What causes nemaline myopathy 2 (NEM2)?

Updated: Mar 11, 2019
  • Author: Matthew Harmelink, MD; Chief Editor: Amy Kao, MD  more...
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Answer

NEM2 is due to a mutation in the gene for nebulin (NEB) and is likely the most common cause of nemaline myopathy. Nebulin is a large protein that extends the whole length of the thin filament. It has a highly repetitive structure (repeats have an α-helical structure) and can bind up to 200 actin molecules. This protein is present in skeletal and cardiac muscle. It is required for the proper assembly of thin filaments and for the maintenance of thin filament length and contractile function. Additionally, it is also likely responsible for proper periodicity of the troponin/tropomyosin complex. Multiple isoforms exist, differing in the C-terminal structure, which binds α-actinin in the Z-disk, and nebulin likely plays a role in Z-disk assembly.

Small deletions and duplications causing frameshifts and point mutations causing stop signals or altered splicing are more common than missense mutations. [11]  No mutational hotspots exist. It is expected that nonsense and frameshift mutations cause mRNA instability or truncated nebulin molecules ,while missense mutations likely disrupt the binding of actin to nebulin or affect the secondary structure of nebulin.

A clear genotype-phenotype correlation does not exist, but, in milder disease, it is likely that several normal isoforms are expressed.

Inheritance in all cases has been autosomal recessive with very variable phenotypes, [12]  with all but the adult-onset form being described in a large series encompassing 55 families. [11]

The severe congenital form presents at birth with severe hypotonia and weakness. Lack of movement, poor suck and swallow, and respiratory failure are frequent findings. Death in utero due to fetal akinesia has been described. Arthrogryposis and severe respiratory failure are associated with early death that usually occurs within the first 2 years of life.

The intermediate congenital form presents with weakness in early childhood and is characterized by delayed motor milestones and contractures. Children with this form usually need a wheelchair or ventilatory support by age 10 years.

The typical (most common) congenital form presents within the first year of life with hypotonia, generalized limb weakness, facial weakness, feeding difficulty, and mild respiratory weakness. Features such as elongated face, tent-shaped mouth, high arched palate, and retrognathia are common. Progression is static or very slow, and, after an initial rocky course, stabilization leads to an independent life.

The childhood-onset form presents with distal leg weakness in the late first or early second decade. Proximal muscles are involved later, and wheelchair dependency occurs in midlife.

The adult-onset form presents with symmetric proximal weakness in persons aged 20–50 years. Other features may include neck extensor weakness, respiratory insufficiency, or rapid progression.

Other forms include patients who do not fit any of the above presentations and can have cardiomyopathy, ophthalmoplegia, or an unusual distribution of weakness.


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