Nemaline myopathy is a rare genetic muscle disorder. Myopathy is a general medical term meaning "disease of the muscle". At least six different forms of nemaline myopathy have been identified. The severity, age of onset, and inheritance pattern varies among these different forms of nemaline myopathy. A severe form that is present at birth (congenital) can cause life-threatening complications. Milder forms and a form with onset in adulthood have also been identified. Most affected individuals have a milder form of the disorder known as typical congenital nemaline myopathy. Most individuals with this form are able to walk and lead active lives. Characteristic symptoms of all forms of nemaline myopathy include muscle weakness, diminished muscle tone (hypotonia), and absence of certain reflexes. In most cases, muscle weakness does not worsen or spread (nonprogressive), though it some cases it may. The inheritance patterns of the six forms of nemaline myopathy also vary; some are inherited as an autosomal recessive trait and some as an autosomal dominant trait.
When certain muscle fibers of individuals with nemaline myopathy are examined under a microscope, they show the presence of fine, thread-like or rod-like structures called "nemaline bodies." The prefix "nemal" is derived from Greek and means "thread-like." Nemaline bodies consist of defective proteins, which are normally required for proper muscle health and function.
The age of onset and severity of symptoms associated with nemaline myopathy vary greatly from case to case even among members of the same family. Some cases of nemaline myopathy may have onset at or shortly after birth (congenital). Less often, the disorder may develop during childhood or even more uncommonly in adulthood.
The major symptoms of nemaline myopathy are muscle weakness, diminished muscle tone (hypotonia) and absence of the certain reflexes. Muscle weakness is usually most severe in muscles of the face, neck and proximal muscles. The 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.
Because facial muscles are involved, affected individuals may develop distinctive facial features including an elongated face, a displaced jaw that is farther back than normal (retrognathia), and a highly-arched roof of the mouth (palate). Muscle weakness may also cause difficulty speaking (dysarthria) and swallowing resulting in feeding difficulties. Some infants with nemaline myopathy may require a feeding tube. Breathing (respiratory) difficulties may also occur because of muscle weakness.
Affected infants often experience delays in attaining motor milestones such as lifting one’s head up, sitting up or standing. Most infants do not have other developmental issues and intelligence is usually unaffected. Many affected infants may have excessive laxity and extension (hypermobility) of the joints in infancy or early childhood.
As affected individuals age they may develop 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), a sunken chest (pectus carinatum), abnormal side-to-side-curvature of the spine (scoliosis) or abnormal rigidity of the spine.
Six different forms of nemaline myopathy have been identified.
Typical (Mild) Congenital Nemaline Myopathy
The typical or mild form is the most common form of nemaline myopathy accounting for approximately 46 percent of cases. This form is present at or shortly after birth (neonatal period) or sometime during the first year of life. Affected infants may exhibit muscle weakness, diminished muscle tone (hypotonia) resulting in abnormal “floppiness”, and feeding difficulties. Muscle weakness is less severe in the typical congenital form than in the severe congenital or intermediate congenital forms. Some infants with this form may have significant muscle weakness at birth that improves with age.
Mild weakness of muscle of the respiratory tract occurs in most cases and may cause breathing difficulties, chronic infections of the lower respiratory tract and nocturnal hypoventilation, a condition in which inadequate breathing results in increased levels of carbon dioxide in the blood (hypercarbia). Some infants may have an abnormal waddling walk (gait), swallowing difficulties (dysphagia), speech difficulties (dysarthria), and a nasally tone to the voice. Affected infants may also experience delays attaining gross motor milestones such as holding one’s head up, sitting or standing. In rare cases, delayed attainment of motor milestones may be the first sign of the disorder.
Muscle weakness in infants with the typical congenital form of nemaline myopathy usually affects the proximal muscles, but, in rare cases, may spread to affect the distal muscles, which are the muscles farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet. The muscle weakness associated with the typical form does not usually progress (become worse or spread). However, during growth spurts associated with puberty, some individuals have experienced progressive worsening of muscle weakness that ultimately may require the use of a wheelchair. Most individuals who have typical congenital nemaline myopathy, however, are eventually able to walk independently and to lead active lives.
