NORD gratefully acknowledges Nigel Clarke, MBChB, PhD, FRACP, Clinical Geneticist, University of Sydney and Children's Hospital, Westmead, Australia, for assistance in the preparation of this report.
Congenital fiber type disproportion (CFTD) is a rare genetic muscle disease that is usually apparent at birth (congenital myopathy). It belongs to a group of muscle conditions called the congenital myopathies that tend to affect people in a similar pattern. 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 also have abnormal side-to-side curvature of the spine (scoliosis), dislocated hips, and the permanent fixation of certain joints in a flexed position (contractures), particularly at the ankle.
The diagnosis of congenital fiber type disproportion is controversial. The changes to muscle tissue that characterize the disorder can also occur in association with many other disorders or conditions including other congenital muscle disorders, myotonic dystrophy nerve disorders (such as spinal muscular atrophy), metabolic conditions, and a variety of brain malformations such as cerebellar hypoplasia. These conditions should be considered and excluded before a diagnosis of CFTD is made. Most patients with CFTD have no other affected relatives (sporadic). Some cases are inherited as an autosomal recessive or dominant trait. In one family, CFTD was inherited as an X-linked recessive trait.
The symptoms of CFTD are similar to other types of congenital myopathy and may vary from case to case. Most individuals have loss of muscle tone (hypotonia) and generalized muscle weakness that is present at or shortly after birth (congenital). In most cases, muscle weakness is a benign, nonprogressive condition that may even improve with age. 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.
A variety of additional abnormalities have been associated with CFTD including 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. Intelligence is typically unaffected. Some infants with CFTD may fail to grow and gain weight at the expected rate (failure to thrive). Infants with CFTD often have distinctive facial features including a long, thin face, an abnormally high roof of the mouth (highly arched palate), and weak facial muscles. CFTD cannot be diagnosed on physical characteristics alone since many other forms of congenital myopathy share these physical features. A combination of physical features and changes on muscle biopsy is used to make the diagnosis.
In approximately 25 percent of cases, affected individuals may have a more severe form of CFTD characterized by severe weakness that may progress and that may cause serious complications including difficulty swallowing (dysphagia) and life-threatening respiratory muscle weakness. In rare cases, CFTD is associated with disease of the heart muscle (cardiomyopathy).
In approximately 20 percent of cases, paralysis of certain eye muscles (ophthalmoplegia) may also occur. Ophthalmoplegia is often associated with a more severe form of the disorder.
Most cases of CFTD occur without any previous family history. However, a number of familial cases have been reported and it is clear that CFTD can arise from changes (mutations) in one of different disease genes (genetic heterogeneity). Familial cases have indicated that the disorder may be inherited as an autosomal recessive or autosomal dominant trait. In one rare case, CFTD was inherited as an X-linked recessive trait.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the 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. The chance of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders are disorders in which individuals only develop the disorder when they inherit two abnormal copies of a gene, one from each parent. If an individual receives one normal copy of the gene and one abnormal gene copyfor the disease, the person will be a carrier for the disease, but usually will not show symptoms. The chance for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The chance of having a child who is a carrier like the parents is 50% with each pregnancy. The chance that a child will receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but in the cells of all normal females, one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because many cells in the body (usually around half) make use of the normal copy of the gene, and inactivate the X chromosome with the abnormal copy, which usually protects them from disease. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy of having a carrier daughter like themselves, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% chance of having an unaffected son.
Investigators have determined that some cases of autosomal dominant CFTD are caused by disruptions or changes of several different genes. These are, in rough order of frequency, the i) alpha-tropomyosin-slow gene (TPM3), ii) alpha-skeletal actin gene (ACTA1), iii) beta-tropomyosin gene (TPM2) and iv) beta-myosin gene (MYH7).
Investigators have identified that some families with autosomal recessive CFTD are caused by disruptions or changes in the ryanodine receptor type 1 gene (RYR1).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q42.1” refers to band 42.1 on the long arm (q) of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Investigators have also determined that X-linked recessive CFTD may be caused by disruptions or changes of an unidentified gene located on the X chromosome. Previously, mutations of the selenoprotein N gene (SEPN1), also located on chromosome 1, were linked to some cases of autosomal recessive CFTD but these are not now usually diagnosed with CFTD based on new diagnostic criteria. At present, a specific genetic cause cannot be identified in around half of affected individuals.
The symptoms and findings associated with CFTD are associated with abnormalities in the relative size and distribution of certain types of muscle fibers (i.e., fiber types I and II). Muscle fibers are the highly organized, specialized, contractile cells of skeletal or cardiac muscle tissue. In individuals with CFTD, type I fibers are abnormally, uniformly small (hypotrophic) and are usually (but not always) present in increased numbers (type I fiber predominance). Previously a diagnosis of CFTD was considered if type I muscle fibers were, on average, at least 12 percent smaller (in diameter) than type II muscle fibers. Now, CFTD is usually only when type I fibres are at least 35-40% smaller than type II fibres, on average. In many CFTD patient, this size disproportion arises because type I fibers are smaller than normal (hypotrophic) and type II fibers are larger than normal (hypertrophic) and often a class of type II fibers (called type IIB fibers) is absent. This same pattern of abnormalities can occur with a number of other, defined neurological conditions and it is important that these are considered before a diagnosis of CFTD is made. Since this pattern of muscle changes is not specific, some researchers have suggested using the term “fiber size disproportion” (FSD) to describe it and to reserve “congenital fiber size disproportion” for individuals with FSD and clinical features of a congenital myopathy when there is no other identifiable diagnosis.
CFTD affects males and females in equal numbers. The incidence of the disorder in the general population is unknown but it is uncommon. The disorder is usually present at birth (congenital) but may not be recognized for many months. 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.
A diagnosis of CFTD is one of exclusion. A diagnosis may be suspected based upon a thorough clinical evaluation, identification of characteristic findings (i.e., hypotonia and muscle weakness) and a variety of specialized tests including one that assesses muscle tissue (electromyography) and a muscle biopsy.
During an electromyography, 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 (i.e., fiber size disproportion).
No specific therapy exists for individuals with CFTD. Treatment is directed toward the specific symptoms that are apparent in each individual. Physical therapy and orthopedic treatment (e.g., braces or surgery) of contractures may be necessary. Physical therapy may also help strengthen muscles.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about congenital fiber type disproportion:
Nigel Clarke, MBChB, PhD, FRACP
University of Sydney
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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