Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis.

PURPOSE OF REVIEW: The aim is to review the recent findings in relation to the genetics, pathophysiology, clinical phenotypes, investigation and treatment of the nondystrophic myotonias (NDMs) and periodic paralyses. RECENT FINDINGS: The number of pathogenic mutations causing NDMs and periodic paralyses in known genes continues to expand. In addition, a mutation has been identified in the ryanodine receptor gene manifesting as an atypical periodic paralysis phenotype. Another recent study indicated that thyrotoxic hypokalaemic periodic paralysis is determined by mutations in a novel gene encoding an inwardly rectifying potassium channel, Kir2.6. Work studying molecular mechanisms indicates that 90% of the known mutations causing hypokalaemic periodic paralysis (HypoPP) result in loss of positively charged arginine residues in the S4 segments of either SCN4A or CACNA1S, possibly creating a gating-pore current that may be important in the pathogenesis of HypoPP. Recent studies evaluating clinical features and health status in NDM patients have provided more detailed insights into the significant morbidity associated with these diseases. Ultrasound has been successfully used to demonstrate muscle abnormalities in NDM patients and magnetic resonance spectroscopy studies applied to HypoPP patients suggest that this technique can demonstrate both disease-related and treatment-related changes. SUMMARY: Recent discoveries in the skeletal muscle channelopathies have increased our understanding of the genetics and pathophysiology of these diseases. Studies reporting imaging techniques raise the possibility of improved disease monitoring and better outcome measures for clinical trials. Randomized controlled trials to establish an evidence base upon which to recommend standard treatments are required.

Contribution of Asian Haplotype of KCNJ18 to Susceptibility to and Ethnic Differences in Thyrotoxic Periodic Paralysis.

CONTEXT AND OBJECTIVES: Thyrotoxic periodic paralysis (TPP) is an acute complication of thyrotoxicosis that can be lethal. TPP is rare in Caucasians but often affects young men in East Asian populations. This study aimed to clarify the contribution of KCNJ18 to susceptibility to TPP in East Asian populations. PARTICIPANTS AND METHODS: The study comprised 635 participants including 13 Japanese patients with TPP, 208 Japanese patients with Graves disease without TPP, and 414 healthy control subjects from the Japanese (n = 208), Korean (n = 111), and Caucasian populations (n = 95). DNA samples from 29 participants (13 with TPP, 8 with Graves disease, and 8 controls) were sequenced for KCNJ18, and all participants (n = 635) were genotyped for six variants of KCNJ18 and a polymorphism of KCNJ2 (rs312691). RESULTS: Six single-nucleotide variants (SNVs) with amino acid substitutions were identified by direct sequencing of KCNJ18. Among these, four SNVs comprised three haplotypes under strong linkage disequilibrium. Haplotype 1 (AAAG) of KCNJ18 was significantly associated with susceptibility to TPP in the Japanese population (OR = 19.6; 95% CI, 1.5 to 256.9; P = 0.013). Haplotype frequencies in the general East Asian (Japanese and Korean) and Caucasian populations differed significantly (haplotype 1: 80.8% vs 48.4%, P = 1.1×10-27). CONCLUSION: A major haplotype of KCNJ18 in East Asian populations is significantly associated with susceptibility to TPP. The haplotype is much more common in East Asian than Caucasian populations, suggesting its contribution to the high prevalence of TPP in East Asian populations.

[The construction and preliminary investigation of the cell model of a novel mutation R675Q in the SCN4A gene identified in a Chinese family with normokalemic periodic paralysis].

