Paramyotonia congenita: genotype to phenotype correlations in two families and report of a new mutation in the sodium channel gene
Introduction
Periodic paralyses and non-dystrophic myotonias including myotonia congenita, both hypo- and hyperkalemic periodic paralysis, paramyotonia congenita and potassium-aggravated myotonia, are a group of hereditary muscle disorders caused by mutations in ion channel genes. Myotonia congenita is due to mutations in the muscle chloride channel gene CLCN-1, and displays both autosomal dominant and recessive inheritance (George et al., 1993a; Koch et al., 1992). Hypokalemic periodic paralysis is an autosomal dominant disorder caused by mutations in the voltage-dependent calcium channel α1-subunit CACNL1A3 (Fontaine et al., 1994; Jurkat-Rott et al., 1994; Ptacek et al., 1994a). The other members of this group of muscle ion channel diseases involve the sodium channel gene, SCN4A. The sodium channel is a voltage-dependent regulator of sodium ion exchanges through the sarcolemmal membrane. Its sequential openings and closures result in generation and conduction of action potentials along the sarcolemmal membrane. The muscle sodium channel is composed of an α-subunit responsible for most of the channel properties, and a β-subunit involved in the inactivation of the channel. The α-subunit gene SCN4A, encodes a 260 kDa glycoprotein comprising approximately 1800 amino acids. The sodium channel α-subunit is composed of four homologous domains (DI to DIV), each containing six transmembrane segments (S1 to S6) (for review see Catterall, 1995).
The sodium channel disorders are transmitted with autosomal dominant inheritance and include hyperkalemic periodic paralysis (hyperPP), paramyotonia congenita (PC) and potassium-aggravated myotonia (PAM). HyperPP patients present potassium-sensitive attacks of muscle weakness lasting from 10 minutes to several hours. Subsequent to the initial linkage studies (Fontaine et al., 1990), two SCN4A mutations were described: the Thr704Met and the Met1592Val mutations (Ptacek et al., 1991; Rojas et al., 1991). These two mutations have now been reported in more than 15 families of different ethnic backgrounds (Feero et al., 1993; Lehmann-Horn et al., 1993; Wang et al., 1993; Plassart et al., 1994; Ptacek et al., 1994b). Patients with PC present muscle stiffness worsened by exercise in addition to a cold-sensitive stiffness and weakness. To date, seven sodium channel mutations have been reported (McClatchey et al., 1992c; Ptacek et al., 1992; Ptacek et al., 1993; Wang et al., 1993; Koch et al., 1995). PAM are myotonic disorders characterized by the worsening of myotonia by the ingestion of potassium and the response to treatment by acetazolamide. PAM were former referred to as ‘sodium channel myotonia’, ‘myotonia fluctuans’, ‘myotonia permanens’ or ‘acetazolamide-responsive myotonia congenita’ (Heine et al., 1993; McClatchey et al., 1992b; Ricker et al., 1994; Ptacek et al., 1994b). The term of PAM was adopted at a meeting on ‘Non-dystrophic myotonias and periodic paralyses’ held at the European Neuromuscular Center in Naarden (The Netherlands) in December 1995 in light of the characterization of sodium channel mutations.
In addition to the three well-characterized groups of sodium channel disorders, molecular analysis of families led to the recognition of clinical variability within families, and of various phenotypes associated with the same mutation in different families (McClatchey et al., 1992b; Lehmann-Horn et al., 1993; Lerche et al., 1993; Plassart et al., 1994). In light of these recent findings, we describe two PC families: one with an already known mutation and a phenotype distinct from the one originally described, the other with a novel phenotype and a new mutation.
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Patients
Two families with PC (29 individuals) were investigated according to classical criteria (Buruma and Schipperheyn, 1979; Rudel and Ricker, 1985; McKusick, 1990; Lehmann-Horn et al., 1993). Clinical features are summarized in Table 1. Pedigrees are shown in Fig. 1Fig. 2.
Patient AIII2 complained of cold-induced stiffness without weakness, occuring only in winter. She also suffered acute attacks of muscle weakness, provoked by exercise and fasting, lasting from several hours to a day. The frequency
Clinical features
The phenotype of family A consisted of PC with cold-induced stiffness but no weakness (Table 1). Associated with PC were attacks of muscle weakness. The paralytic episodes, less frequent than the cold-induced stiffness, occurring no more than several times a year, were potassium-sensitive, suppressed by acetazolamide, provoked by exercice and fasting, ameliorated by resuming exercice. The final diagnosis was PC (cold-induced stiffness) with hyperPP.
Family B presented a phenotype of PC with
Discussion
In this paper, we describe two families with an atypical form of PC. Characteristic of the PC phenotype is the presence of both cold-induced stiffness and weakness. Our families display either cold-induced stiffness without cold-induced weakness (family A) or cold-induced weakness without cold-induced stiffness (family B). Cold-induced stiffness without weakness was recently described in three German families with the Val1293Ile sodium channel mutation (Koch et al., 1995). Patients in family A
Acknowledgements
Grants by INSERM, AFM and the French Ministry of Research (contract ACSV-2) made this work possible. We thank Professor Y. Agid and Dr. N. Baumann for their support. We acknowledge the help of C. Colin for the figures and Dr. M. Ruberg for English revision. We thank Genethon for allowing us the use of their automatic DNA sequencer.
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