Nemaline Myopathy

Nemaline myopathy is a rare genetic muscle disorder. Six different clinical subtypes of nemaline myopathy have been identified based on disease severity and age of onset, ranging from a severe congenital-onset (at birth) form that is usually lethal in the first few months of life, through to less severe forms with onset in childhood or adulthood. Most affected individuals have a milder form of the disorder known as typical congenital nemaline myopathy and are able to walk and lead active lives. The inheritance pattern is variable depending on the underlying genetic cause. Characteristic symptoms of all forms of nemaline myopathy include muscle weakness, diminished muscle tone (hypotonia), and reduced or absent reflexes. In most people, muscle weakness is static (nonprogressive) over time. Weakness of the muscles of breathing and swallowing are the major cause of morbidity and mortality.


Nemaline myopathy is defined by muscle weakness and the presence of fine, thread-like or rod-like structures called “nemaline bodies”, when muscle biopsies are viewed under the microscope.  The prefix “nema-” is derived from Greek and means “thread-like.” Nemaline bodies consist of accumulations of muscle proteins due to mutations in genes which encode proteins components of the muscle thin filament.

Signs & Symptoms

The age of onset and severity of symptoms and signs associated with nemaline myopathy vary greatly from patient to patient. Some patients with nemaline myopathy present at or shortly after birth (congenital onset). Less often, the disorder may develop during childhood or even more uncommonly in adulthood.

The major clinical features of nemaline myopathy are muscle weakness, hypotonia and reduced or absent 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 head control, sitting up or standing. Most infants do not have other developmental issues and intelligence is usually unaffected.

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 excavatum), abnormal side-to-side-curvature of the spine (scoliosis) or abnormal rigidity of the spine.

Six different clinical presentations of nemaline myopathy have been identified.

Typical Congenital Nemaline Myopathy
This is the most common form of nemaline myopathy accounting for approximately half of all cases. This form is present at or shortly after birth or sometime during the first year of life. Affected infants may exhibit muscle weakness, hypotonia leading to 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.

Weakness of respiratory muscles is common and may cause breathing difficulties, and nocturnal hypoventilation, a condition in which inadequate breathing during sleep 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 nasal 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. 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 are eventually able to walk independently.

Severe Congenital (Neonatal) Nemaline Myopathy
This form of nemaline myopathy is apparent at birth and accounts for approximately 16 percent of cases. Affected infants have profound muscle weakness and severe hypotonia. Infants with this form of nemaline myopathy experience difficulty sucking and swallowing leading to feeding difficulties, show little spontaneous movement, and exhibit 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 often leads to life-threatening respiratory failure and weakness of the bulbar (swallowing) muscles increases the risk of aspiration pneumonia (in which liquid or food is inhaled into the lungs).

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. 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 often require a wheelchair or ongoing breathing (ventilatory) support during childhhood.

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. This form of nemaline myopathy may be distinct form the genetic or inherited forms of the disorder.

Amish Nemaline Myopathy
This form of myopathy was identified in several related families within an Amish community. Onset is shortly after birth and affected infants may have hypotonia, multiple contractures, and tremors, which usually diminish over the first few months of life. Affected infants have progressive muscle weakness, a severely deformed chest with a prominent sternum (pectus carinatum), muscle wasting (atrophy) and life-threatening respiratory insufficiency.
Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita (joint contractures, which are permanent shortening of a muscle) often lead to death in the second year of life.


Ten genes have been found to cause nemaline myopathy. Nemaline myopathy can be inherited as an autosomal recessive or dominant trait. At least 50% of cases of nemaline myopathy follow autosomal recessive inheritance, and the remainder are inherited in an autosomal dominant manner or are sporadic (new dominant cases – the first occurrence in the family).
Genetic disorders 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.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
Mutations in the ACTA1 gene have been found to cause approximately 15-25 percent of nemaline myopathy. Most ACTA1 mutations are a spontaneous (de novo) genetic change (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.

Mutations in the NEB gene have been identified as a cause of about 50% of nemaline myopathy. Mutations in 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 in the TPM2, TPM3, TNNT1, CFL2, KBTBD13, KLHL40, KLHL41 and LMOD3 genes are rarer causes of nemaline myopathy, with only smaller numbers of affected families reported to date.

The genes involved in nemaline myopathy contain instructions for creating (encoding) certain proteins that play an essential role in the normal structure and function of the contractile apparatus of skeletal muscle. Mutations to these genes result in deficiency or dysfunction of these proteins. 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 contractile function of skeletal muscle fibers. Therefore, if these proteins are deficient or defective, the strength of muscle contraction and in some cases the development of normal muscle structure is impaired.

Affected Populations

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 to be 1 in 50,000 live births. An incidence of 1/500 has been reported in the Amish community.


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 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 when stained with Gomori trichrome. A biopsy is the surgical removal and microscopic evaluation of affected tissue. Increasingly the diagnosis is made or confirmed by molecular genetic testing for mutations in the genes known to cause nemaline myopathy.


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