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Last updated:
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Summary
Congenital fiber type disproportion (CFTD) is a rare genetic muscle disease that is usually apparent at birth (congenital) or in early infancy. Major symptoms may include loss of muscle tone (hypotonia) and generalized muscle weakness. Delays in motor development are common and people with more marked muscle weakness may have abnormal side-to-side curvature of the spine (scoliosis), dislocated hips and/or permanent fixation of certain joints in a flexed position (contractures), particularly at the ankle. The health problems tend to be static (i.e., non-progressive) in many but not all patients with CFTD.
A disease-modifying therapy for CFTD is not yet available, and treatment is focused on the specific symptoms in each individual.
Introduction
CFTD belongs to a group of muscle conditions called the congenital myopathies, genetic muscle disorders that are generally characterized by muscle weakness and low muscle tone typically present at birth or early childhood. Case reports describing children with the features of CFTD first appeared in the medical literature in the 1960s and 70s. The term congenital fiber type disproportion was first used in 1973.
The symptoms of CFTD are similar to other types of congenital myopathy and may vary from person to person. Onset of symptoms occurs at birth or in early infancy. The severity of symptoms is highly variable, ranging from mild deficits to severe weakness that may result in death in early childhood. In many patients with CFTD, the health problems are less severe than those of other classic congenital myopathies.
The mother may have noticed reduced fetal movements during pregnancy and there may have been excess amniotic fluid in the uterus (polyhydramnios).
Most individuals have loss of muscle tone (hypotonia) and non-progressive generalized muscle weakness that is present at or shortly after birth (congenital). Muscles closest to the trunk of the body (proximal muscles) such as those of the hip and shoulder area (limb-girdle) and muscles of the spine and neck (truncal muscles) are usually affected the most.
Other abnormalities that have been associated with CFTD include side to-side curvature of the spine (scoliosis), dislocation of the hips, permanent fixation of certain joints in a flexed position (contractures), diminished reflexes and delays in attaining motor milestones. Some infants with CFTD may fail to grow and gain weight at the expected rate (failure to thrive). Infants with CFTD may have distinct facial features (myopathic facies) including a long, thin face, an abnormally high roof of the mouth (highly arched palate) and weak facial muscles. Additional facial characteristics include sunken cheeks and droopy eyelids (bilateral ptosis). Intelligence is usually normal in people with CFTD.
Other symptoms may include weak or hoarse voice, abnormalities of lung function, difficulty chewing (impaired mastication), underdevelopment of the jawbone (micrognathia), high-arched foot (pes cavus), inability to walk on heels (foot dorsiflexor weakness) and inward twisting of the foot (talipes equinovarus).
Some affected individuals may have a more severe form of CFTD characterized by severe weakness that may progress and cause serious complications including difficulty swallowing (dysphagia) and/or life-threatening respiratory muscle weakness. Paralysis of eye muscles (ophthalmoplegia) also occurs in some patients. Rarely, CFTD is associated with disease of the heart muscle (cardiomyopathy). Other rare cardiac symptoms related to CFTD include abnormal heart structures, right-sided heart failure resulting from chronically high blood pressure in the pulmonary arteries (cor pulmonale), and the appearance of a “caved-in” chest resulting from a chest wall structural abnormality (pectus excavatum).
The clinical features of CFTD arise at least in part from abnormalities in the relative size and distribution of certain types of muscle fibers, most notably fiber types I and II. Muscle fibers are the highly organized, specialized, contractile cells of skeletal or cardiac muscle tissue. Type I fibers are considered “slow twitch” and participate in longer, more-sustained periods of contraction, whereas type II fibers are considered “fast twitch” and participate in faster bursts of activity. Ordinarily, type I fibers are slightly larger than type II fibers. In individuals with CFTD, type I fibers are abnormally, uniformly small (hypotrophy) and are usually (but not always) present in increased numbers.
CFTD is a genetic disorder caused by changes (disease-causing variants) in several different genes. genes. CFTD may occur without any previous family history.
CFTD can follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Genes that have been associated with autosomal dominant inheritance of CFTD include alpha-tropomyosin-slow gene (TPM3), alpha-skeletal actin gene (ACTA1), beta-tropomyosin gene (TPM2) and the beta-myosin gene (MYH7).
CFTD can also follow autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Genes that have been associated with autosomal recessive inheritance of CFTD include ryanodine receptor type 1 (RYR1), selenoprotein N (SEPN1/SELENON), myosin light chain 2 (MYL2), titin (TTN), sodium voltage channel, alpha subunit 4 (SCN4A) and HACD1.
