NORD is very grateful to Anne M. Connolly, MD, Professor Neurology and Pediatrics, Department of Neurology, Washington University School of Medicine, for assistance in the preparation of this report.
Synonyms of Myopathy, Myofibrillar
- No synonyms found.
- alpha-B crystallinopathy
- BAG3-related myofibrillar myopathy
Myofibrillar myopathies are a group of rare genetic neuromuscular disorders that may be diagnosed in childhood but most often appear after 40 years of age. These conditions are highly variable but are characterized by a slowly progressive muscle weakness that can involve skeletal and smooth muscle. Skeletal muscle weakness can be present in the muscles close to the center of the body (proximal) as well as the distal muscles. A weakening of the heart muscle (cardiomyopathy) is common and may manifest as arrhythmia, conduction defects or congestive heart failure.
Most affected individuals with mofibrillar myopathy secondary to desmin mutations present with a slowly progressive muscle weakness. Distal muscle weakness is more common than proximal weakness but variable presentation within the same family occurs. Some also have muscle stiffness, aching, cramps or decreased muscle mass (atrophy). Pain, loss of sensation and inability to control muscles may also occur in one form (Filamin C protein mutations). Cardiomyopathy is sometimes the presenting symptom and may manifest as arrhythmia, conduction defects or congestive heart failure.
Children with desminopthies may present with cardiomyopathy. Children with BAG3-related myofibrillar myopathies may present in the first or second decade with proximal weakness, respiratory failure and restrictive cardiomyopathy and are frequently rapidly progressive and fatal.
Myofibrillar myopathies are usually inherited as adult autosomal dominant genetic conditions though children with recessive presentation of Desmin mutation do occur and in this case presentation can be in early childhood. It is not always possible to determine the mode of inheritance in families because some mildly affected individuals remain undiagnosed and others are diagnosed late in life.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Approximately 25% of affected individuals have an affected parent. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
The genes responsible for myofibrillar myopathies have been identified in approximately 20% of affected individuals. These disorders have been categorized by the gene involved. The gene abnormality results in excess amounts of a particular protein in muscle.
Desminopathy---(onset 20-30) DES gene/desmin protein
Alpha-B crystallinopathy---(onset 20-40 years)CRYAB gene/a-B crystallin protein
Myotilinopathy---(Onset 27-77) Titin immunoglobulin domain protein TTID gene/myotilin protein
Filaminopathy---(onset 37-57) FLNC gene/filamin C protein
BAG3-related myofibrillar myopathy---(onset childhood) BCL2-associated athanogene 3/ BaG3 protein
Zaspopathy---(onset 44-73 years)LDB3 (ZASP) gene/LIM domain-binding protein 3
The frequency of myofibrillar myopathies has not been estimated. It is likely that these conditions are unrecognized and underdiagnosed.
Signs of the following muscle disorders can be similar to those of myofibrillar myopathies. Comparisons may be useful for a differential diagnosis:
Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multi-system disorder that affects both smooth and skeletal muscles and may affect the central nervous system, heart, eyes, and/or endocrine systems. Classic DM1 is characterized by muscle weakness and atrophy, cataracts, myotonia and abnormalities in the heart's conduction of electrical impulses. Myotonic dystrophy type 2 (DM2), formerly called proximal myotonic myopathy (PROMM) is an autosomal dominant disorder with symptoms that are similar to DM1, but tend to be milder and more variable than DM1. (For more information on this disorder, choose "dystrophy, myotonic" as your search term in the Rare Disease Database.)
Inclusion body myositis (IBM) is a rare inflammatory muscular disorder that usually becomes apparent during adulthood. The disorder presents as slow progressive muscle weakness and atrophy, especially of the arms and legs. IBM is frequently diagnosed when a patient is unresponsive to therapy prescribed for polymyositis. IBM is characterized by the gradual progression of muscle fatigue and weakness; a tendency to affect men more frequently than women; and affecting both proximal and distal muscles. Onset is usually after age 50, although it may occur earlier. (For more information on this disorder, choose "myositis, inclusion body" as your search term in the Rare Disease Database.)
Inclusion body myopathy 2 (IBM2) is characterized by slowly progressive distal muscle weakness that begins in the late teens to early adult years with gait disturbance and foot drop. Muscle weakness progresses to include the hand and thigh muscles but does not usually affect the quadriceps muscles. Affected individuals are usually wheelchair bound about 20 years after the onset of disease.
A diagnosis of myofibrillar myopathies is made based on clinical findings, electromyography, nerve conduction studies and muscle biopsy. Molecular genetic testing for the DES, CRYAB, MYOT, LDB3 and ZASP genes is available to confirm the diagnosis. Molecular genetic testing for the BAG3 gene is available on a research basis only.
Individuals affected with cardiomyopathy may consider implantation of a mechanical device to regulate heartbeat (pacemaker) and cardioverter defibrillator (ICD). Heart transplantation may be considered if the cardiomyopathy is progressive or life threatening. Respiratory therapy and physical therapy may be helpful for those with advanced muscle weakness. Orthotics may be helpful if foot drop develops.
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Myopathy, Myofibrillar Resources
Connolly AM. Myofibrillar (Desmin and Desmin-Related) Myopathy. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:630-631.
Selcen D, Muntoni F, Burton BK, et al. Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol. 2009; 65: 83
Fischer D, Clemen CS, Olive M, et al. Different early pathogenesis in myotilinopathy compared to primary desminopathy. Neuromuscul Disord. 2006; 16: 361-7.
Penisson-Besnier I, Talvinen K, Dumez C, et al. Myotilinopathy in a family with late onset myopathy. Neuromuscul Disord. 2006; 16: 427-31.
Selcen D, Engel AG. Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol. 2005; 57: 269-76.
Selcen D, Ohno K, Engel AG. Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. Brain. 2004; 127: 439-51.
Goldfarb LG, Vicart P, Goebel HH, et al.. Desmin myopathy. Brain. 2004; 127: 723-34.
Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopathy. Neurology. 2004; 62: 1363-71.
Selcen D, Engel AG. Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations. Ann Neurol. 2003; 54: 804-10.
Sugawara M, et al. A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates. Neurology. 2000;55:986-90.
Dalakas MC, et al. Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. New Engl J Med. 2000;342:770-80.
Li D, et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation. 1999;100:461-64.
Fidzianska A, et al. Familial inclusion body myopathy with desmin storage. Acta Neuropathol (Berl). 1999;97:509-14.
Goldfarb LG, et al. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nature Genet. 1998;19:402-03.
Horowitz SH, et al. Autosomal dominant distal myopathy with desmin storage: a clinicopathologic and electrophysiologic study of a large kinship. Muscle Nerve. 1994;17:151-60.
Vajsar j, et al. Familial desminopathy: myopathy with accumulation of desmin-type intermediate filaments. J Neurol Neurosurg Psychiatry. 1993;56:644-48.
FROM THE INTERNET
Selcen, D and Engel, AG, (Updated 2/2/10). Myofibrillar Myopathy. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2010, Available at http://www.genetests.org. Accessed 3/10.
Haberler C, Gelpi E and Budka H. Myofibrillar Myopathies; Orphanet: http://www.orpha.net/data/patho/GB/uk-MyofibrillarMyopathies.pdf, Last Update: 3/05, Accessed 3/10.
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Report last updated: 2010/04/26 00:00:00 GMT+0
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