 60% penetrance for D10S412. The centromere-proximal and -distal boundaries of the critical genetic interval of about 15 Mb at 10q21.3-q22.3 were defined by D10S581 and D10S201, respectively. Sequence analysis of a group of functional candidate genes, the ion channels KCNMA1, VDAC2 and solute carriers SLC25A16, SLC29A3 revealed no potentially pathogenic mutation. We propose to carry out further analysis of positional candidate genes from this region to identify the gene responsible for this unusual neurobehavioral phenotype