While variants in TPM3 most commonly follow a dominant inheritance, they have also been associated with the recessive types of CFTD. In patients where the TPM3 gene variants follow recessive inheritance, the condition is generally more severe.
Current data suggests that 25-40% of CFTD cases are caused by variants in TPM3, 10-20% of CFTD cases are caused by variants in RYR1, and 5% are caused by variants in ACTA1.
Infrequently, CFTD can also follow X-linked inheritance. Specific genes associated with X-linked CFTD have not yet been identified. X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
Disease-causing variants in the SPEG and LMNA genes have also been linked to fiber type disproportion. There is current debate over whether the fiber type disproportion caused by variants in these genes can be classified as CFTD, as they are characterized by the type 2 fibers being abnormally small (hypotrophy) as opposed to the hypotrophy of type 1 fibers characteristic of classic CFTD.
Research into the genetic causes of CFTD is ongoing, and at present, a specific genetic cause cannot be identified in some affected individuals.
CFTD affects males and females in equal numbers. In a meta-analysis examining CFTD prevalence across European, North American and Asian populations, a pooled prevalence of the disorder for all-age population was estimated to be between 0.23 per 100,000 and between 0.25 per 100,000 for a pediatric population. Based on these prevalence estimates, CFTD is considered a rare disease.
The diagnosis of CFTD may be suspected based on a thorough clinical evaluation and identification of characteristic findings (i.e., hypotonia and muscle weakness). However, clinical presentation alone is not enough to diagnose CFTD because symptoms are similar to other types of congenital myopathies. A diagnosis of CFTD is confirmed if type I muscle fibers are, on average, significantly (12-40%) smaller in diameter than type II muscle fibers on muscle biopsy.
Electrodiagnostic studies (including nerve conduction studies (NCS) and electromyography (EMG)) can help determine whether an individual is more likely to have a nerve-related or muscle-related disease but cannot diagnose CFTD specifically. During the EMG portion of the study, a needle with an attached electrode is inserted through the skin into the muscle. The electrode detects and records the electrical activity of the muscle at rest and when it contracts. This information can determine whether damage to muscle or nerves is present. During a muscle biopsy, muscle tissue is surgically removed and examined under a microscope to detect characteristic changes to muscle tissue. An imbalance of fiber proportions or absence of type IIB fibers suggest the possibility of CFTD.
The diagnosis of CFTD is challenging. It is important to remember that the type I fiber hypotrophy is observed in other types of congenital myopathy and sometimes other neuromuscular disorders. CFTD is defined as the presence of this finding in the absence of features associated with those other diseases.
Treatment
No specific therapy exists for individuals with CFTD. It is important for affected individuals to receive ongoing supportive care. Physical therapy, orthotics, and/or orthopedic surgery may be helpful in some patients. Cardiac and pulmonary screening may be warranted in some patients.
Genetic counseling is often helpful before and after a genetic diagnosis is found.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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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Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com.
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia, PA: Elsevier Saunders; 2005:2057-8.
Connolly AM. Congenital Myopathy with Fiber-Type Disproportion. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:629-30.
JOURNAL ARTICLES
Jabbarpour N, Poorshiri B, Saei H, Barzegar M, Bonyadi M. Identification of a novel mutation in the HACD1 gene in an Iranian family with autosomal recessive congenital myopathy, with fibre-type disproportion. J Genet. 2023;102:18.