Severe Congenital (Neonatal) Nemaline Myopathy
This form of nemaline myopathy is apparent at birth (congenital) and account for approximately 16 percent of cases. Affected infants have profound muscle weakness and severely diminished muscle tone (severe hypotonia), resulting in the so-called “floppy infant”. Infants with this form of nemaline myopathy may also experience difficulty sucking and swallowing leading to feeding difficulties, show little spontaneous movement, and exhibit breathing (respiratory) insufficiency. Some infants may experience the passage or backflow (reflux) of the contents of the stomach or small intestines into the esophagus (gastroesophageal reflux).
In rare cases, this form of nemaline myopathy has been associated with disease of the heart muscle (cardiomyopathy) and the presence of multiple contractures (arthrogryposis multiplex congenita). Fractures may also occur. The severe involvement of respiratory muscles such as the muscle that separates the chest cavity from the abdomen (diaphragm) often leads to life-threatening breathing complications or aspiration pneumonia during infancy. Aspiration pneumonia is a condition in which liquid or food is inhaled into the lungs.
Researchers have noted that long-term survival of some individuals with severe congenital nemaline myopathy who have generalized muscle weakness and difficulty breathing (inadequate respiration) has occurred.
Intermediate Congenital Nemaline Myopathy
This form of nemaline myopathy is less severe than the severe congenital form and more severe than the typical congenital form. It accounts for approximately 20 percent of cases. Affected infants can usually breathe independently at birth. The early development of contractures is characteristic of this form of nemaline myopathy. As affected infants age, they often experience delays in attaining motor milestones or may not be able to sit up or walk independently. Children with intermediate congenital nemaline myopathy eventually require a wheelchair or breathing (ventilatory) support by age 11, findings which distinguish this form from the typical congenital form.
Childhood-Onset Nemaline Myopathy
This form of nemaline myopathy usually becomes apparent between 10-20 years of age and accounts for approximately 13 percent of cases. The development of early motor skills is usually unaffected. Sometime during the late teens or early twenties, affected individuals develop slowly progressive muscle weakness. Affected individuals may be unable to bend the foot upward toward the leg (foot drop). Eventually the entire ankle and lower legs muscles are involved. In one family with this form of nemaline myopathy, two members required wheelchairs by age 40.
Adult-Onset Nemaline Myopathy
The onset and severity of this form of nemaline myopathy varies. It is extremely rare accounting for only 4 percent of cases. It occurs in individuals between the ages of 20-50, who develop generalized muscle weakness that may progress rapidly. Muscle pain (myalgia) may also occur. Involvement of certain neck muscles may make it difficult to hold one’s head up and cause the head to drop.
Although uncommon, some individuals may develop respiratory or cardiac complications often in conjunction with increasing muscle weakness. In some cases, the initial manifestation of adult-onset nemaline myopathy is disease of the heart muscle (cardiomyopathy) in the absence of significant muscle weakness.
Amish Nemaline Myopathy
This form of myopathy was identified in several related families within an Amish community. Onset is shortly after birth (neonatal period) and affected infants may have diminished muscle tone (hypotonia), multiple contractures, and tremors, which usually diminish over the first few months of life. Affected infants have progressive muscle weakness, a severely sunken chest (pectus carinatum), muscle degeneration (atrophy) and life-threatening respiratory insufficiency.
As of 2007, six different disease genes have been identified as causing nemaline myopathy. These genes may be inherited as autosomal recessive or dominant 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.
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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.
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 risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Disruptions or errors (mutations) of the ACTA1 gene have been linked to approximately 15-20 percent of nemaline myopathy cases. Most ACTA1 mutations are a spontaneous (de novo) genetic change (i.e., new mutation) and not inherited. However, some cases have resulted from autosomal dominant and, more rarely, autosomal recessive inheritance. Mutations of the ACTA1 gene may cause the severe, intermediate or typical congenital forms of nemaline myopathy.