OBJECTIVE: To construct and investigate the cell model of a novel mutation R675Q in the skeletal muscle Na channel type 4 alpha subunit gene (SCN4A) identified from a Chinese family with normokalemic periodic paralysis. METHODS: cDNA encoding the adult isoform of SCN4A was used as a template for in vitro site-directed mutagenesis by PCR method. The mutated plasmid was transiently transfected into HEK-293 cells by calcium phosphate precipitation. Twenty four and 48 hours after transfection, the expression level of SCN4A was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Whole cell voltage-clamp recording was used to study the current of sodium channels. RESULTS: The site-mutagenesis of the plasmid was confirmed by sequencing. The expression of SCN4A gene was significantly elevated 24 h and 48 h after transfection. The relative current of R675Q is smaller than that of wide type before reaching peak current under the same test voltage, but larger than that of wild type current after reaching peak current. They both had the largest peak current under 0 mV test pulse. CONCLUSION: A cell model of normokalemic periodic paralysis was successfully constructed. The R675Q mutation of the SCN4A gene enhances the activation and inactivation of the sodium channel, and the S4 transmembrane segment may have intimate relationship with the attack of weakness in normoKPP patients.

Familial hypokalemic periodic paralysis. 50-year follow-up of a large family.

A large family with hypokalemic periodic paralysis was reexamined after 50 years. Two new cases were found in the third generation and 12 in the fourth generation. This family now includes 28 affected patients in four generations. The reexamination ascertained the presence of permanent muscle weakness (PMW) in all investigated affected sibs. This fact, and the fact that indications of the presence of PMW without paralytic attacks were found in only one subject, is strong evidence that both are manifestations of the same more or less fully penetrant dominant gene. A linkage study in this family could not localize the gene on the human genome, but close linkage with 25 genetic marker systems could be excluded.

Progressive myopathy in hyperkalemic periodic paralysis.

A progressive degenerative myopathy has been well described in hypokalemic periodic paralysis but is not as widely recognized in hyperkalemic periodic paralysis. We studied four families with the latter disease in which some members developed a progressive myopathy. Episodes of paralysis were prolonged, lasting for months in some cases, and in one case paralysis was sufficiently severe to require ventilatory support. The progressive myopathy tended to develop at a time when attacks of paralysis were decreasing in frequency. Muscle biopsy specimens showed variability in fiber size, internal nuclei, and fibers with vacuoles. Electron microscopy showed myofibrillary degeneration and tubular aggregates. An abnormal biopsy specimen was more common in older patients. Our experience suggests that a progressive myopathy is as common in hyperkalemic periodic paralysis as it is in the hypokalemic disorder.

Genotype-phenotype correlations in human skeletal muscle sodium channel diseases.

BACKGROUND: Over the past 3 years, the genetics of the myotonic diseases have been substantially elaborated. Three genetically different groups of myotonic disease can be discerned: (1) the chloride channel myotonias, (2) the adynamia-paramyotonia complex, and (3) myotonic dystrophy. METHODS AND RESULTS: Electrophysiology has suggested and molecular biology has proven that the diseases belonging to the adynamia-paramyotonia complex, ie, paramyotonia congenita, hyperkalemic and normokalemic periodic paralysis, and some rare forms of myotonic disease, are caused by point mutations in the gene encoding the alpha subunit of the sodium channel in adult human skeletal muscle, located on chromosome 17q23. Thirteen different mutations have been described by various groups in the United States and Germany. The various mutations causing a particular form of the complex are not located in the gene in a predictable or easily understandable regular manner. CONCLUSIONS: Further study of the genotype-phenotype correlations should not only increase our understanding of the variability of signs in this group of diseases, it could also provide us with a deeper insight in the function of the various regions of the sodium channel protein.

Histochemistry and electron microscopy of muscle fibres in a case of congenital paramyotonia.

In a case of congenital paramyotonia a muscle biopsy was performed and studied morphologically, histochemically and ultrastructurally. A clearcut pattern of changes has been observed with ATPase and oxidative enzymes. On electron microscopy special changes known as "tubular aggregates" were found. The relationship between the two findings, as well as the significance of such alterations in the range of periodic paralyses and myotonic phenomena, are discussed.

Multiple deletions of mitochondrial DNA in a patient with periodic attacks of paralysis.

