Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations.
Desmin myopathy is a familial or sporadic disorder characterized by the presence of desmin mutations that cause skeletal muscle weakness associated with cardiac conduction block, arrhythmia and heart failure. Distinctive histopathologic features include intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates in skeletal and cardiac muscle cells. We describe two families with features of adult-onset slowly progressive skeletal myopathy without cardiomyopathy. N342D point mutation was present in the desmin helical rod domain in patients of family 1, and I451M mutation was found in the non-helical tail domain in patients of family 2. Of interest, the same I451M mutation has previously been reported in patients with cardiomyopathy and no signs of skeletal myopathy. Some carriers of the I451M mutation did not develop any disease, suggesting incomplete penetrance. Expression studies demonstrated inability of the N342D mutant desmin to form cellular filamentous network, confirming the pathogenic role of this mutation, but the network was not affected by the tail-domain I451M mutation. Progressive skeletal myopathy is a rare phenotypic variant of desmin myopathy allelic to the more frequent cardio-skeletal form.
Dalakas
Marinos C
MC
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 4B37, 10 Central Drive, MSC 1361, Bethesda, MD 20892, USA.
Dagvadorj
Ayush
A
Goudeau
Bertrand
B
Park
Kye-Yoon
KY
Takeda
Kazuyo
K
Simon-Casteras
Monique
M
Vasconcelos
Olavo
O
Sambuughin
Nyamkhishig
N
Shatunov
Alexey
A
Nagle
James W
JW
Sivakumar
Kumaraswamy
K
Vicart
Patrick
P
Goldfarb
Lev G
LG
D000409:Alanine / Q000235:genetics; D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D002460:Cell Line; D003545:Cysteine / Q000235:genetics; D004252:DNA Mutational Analysis; D003893:Desmin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D014162:Transfection / Q000379:methods
D003893:Desmin; D008715:Methionine; D003545:Cysteine; D000409:Alanine; D005998:Glycine