Welander distal myopathy : clinical and genetic studies

Abstract: Distal myopathies are a group of muscular disorders described in many countries with different inheritance patterns and variable progression rates. Welander distal myopathy (WDM) is characterised by autosomal dominant inheritance, late onset and distal distribution of muscular weakness. Most cases originate from the middle parts of Sweden. The hands are first affected with weakness of finger extensor muscles. In the lower extremity it is mainly the anterior tibial muscle that is affected. Cardiac involvement is never seen. Progression rate is very slow, anticipation is not detected and life-span is not shortened. Histopathological changes in muscle biopsies are mainly of myopathic type and include rimmed vacuoles. Neurophysiological findings are of both myopathic and neuropathic type. This thesis is based on the clinicopathologic and genetic studies of WDM. The clinical features of the disorder were analysed with patient examinations, quantitative sensory testing, histopathology, neurophysiology and magnetic resonance imaging of the musculature. The manifestations were shown to be not purely muscular, a neurogenic component was demonstrated to be an early phenomenon in WDM. This presents as a sensory dysfunction in the distal parts of upper and lower extremities. In early cases of WDM, muscle biopsies were normal and neurophysiological examination revealed a myopathic pattern in half of the subjects. The strict distal distribution in manifest and heterozygous cases was confirmed in with magnetic resonance imaging, where also affection of posterior muscle groups of the lower extremity was demonstrated. Distinct clinical and histological features distinguishes WDM from Miyoshi myopathy and the distal myopathy described by Laing. The histopathological observation of rimmed vacuoles corresponds to autophagic vacuoles with tubulo-filamentous inclusions at the ultrastructural level. Inclusions of the same type are found in hereditary inclusion body myopathy, distal myopathy with rimmed vacuoles described by Nonaka and in the Finnish tibial muscular dystrophy (TMD). TMD is phenotypically highly similar to WDM but has, together with the other myopathies with inclusion bodies, been demonstrated not to be allelic to WDM. A genome-wide linkage scan was performed in a Swedish material of 62 affected cases from nine families (a total of 122 family members included) and genetic linkage was demonstrated to chromosome 2p13 with a cumulative lod score of 17.97 for the marker D2S2113 at recombination fraction 0.0. Positive lod-scores were obtained for markers in a 12 cM region. Critical recombinations and identification of a common shared haplotype in all affected subjects have restricted the candidate region to 2.4 cM. With a positional candidate gene approach selected genes were screened for mutations, the best candidate being the dysferlin gene and muscle-specific ESTs in the 2pl3 region. The common shared haplotype makes it plausible that one single ancestor mutation is responsible for the gene-disruption in this myopathy. WDM was shown to have a high degree of clinical heterogeneity but a complete genetic homogeneity in Swedish cases. This variable clinical expression pattern is found both intra- and interfamilially, with symptoms ranging from slight, distal muscle weakness and sensory impairment to more severe with proximal muscle weakness without obvious correlation to the duration. A severe homozygous form with proximal muscle weakness and more rapid progression rate was identified clinically and highly supported genetically through inheritance of double haplotypes.