In this study multiple deletions of mitochondrial genome were found in a patient presenting with periodic attacks of paralysis. Morphological studies revealed mitochondrial abnormalities along with typical histopathological features of periodic paralysis. Southern blot and PCR analysis revealed multiple mtDNA deletions. Our patient could be affected by two unrelated diseases, idiopathic periodic paralysis and presymptomatic mitochondrial myopathy. Alternatively, mtDNA alterations and oxidative deficiency might express themselves phenotypically as periodic paralytic attacks, although this correlation has never been reported.

Periodic paralyses.

The periodic paralyses are a group of muscle diseases with abnormalities of channels. These abnormalities result in paralysis or weakness with or without poor relaxation of muscle. Hypokalemic periodic paralyses, potassium-sensitive periodic paralyses, and paramyotonia congenita are reviewed. The clinical findings, pathophysiologic abnormalities, diagnostic evaluations, and possible treatments are included in this article.

Familial periodic paralysis with hypokalaemia. Study of a muscle biopsy in the myopathic stage of the disorder.

A 51 year-old male patient was affected by a dominantly inherited periodic paralysis. With large potassium supplements and ageing, the number and severity of attacks became considerably reduced. Increasing weakness and atrophy of the lower extremities were documented by clinical examination and by computer-assisted tomography of the muscles. A biopsy was taken in the vastus lateralis muscle without any attempt to induce a hypokalaemic paralytic attack. Light microscopy showed multiple intra- and extracellular vacuoles, rimmed vacuoles, myonecrosis, fatty degeneration and endomysial fibrosis. The endomysial nerve bundles were normal. Both fiber types were vacuolated. Quantitative studies revealed abnormal variability coefficients and increased atrophy factors for all types. Electron microscopy showed dilatations of the tubular system and of the sarcoplasmic reticulum communicating with large vacuoles limited by a single membrane. Other vacuoles were covered by a basement membrane and could contain collagen fibers or capillaries. Accumulation of myeloid bodies and of 10-13 nm filaments were also noted in the sarcoplasm. Cytoplasmic bodies were present. No tubular aggregates could be found. The nerve bundles were normal. These findings were in part similar to the ones reported by Gérard et al. (1978) in the son's biopsy during an induced paralytic attack. Significant findings in our case are the sequence of events leading to muscle fibre destruction, still detectable at an advanced stage of the disease. Myopathic changes represent a delayed but severe complication of the disorder.

[Hypokalemic periodic paralysis. Report of two cases (author's transl)]. / Estudio de dos casos de parálisis periódica hipopotasémica.

The familial periodic hypokalemic paralysis is an infrequent disease characterized by paralytic attacks of sudden appearance affecting the muscles of the trunk and limbs. There is a marked hypokalemia during the paralytic episodes of the disease, and a family history in 80 percent of the cases. The differential diagnosis includes hyperthyroidism with periodic paralysis, congenital paramyotony and adynamia episodica hereditaria. Two typical cases of hypokalemic periodic paralysis are presented, with biological, electrophysiological, clinical, and ultrastructural pictures characteristics of the disease. The clinical manifestations of both patients are discussed, stressing the diagnostic importance of the electrophysiological study during the insulin test, and the interest of the histologic and ultrastructural studies. The spectacular response during the acute episodes to the intravenous perfusion of potassium salts, and the usefulness of the acetazolamide administration to prevent the paralytic episodes are emphasized.

[Familial periodic paralysis with hypokaliemia, hyperaldosteronism and extracellular vacuolization (author's transl)]. / Paralysie périodique familiale avec hypokaliémie, hyperaldostéronisme et vacuolisation extra-cellulaire.

The observation of a 20 years old patient with a periodic paralysis is reported. During a crisis induced by 20 U of insulin and 150 g of glucose, transient hyperaldosteronism was found and the muscular biopsy performed in the left biceps brachii, disclosed vacuoles with a double membrane. The significance of these findings is discussed.

[Periodic paralysis: anatomo-pathological study of skeletal muscles in 14 patients]. / Paralisia periódica estudo anátomo-patológico do músculo esquelético de 14 pacientes.

