ClinVar Genomic variation as it relates to human health

In 3 of 7 unrelated patients with hyperkalemic periodic paralysis (HYPP; 170500), Ptacek et al. (1991) identified a heterozygous C-to-T change at a CpG dimer in the SCN4A gene, resulting in a thr704-to-met (T704M) substitution in S5 of domain II in the membrane-spanning segment of the sodium channel protein. All 3 patients had prominent fixed muscle weakness, whereas the remaining 4 did not. In 2 of the families, the mutation cosegregated with HYPP; in the third it appeared to be a de novo mutation. The authors noted that threonine-704 is absolutely conserved in sodium channel genes across highly divergent species. Sillen et al. (1996) found the T704M mutation in 2 Swedish families with HYPP. The mutation was linked to different microsatellite alleles, suggesting that the mutation may have arisen independently in the 2 families. In a family with features of both HYPP and paramyotonia congenita (PMC; 168300), which the authors termed 'paralysis periodica paramyotonica,' Kim et al. (2001) identified the T704M mutation. Both exercise sensitivity and temperature sensitivity were present, and the authors commented on the phenotypic variation resulting from this mutation. In an Italian kindred in which 9 members were affected with a severe form of HYPP/PMC, Brancati et al. (2003) found the T704M mutation. Onset of the disorder was in the first months of life in all affected patients and the episodes of paralysis increased in severity and frequency, sometimes up to several times a day, with age. Miller et al. (2004) identified the T704M mutation in affected members of 10 kindreds with HYPP. All patients had onset before 1 year of age and overall showed only a 50% chance of favorable response to acetazolamide. Hisama (2005) described a 7-generation family in which multiple members were affected with a complicated neurologic phenotype including variable features of neuropathy, myotonia, and periodic paralysis. The same family had been described in the medical literature since 1934. The proband had late-onset demyelinating Charcot-Marie-Tooth disease (CMT1B; 118200), muscle cramping, and myotonia. His sister had HYPP, and his father had severe childhood-onset CMT and periodic paralysis. Multiple other relatives had similar features of 1 or both disorders. Molecular analysis identified a missense mutation in the MPZ gene (159440) in the proband and the SCN4A T704M mutation in the sister; the father was deceased. One other family member tested had the MPZ mutation, and 4 other family members had the SCN4A mutation. Hisama (2005) commented on the unusual occurrence of 2 genetically unlinked neurologic disorders in this family and emphasized the diagnostic difficulties. (less)

In 3 of 7 unrelated patients with hyperkalemic periodic paralysis (HYPP; 170500), Ptacek et al. (1991) identified a heterozygous C-to-T change at a CpG dimer in the SCN4A gene, resulting in a thr704-to-met (T704M) substitution in S5 of domain II in the membrane-spanning segment of the sodium channel protein. All 3 patients had prominent fixed muscle weakness, whereas the remaining 4 did not. In 2 of the families, the mutation cosegregated with HYPP; in the third it appeared to be a de novo mutation. The authors noted that threonine-704 is absolutely conserved in sodium channel genes across highly divergent species. Sillen et al. (1996) found the T704M mutation in 2 Swedish families with HYPP. The mutation was linked to different microsatellite alleles, suggesting that the mutation may have arisen independently in the 2 families. In a family with features of both HYPP and paramyotonia congenita (PMC; 168300), which the authors termed 'paralysis periodica paramyotonica,' Kim et al. (2001) identified the T704M mutation. Both exercise sensitivity and temperature sensitivity were present, and the authors commented on the phenotypic variation resulting from this mutation. In an Italian kindred in which 9 members were affected with a severe form of HYPP/PMC, Brancati et al. (2003) found the T704M mutation. Onset of the disorder was in the first months of life in all affected patients and the episodes of paralysis increased in severity and frequency, sometimes up to several times a day, with age. Miller et al. (2004) identified the T704M mutation in affected members of 10 kindreds with HYPP. All patients had onset before 1 year of age and overall showed only a 50% chance of favorable response to acetazolamide. Hisama (2005) described a 7-generation family in which multiple members were affected with a complicated neurologic phenotype including variable features of neuropathy, myotonia, and periodic paralysis. The same family had been described in the medical literature since 1934. The proband had late-onset demyelinating Charcot-Marie-Tooth disease (CMT1B; 118200), muscle cramping, and myotonia. His sister had HYPP, and his father had severe childhood-onset CMT and periodic paralysis. Multiple other relatives had similar features of 1 or both disorders. Molecular analysis identified a missense mutation in the MPZ gene (159440) in the proband and the SCN4A T704M mutation in the sister; the father was deceased. One other family member tested had the MPZ mutation, and 4 other family members had the SCN4A mutation. Hisama (2005) commented on the unusual occurrence of 2 genetically unlinked neurologic disorders in this family and emphasized the diagnostic difficulties. (less)