Collagen Type VI-Related Disorders
Collagen Type VI-Related Disorders
National Organization for Rare Disorders, Inc.
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Related Disorders List
Information on the following diseases can be found in the Related Disorders section of this report:
Collagen type VI-related disorders encompass two genetic muscle disorders formerly thought to be separate entities: Bethlem myopathy and Ullrich congenital muscular dystrophy. Researchers have determined that these disorders represent a disease spectrum associated with disruptions or changes (mutations) of certain genes that contain instructions to produce (encode) collagen type VI proteins. Bethlem myopathy represents the milder form of this spectrum and Ullrich congenital muscular dystrophy represents the severe end. Common symptoms include progressive muscle weakness and degeneration (atrophy) and abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected area (contractures). Both Bethlem myopathy and Ullrich CMD can be inherited as autosomal dominant or autosomal recessive traits.
The symptoms, severity, and age of onset of collagen type VI-related disorders vary greatly. In most cases, affected individuals have muscle weakness and degeneration and skeletal abnormalities such as curvature of the spine (scoliosis) and contractures.
Bethlem Myopathy (Benign Congenital Myopathy with Contractures)
Bethlem myopathy is a disorder characterized by mild muscle weakness of the proximal muscles. Proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Muscle weakness may eventually affect the distal muscles to a lesser degree. Distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet.
The symptoms of Bethlem myopathy may be apparent before birth (prenatally), shortly after birth (neonatally), or during adolescence or adulthood. In addition to muscle weakness, newborns and infants with Bethlem myopathy may develop diminished muscle tone (hypotonia), repeated mild contractures of certain joints especially the fingers, elbows, ankles, and knees, muscles spasms of the neck (torticollis), and delays in achieving motor milestones.
Bethlem myopathy is slowly progressive. In some adults, noticeable muscle weakness may not occur until after 40 years of age. Many individuals with Bethlem retain the ability to walk either independently or with assistance (e.g., cane or crutches) throughout life. Some individuals may eventually require a wheelchair.
In rare cases, breathing (respiratory) difficulties may occur late in life due to weakness of the diaphragm muscles. Heart (cardiac) function, which may become impaired in other forms of myopathy, is usually unaffected in individuals with Bethlem myopathy.
In some cases, a skin condition may occur that is characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules) on the skin.
Ullrich Congenital Muscular Dystrophy (UCMD)
Ullrich CMD is characterized by diminished muscle tone (hypotonia), weakness and degeneration of the proximal muscles, and abnormally flexible (hyperelastic) joints of the wrists and ankles. Additional early symptoms of Ullrich CMD include the failure to gain weight and grow at the expected rate (failure to thrive), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), muscles spasms of the neck (torticollis), congenital dislocation of the hip, contractures of the joints, and stiffness (rigidity) of the spine.
Intelligence is normal in most cases. The amount of motor development varies from case to case. Some children are able to walk independently; others require assistance to walk. In some cases, affected children may never be able to walk. In addition, some children who develop the ability to walk independently lose that ability because of the progression of the disease (e.g., worsening contractures, rigidity of spine).
Additional symptoms may occur including breathing (respiratory) difficulties and frequent chest infections. Breathing difficulties can result in life-threatening complications and may require respiratory support, especially at night.
As the disorder progress, previously flexible (lax) joints such as those of the wrists and ankles may stiffen. Some affected individuals may exhibit a skin condition characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules). In some cases, scars may heal slowly or affected individuals may develop hardened, raised bumps at the site of an injury (hypertrophic keloid scars).
Some individuals with Ullrich CMD may have a distinctive facial appearance with a rounded face with prominent ears.
Bethlem myopathy and Ullrich CMD are caused by mutations in one of three different genes that carry the instructions to produce (encode) various parts of collagen VI. Collagen VI is a protein that plays an essential role in the proper function and health of muscle cells.
Two of the genes are located on the long arm of chromosome 21 (21q22.3) and the other is found on the long arm of chromosome 2 (2q37). 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 21q22.3" refers to band 22.3 on the long arm of chromosome 21. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Both Bethlem myopathy and Ullrich CMD can be inherited as autosomal dominant or autosomal recessive traits. 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. If an affected parent has a dominant mutation the risk of passing the abnormal gene from parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. If the disorder is the result of a new mutation in the affected individual then the chance of the parents having another affected child is very low.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, 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 defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Collagen type VI-related disorders affect males and females in equal numbers. The incidence and prevalence of these disorders are unknown. Because these disorders often go unrecognized, they may be underdiagnosed making it difficult to determine their true frequency in the general population.
Bethlem myopathy was first described in the medical literature in 1976. Ullrich CMD was first described in the medical literature in 1930. The disorders have been described in individuals of varied ethnic backgrounds.
Symptoms of the following disorders can be similar to those of collagen type VI-related disorders. Comparisons may be useful for a differential diagnosis.
