Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.

Mitochondrial dysfunction reduces aerobic energy production and results in symptoms from various tissues, depending on metabolic demands. Mitochondrial adenosine triphosphate (ATP) is essential for sperm motility. Sperm motility was investigated in a patient with a mitochondrial disease caused by reduced activity of the mitochondrial enzyme complexes I and IV, and in two control subjects. Spermatozoa were cultured in media containing various energy substrates. Motility was judged by light microscopy, and ultrastructure by transmission electron microscopy. In the patient with mitochondrial disease, 12% of the spermatozoa were motile in the medium containing only glucose. There was a three-fold increase in motile spermatozoa when pyruvate and succinate were present together with glucose. In contrast, the spermatozoa of both control subjects had best motility in the presence of substrates for complex I, and no further increase was observed when succinate was added. Glucose and pyruvate enter the respiratory chain at complex I, and succinate at complex II. Electron microscopy of spermatozoa from the patient with mitochondrial disease revealed mitochondria with increased matrix, thickening of membranes, parallelization of cristae and lipid inclusions, which are characteristic findings in mitochondrial disorders. Abnormal mitochondria were also found in a spermatid, suggesting that the ultrastructural changes of mitochondria are primary rather than secondary to degeneration of the spermatozoa. The results indicate that mitochondrial dysfunction causes reduced sperm motility in some men.

Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C4T) were novel while the others (IVS1+3A4T, 979G4A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita. European Journal of Human Genetics (2001) 9, 903 ± 909.

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3 Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations.

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