Last updated:
10/15/2024
Years published: 1986, 1987, 1989, 1990, 1994, 1998, 1999, 2001, 2007, 2015, 2024
NORD gratefully acknowledges Brooke Friedman and Evie Li, NORD Editorial Interns, Icahn School of Medicine at Mount Sinai and University of California, Los Angeles (respectively) and Dr. Jenni Laitila and Dr. Carina Wallgren-Pettersson, Folkhälsan Research Center, Helsinki, Finland, for assistance in the preparation of this report.
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Summary
Nemaline myopathy is a rare genetic muscle disorder characterized by thread-like structures (nemaline bodies) in the muscle.1
At least six different clinical subtypes of nemaline myopathy have been identified based on disease severity and age of onset, ranging from a severe congenital (at birth) form that is usually lethal in the first few months of life, to less severe forms with onset in childhood or adulthood.2 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.3
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.4 Weakness of the muscles responsible for breathing and swallowing is the major cause of morbidity and mortality. 5-6
Introduction
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.1 The prefix “nema-” is derived from Greek and means “thread.” Nemaline bodies consist of accumulations of muscle proteins due to variants in genes which encode protein components of the thin muscle filament.1
The age of onset and severity of symptoms and signs associated with nemaline myopathy vary greatly from person to person.5 Some people with nemaline myopathy show symptoms shortly after birth (congenital onset).3 Less often, the disorder may develop during childhood or even more uncommonly in adulthood.2
The major clinical features of nemaline myopathy are muscle weakness, hypotonia and reduced or absent reflexes.7,8 Muscle weakness is usually most severe in muscles of the face, neck and proximal muscles.2 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 small, displaced jaw that is farther back than normal (retrognathia), small tongue and mouth and a highly-arched roof of the mouth (palate).2 Muscle weakness may also cause difficulty speaking (dysarthria), swallowing, breathing (respiration), restlessness during sleep and feeding problems.6 Though rare, if left untreated, respiratory insufficiency can lead to cardiac issues, specifically enlargement and failure of the right ventricle (cor pulmonale) due to increased pressure in the pulmonary trunk.2 Paralysis of the eye muscles (ophthalmoplegia), though very rare, has also been observed.2
Affected infants often have delays in obtaining motor milestones such as head control, sitting up, standing, or walking.2 A sunken chest (pectus excavatum) is often present in infancy and early childhood. 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), abnormal side-to-side-curvature of the spine (scoliosis) or abnormal rigidity of the spine.7
As of 2021, a revised classification of the different categories of NM has been proposed to more accurately reflect the genetic causes and characteristics of each category.2
Severe (neonatal) NM
This form of nemaline myopathy is apparent at birth. Affected infants have severe hypotonia and muscle weakness, which leads to difficulty sucking, swallowing (dysphagia) and feeding.6 Infants also show profound muscle weakness, which leads to little spontaneous movement and respiratory insufficiency.9 Some infants may experience the passage or backflow (reflux) of the contents of the stomach or small intestines into the esophagus (gastroesophageal reflux) and need a feeding tubeas they grow older.9 Research has also shown that about 50% of affected individuals show tongue atrophy in a triple furrow pattern and the presence of multiple contractures (arthrogryposis multiplex congenita).9-10
In rare cases, this form of nemaline myopathy has been associated with disease of the heart muscle (cardiomyopathy).2 The severe involvement of respiratory muscles often leads to life-threatening respiratory failure and weakness of the bulbar (swallowing) muscles and increases the risk of aspiration pneumonia (in which liquid or food is inhaled into the lungs).9
Recessive TNNT1 (formerly Amish) NM
