Qualitative or quantitative defects of myofibrillar proteins

Qualitative or quantitative defects of myofibrillar proteins is a broad category of rare genetic muscle disorders, also known as myofibrillar myopathies (MFM). These conditions are characterized by the progressive disintegration of myofibrils — the contractile units of skeletal and cardiac muscle — and the abnormal accumulation of degraded myofibrillar proteins within muscle fibers. The primary body systems affected include skeletal muscle, the heart, and in some cases the peripheral nervous system. Clinically, patients typically present with progressive muscle weakness, which may begin in the distal limbs (hands and feet) or proximal limbs depending on the specific genetic subtype. Cardiomyopathy (both dilated and hypertrophic forms) and cardiac conduction defects are common and can be life-threatening. Peripheral neuropathy and respiratory insufficiency may also develop over time. Muscle biopsy characteristically shows amorphous or granular deposits that stain positive for desmin, alphaB-crystallin, myotilin, and other sarcomeric proteins. Multiple genes have been implicated in myofibrillar myopathies, including DES (desmin), CRYAB (alphaB-crystallin), MYOT (myotilin), ZASP/LDB3, FLNC (filamin C), BAG3, FHL1, and TTN (titin), among others. The age of onset and severity vary considerably depending on the causative gene and specific mutation. There is currently no curative treatment. Management is supportive and includes physical therapy, cardiac monitoring and treatment of arrhythmias or heart failure, respiratory support when needed, and genetic counseling for affected families.

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