LGMD1A AND MFM ASSOCIATED WITH THE MYOTILIN MUTATION S55F ARE CLINICALLY DIFFERENT AND PATHOLOGICALLY SIMILAR ENTITIES

ROSA AL; CONDE CB; TARATUTO AL; HAUSER MA

Nantes, Francia

Congreso; Myologie 2005; 2005

Association Francaise contre les Myopathies

Mutations in the gene encoding myotilin cause autosomal dominant limb-girdle muscular dystrophy type 1A (LGMD1A). Only two LGMD1A pedigrees, carrying the mutations T57I and S55F, have been recognized after extensive world-wide screening (1). We report here the first clinical and pathological study of the LGMD1A–S55F pedigree. Affected individuals have a late-onset slowly progressive proximal muscle weakness. CK levels are only mildly above the normal limit. Cardiomyopathy is present in older affected patients. Affected subjects have minor signs of peripheral neuropathy. Hypernasal speech is only recognized in two patients. Muscle scan studies show a selective asymmetrical wasting of the semimembranosus. Muscle pathology show focal sarcomere disorganization. No deficiencies are observed for dystrophin, a, ß, ?, d-sarcoglycans, a-2 laminin and desmin. Staining for dystrophin and desmin, however, shows focal immunoreactivity of abnormal deposits. Intense immunostaining of myotilin is observed in affected muscle. Western blot analyses, however, show similar levels of myotilin to that present in controls. Mutations in myotilin have recently been found in patients affected with myofibrillar myopathy (MFM). A patient with an autosomal dominant family history of MFM, with distal>proximal muscle weakness, carries the S55F mutation in myotilin (2). Thus, LGMD1A and MFM myotilinopaties associated with the mutation S55F are clinically different and pathologically similar. Interestingly, 5 out of 6 mutations found in myotilin and 3 out of 15 mutations found in desmin-associated MFMs occur in serines at the Nterminus of these proteins. This observation highlights the biological relevance of serines at the N-terminus of myotilin and desmin. The role of these serines in sarcomere structure or function has not been assigned. (1) Hauser et al. AJHG 2002 71,1428-32; (2) Selcen & Engel Neurology 2004 62:1363-71. Supported by grants from CONICET and ANPCyT (Argentina) and NIH/NINDS NS26630 and the Muscular Dystrophy Association (USA).