Association between muscle strength, histopathology, and magnetic resonance imaging in sporadic inclusion body myositis.

OBJECTIVES: Inclusion body myositis is characterized by inflammatory and degenerative changes, but the temporal relation of these events is unknown. MATERIALS AND METHODS: In nineteen patients with inclusion body myositis, muscle strength was correlated with inflammatory and degenerative findings on magnetic resonance imaging (MRI) and in muscle biopsies in three different muscles (tibialis anterior, vastus lateralis, and biceps brachii). Muscle strength, measured with a handheld dynamometer, was described as percentage of muscle strength in age- and sex-matched normal individuals. The muscles were categorized as the strongest, the intermediate, and the weakest muscle in each individual. T1-weighted sequences on MRI were used to evaluate the degree of fatty infiltration and muscle atrophy and STIR sequences to evaluate edematous changes. RESULTS: The vastus lateralis, which in general was the weakest muscle, was significantly more atrophic compared to the other two muscles and also demonstrated most edema. The biceps brachii had in most cases an intermediate degree of weakness and atrophy but the most pronounced inflammatory cell infiltration on biopsy. Cytochrome c oxidase-negative muscle fibers were significantly more prevalent in the vastus lateralis and biceps brachii muscles than in the tibialis anterior and thus correlated with muscular atrophy, indicating that this is a secondary change. Inflammatory changes as assessed by MRI and muscle biopsy were seen in all muscles irrespective of atrophy and thus appear to be prevalent at all stages of the disease. CONCLUSIONS: Our study could not provide an answer to the question which comes first, the inflammation or the degenerative changes.

A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.

Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation screening. In this investigation, we report 37 individuals (age range: 21-85 years, 21 females and 16 males) from 10 families in whom only one mutation in CAPN3 could be identified; a 21-bp, in-frame deletion (c.643_663del21). This mutation co-segregated with evidence of muscle disease and autosomal dominant transmission in several generations. Evidence of muscle disease was indicated by muscle pain, muscle weakness and wasting, significant fat replacement of muscles on imaging, myopathic changes on muscle biopsy and loss of calpain 3 protein on western blotting. Thirty-one of 34 patients had elevated creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did not affect mRNA maturation. Calpain 3 expression in muscle, assessed by western blot, was below 15% of normal levels in the nine mutation carriers in whom this could be tested. Haplotype analysis in four families from three different countries suggests that the 21-bp deletion is a founder mutation. This study provides strong evidence that heterozygosity for the c.643_663del21 deletion in CAPN3 results in a dominantly inherited muscle disease. The normal expression of mutated mRNA and the severe loss of calpain 3 on western blotting, suggest a dominant negative effect with a loss-of-function mechanism affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings in 10 families, our study indicates that a dominantly inherited pattern of calpainopathy exists, and should be considered in the diagnostic work-up and genetic counselling of patients with calpainopathy and single-allele aberrations in CAPN3.