Periodic paralysis is a rare disease, characterized by transient weakness associated with abnormal levels of serum potassium. Muscle biopsy may show a wide range of abnormalities, vacuoles being more specifically linked to the disease. We analysed 17 muscle biopsies from 14 patients with periodic paralysis (14 hypokalemic, 2 hyperkalemic). All of them showed at least one histological abnormality. Fourteen specimens showed vacuoles that were peripheral, single, frequent and preferentially found in type I fibers. Frequency or severity of attacks did not correlate with the presence of vacuoles but those were more easily found in patients with long term disease. Ten biopsies showed tubular aggregates, specially on the patients with frequent crises or long term disease. A second biopsy was done in three patients and in two we observed a worsening of the histopathologic picture. One patient manifested interictal weakness with evident myopathic changes on the muscle biopsy. Nonspecific changes were found in variable degrees in 15 biopsies. Our study shows that vacuoles and tubular aggregates are frequent changes in periodic paralysis and therefore helpful for the diagnosis. Important myopathic findings in the muscle biopsy suggest a permanent myopathy which probably develops after severe crises or long term disease.

[Familial periodic paralysis: study of 8 cases]. / Paralisia periódica familiar: estudo de oito casos.

The authors studied 8 patients with Familial Periodic Paralysis on the clinical, hydroelectrolytic, electrophysiologic, histologic and therapeutic points of view. There was significant predominance in males. The onset of the symptoms in our group began under fifteen years of age. The clinical manifestations were similar to those referred in the literature. The hypokalemic form was found in all patients except in one case that had hyperkalemic form. Natremias on the superior border of the normality, were seen in 21.4% of the cases, and in 21.4% the natremias were higher; this fact suggested aldosterone liberation of the muscle. The histologic examination performed in 5 patients, was normal in 20% of them and, in those cases with repetitive and frequent crises, atrophic muscle fibers were seen. Prophylactic treatments were made. The patients with hypokalemic form received supplementary doses of potassium.

[Skeletal muscles in myotonic disorders and periodic paralysis]. / Skeletnye myshtsy pri miotonicheskikh narusheniiakh i periodicheskom paraliche.

Recommendations for histological criteria of diagnosis of dystrophic and congenital myotony as well as familial hypopotassemic periodic paralysis based on the results of skeletal muscles biopsies are presented.

[Clinical and molecular genetic analysis of a family with normokalemic periodic paralysis].

OBJECTIVE: Periodic paralysis (PP) is one type of skeletal muscle channelopathies characterized by episodic attacks of weakness. It is usually classified into hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis (HypoPP) and normokalemic periodic paralysis (NormoPP) based on the blood potassium levels. HypoPP is the most common type of these three and NormoPP is the rarest one. The aim of this study was to explore the clinical and genetic features of a Chinese family with normokalemic periodic paralysis (NormoKPP). METHOD: Clinical features of all patients in the family with NormoKPP were analyzed. Genomic DNA was extracted from peripheral blood leukocytes and amplified with PCR. We screened all 24 exons of SCN4A gene and then sequence analysis was performed in those who showed heteroduplex as compared with unaffected controls. RESULT: (1) Fifteen members of the family were clinically diagnosed NormoKPP, and their common features are: onset within infacy, episodic attacks of weakness, the blood potassium levels were within normal ranges, high sodium diet or large dosage of normal saline could attenuate the symptom. One muscle biopsy was performed and examination of light and electronic microscopy showed occasionally degenerating myofibers. (2) Gene of 12 patients were screened and confirmed mutations of SCN4A genes--c. 2111 T > C/p. Thr704Met. CONCLUSION: The study further defined the clinical features of patients with NormoKPP, and molecular genetic analysis found SCN4A gene c. 2111 T > C/p. Thr704Met point mutation contributed to the disease. In line with the autosomal dominant inheritance laws, this family can be diagnosed with periodic paralysis, and be provided with genetic counseling. And the study may also help the clinical diagnosis, guide treatment and genetic counseling of this rare disease in China.