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J Neurol Neurosurg Psychiatry 2001;70:618–623
Phenotypic variation of a Thr704Met mutation in skeletal sodium channel gene in a family with paralysis periodica paramyotonica J Kim, Y Hahn, E H Sohn, Y J Lee, J H Yun, J M Kim, J H Chung
Department of Neurology, College of Medicine, Chungnam National University, 640 Daesa-dong, Joong-ku, Taejon, Korea J Kim E H Sohn J M Kim Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373–1 Kusung-dong, Taejon, 305–701 Korea J Kim Y Hahn Y J Lee J H Yun J H Chung Correspondence to: Dr J H Chung, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon, 305–701 Korea,
[email protected] Received 31 May 2000 and in final form 30 November 2000 Accepted 11 December 2000
Abstract Objectives—Patients with paralysis periodica paramyotonica exhibit a clinical syndrome with characteristics of both hyperkalaemic periodic paralysis and paramyotonia congenita. In several types of periodic paralysis associated with hyperkalaemia, mutations in the skeletal muscle sodium channel (SCN4A) gene have been previously reported. Phenotypic variations of mutations in SCN4A, however, have not been described yet. The present study aimed to evaluate genetic variations in a family with clinical and electrophysiological characteristics of paralysis periodica paramyotonia. Methods—Seven members of a family affected with symptoms of paralysis periodica paramyotonia were studied by electrophysiological and genetic analyses. There were increased serum potassium concentrations in four members during paralytic attacks induced by hyperkalaemic periodic paralysis provocation tests. Short exercise tests before and after cold immersion were carried out in four patients to distinguish electrophysiological characteristics of hyperkalaemic periodic paralysis and paramyotonia. Sequencing analyses of SCN4A were performed on one patient and a normal control to identify polymorphisms. Restriction fragment length polymorphism (RFLP) analysis was then performed at the identified polymorphic sites. Results—Electrophysiological studies showed both exercise sensitivity and temperature sensitivity. Compound motor action potential (CMAP) amplitudes were decreased (7.3%-28.6%) after short exercise tests. The CMAP amplitudes were even more severely decreased (21.7%-56.5%) in short exercise tests after cold exposure. Three polymorphic sites, Gln371Glu, Thr704Met, and Aspl376Asn were identified in SCN4A. RFLP analyses showed that all aVected patients carried the Thr704Met mutation, whereas unaVected family members and a normal control did not. Conclusion— Phenotypic variation of the Thr704Met mutation, which was previously reported in patients with hyperkalaemic periodic paralysis, is described in a family aVected with paralysis periodica paramyotonia. (J Neurol Neurosurg Psychiatry 2001;70:618–623) Keywords: paralysis periodica paramyotonica; hyperkalaemic periodic paralysis; paramyotonia congenita; human skeletal muscle sodium channel (SCN4A) gene
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Patients with periodic paralysis exhibit recurrent episodes of skeletal muscle weakness followed by complete recovery.1 To date, four syndromes of periodic paralysis have been described associated with hyperkalaemia: (1) hyperkalaemic periodic paralysis, (2) myotonic hyperkalaemic periodic paralysis, (3) paramyotonia congenita, and (4) paralysis periodica paramyotonica.2 3 Patients with paralysis periodica paramyotonia exhibit both paralytic attacks of hyperkalaemic periodic paralysis and paramyotonia of paramyotonia congenita.4 5 Genetic analyses of patients with hyperkalaemic periodic paralysis, paramyotonia congenita, and paralysis periodica paramyotonia have shown that mutations of a gene at chromosome 17q, encoding the á-subunit of human skeletal muscle sodium channel (SCN4A), were responsible for the symptoms.6 7 Up to 20 diVerent mutations in hyperkalaemic periodic paralysis, paramyotonia congenita, and paralysis periodica paramyotonia have been identified.1 4 Clinically delineated phenotypes of potassium sensitive periodic paralyses are consistently associated with diVerent mutations. For example, the Thr704Met, Met1592Val, or Thr698Met mutations in SCN4A was found in hyperkalaemic periodic paralysis.4 8 Cold sensitive myotonia and paradoxical myotonia were often found in the Thr1313Met and Arg1448His mutations.4 8 These genotype-phenotype relations suggest that each mutation correlates with a specific functional alteration in sodium channels leading to a unique phenotype.8 However, the diVerent phenotypes caused by an identical mutation have been described in an atypical family with periodic paralysis.9 In addition, three clinically distinct myotonic syndromes were reported in three diVerent mutations at the same position.10–12 A Thr704Met mutation has been well documented in hyperkalaemic periodic paralysis.4 8 13 Phenotypic variation of the Thr704Met mutation in the SCN4A gene, however, has been rarely described to date. In this study, we report a phenotypic variation of the Thr704Met mutation in the SCN4A gene in a Korean family with paralysis periodica paramyotonia. Methods PATIENTS
AVected members in the investigated family had periodic paralyses and paramyotonic symptoms (table 1, fig 1 A). Among adult patients, periodic paralysis was first noted during their first decade. Among aVected children,
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Thr704Met in paralysis periodica paramyotonica Table 1
Clinical characteristics of a family with paralysis periodica paramyotonica
Patient
Age (y)
Age at onset
Number of episodes /month
Duration of each episode
Paramyotonia/ Paradoxical myotonia
Precipitating factors of periodic paralysis
I-1 II-1 II-3 II-6 III-1 III-2 III-3
68 38 35 30 4 11 7
9y 7y 7y 8y 4 months 1y 2 months
3–4 2 2–3 1 3–4 3–4 4–5
7–10 d 5–7 d 2–3 d 1–2 d
