A sodium channel myotonia due to a novel SCN4A mutation accompanied by acquired autoimmune myasthenia gravis.

Mutations of the voltage gated sodium channel gene (SCN4A) are responsible for non-dystrophic myotonia including hyperkalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonia, as well as congenital myasthenic syndrome. In vitro functional analyses have demonstrated the non-dystrophic mutants to show a gain-of-function defect of the channel; a disruption of fast inactivation, an enhancement of activation, or both, while the myasthenic mutation presents a loss-of function defect. This report presents a case of non-dystrophic myotonia that is incidentally accompanied with acquired myasthenia. The patient presented a marked warm-up phenomenon of myotonia but the repeated short exercise test suggested mutations of the sodium channel. The genetic analysis identified a novel mutation, G1292D, of SCN4A. A functional study of the mutant channel revealed marked enhancement of activation and slight impairment of fast inactivation, which should induce muscle hyperexcitability. The effects of the alteration of channel function to the myasthenic symptoms were explored by using stimulation of repetitive depolarization pulses. A use-dependent channel inactivation was reduced in the mutant in comparison to normal channel, thus suggesting an opposing effect to myasthenia.

[A survey of cardiologists, diabetologists, gynecologists and ophthalmologists practicing in Osaka on the medical consultation behaviors of myotonic dystrophy patients].

An anonymous postal survey of cardiologists, diabetologists, gynecologists, and ophthalmologists in Osaka was performed to assess the medical care-seeking behaviors of and problems associated with the medical management of patients with myotonic dystrophy (DM). The questionnaires were sent to 927 cardiologists, 357 diabetologists, 882 gynecologists, and 915 ophthalmologists. Of these, 172 cardiologists, 85 diabetologists, 220 gynecologists, and 154 ophthalmologists responded. More than 30% of responders had provided care to DM patients, and approximately 10% had experience diagnosing DM patients. These facts suggest that DM patients receive medical care from various specialists due to complications involving multiple systems and some of them visit other specialists prior to neurologists. Some patients were diagnosed after perinatal or perioperative difficulties. Therefore, it seems important to improve the ability of physicians to identify DM patients. Because specialists with experience diagnosing DM paid more attention to the characteristic features of DM, such as grip myotonia and hatchet face, a simple screening test may be useful for detecting DM. Some responders pointed out the negative attitude of DM patients toward medical care and the lack of neurologists for consultation as problems in the medical management of DM patients. Cooperation among neurologists and other specialists and education of DM patients are important to improve the medical management of DM patients.

Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy.

Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy.