Résumé :
|
Myofibrillar myopathies (MFM) comprise sporadic and familial neuromuscular conditions of considerable clinical and genetic heterogeneity. Desmin-positive sarcoplasmic protein aggregates and signs of myofibrillar degeneration are the pathomorphological denominators of all MFM. While about half of all MFM are due to desmin, _Bcrystallin, myotilin, ZASP, filamin C, FHL1, VCP, BAG3, or plectin gene mutations, the other half of MFM are due to so far unidentified gene defects. In general, MFM-causing gene defects follow an autosomal-dominant mode of inheritance. Exceptions from this rule are MFM due to plectin (autosomal recessive) and FHL1 (X-linked) mutations, very rare cases of autosomal recessive desminopathies and a significant number of sporadic MFM.. The vast majority of patients have an adult onset of their progressive muscle symptoms. Desmin- and _B-crystallin-related MFM tend to manifest in early and middle adulthood, whereas disease onset beyond the forth decade of life is typical for myotilin-, ZASP-, VCP and filamin C-gene mutations and BAG3-, FHL1- and plectin-related MFM may manifest either in childhood, adolescence or adulthood. MFM are associated with marked clinical variability. Skeletal muscle weakness in the lower extremities is the most frequent initial clinical symptom. MFM may manifest with the phenotypic presentation of i) distal myopathy, ii) limb girdle muscular dystrophy, iii) scapuloperoneal syndrome, iv) isolated muscle group involvement or v) generalized myopathy. To date no causative or ameliorating therapy is available for this significant cohort of hereditary myopathies.. The precise molecular pathways leading from an individual gene defect to a mutually shared myopathological disease manifestation remain to be determined. This presentation will give an overview on clinical, myopathological and genetic aspects of myofibrillar myopathies with special focus on MFMs presenting with a distal myopathy phenotype. Furthermore, recent advances in the understanding of the pathophysiological mechanisms leading to desmin-positive protein aggregation in striated muscle will be discussed. For more detailed information please refer to:Schrder, R, Schoser B. Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathology 2009; 19:483-492.
|