Myofibrillar myopathy

Clinical features

Myofibrillar myopathies (MFM) are group of neuromuscular diseases characterized by slowly progressive weakness that can involve both proximal and distal muscles. MFM primarily affects skeletal muscles and in some cases cardiac muscle. The signs and symptoms of MFM vary widely among affected individuals, typically depending on the genetic cause. Most people with this disorder begin to develop muscle weakness in mid-adulthood.

Myofibrillar myopathy includes following disorders:

• Alpha-B crystallinopathy, associated with pathogenic variants in the CRYAB gene, encoding α-crystallin B chain ²
• BAG3-related myofibrillar myopathy, associated with pathogenic variants in BAG3, encoding BAG family molecular chaperone regulator 3 ³
• Desminopathy, caused by mutations in DES, encoding desmin ⁴
• DNAJB6-related myofibrillar myopathy caused by mutations in DNAJB6, encoding DnaJ homolog subfamily B member 6 (heat shock protein 40) ⁵
• FHL1-related myofibrillar myopathy caused by mutations in FLH1, encoding four and a half LIM containing protein 1 ⁶
• Filaminopathy caused by mutations in FLCN, encoding filamin-C ⁷
• Myotilinopathy associated with pathogenic variants in MYOT, encoding myotilin ⁸
• Zaspopathy caused by mutations in LDB3 (ZASP) encoding LIM domain-binding protein 3 ⁹

The diagnosis of myofibrillar myopathy is based on the following signs and symptoms:

• History of slowly progressive weakness accompanied by paresthesia, muscle atrophy, stiffness or aching, cramps, dyspnea, and dysphagia. The majority of affected individuals show proximal and distal weakness. Facial weakness is uncommon, while tendon reflexes are usually normal.
• Electromyography (EMG) shows abnormal electrical irritability, including fibrillation potentials, complex repetitive discharges, and myotonic discharges.
• Abnormal nerve conduction studies are detected in about 20% of individuals ¹.

Histological analysis of muscle samples reveals characteristic changes in almost all myofibrillar myopathy-affected patients:

• Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers
• Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions
• Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics
• Presence of small vacuoles in affected fibers
• Abnormal ectopic expression of myotilin (90% of abnormal fibers), desmin (75%), α-B crystallin (75%), dystrophin (70%), and β-amyloid precursor protein (70%)
• Progressive myofibrillar degeneration commencing at the Z-disk, disintegration of sarcomeres, high number of pleomorphic hyaline inclusions and autophagic vacuoles.

Peripheral nerve biopsies show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids. Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis. Serum creatine kinase concentration can be normal or elevated to no greater than seven times the upper normal limit.

Because myofibrillar myopathy is caused by mutations in any of eight different genes (BAG3, CRYAB, DES, DNAJB6, FHL1, FLNC, LDB3, MYOT; see table) and each disease-associated gene may have different types of mutations, the molecular pathogenesis may be highly variable. The initial pathologic change in myofibrillar myopathy involves disintegration of the Z-disk in muscle cells, and all disease proteins identified to date are involved in maintaining the structural integrity of the Z-disk. Because the Z-disks are sites of tension transmission between sarcomeres, the myofibrils fall apart when the Z-disks disintegrate.

Treatment for patients affected with myofibrillar myopathy commonly includes supportive therapies, including pacemakers and implantable cardioverter defibrillators in individuals with arrhythmia and/or cardiac conduction defects. Cardiac transplantation could be considered in individuals with life-threatening cardiomyopathy, and respiratory support could be applied in individuals with respiratory failure.

CENTOGENE offers sequencing and deletion/duplication analysis for the Myofibrillar myopathy panel (genes: BAG3, CRYAB, DES, DNAJB6, FHL1, FLNC, LDB3, MYOT).

The differential diagnosis of myofibrillar myopathy-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

• Myotonic dystrophy type 1 (DM1) caused by expansion of a CTG trinucleotide repeat in DMPK
• Myotonic dystrophy type 2 (DM2) caused by a complex repeat expansion (TG)n(TCTG)n(CCTG)n in ZNF9 (CNBP)
• Inclusion body myopathy type 2 (IBM2) caused by mutations in GNE
• Dysferlinopathy, caused by mutations in DYSF
• Other muscular dystrophies including tibial muscular dystrophy (Udd distal myopathy), telethoninopathy, Laing distal myopathy, facioscapulohumeral dystrophy and others.

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for myofibrillar myopathy using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Myofibrillar myopathy panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the myofibrillar myopathy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.

The following individuals are candidates for myofibrillar myopathy testing:

• Individuals with a family history of myofibrillar myopathy and presentation of the most common symptoms
• Individuals without a positive family history, but with symptoms resembling myofibrillar myopathy
• Individuals with a negative but suspected family history of myofibrillar myopathy, in order to perform proper genetic counseling.

Sequencing, deletion/duplication of the panel genes should be performed in all individuals suspected of having myofibrillar myopathy and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the myofibrillar myopathy and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.

More information on CENTOGENE´s Myofibrillar myopathy panel can be found in our genetic test catalogue.