Résumé :
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Myofibrillar myopathies (MFMs) are rare inherited or sporadic progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. To date, mutations in five genes are known to cause MFM. These genes encode desmin, ?B-crystallin, myotilin, Z-band alternatively spliced PDZ motif containing protein (ZASP), and filamin C. Although clinical observations can provide clues, the overlap in clinical phenotypes associated with the known genes often makes an accurate prediction of the causative gene difficult. Furthermore, the histopathological results and the findings by current immunohistochemical stainings cannot differentiate between the distinct genetic causes. We studied the ultrastructural characteristics in patients with MFM, and differentiated between the MFM subtypes using electron microscopic findings. We analyzed the ultrastructural data in 18 patients with different genetically-proven MFMs, including 8 patients with mutations in desmin, 5 patients with ?B-crystallin mutations, 3 patients with ZASP mutations and 2 patients with mutations in myotilin. In one patient with a ZASP mutation, we additionally performed an immunoelectron microscopic (EM) study, using antibodies against desmin, ?B-crystallin, ZASP and myotilin. The ultrastructural findings in desminopathies and ?B-crystallinopathies were very similar and consisted of electrondense granulofilamentous accumulations and sandwich formations. They differed in the presence of early apoptotic nuclear changes in ?B-crystallinopathies. ZASPopathies were characterized by floccular accumulations of thin filamentous material, and filamentous bundles, which were labeled with the myotilin antibody on immunoEM. The presence of tubulofilamentous inclusions with a diameter of 15-18 nm in the sarcoplasm and in some myonuclei in combination with filamentous bundles were characteristic for myotilinopathies. We conclude that MFMs ultrastructural findings can direct diagnostic efforts towards the causal gene mutated, and that electron microscopy should be included in the diagnostic workup of MFMs.
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