title: A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene.
abstract: Muscle sodium-channel disorders cover a spectrum of rare myotonic diseases. In a German family with 17 affected individuals in four generations, we identified a heterozygous missense mutation in exon 24 A1481D (c.4442 C>A) of the voltage-gated sodium channel gene (SCN4A) alpha subunit. Phenotypes of 12 family members were characterized by a mild myotonia with cold sensitivity but without paramyotonia. The index patient presented with fluctuating cold- and exercise-induced stiffness of ocular, facial, and distal muscles. The myotonia became more severe at the age of 22 years. His father had had cold- and exercise-induced periodic weakness with fluctuating myotonia since age 10. Later he developed a more severe, purely exercise- and cold-aggravated myotonia of arms, hands, and facial muscles. The father's mother presented with cold-induced myotonia until age 65, when progressive weakness of proximal limb muscles developed. Her muscle biopsies revealed considerable myopathic changes with a variety of fine structural alterations. This study presents a family with cold-aggravated myotonia and progression of myopathic changes in the muscle biopsy with increasing age. In older patients, sodium channelopathies may mimic the phenotypic features of myotonic dystrophy type 2.
authors.affiliation: Friedrich Baur Institute, Department of Neurology, Ludwig Maximilians University Munich, Ziemssenstrasse 1a, 80336 Munich, and Department of Neuropathology, University Hospital, RWTH Aachen, Germany. bschoser@med.uni-muenchen.de
authors.forename: Benedikt G H
authors.initials: BG
authors.lastname: Schoser
authors.forename: J Michael
authors.initials: JM
authors.lastname: Schröder
authors.forename: Timo
authors.initials: T
authors.lastname: Grimm
authors.forename: Damien
authors.initials: D
authors.lastname: Sternberg
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000737:chemistry / Q000235:genetics; D019943:Amino Acid Substitution; D001224:Aspartic Acid / Q000737:chemistry / Q000235:genetics; D003080:Cold Temperature; D004252:DNA Mutational Analysis; D005260:Female; D005858:Germany; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009224:Myotonia Congenita / Q000235:genetics* / Q000473:pathology; D062553:NAV1.4 Voltage-Gated Sodium Channel; D010375:Pedigree; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D001224:Aspartic Acid; D000409:Alanine