Nemaline myopathy

ALSO KNOWN AS: NM; nemaline rod myopathy; rod myopathy

DEFINITION Nemaline myopathy (NM) is a neuromuscular disease that is inherited in an autosomal recessive or autosomal dominant pattern. It is classified into six types according to disease onset and severity. Muscle weakness is a prominent feature and is most severe in the muscles of the face, neck, and proximal limbs. Histological examination of muscle biopsies reveals rod-shaped structures called nemaline bodies or rods in affected muscle fibers.

Risk Factors

A family history of NM and/or the identification of an NM gene mutation are risk factors. NM is present in many ethnicities; men and women are affected equally. Those of the Old Order Amish population of Pennsylvania are at an increased risk of inheriting NM, with an estimated incidence of 1 in 500 compared to the worldwide estimated incidence of 1 in 50,000. The Old Amish type of nemaline myopathy is usually fatal by early childhood.

Etiology and Genetics

Currently, six genes are associated with NM, some of which exhibit both autosomal dominant and autosomal recessive transmission. Two genes account for most cases of nemaline myopathy, with mutations on the nebulin (NEB) gene on chromosome 2q22 accounting for approximately 50 percent of cases and mutations on the alpha-actin-1 (ACTA1) gene on chromosome 1q42 accounting for 15 to 25 percent of cases. The remaining four genes are alpha-tropomyosin-3 (TPM3) on chromosome 1q22, beta-tropomyosin (TPM2) on chromosome 9p13.2-p13.1, troponin T type 1 (TNNT1) on chromosome 19q13, and cofilin-2 (CFL2) on chromosome 14q12. Additional genetic heterogeneity likely exists, as some individuals with NM do not have mutations in the known NM genes.

The NEB, ACTA1, TPM3, TPM2, and TNNT1 genes encode proteins that constitute the thin filaments of a sarcomere, the basic structural and functional unit of muscle contraction. Cofilin-2 is an actin-binding protein that helps to assemble and disassemble the actin filaments of muscles.

The different genetic forms of NM demonstrate considerable clinical overlap, and thus genotype-phenotype correlations are not reliable. In addition, no association has been established between the different gene mutations and muscle pathology.

Symptoms

Symptoms of nemaline myopathy can range from severe, leading to neonatal death, to mild symptoms with late onset that present in adulthood. The current classification system includes six forms of NM based on the motor and respiratory involvement and age at onset. All forms include muscle weakness, most prominently in the muscles of the face, neck, and proximal limbs. Distal muscles, respiration, and swallowing may be compromised. Hypotonia and depressed or absent deep tendon reflexes are generally observed.

The most common type, typical congenital, affects 46 percent of individuals with nemaline myopathy and is usually evident within the first year of life or shortly thereafter. Symptoms may include feeding difficulties, weakness of the respiratory muscles, and some distal weakness. Ambulation generally can be achieved.

The severe congenital form, affecting 16 percent of individuals with nemaline myopathy, manifests neonatally with hypotonia, absent spontaneous movement, respiratory insufficiency, and arthrogryposis. Sucking and swallowing difficulties and gastroesophageal reflux may be present. Death in infancy is common, but some patients survive long-term. Pregnancy symptoms, including decreased fetal movement and polyhyramnios (an excessive accumulation of amniotic fluid), may have been present, indicating a potential neonatal complication.

The intermediate congenital form is more severe than the typical congenital form but less severe than the severe congenital form. The intermediate congenital form affects approximately 20 percent of individuals with nemaline myopathy. This form is sometimes not diagnosed until symptom progression is clear, and the typical and severe congenital forms are ruled out. Neonatal respiration is usually intact, but later ventilatory support may be needed. Early symptoms include joint contractures and delayed milestones. Wheelchair support may be required.

Childhood-onset NM usually presents in adolescence and affects 13 percent of individuals with nemaline myopathy. Foot drop from symmetric ankle weakness is often a presenting symptom. Limb weakness is slowly progressive and may affect more proximal muscles. Wheelchair support may be required.

