Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%. A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. Peripheral neuropathy is present in about 20% of affected individuals. Overt cardiomyopathy is present in 15%-30%.

Diagnosis/testing: The diagnosis of myofibrillar myopathy is based on clinical findings, electromyography (EMG), nerve conduction studies, and, most importantly, muscle histology. To date, the genetic basis of myofibrillar myopathy has been elucidated in only about 50% of cases. Pathogenic variants have been identified in DES, the gene encoding desmin; CRYAB, encoding alpha-crystallin B chain; MYOT, encoding myotilin; LDB3 (ZASP), encoding LIM domain-binding protein 3; FLNC, encoding filamin-C, and BAG3, encoding BAG family molecular chaperone regulator 3. Recently, pathogenic variants in FHL1, encoding four and a half LIM domains protein 1, and DNAJB6, encoding DnaJ homolog subfamily B member 6 were also identified.

Management: Treatment of manifestations: Consider pacemaker and implantable cardioverter defibrillator (ICD) in individuals with arrhythmia and/or cardiac conduction defects; consider cardiac transplantation in individuals with progressive or life-threatening cardiomyopathy; respiratory support (continuous or bilevel positive airway pressure), initially at night and later in the daytime, in individuals with hypercapnea and other signs of incipient respiratory failure; range-of-motion physical therapy and assistive devices for those with advanced muscle weakness.

Other: The role of strengthening exercises has not been defined.

Genetic counseling: Myofibrillar myopathy is most commonly inherited in an autosomal dominant manner. Exceptions include: X-linked inheritance of FHL1 pathogenic variants and autosomal recessive inheritance of CRYAB pathogenic frameshift variants that lead to premature termination of the translational chain resulting in non-transcription of the mutated protein. The inheritance in some families cannot be determined with confidence. When the pathogenic variant(s) in the family are known, carrier testing and prenatal testing for pregnancies at increased risk is possible.