Mitochondrial changes, including COX-deficient fibers (n = 8), biochemical activities of respiratory chain complexes (n = 7), and multiple mtDNA deletions by long-range PCR (n = 9) were examined in patients with genetically confirmed MFMs [MYOT (n = 2), DES (n = 1), ZASP (n = 2), FLNC (n = 4)] and compared with age and sex matched normal controls (n = 27) and patients with a mitochondrial disorder with multiple mtDNA deletions due to nuclear genetic defects (n = 8).
Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy.
In addition, the expressed S60C mutant myotilin protein displayed marked detergent insolubility in electroporated mouse muscle, similar to that observed in human MFM muscle with the same mutation.
Mutations in MYOT were the predominant cause of MFM in Spain affecting 18 of 35 families, followed by DES in 11 and ZASP in 3; in 3 families the cause of MFM remains undetermined.
Immunohistochemistry showed that in MFM only a subset of Z-disc proteins, such as filamin C and its ligands myotilin and Xin, exhibited significant alterations in their localization, whereas other Z-disc proteins like alpha-actinin, myopodin and tritopodin, did not.
The most important recent advance in the myofibrillar myopathies has been the discovery that mutations in Z band alternatively spliced PDZ-containing protein and filamin C, as well as in desmin, alphaB-crystallin and myotilin, result in similar pathologic alterations in skeletal muscle that are typical of myofibrillar myopathy.
Recent findings, however, have indicated that patients affected with myofibrillar myopathy have a more distal than proximal muscle phenotype and a proportion of these may have mutations in myotilin, ZASP or filamin C, besides previously known desmin and alphaB-crystallin.
Similar to LGMD1A and MFM patients, these mice develop progressive myofibrillar pathology that includes Z-disc streaming, excess myofibrillar vacuolization and plaque-like myofibrillar aggregation.
Expression of mutant myotilin leads to sarcomeric alterations in the dominantly inherited limb-girdle muscular dystrophy 1A and in myofibrillar myopathy/desmin-related myopathy.
The essential role of myotilin in skeletal muscle is attested by the observation that certain forms of myofibrillar myopathy and limb girdle muscular dystrophy are caused by mutations in the human myotilin gene.
Mutations in myotilin gene (MYOT) have been associated with variable syndromes including limb girdle muscular dystrophy type 1A (LGMD1A) and a subgroup of myofibrillar myopathy (MFM/MYOT).
Recent findings include: the beginnings of an understanding of the role of the sarcomere in controlling muscle gene expression; the theoretical analysis of the increasing number of mutations identified in the skeletal muscle actin gene; the identification of mutations in myosin causing hereditary inclusion body myopathy and hyaline body myopathy and the identification of mutations in myotilin in myofibrillar myopathy.
The authors detected four missense mutations in 6 of 57 patients with MFM in the serine-rich exon 2 of MYOT, where the two previously identified LGMD1A mutations are located.