myotilinrelated

Myotilinrelated refers to diseases associated with variants in the MYOT gene, which encodes the sarcomeric protein myotilin. This term encompasses a spectrum of muscle disorders collectively known as myotilinopathy, including distal myopathy and myofibrillar myopathy, characterized by muscle weakness and structural abnormalities of muscle fibers.

Myotilin is a Z-disk–associated protein expressed in skeletal muscle and, to a lesser extent, cardiac muscle. It contains two immunoglobulin-like domains and participates in Z-disc integrity by binding actin filaments and other Z-disc components, contributing to sarcomere assembly and stability. Through these interactions, myotilin helps maintain proper sarcomere structure during muscle contraction.

Pathogenic MYOT variants—often missense, truncating, or splice-site mutations—are thought to disrupt myotilin's structure or interactions, promoting misfolding and aggregation that disturb sarcomere organization and promote fiber degeneration. The disease shows variable penetrance and age of onset, with a range of clinical presentations.

Clinical features commonly include distal weakness, particularly affecting ankle dorsiflexion, with variable proximal involvement and scapuloperoneal distribution. Onset typically occurs in adolescence or adulthood. Muscle histology may reveal myofibrillar disarray, ragged-red fibers, and rimmed vacuoles; immunostaining can show myotilin-containing inclusions. Diagnosis relies on clinical evaluation, muscle biopsy findings, and genetic testing that confirms MYOT variants, with family history providing supporting context.

There is no disease-modifying cure; management focuses on supportive care, including physical therapy, orthotic devices for contractures, and monitoring for potential cardiac involvement in certain cases. Genetic counseling is often recommended. Ongoing research aims to clarify genotype-phenotype relationships, pathogenic mechanisms, and potential targeted therapies for myotilinrelated conditions.