Myotonia fluctuans. A third type of muscle sodium channel disease

Department of Neurology, University of Würzburg, Germany.
JAMA Neurology (Impact Factor: 7.42). 12/1994; 51(11):1095-102. DOI: 10.1001/archneur.1994.00540230033009
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To define a new type of dominant myotonic muscle disorder and to identify the gene lesion.
Case series, clinical examination and electromyography, measurements of grip force and relaxation time, and DNA analysis to probe for mutation in the gene for the skeletal muscle sodium channel.
Outpatient clinic and home.
Three families studied; all together, 17 affected and nine unaffected individuals.
The findings in these three families confirm the existence of myotonia fluctuans as we described it previously in another family. Myotonia (prolongation of relaxation time) developed 20 to 40 minutes after exercise. Potassium caused generalized myotonia. Cooling had no major effect on muscle function. Three families had a common mutation in exon 22 and one family had a mutation in exon 14 of the gene for the sodium channel alpha subunit.
Myotonia fluctuans is a disorder of the muscle sodium channel. There are at present two other distinct clinical muscle disorders associated with mutations in the sodium channel: hyperkalemic periodic paralysis and paramyotonia congenita. The findings in the present report indicate that myotonia fluctuans belongs to a third type of sodium channel disorder. Further work is needed to understand the complex genotype-phenotype correlations in sodium channel disorders.

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Available from: Frank Lehmann-Horn, Sep 29, 2015
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    • "Patients with paramyotonia congenita demonstrate cold sensitivity, myotonia that 'paradoxically' worsens with repetitive activity, and episodic weakness (Ptacek et al., 1993; Miller et al., 2004; Cannon, 2006; Matthews et al., 2010). In contrast, patients with sodium channel myotonia, including the potassium aggravated myotonias, have variable cold-sensitivity and no episodic weakness (Trudell et al., 1987; Ptacek et al., 1992; Ricker et al., 1994; Orrell et al., 1998; Matthews et al., 2010). Patients with hyperkalemic periodic paralysis may have myotonia, but episodic weakness is usually the dominant feature. "
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    ABSTRACT: Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed 510% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium Downloaded from channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.
    Brain 06/2013; 2013(7). DOI:10.1093/brain/awt133 · 9.20 Impact Factor
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    • "In potassium-aggravated myotonia (PAM), episodes of weakness do not occur (5). This myotonia is exacerbated by rest following exercise (delayed myotonia) (6, 7). The potassium dependence can be used to differentiate PAM from chloride channel myotonias. "
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    ABSTRACT: We report a 4-generation Turkish family with 10 affected members presenting with myotonia and potassium- and exercise-induced paralytic attacks. The clinical presentation was neither typical for the chloride channel myotonias Thomsen and Becker nor for the separate sodium channel myotonia entities potassium-aggravated myotonia, paramyotonia congenita, and hyperkalemic periodic paralysis. It is best described by a combination of potassium-aggravated myotonia and hyperkalemic periodic paralysis. We excluded exonic chloride channel mutations including CLCN1 exon deletion/duplication by MLPA. Instead we identified a novel p.N440K sodium channel mutation that is located at the inner end of segment S6 of repeat I. We discuss the genotype phenotype relation.
    Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 10/2011; 30(2):133-7.
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    • "Functional consequences of these mutations include changes in fast inactivation and persistent currents (Green et al. 1998; Schwartz et al. 2000). Intriguingly, symptoms in these four human disorders are episodic, and believed or known to be precipitated by external or internal stimuli: the paroxysmal muscular disorders, paramyotonia congenita/myotonia congenita and myotonia fluctuans (SCN4A) (McClatchey et al. 1992; Ricker et al. 1994); near-sudden infant death syndrome (SIDS) caused by the cardiac condition long QT syndrome type 3 (LQT3) (SCN5A) (Schwartz et al. 2000) and severe myoclonic epilepsy of infancy (SMEI) (SCN1A) (Claes et al. 2001; Escayg et al. 2000). Thus, we predict that the Scn8a Clth Asp981Val mutation could alter SCN8A channel kinetics or sodium current properties in Scn8a Clth neurons, which could be assessed in vitro and in vivo. "
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    ABSTRACT: Deafness is the most common sensory disorder in humans and the aetiology of genetic deafness is complex. Mouse mutants have been crucial in identifying genes involved in hearing. However, many deafness genes remain unidentified. Using N-ethyl N-nitrosourea (ENU) mutagenesis to generate new mouse models of deafness, we identified a novel semi-dominant mouse mutant, Cloth-ears (Clth). Cloth-ears mice show reduced acoustic startle response and mild hearing loss from approximately 30 days old. Auditory-evoked brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) analyses indicate that the peripheral neural auditory pathway is impaired in Cloth-ears mice, but that cochlear function is normal. In addition, both Clth/Clth and Clth/+ mice display paroxysmal tremor episodes with behavioural arrest. Clth/Clth mice also show a milder continuous tremor during movement and rest. Longitudinal phenotypic analysis showed that Clth/+ and Clth/Clth mice also have complex defects in behaviour, growth, neurological and motor function. Positional cloning of Cloth-ears identified a point mutation in the neuronal voltage-gated sodium channel alpha-subunit gene, Scn8a, causing an aspartic acid to valine (D981V) change six amino acids downstream of the sixth transmembrane segment of the second domain (D2S6). Complementation testing with a known Scn8a mouse mutant confirmed that this mutation is responsible for the Cloth-ears phenotype. Our findings suggest a novel role for Scn8a in peripheral neural hearing loss and paroxysmal motor dysfunction.
    Genes Brain and Behavior 07/2009; 8(7):699-713. DOI:10.1111/j.1601-183X.2009.00514.x · 3.66 Impact Factor
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