Huang K, Bi FF, Yang H. A Systematic Review and Meta-Analysis of the Prevalence of Congenital Myopathy [published correction appears in Front Neurol. 2022 Feb 14;13:857959]. Front Neurol. 2021;12:761636. Published 2021 Nov 2. doi:10.3389/fneur.2021.761636
Matsumoto A, Tsuda H, Furui S, et al. A case of congenital fiber-type disproportion syndrome presenting dilated cardiomyopathy with ACTA1 mutation. Mol Genet Genomic Med. 2022;10(9):e2008. doi:10.1002/mgg3.2008
Gurgel-Giannetti J, Souza LS, Messina de Pádua Andrade GF, et al. A Novel SPEG mutation causing congenital myopathy with fiber size disproportion and dilated cardiomyopathy with heart transplantation. Neuromuscul Disord. 2021;31(11):1199-1206. doi:10.1016/j.nmd.2021.09.005
Claeys KG. Congenital myopathies: an update. Dev Med Child Neurol. 2020;62(3):297-302. doi:10.1111/dmcn.14365
Moreno CA, Estephan Ede, Fappi A, et al. Congenital fiber type disproportion caused by TPM3 mutation: A report of two atypical cases. Neuromuscular Disorders. 2020;30(1):54-58. doi:10.1016/j.nmd.2019.11.001
Marttila M, Win W, Al-Ghamdi F, Abdel-Hamid HZ, Lacomis D, Beggs AH. MYL2-associated congenital fiber-type disproportion and cardiomyopathy with variants in additional neuromuscular disease genes; the dilemma of panel testing. Cold Spring Harb Mol Case Stud. 2019;5(4):a004184. Published 2019 Aug 1. doi:10.1101/mcs.a004184
Kajino S, Ishihara K, Goto K, et al. Congenital fiber type disproportion myopathy caused by LMNA mutations. J Neurol Sci. 2014;340(1-2):94-98. doi:10.1016/j.jns.2014.02.036
Marttila M, Lehtokari VL, Marston S, et al. Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies. Hum Mutat. 2014;35(7):779-790. doi:10.1002/humu.22554
Clarke NF. Congenital fiber-type disproportion. Semin Pediatr Neurol. 2011;18(4):264-271. doi:10.1016/j.spen.2011.10.008
Ortolano S, Tarrío R, Blanco-Arias P, et al. A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy. Neuromuscul Disord. 2011;21(4):254-62.
Clarke NF, Waddell LB, Cooper ST, et al. Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. Hum Mutat. 2010;31(7):E1544-50.
Lawlor MW, Dechene ET, Roumm E, Geggel AS, Moghadaszadeh B, Beggs AH. Mutations of tropomyosin 3 (TPM3) are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion. Hum Mutat. 2010;31(2):176-83.
Brandis A, Aronica E, Goebel HH. TPM2 mutation. Neuromuscul Disord. 2008;18(12):1005.
Clarke NF, Kolski H, Dye DE, et al. Mutations in TPM3 are a common cause of congenital fiber type disproportion. Ann Neurol. 2008;63(3):329-37.
Clarke NF, Kidson W, Quijano-Roy S, et al. SEPN1: associated with congenital fiber- type disproportion and insulin resistance. Ann Neurol. 2006;59:546-52.
Clarke NF, Smith RL, Bahlo M, North KN. A novel X-linked form of congenital fiber- type disproportion. Ann Neurol. 2005;58:767-72.
Sobrido MJ, Fernandez JM, Fontoira E, et al. Autosomal dominant congenital fiber type disproportion: a clinicopathological and imaging study of a large family. Brain. 2005;28:1716-27.
Laing NG, Clarke NF, Dye DE, et al. Actin mutations are one cause of congenital fiber type disproportion. Ann Neurol. 2004;56:689-94.
Clarke NF, North KN. Congenital fiber type disproportion–30 years on. J Neuropathol Exp Neurol. 2003;62:977-89.
Tsuji M, Higuchi Y, Shiraishi K, Mitsuyoshi I, Hattori H. Congenital fiber type disproportion: severe form with marked improvement. Pediatr Neurol. 1999;21:658-60.
Banwell BL, Becker LE, Jay V, Taylor GP, Vajsar J. Cardiac manifestations of congenital fiber-type disproportion myopathy. J Child Neurol. 1999;14:83-7.
INTERNET
Congenital fiber type disproportion. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/6161/congenital-fiber-type-%20disproportion. Accessed March 26, 2024.
Congenital fiber type disproportion. Beggs Laboratory, Boston Children’s Hospital. https://www.childrenshospital.org/research/labs/beggs-laboratory-research/science/myopathies/congenital-fiber-type-disproportion Accessed March 26, 2024.
Myopathy, Congenital, with Fiber-type disproportion; CFTD. Online Mendelian Inheritance in Man (OMIM). 06/01/2023. https://omim.org/entry/255310 Accessed March 26, 2024.
Myopathy, Congenital, With Fiber-Type Disproportion, X-linked; CFTDX. Online Mendelian Inheritance in Man (OMIM). No: 300580. 08/09/2013. https://www.omim.org/entry/300580 Accessed March 26, 2024.
DeChene ET, Kang PB, Beggs AH. Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2007 Jan 12 [Updated 2013 Apr 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1259/ Accessed March 26, 2024.
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