Limb-girdle muscular dystrophy (LGMD) is a generic term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability. The term limb-girdle muscular dystrophy is a general term encompasses several disorders. These disorders can now be distinguished by genetic and protein analysis. At least 15 subtypes have been identified. The various forms of LGMD may be inherited as an autosomal dominant or recessive trait. Autosomal dominant LGMD is known as LGMD1 and has five subtypes (LGMDA-E). Autosomal recessive LGMD is known as LGMD2 and has 10 subtypes (LGMDA-J). (For more information on this disorder, choose "limb-girdle muscular dystrophy" as your search term in the Rare Disease Database.)
Emery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive genetic disorder affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of the clinical triad of weakness and degeneration (atrophy) of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy). Major symptoms may include muscle wasting and weakness particularly in arms and lower legs (humeroperoneal regions) and contractures of the elbows, Achilles tendons, and upper back muscles. In some cases, additional abnormalities may be present. In most cases, EDMD is inherited as an X-linked recessive or autosomal dominant trait. In extremely rare cases, autosomal recessive inheritance has been reported. Although EDMD has different modes of inheritance, the symptoms are nearly the same. (For more information on this disorder, choose "Emery-Dreifuss" as your search term in the Rare Disease Database.)
Congenital muscular dystrophy (CMD) is a general term for a group of genetic muscle diseases that occur at birth (congenital) or early during infancy. CMDs are generally characterized by diminished muscle tone (hypotonia), which is sometimes referred to as "floppy baby"; progressive muscle weakness and degeneration (atrophy); abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected area (contractures); and delays in reaching motor milestones such as sitting or standing unassisted. Some forms of CMD may be associated with structural brain defects and, potentially, mental retardation. The severity, specific symptoms, and progression of these disorders vary greatly. Almost all known forms of CMD are inherited as autosomal recessive traits. (For more information on this disorder, choose "congenital muscular dystrophy" as your search term in the Rare Disease Database.)
Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (motor nuclei) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. (For more information on this disorder, choose "spinal muscular atrophy" as your search term in the Rare Disease Database.)
A diagnosis of Bethlem myopathy or Ullrich CMD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms (e.g., specific distribution of muscle weakness and atrophy), and a variety of specialized tests including surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers; a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; and tests that evaluate the presence and number of certain muscle proteins (immunohistochemistry).
During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.
Blood tests may reveal slightly elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Slightly elevated CK levels occur in some, but not all cases of collagen type VI-related disorders. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis.
In some cases of Ullrich CMD, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific muscle proteins within muscle cells or tissue (immunolabeling). Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain muscle proteins. Samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present and in what quantity. In Ullrich CMD, collagen VI can be markedly reduced or absent or show abnormal localization in the muscle. In Bethlem myopathy, immunolabeling usually only shows subtle changes or normal collagen VI, therefore the test cannot usually aid in diagnosis.
The treatment of collagen type VI-related disorders is directed toward the specific symptoms that are apparent in each individual. Treatment various based upon the specific symptoms present, their severity, and the age of onset.
In individuals with Ullrich CMD, early intervention is essential to promote mobility and independence. The use of a standing frame may be necessary to achieve an upright posture and protect against the development of scoliosis and contractures. Physical and occupational therapy to improve muscle strength and prevent contractures is beneficial to individuals with Ullrich CMD or Bethlem myopathy. Surgery may be necessary to correct contractures or scoliosis, especially in individuals with Ullrich CMD.
Regular monitoring of breathing (respiratory function) is recommended. Individuals with Ullrich CMD may need respiratory support such as (nocturnal ventilation). Individuals with Bethlem myopathy may develop respiratory difficulties later in life and may eventually require respiratory support such as mask ventilation. Antibiotics, vaccinations, and physiotherapy may be beneficial in preventing or treating repeated chest infections and preventing additional respiratory problems.
Feeding difficulties that may occur in individuals with Ullrich CMD may require seeing a nutritionist to create a plan to ensure proper caloric intake. In severe cases, it may be necessary to use a gastrostomy tube, in which a tube is inserted into a surgical opening in the stomach to provide direct nutritional support.
Individuals with Ullrich CMD may require use of various devices (e.g., canes, braces, walkers, wheelchairs) to assist with walking (ambulation) and mobility. Such assistive devices are necessary for approximately two-thirds of individuals with Bethlem myopathy over 50 years of age.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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March of Dimes Birth Defects Foundation
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Muscular Dystrophy Association
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Tucson, AZ 85718-3208
Muscular Dystrophy Campaign
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NIH/National Institute of Neurological Disorders and Stroke
P.O. Box 5801
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Society for Muscular Dystrophy Information International
P.O. Box 7490
Nova Scotia, B4V 2X6
Muscular Dystrophy Australia
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European Alliance of Neuromuscular Disorders Associations
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New Horizons Un-Limited, Inc.
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Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Cure CMD (Congenital Muscular Dystrophy)
P.O. Box 701
Olathe, KS 66051
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Last Updated: 4/5/2012
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