The ACTA1 gene is located on chromosome 1 (1q42). 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″ refers to band 42 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Mutations of the NEB gene located on long arm (q) of chromosome 2 (2q22) have been identified as a cause of nemaline myopathy. Mutations of this gene can cause any form of the disorder, but most individuals with a NEB mutation have the typical congenital form. Mutations of the NEB gene are inherited as an autosomal recessive trait.
Mutations of the TPM2, TPM3 and TNNT1 genes have also been demonstrated to causes cases of nemaline myopathy. Mutations in these genes in nemaline myopathy occur rarely and have been reported in only one or several families affected by nemaline myopathy. The TPM2 gene is located on the short arm of chromosome 9 (9p13.2-p13.1). The TPM3 gene is located on the long arm of chromosome 1 (1q22-qq23). The TNNT1 gene is located on the long arm of chromosome 19 (19q13.4).
The genes involved in nemaline myopathy contain instructions for creating (encoding) certain proteins that play an essential role in the proper function and health of muscle cells. Mutations to these genes result in deficiency or dysfunction of these proteins. The ACTA1 gene encodes for a protein called actin; the NEB gene encodes a protein called nebulin; the TPM2 gene encodes a protein called beta-tropomyosin 2; the TPM3 gene encodes a protein called slow alpha-tropomyosin 3; and the TNNT1 gene encodes a protein called troponin T1.
These proteins are work together to form structures known as thin filaments, which are basically long chains of proteins. Thin filaments are found in the sarcomere the basic structural and functional unit of striated muscle and they play a role in the formation and proper function of skeletal muscle fibers. Therefore, if these proteins are deficient or defective, as is the case with mutated genes, it impairs the proper function and development of muscles.
In the January 2007 issue of the American Journal of Medical Genetics, researchers reported two siblings with nemaline myopathy who had mutations of the cofilin-2 (CFL2) gene. This is the sixth gene to be associated with nemaline myopathy. CFL2 encodes for a protein known as cofilin-2, which (as with the other proteins linked to nemaline myopathy) is involved with the development of thin filaments. The CFL2 gene is located on the long arm of chromosome 14 (14q12).
Nemaline myopathy is a rare disorder that affects males and females. The incidence is unknown although two studies (one in Finland and one in an American Ashkenazi Jewish population) estimated the incidence at 1 in 50,000 live births. It may be more common in certain populations. Nemaline myopathy is the most common form of muscle disease present at birth (congenital myopathy). The disorder was first described in the medical literature in 1963.
A diagnosis of nemaline myopathy is suspected based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings. A diagnosis may be confirmed by the presence of thread- or rod-like structures (nemaline bodies) on muscle biopsy. A biopsy is the surgical removal and microscopic evaluation of affected tissue (e.g., muscle tissue).
No specific treatment exists for nemaline myopathy. Treatment is supportive and directed toward the specific symptoms that are apparent in each individual. Infants with nemaline myopathy may benefit from a program involving mild-to-moderate, low-impact exercise, massage, and stretching techniques. Such therapy is aimed at preserving muscle strength and function and to prevent the development of contractures.
In addition, breathing (respiratory) support may be necessary, potentially including mechanical ventilation to prevent nocturnal hypoventilation. Carefully monitoring of breathing is essential because even individuals with minimal muscle weakness in the arms and legs can develop breathing irregularities especially during sleep.
Lower respiratory infections must be promptly and aggressively treated to avoid complications. Since some affected individuals may experience feeding difficulties, tube-feeding may be required to ensure proper caloric and nutritional intake. Speech therapy may be necessary for individuals with difficulty speaking (dysarthria) or nasally speech.
In some cases, various orthopedic techniques, such as the use of special braces, other devices, and/or surgical measures, may be recommended to help prevent and/or treat certain musculoskeletal abnormalities such as scoliosis and joint contractures. Individuals with significant muscle weakness in the legs may eventually require a wheelchair.
Affected individuals should receive an assessment of heart function because a risk for heart (cardiac) abnormalities does exist, although it is a rare complication. Genetic counseling may be of benefit for affected individuals and their families.
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