Hereditary proximal myopathy with early respiratory failure
General Information (adopted from Orphanet):
Synonyms, Signs:
ADMERF
HIBM-ERF
MPRM
HMERF
Hereditary inclusion body myopathy with early respiratory failure
Edstrom Myopathy
Myofibrillar myopathy with early respiratory failure
Myopathy, proximal, with early Respiratory Muscle Involvement
Edström Myopathy
Edstrom et al. (1990) described 16 individuals, from 7 families, who had autosomal dominant, adult-onset myopathy with early respiratory muscle involvement. All patients showed proximal weakness of the upper and lower extremities. In many patients, the respiratory muscles, ... Edstrom et al. (1990) described 16 individuals, from 7 families, who had autosomal dominant, adult-onset myopathy with early respiratory muscle involvement. All patients showed proximal weakness of the upper and lower extremities. In many patients, the respiratory muscles, especially the diaphragm, were involved. Neck flexors were typically affected, and foot extensor weakness was also present in some patients. The age at onset of significant symptoms varied from the second to the fifth decade, with an average age of approximately 35 years. The creatine kinase (CK) levels were normal or slightly elevated in all cases. Typical muscle biopsy samples showed, at the light microscopic level, cytoplasmic bodies that were highly positive for rhodamine-conjugated phalloidin. Rhodamine-conjugated phalloidin selectively binds to F-actin. At the ultrastructural level, these bodies were seen to be composed of thin filaments and dense material related to the Z discs.
Nicolao et al. (1999) considered the titin gene (TTN; 188840) to be a strong candidate. Titin, or connectin, is the largest polypeptide known and forms filaments that span from the Z discs to the M lines. The entire ... Nicolao et al. (1999) considered the titin gene (TTN; 188840) to be a strong candidate. Titin, or connectin, is the largest polypeptide known and forms filaments that span from the Z discs to the M lines. The entire coding region of the gene (approximately 300 kb) maps within the candidate region demonstrated by Nicolao et al. (1999) for Edstrom myopathy. In the 2 Swedish families described by Nicolao et al. (1999) as well as in 1 additional Swedish patient with an identical phenotype, Lange et al. (2005) identified a C-to-T transition resulting in an arginine-to-tryptophan substitution at codon 279 of the titin gene (R279W; 188840.0011), which lies within alpha helix R1 (alpha-R1) of the protein kinase domain. The single patient had no known genealogic relationship to any of the 2 original families but had the same mutation on the same haplotype, indicating a common ancestry. Lange et al. (2005) found no difference in calmodulin (114180)-stimulated catalytic activity between recombinant R279W mutant titin kinase domain (TK) and wildtype. Because the R279W mutation in alpha-R1 results in a drastic change of a surface-exposed basic to a nonpolar, bulky amino acid in the NBR1 (166945) binding site, Lange et al. (2005) tested the interaction of TK with NBR1, which was dramatically reduced in the mutant protein kinase domain. In patient biopsies, NBR1 was localized abnormally diffusely in diseased muscle instead of being M band- and Z disc-associated, although in HMERF 50% of TK was expected to be wildtype. P62 (601530) accumulated in many diseased muscle fibers of HMERF patients. MURF2 (606469) showed unusual nuclear localization in centralized nuclei of patient muscle fibers not observed in peripheral nuclei of normal muscle or in 3 other myopathies with centralized nuclei (DMD, 310200; tibial muscular dystrophy, 600334; and myotubular myopathy, 310400). Furthermore, MURF1 (606131), a close homolog of MURF2, did not show nuclear localization in HMERF patients or in the other myopathies tested with centralized nuclei.