[Familial myopathy with desmin storage seen as a granulo-filamentar, electron-dense material without mutation of the alphabeta-crystallin gene].

Background: Desmin-related myopathy is a familial myopathy and cardiomyopathy. Three subgroups have been outlined, an autosomal dominant (AD) granulofilamentous type with cardiomyopathy, an AD cytoplasmic/spheroid inclusion body type and an autosomic recessive Mallory body-like inclusion type. Recently, in one family belonging to the first group it has been identified a mutation within a gene coding for a chaperone protein, alphabeta-crystallin (CRYAB gene).

Objective: To describe a Spanish family with a desmin-related myopathy, an AD granulofilamentous type with cardiomyopathy, with a molecular study that does not express any point mutation in the CRYAB gene.

Patients, Methods And Results: This report concerns a family from southern Spain in which 2 sisters (37 and 44 and 36 years old respectively) present an involvement of skeletal (distal more than proximal) and velo-pharyngeal muscles with onset at the third decade of life and with a rather severe progression, leading soon to bilateral foot drops. The mode of transmission is autosomal dominant. Two other members, the mother and one brother _the latter with hypertrophic cardiomyopathy, atrioventricular block and severe heart failure_, have already died. The electrophysiological study carried out in the sisters shows myogenic patterns with abundant spontaneous activity but not genuine myotonic discharges. Muscle biopsy, also purchased in both sisters, shows myopathic changes, a few rimmed vacuoles in one of them, and several "rubbed-out" fibers or fibers "effacées" visible within the intramyofibrilary network on the enzymatic stainings. The ultrastructural findings in both biopsies reveal a similar pattern of structural damage: an intrasarcoplasmic (specially subsarcolemmal) accumulation of an electro-dense filamentous material arising from the Z-bands and a focal disruption of the myofibrils. Immunohistochemically the subsarcolemmal material stained positively for the intermediate filament protein desmin but other proteins as ubiquitin, tropomyosine and actin were found overexpressed. Genetic studies have excluded myotonic dystrophy, any point mutation in the CRYAB gene, and different markers failled to express linkage to any loci on chromosome 12. The possible mutations in desmin gene are to be studied.

Conclusion: The distinct intrafamilial phenotype observed in this family confirms the multisystemic character of the desmin-related myopathyies. The genetic results also support the genetic heterogeneity of these myopathies and reinforce the concept that mutations in the desmin gene must be investigated as a cause of the disease.