Hereditary Inclusion Body Myopathies

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BACKGROUND AND CLINICAL INFORMATION: Head  

Summary: Hereditary inclusion body myopathies are a heterogeneous group of disease that could be transmitted in an autosomal dominant or recessive fashion. Clinically, they affect primarily limb muscles and adolescenece or early adulthood onset. Some subtypes have late onset in the 5^th decades. Histologically, their histological features are almost identical to that of inclusion body myositis except that there is no inflammation. The salient diagnostic feature is 15 to 21 nm tubular filamentous inclusions.

Diagnostic criteria:

·         Primarily limb muscle weakness (ophthalmoplegia or facial weakness are possible)

·         Onset in adolescence or early adulthood (early and late onset may occur)

·         At least 2 affected members in the same family (typically phenotype in a known ethnic cluster suffices).

·         Presence of rimmed vacuoles and 15 to 21 nm tubular filamentous inclusions.

·         No inflammation.

Behavior: Heterogeneous among different subtypes but most commonly they are slowly progressibe.

Age: Except for some subtypes, most of them have onset in adolescence or early adulthood. Childhood onset and late onset (5^th decade) can be seen in some subtypes.

Incidence: Rare.

Location: The limb mucles are most commonly affected. Some of the subtypes may be present as quadriceps-sparing myopathy or affecting the oculopharyngodistal myopathy.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

General: Other than no inflammation, the histology is very similar if not identical to inclusion body myositis. Typically, there are vacuolated fibers, endomysial fibrosis, and a variable degree of neurogenic atrophy.

Vacuoles: Rimmed vacuoles are typically seen in frozen sections and they range from 2-25 mm. Both type I and type II fibers are affected. On paraffin sections, the content of the vacuoles dissolves away and only empty vacuoles are present. The vacuoles are often found in subsarcolemmal locations and sometimes the center of the fibers. The number of vacuolated fibers varies from a few to up to 70% of the fibers. Small refractive eosinophilic bodies are often seen in the cytoplasm near the vacuoles.

Immunohistochemistry: The content of the vacuoles are reactive for an antibody (SM-31) that recognize phosphorylated high molecular weight neurofilament proteins and interestingly these antibodies also cross react with hyperphosphorylated tau. Similar to the rimmed vacuoles in inclusion body myositis, accumulation of cellular prion protein and several proteins that are characteristically seen in Alzheimer’s disease brain such as beta-amyloid, a-synuclein have also been documented.

Electron microscopy:

·         Filamentous inclusions: Cytoplasmic, and sometime myonuclear, collections of 15 to 21 nm tubular filaments. These filaments are randomly dispersed, but sometimes run parallel to one another and they are believed to be made of paired helical filaments. The filamentous inclusions are typically present near the vacuoles. Diagnostic criteria: A minmum of 3 vacuolated fibers must be examined.

Others: Concentric “myeloid bodies”, cytoplasmic debris, cytoplasmic inclusion bodies, and occasional abnormal mitochondria.

DIFFERENTIAL DIAGNOSIS: Head  

Inclusion body myositis: They have adult onset and inflammation.

Argov Z, Eisenberg I, Mitrani-Rosenbaum S. Genetics of inclusion body myopathies. Curr Opin Rheumatol. 1998 Nov;10(6):543-7.