This form of myopathy is a subtype of severe NM.2 It was originally identified in several related families within an Amish community, but has since been recorded in patients of non-Amish origin.2 Since it is caused by changes (variants) in the TNNT1 gene and may occur in other populations too,11 it has been renamed as “TNNT1” instead of “Amish” nemaline myopathy to be more accurate.2 Onset is shortly after birth but is also progressive, meaning it worsens with time.2 Affected infants may have low muscle tone (hypotonia), multiple contractures and tremors, which usually diminish over the first few months of life.11 Affected infants have progressive muscle weakness, a severely deformed and stiff chest with a prominent sternum (pectus carinatum), muscle wasting (atrophy) and life-threatening respiratory insufficiency.11 Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita (joint contractures, which are restrictions of the movement of the joints) often lead to death in the second year of life.11 There is one report in the medical literature about an affected person with a TNNT1 recessive gene variant in an Italian family who presented with mild symptoms that increased in severity during adulthood.11
Typical NM
This is the most common form of nemaline myopathy accounting for approximately half of all affected people.3 This form is present at or shortly after birth or sometime during the first year of life and generally does not limit life.2-3 Affected infants may have muscle weakness (hypotonia) leading to abnormal “floppiness” and feeding difficulties, however these motor milestones are often reached after this initial delay.2 Similar to severe NM, a small, furrowed tongue and multiple contractures has also been described in typical NM.10 Muscle weakness is less severe in the typical congenital form than in the severe congenital form.3
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).6 Some infants may have an abnormal waddling walk (gait), swallowing difficulties (dysphagia), speech difficulties (dysarthria) and a nasal tone to the voice.6 Affected infants may also have delays attaining gross motor milestones such as holding one’s head up, sitting or standing.2
Muscle weakness in infants with the typical congenital form of nemaline myopathy usually affects the proximal muscles, but may spread over time 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.3 The muscle weakness associated with the typical form does not usually progress or progresses very slowly.2,3 Some individuals have even seen an improvement in motor functioning as a result of active physical training.3
Mild NM
Mild NM is generally associated with onset in childhood or adolescence3 and is associated with milder symptoms of muscular weakness in the facial, respiratory and neck muscles12 that can manifest as poor sucking, slight difficulties walking and fatigue.12,13 People with mild NM exhibit these symptoms in childhood or adolescence but can show improvement in muscle strength later in life.
Distal NM
Distal NM presents with weakness of distal musculature,2 such as in the hands, feet, lower legs and forearms. It can also cause the stiffening of multiple distal joints, causing limited range of motion and the inability to extend or bend the joint.14
Childhood onset NM with slowness
This form of nemaline myopathy usually becomes apparent between 10-20 years of age. The development of early motor skills is usually unaffected. Sometime during the late teens or early twenties, affected individuals develop slowly progressive muscle weakness (hypotonia), and over half exhibit signs of respiratory complications.15 A key characteristic of this subtype is slowness of movements.2 Muscle biopsy of affected individuals will show a core-rod combination.2 In rare cases, the heart and urinary tract have been shown to be affected, and paralysis of the eye muscles (ophthalmoplegia) can occur.2
Other (unusual) forms
This encompasses forms of nemaline myopathy with unusual clinical symptoms and signs, such as usual patterns of muscle weakness or a heart problem, for example thickened left ventricle of the heart (hypertrophic cardiomyopathy).2 This category also includes cases of NM that differ histologically. This can include the presence of actin aggregates, intranuclear rods and lipid droplets.2
One example is of ADSSL1 myopathy, the most common form of NM in Japan that has been associated with adult onset and patients have both distal and proximal muscle weakness.8 This NM is characterized by a combination of nemaline bodies and increased lipid droplets and myofibrillar disorganization8. Other signs and symptoms for ADSSL1 nemaline myopathy include difficulty swallowing from loss of teeth (41% of patients), abnormally thick heart muscle (25% of patients) and reduced total lung capacity (76% of patients).
NM can follow autosomal recessive inheritance, autosomal dominant, or sporadic (new dominant cases – the first occurrence in the family).16
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.
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. 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.
