Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease

Heterozygous missense mutations in the caveolin-3 gene (CAV3) cause different muscle disorders. Most patients with CAV3 alterations present with rippling muscle disease (RMD) characterized by signs of increased muscle irritability without muscle weakness. In some patients, CAV3 mutations underlie the progressive limb-girdle muscular dystrophy type 1C (LGMD1C). Here, we report two unrelated patients with novel homozygous mutations (L86P and A92T) in CAV3. Both presented with a more severe clinical phenotype than usually seen in RMD. Immunohistochemical and immunoblot analyses of muscle biopsies showed a strong reduction of caveolin-3 in both homozygous RMD patients similar to the findings in heterozygous RMD. Electron microscopy studies showed a nearly complete absence of caveolae in the sarcolemma in all RMD patients analyzed. Additional plasma membrane irregularities (small plasmalemmal discontinuities, subsarcolemmal vacuoles, abnormal papillary projections) were more pronounced in homozygous than in heterozygous RMD patients. A stronger activation of nitric oxide synthase was observed in both homozygous patients compared with heterozygous RMD. Like in LGMD1C, dysferlin immunoreactivity is reduced in RMD but more pronounced in homozygous as compared with heterozygous RMD. Thus, we further extend the phenotypic variability of muscle caveolinopathies by identification of a severe form of RMD associated with homozygous CAV3 mutations.     

Painful cramps and giant myotonic discharges in a family with the Nav1.4‐G1306A mutation

Introduction: Two previously reported Norwegian patients with painful muscle cramps and giant myotonic discharges were genotyped and compared with those of members of 21 families harboring the same mutation. Methods: Using primers specific for SCN4A and CLCN1, the DNA of the Norwegian family members was amplified and bidirectionally sequenced. Clinical and neurophysiological features of other families harboring the same mutation were studied. Results: A G1306A mutation in the Nav1.4 voltage‐gated sodium channel of skeletal muscle was identified. This mutation is known to cause myotonia fluctuans. No giant myotonic discharges or painful muscle cramps were found in the other G1306A families. Conclusions: Ephaptic transmission between neighboring muscle fibers may not only cause the unusual size of the myotonic discharges in this family, but also a more severe type of potassium‐aggravated myotonia than myotonia fluctuans. Muscle Nerve 52: 680–683, 2015     

Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with Limb Girdle Muscular Dystrophy 2I

Mutations in the FKRP (Fukutin Related Protein) gene produce a range of phenotypes including Limb Girdle Muscular Dystrophy Type 2I (LGMD2I). In order to investigate the prevalence, the mutation spectrum and possible genotype-phenotype correlation, we studied a cohort of Norwegian patients with LGMD2I, ascertained in a 4-year period.In this retrospective study of genetically tested patients, we identified 88 patients from 69 families, who were either homozygous or compound heterozygous for FKRP mutations. This gives a minimum prevalence of 1/54,000 and a corresponding carrier frequency of 1/116 in the Norwegian population. Seven different FKRP mutations, including three novel changes, were detected. Seventy-six patients were homozygous for the common c.826C>A mutation. These patients had later disease onset than patients who were compound heterozygous - 14.0 vs. 6.1 years. We detected substantial variability in disease severity among homozygous patients.     

Nerve-muscle involvement in a large family with mitochondrial cytopathy: electrophysiological studies.

Thirteen patients with mitochondrial cytopathy were investigated. They represent different generations, ages, stages, and severities of the disease. All were assumed to have the same metabolic defect. The disease is a multisystem disorder with a metabolic defect located at complex 1 in the respiratory chain. Clinically, the disorder gives symptoms such as hearing loss, retinal pigmental degeneration, ataxia, cardiomyopathy, muscular fatiguability and neuropathy. The patients were investigated with nerve conduction studies, concentric needle EMG, SFEMG, and macro EMG examinations. Neurophysiologic studies revealed signs of myopathy in both the younger members and in those with slight muscular symptoms. In the more advanced stages, neuropathic changes of the axonal type were seen as well. Macro EMG was interpreted as indicating muscle fiber membrane abnormalities in the early stages. Single fiber EMG studies indicate that this metabolic defect does not disturb neuromuscular transmission.     

Acute postasthmatic amyotrophy (Hopkins' syndrome)

Acute postasthmatic amyotrophy is a rare condition, previously reported in only 26 cases. It is characterized by a sudden onset of a flaccid paralysis of an arm or a leg with completely preserved sensibility, about 1 week after an asthmatic attack. The cause is probably due to a lesion of the anterior horn of the spinal cord, but evidence indicates a more widespread pathological process. The etiology is unknown. but infectious or immunological mechanisms are likely. © 1994 John Wiley & Sons, Inc.     

A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of inherited neuromuscular disorders and have been associated with a wide clinical spectrum, ranging from various congenital myopathies to the malignant hyperthermia susceptibility (MHS) trait without any associated weakness. RYR1-related myopathies are usually of early-childhood onset. Here we present 11 patients from 8 families with a late-onset axial myopathy associated with RYR1 variants. Patients presented between the third and seventh decade of life to neuromuscular centres in Norway, the Netherlands and the United Kingdom with predominant axial muscle involvement, comprising variable degrees of lumbar hyperlordosis, scapular winging and/or camptocormia. Marked myalgia was commonly associated. Serum creatine kinase levels were normal or moderately elevated. Muscle imaging showed consistent involvement of the lower paravertebral muscles and the posterior thigh. Muscle biopsy findings were often discrete, featuring variability in fibre size, increased internal nuclei and unevenness of oxidative enzyme staining, but only rarely overt cores. RYR1 sequencing revealed heterozygous missense variants, either previously associated with the MHS trait or localizing to known MHS mutational hotspots. These findings indicate that MHS-related RYR1 mutations may present later in life with prominent axial weakness but not always typical histopathological features. We propose a combined effect of RyR1 dysfunction, aging and particular vulnerability of axial muscle groups as a possible pathogenic mechanism. RYR1 is a candidate for cases with “idiopathic” camptocormia or bent spine syndrome (BSS).     

Increased risk of median nerve dysfunction in floor cleaners: a controlled clinical and neurophysiological study

We studied median nerve involvement in a group of asymptomatic handworkers at risk for carpal tunnel syndrome, and we evaluated damage to thin and thick nerve fibres in the distribution area of the median nerve. Considering floor cleaners as workers at high risk of developing cumulative traumatic disorders in the wrist, we included 42 cleaners and 41 controls. We assessed nerve conduction studies, vibration threshold, and temperature and pain thresholds of the median nerve. The cleaners had significantly impaired motor nerve conduction velocity (p = 0.006), longer sensory distal latency (p = 0.01), lower sensory amplitude (p = 0.0005), and increased difference in heat and cold threshold of the median nerve (p = 0.0002). Increased temperature threshold was associated with prolonged sensory distal latency of the median nerve in the cleaners. In conclusion, impaired neurophysiological variables in the median nerve in floor cleaners compared with controls confirm the hypothesis that those workers are at risk of developing median nerve dysfunction. Sensory nerves seem to be more susceptible to injury than motor branches.