Summary: Onset of weakness is usually in the third decade and initially with distal weakness that may spread to proximal muscles or become generalized. Cardiac involvement may occur [See also cardioskeletal myopathy] . There is marked variation in severity and some patients may be almost asymptomatic. Pathologically they are characterized by cytoplasmic masses that are strongly immunoreactive for desmin.

Genetics: Many of these cases are familial and usually autosomal dominant; recessive pattern of inheritance has also been reported. Mutations have been demonstrated in desmin gene on chromosome 2q35 and also a-B crystalline (CRYAB) gene on chromosome 11q22.

Pathogenesis: The pathogenesis is uncertain. The accumulation of desmin may be a primary or secondary event. However, the accumulation of desmin in muscle and in cardiac muscle of some patients and accumulation of neurofilaments in peripheral nerve suggest that abnormalities in intermediate filaments or its regulatory processes may be central to the pathogenesis.

Clinical features:

· Age: Onset of muscular weakness is usually at the third decade but childhood onset may also be seen.

· Severity: Highly variable, some patients may be asymptomatic.

· Location: Onset of muscle weakness is usually distal in the early phase but may spread to proximal muscles in more severe cases.

· Cardiac involvement: The patients may have arrhythmias, restrictive or hypertrophic cardiomyopathy. Cardiac involvement may precede muscle weakness for years. [See also cardioskeletal myopathy]

· Others: Some patients may have peripheral neuropathy.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Fiber type: Type I fibers are predominantly affected.

Histochemistry: Four patterns may be seen.

· Pattern 1: Blue cytoplasmic masses that can be demonstrated in some biopsies by trichrome stain may be seen in subsarcolemmal areas or among the myofibrils. These masses are negative for routine enzyme reaction and have strong staining with antidesmin antibodies.

· Pattern 2: There is Z-disc streaming but no masses are demosntrable by trichrome stain. Numerous negative areas may be demonstrated by oxidative enzyme reactions. An accentuated intermyofibrillar network is seen by antidesmin antibody staining.

· Pattern 3: Cytoplasmic 10-20 mm oval or spherical inclusions (spheroid bodies) are present. These inclusions have intense staining for desmin on their periphery and contain fragments of myofibrils, often with a swirling pattern, along with some granular deposits.

· Pattern 4: This appears to be an advanced stage of pattern 3. There is distortion of most fibers by large abnormal areas with a variety of substructure, ranging from vacuolar to granular to hyaline; they are strongly positive for desmin except in the hyaline areas. The hyaline areas contain a large amount of actin and other myofibrillar proteins. Other proteins also accumulate in these fibers. Rimmed vacuoles may be present.

Semithin sections: This may not be very helpful since the desmin accumulation may not be easily distinguished from Z-disc streaming that is often seen in desminopathy.

Electron microscopy: Characteristic lesions are seen in earlier lesions.

· Accumulation of dense granular material: Dense anatomosing and trabeculated granular material that is about 100 nm in diameter is accumulated in between myofibrils or under the sarcolemma. The Z-disc streaming may appear contiguous to the granular deposits.

· Spheroid bodies: They are cytoplasmic bodies with a dense core and radiating actin filaments.

· Membranous whorls are sometimes present.

Peripheral neuropathy: Enlarged myelinated fibers filled with neurofilaments. Non-myelinated fibers and Schwanncells do not have increase in intermediate filament; a feature that distinguish them from giant axon neuropathy.

Cardiac cells: There are large aggregates of intermediate filaments without granular deposits.