As of 2024, variants in at least 14 genes have been found to cause nemaline myopathy, all of which encode proteins of the muscle contractile apparatus (sarcomere).17 These genes include ACTA1, NEB, LMOD3, TPM3, TPM2, TNNT1, ADSSL1, TNNT3, CFL2, MYPN, KBTBD13, KLHL40, KLHL41, and MYO18B.17 Patients with the same genetic variant typically exhibit similar physical NM symptoms, however this is not always the case.5
Variants in the ACTA1 gene have been found to cause approximately 20-25% percent of all nemaline myopathy cases, and about 50% of severe cases.18 Most ACTA1 variants are a spontaneous (de novo) genetic change (new variant ) and are not inherited.16 However, some cases have resulted from autosomal dominant and, more rarely, autosomal recessive inheritance.16 The severe, intermediate or typical congenital forms of nemaline myopathy may be caused by ACTA1 gene variants.19
Variants in the ACTA1 gene have been found to cause approximately 20-25% of all nemaline myopathy cases, and about 50% of severe cases.18 Most ACTA1 variants are a spontaneous (de novo) genetic change (new variant ) and are not inherited.16 However, some cases have resulted from autosomal dominant and, more rarely, autosomal recessive inheritance.16 of the ACTA1 gene may cause the severe, intermediate or typical congenital forms of nemaline myopathy.19
About 35% of cases of nemaline myopathy are caused by variants in the NEB gene.17 Variants in this gene can cause any form of the disorder and affected people may have a broad symptoms of muscle hypotrophy (small muscle bulk) as well as respiratory and bulbar function involvement. Symptoms can range from mild to severe, though most individuals with a NEB variant have the typical congenital form.9 Variants of the NEB gene are inherited in an autosomal recessive pattern.17 One study of 30 Brazilian individuals with NM showed that within the NEB gene, there were 25 different variants shown to cause NM.5
Variants in the TPM2, TPM3, ADSSL1, TNNT1, TNNT3, MYPN, CFL2, KBTBD13, KLHL40, KLHL41, MYO18B, and LMOD3 genes are rarer causes of nemaline myopathy, with only smaller numbers of affected families reported to date.5 In a recent study of nemaline myopathy, 30% of participants did not have variants in these genes, indicating that there are likely more disease-causing genes yet to be discovered.3
The genes involved in nemaline myopathy contain instructions (encode) for certain proteins that play an essential role in the normal structure and function of the contractile apparatus of skeletal muscle.20 Variants in these genes result in deficiency or dysfunction of these proteins. These proteins work together to form structures known as thin filaments, which are long chains of proteins.21 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.21
The muscle weakness associated with NM is thought to be caused by shortened or elongated thin filaments, reduced efficiency in actin-myosin interactions, or decreased calcium sensitivity.17 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.
Nemaline myopathy is a rare disorder that affects males and females. The incidence is estimated to be 1 in 50,000 live births.15 There is a carrier frequency of 6.5% in the Old Order Amish population.22
A diagnosis of nemaline myopathy is suspected based upon a thorough clinical evaluation, a detailed patient and family history, identification of characteristic findings and molecular testing for genetic variants.9 A diagnosis may be confirmed by the presence of thread- or rod-like structures (nemaline bodies) on muscle biopsy when stained with Gomori trichrome.4 A biopsy is the surgical removal and microscopic evaluation of affected tissue.
Treatment
No curative treatment exists for nemaline myopathy. Treatment is supportive and directed toward the specific symptoms that are apparent in each individual.2 Infants with nemaline myopathy may benefit from a program involving mild-to-moderate, low-impact exercise, speech therapy, massage and stretching techniques. Such therapy is aimed at preserving muscle strength and function and to prevent the development of contractures.
In addition, respiratory support may be necessary, potentially including mechanical ventilation to prevent nocturnal hypoventilation.6 Careful monitoring of breathing is essential because even individuals with minimal muscle weakness in the arms and legs can have impaired breathing especially during sleep.6
Lower respiratory infections must be promptly and aggressively treated to avoid complications. Since some affected people may experience feeding difficulties,2 tube-feeding may be required to ensure proper caloric and nutritional intake. Speech therapy may be necessary for individuals with difficulty speaking or nasally speech and may potentially improve feeding in infants.
In some people, 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.2 Long periods of immobilization should, however, be avoided. People with significant muscle weakness in the legs may eventually require a wheelchair.
Genetic counseling is recommended for affected individuals and their families.
There is ongoing investigation to find a curative treatment for nemaline myopathy. At least eleven experimental treatments are underway, which target (1) affected genes, (2) biological pathways that affect muscle contraction, (3) the formation of skeletal muscular tissue in the womb (4) general therapies to improve muscle function and (5) a combination of the above.4 There is some evidence to suggest that Omecamtiv mecarbil, a medication which generally treats heart failure, can improve skeletal muscle function in nemaline myopathy patients with the NEB gene variant.17
Another new treatment is inspiratory muscle training, which has been shown to improve respiratory muscle strength by using a specific training device.25 A study published in 2023 showed that nemaline myopathy patients who underwent this treatment for eight weeks showed improvement in respiratory muscle strength.25
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 website.
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 website.
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
Email: [email protected]
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
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