Adult-onset NM is phenotypically variable with sporadic onset; it affects 4 percent of individuals with nemaline myopathy. It usually manifests between ages twenty and fifty with general weakness and muscle pain. It is progressive and may involve respiratory and cardiac compromise, in addition to inflammatory changes on biopsy. A minority of sufferers develop monoclonal gammopathy, which generally indicates a poor prognosis. There is speculation whether this form represents a different disease.

Amish NM, caused by mutations in troponin T type 1, has been described only in Old Order Amish families. This severe, autosomal recessive form presents at birth with hypotonia, contractures, pectus carinatum, and transient tremors. Progressive muscle atrophy and respiratory insufficiency often lead to death between the ages of two and three.

Screening and Diagnosis

When NM is suspected, muscle biopsy in association with a careful medical examination should be performed. Serum creatine kinase studies may be ordered and are generally within normal limits or slightly elevated. Both electromyography (EMG) and nerve conduction studies may be normal in many cases. Genetic analysis of the ACTA1, NEB, TNNT1, TPM2, and TPM3 genes is clinically available to confirm diagnosis. In addition, participation in research on NM may result in molecular confirmation of this condition as new genes related to NM are identified.

Pregnancy screening for congenital myopathies may include a fetal anatomy scan in the mid-trimester and periodic growth scans, with careful attention to amniotic fluid volume and fetal activity. Fetal diagnostic testing may be available to families in which a confirmed mutation has been identified.

Treatment and Therapy

Currently, there is no cure for NM, and treatment is supportive. The use of gastrostomy tubes, mechanical ventilation, and supportive devices for moving are not uncommon. For more severely affected patients, medical treatment may be aimed at providing comfort.

Experimental therapies are being investigated in different laboratories worldwide. Some investigators are focusing on molecular approaches to treatment, while other laboratories are focusing efforts on possible drug therapies. An Australian investigator has found that a dietary supplement of L-tyrosine may improve bulbar function, exercise capabilities, and activity level.

Prevention and Outcomes

In families with a history of NM, genetic counseling should always be offered. In families where a genetic mutation is identified, preimplantation genetic diagnosis may be possible, as are the options of using a donor egg or sperm. Otherwise, there is no effective means of prevention.

Symptomatic treatment, such as ventilation and feeding tubes, may prolong survival. Researchers have reported various symptomatic findings that may adversely affect prognosis and survival. These include neonatal hypotonia, severe respiratory compromise, arthrogryposis multiplex congenita, and lack of independent ambulation before eighteen months. Severe cases of NM may lead to early death due to respiratory failure, whereas patients with less severe types of NM may survive into adulthood.

Bibliography

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Laing, Nigel G., and Carina Wallgren-Pettersson. “161st ENMC International Workshop on Nemaline Myopathy and Related Disorders, Newcastle upon Tyne 2008.” Neuromuscular Disorders 19 (2009): 300–05. Print.

Miyatake, Satoko, et al. "Deep Sequencing Detects Very-Low-Grade Somatic Mosaicism in the Unaffected Mother of Siblings with Nemaline Myopathy." Neuromuscular Disorders 24.7 (2014): 642–47. Print.

"Nemaline Myopathy." Cleveland Clinic, 17 Sept. 2022, my.clevelandclinic.org/health/diseases/24180-nemaline-myopathy. Accessed 5 Sept. 2024.

"Nemaline Myopathy." Medline Plus, 1 Dec. 2015, medlineplus.gov/genetics/condition/nemaline-myopathy/. Accessed 5 Sept. 2024.

Piteau, Shalea J. "Congenital Myopathy with Cap-Like Structures and Nemaline Rods: Case Report and Literature Review." Pediatric Neurology 512 (2014): 192–97. Print.

Sanoudou, Despina, and Alan H. Beggs. “Clinical and Genetic Heterogeneity in Nemaline Myopathy—A Disease of Skeletal Muscle Thin Filaments.” Trends in Molecular Medicine 7.8 (2001): 362–68. Print.