Myofibrillar myopathy types 1, 2, 3, 4, 5 and 6 (Myofibrillar myopathy types 1, 2, 3, 4, 5 and 6) - Genes DES, Myot (= TTID), LDB3, CRYAB, CNLF and BAG3.  

Myofibrillar myopathies are a group of disorders, also known as muscular dystrophies, affecting muscle function and cause weakness. The disease mainly affects skeletal muscles. In some cases, the heart muscle is also affected.

Signs and symptoms of myofibrillar myopathy vary widely among affected individuals, usually depending on the genetic cause of the disease. Although the characteristics of the disease can occur at any time between childhood and late adulthood, most of those affected begin to develop myopathy in mid-adulthood. More often, muscle weakness begins in the distal muscles of the hands and feet, but some people manifest in the proximal muscles. Other individuals the manifest anywhere in the body. The involvement of the facial muscles can affect swallowing and speech. Other signs and symptoms may include cardiomyopathy, myalgia, peripheral neuropathy, respiratory failure and bone problems, including contractures and scoliosis. Rarely, affected people develop cataracts.

Myofibrillar myopathy are due to mutations in the DES, CRYAB, Myot LDB3, CNLF and BAG3 genes.

Mutations in genes DES, located on the long arm of chromosome 2 (2q35), Myot located on the long arm of chromosome 5 (5q31) and LDB3 located on the long arm of chromosome 10 (10q22.3 - q23.2 ) they are responsible for most cases. These genes encode proteins desmin, myotilin and LIM domain binding 3, respectively, which play an important role in muscle fibers. Inside muscle fibers, these proteins are involved in the sarcomeres, necessary for the muscles to contract. These proteins are active in the internal structures of the sarcomere called Z disks, each connecting neighboring sarcomeres to form myofibers, the basic unit of muscle fibers. Linking sarcomeres and forming myofibrils provide resistance to muscle fibers for muscle contraction and relaxation, repeated.

Have identified more than 40 mutations in the DES gene, at least five mutations in the Myot gene and 3 mutations LDB3 gene, causing types of myofibrillar myopathy 1 (MFm1), 3 (MFM3) and 4 (MFM4), respectively. These mutations change amino acids in the protein, causing the protein is grouped together with other muscle proteins in the sarcomere forming aggregates. Aggregates keep protein interacts correctly on disks, resulting in abnormalities sarcomere structure and problems with the formation of myofibrils. People with mutations in the DES gene are more likely to have cardiomyopathy, compared to those whose disease is due to mutations in other genes.

The CRYAB gene, located on the long arm of chromosome 11 (11q22.3-q23.1), encodes a protein called alpha-B crystalline. This protein may have an important role to prevent the formation of intermediate filaments, in which formation mechanism involved other proteins such as desmin. Mutations in the gene CRYAB, give rise to type 2 myofibrillar myopathy (MFM2). Mutations in this gene cause in adulthood progressive muscle weakness of the proximal muscles and muscles of the distal limbs and weakness of the muscles associated with respiratory failure, hypertrophic cardiomyopathy and cataracts.

The CNLF gene, located on the long arm of chromosome 7 (7q32-q35), encoding one of three related filaminas, specifically gamma filamin protein. These proteins crisscross actin filaments in orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins to the actin cytoskeleton. There are three functional domains in filamin: an N-terminal domain of filamentous actin binding domain C-terminal self - association and a binding domain to the membrane glycoprotein. Found in this gene transcription two variants encoding different isoforms. Mutations in the gene result CNLF myofibrillar myopathy the type 4 (MFM4) myofibrillar myopathy and type 5 (MFM5). Signs and symptoms of these types of the disease appear in adulthood and cause focal myofibrillar destruction, pathological aggregation of cytoplasmic proteins and clinical features of myopathy bone ring.

The BAG3 gene, located on the long arm of chromosome 10 (10q25.2-q26.2), encodes a protein with antiapoptotic function BAG located in the sarcomeric Z disc. Mutations in the BAG3 gene, resulting in myofibrillar myopathy the type 6 (MFM6). These mutations result in atrophic fibers, focal myofibrillar disorganization, sarcoplasmic accumulation of electrondense material granulofilamentoso myofibrillar degeneration with minicentres. In general, the signs and symptoms of type 6 myofibrillar myopathy appear in the first decade of life and include generalized weakness and muscle proximal rapidly progressive respiratory failure, cardiomyopathy and skeletal abnormalities related to muscular weakness. Most people affected with type 6 disease are severely injured in the second decade and need a heart transplant, mechanical ventilation and / or use wheelchairs.

Myofibrillar myopathy inherited the with an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to cause the alteration. In some cases, an affected person inherits the mutation from an affected parent. Other cases result from new mutations in the gene and occur in people with no history of disease in your family.  

Tests in IVAMI: in IVAMI perform the detection of mutations associated with myofibrillar myopathy types 1, 2, 3, 4, 5 and 6, by complete PCR amplification of the exons of the DES, Myot LDB3, CRYAB genes, CNLF and BAG3, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).