RESUMO
Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant disorder, which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. A major disease-causing gene for HypoPP has been identified as CACNA1S, which encodes the skeletal muscle calcium channel alpha-subunit with four transmembrane domains (I-IV), each with six transmembrane segments (S1-S6). To date, all CACNA1S mutations identified in HypoPP patients are located within the voltage-sensor S4 segment. In this study we report a novel CACNA1S mutation in a new region of the protein, the S3 segment of domain III. We characterized a four-generation South American family with HypoPP. Genetic analysis identified a novel V876E mutation in all HypoPP patients in the family, but not in normal family members or 160 control people. Clinical analysis indicates that mutation V876E is associated with a severe outcome as characterized by a very early age of onset, complete penetrance and a severe prognosis including death. These results identify a new mutation in CACNA1S and expand the spectrum of CACNA1S mutations associated with HypoPP.
Assuntos
Canais de Cálcio/genética , Paralisia Periódica Hipopotassêmica/genética , Mutação , Sequência de Aminoácidos , Sequência de Bases , Canais de Cálcio Tipo L , Colômbia , Análise Mutacional de DNA , Saúde da Família , Feminino , Genes Dominantes , Humanos , Paralisia Periódica Hipopotassêmica/patologia , Masculino , Dados de Sequência Molecular , LinhagemRESUMO
OBJECTIVE: To evaluate exercise test responses in hypokalaemic periodic paralysis (HPP), to determine its value as a diagnostic tool and the factors that could affect the responses. METHODS: 22 subjects were studied from two families with HPP caused by R528H mutation, four patients with thyrotoxic periodic paralysis, 15 normal controls, and four controls with hyperthyroidism. All family members were submitted to clinical evaluation, electrophysiological exercise testing, and DNA analysis. Patients with thyrotoxic periodic paralysis had exercise tests before and after treatment of their hyperthyroidism. RESULTS: Abnormal responses to the exercise tests were obtained only in subjects with recent attacks of weakness. They were not correlated with genotype, as asymptomatic carriers were unaffected. Patients with thyrotoxic periodic paralysis showed pronounced impairment while they were hyperthyroid, but improved when they were euthyroid. One patient with HPP and chronic KCl use had an increase in amplitude potentials over approximately 20 minutes, possibly related to alteration of potassium homeostasis. CONCLUSIONS: The exercise test is a useful diagnostic test for periodic paralysis, but in the absence of recent weakness negative results must be viewed with caution. It has advantages over the DNA test in being a non-invasive functional test that can provide insights into abnormalities of muscle excitability.