Nemaline myopathy (NM) is a rare genetic disorder whose name is derived from characteristic rod-shaped structures visible upon histopathological examination of biopsy samples. These are so-called nemaline bodies; they are also the reason why NM is sometimes referred to as rod myopathy. Nemaline bodies presumably consist of accumulated, abnormal protein, although their precise source is not yet known.
NM mainly affects skeletal muscles and the vast majority of NM patients primarily suffers from hypotonia and weakness of facial, neck and proximal limb musculature . Reflexes are generally blunted. Myopathy of facial and neck muscles may lead to feeding difficulties, dysphagia, dysarthria and respiratory insufficiency. With regards to arms and legs, muscle contractures and consequent restriction of joint movements, deformities and claudication are most frequently observed. A wheelchair may be required at some point. Because trunk musculature is not entirely spared, an abnormal curvature of the spine is noted in many cases. Functional impairment of respiratory muscles and heart is not uncommon and does significantly worsen prognosis.
According to the age at symptom onset, severity of myopathy and possible progression, six types of NM are clinically distinguished:
A variety of gene defects has been associated with NM. To date, mutations in ten distinct genes have been identified as possible triggers of this disease . Few NM patients don't present any mutation described so far . Most likely, future publications will report additional gene variants that contribute to muscle weakness and modulate severity of symptoms.
Mutations of the following genes account for the majority of NM cases:
Less often, mutations of genes CFL2 (cofilin 2), KBTBD13 (kelch repeat and BTB domain containing 13), KLHL40 (kelch-like family member 40), KLHL41 (kelch-like family member 41) and LMOD3 (leiomodin 3) are identified in DNA samples obtained from NM patients.
Specific gene mutations cannot in all cases be assigned to a determined clinical form of the disease.
Disease incidence and prevalence varies largely between distinct ethnicities. In general, incidence is assumed to be about 1 per 50,000 live births . Highest prevalence rates have been reported for Ashkenazi Jews. Here, one out of 108 individuals carries a defective copy of NEB .
With regards to clinical presentation of NM, the following shares have been reported: severe congenital NM - 16%, intermediate congenital NM - 20%, typical congenital NM - 46%, childhood-onset NM - 13%, adult-onset NM - 4%. Amish NM was not considered in that evaluation .
As can be seen in the above given list of gene defects associated with NM, the disease is triggered by malfunction of proteins required for regulation and execution of muscle contraction.
Actin, myosin, nebulin, troponin and tropomyosin constitute contractile, stabilizing and regulatory components of sarcomers, the smallest contractile unit of a muscle. In order for a muscle to contract significantly, many cross-bridge cycles have to occur:
Any pathological alteration of the involved proteins will cause insufficient muscle shortening and consequent hypotonia and muscle weakness. Characteristic distribution of symptoms, i.e., predilection of facial, neck and proximal limb muscles, may partially be explained by the fact that gene mutations interfere with expression of determined isoforms of those proteins forming the contractile unit of a muscle. For instance, TMP3 and TNNT1 are mainly expressed in slow twitch fibers.
Abnormal proteins may accumulate and become visible as nemaline bodies upon pathohistological analysis.
Prognosis largely depends on the type of NM. Severe congenital and Amish NM are the most severe forms of the disease and are generally associated with death due to respiratory failure in infancy. The most common form of the disease, typical congenital NM, may reduce quality of life but does not significantly diminish life expectancy.
Presentation varies between distinct forms of NM. However, some general observations can be made.
Primary involvement of facial, neck and proximal limb musculature is characteristic for NM. All affected muscles are hypotonic and weak. Reflexes that depend on those muscles are blunted. In case of congenital NM, facial and neck myopathy manifests soon after birth in altered facial expression, feeding difficulties, dysphagia, delayed speech, dysarthria and difficulties to lift the head. Respiratory insufficiency may be an issue that tends to aggravate while the child is sleeping. Additionally, malformations such as retrognathia and palate deformities are often noted. Involvement of limb muscles delays motor development and affected children usually sit, stand and walk later than their peers. Muscle contractures are very common. They may cause joints to loose their active and passive mobility. With regards to the trunk, pectus carinatum and scoliosis are frequent findings.
Additionally, the following applies to the individual types of NM:
A family history of NM and clinical findings prompt a strong suspicion for NM. In order to confirm that diagnosis, a muscle biopsy needs to be obtained and has to be analyzed histopathologically. Rod-shaped nemaline bodies are pathognomonic for NM and are best visualized after Gomori trichrome staining. Additional findings may consist in altered ratios of muscle fiber types and sizes. Biopsy samples should be taken from most severely affected muscles. Subsequent genetic screens may reveal the causative gene defect and allow for an evaluation of inheritance patterns.
If blood samples are analyzed, creatine kinase levels may be normal or moderately elevated.
Causative treatment for NM is not available.
Supportive therapy has to be adjusted to the needs of the individual patient and may, for instance, consist in placing a feeding tube, supplying oxygen or offering respiratory assistance. If a child is diagnosed with congenital NM, oxygen saturation should at least be monitored since general muscle weakness does not necessarily correlate with the risk of respiratory failure. This applies particularly while the child is sleeping.
Speech therapy may improve articulation.
Stretching, low-intensity exercise and massages may help to relieve muscle complaints: Muscle strength is conserved and contractures are prevented. Functional impairment of determined muscles may require wearing a brace or an orthosis or using a wheelchair. Surgical interventions may be indicated in some cases.
No specific measures can be recommended to prevent NM. Affected individuals and families may benefit from genetic counseling before deciding on having children.
Nemaline myopathy (NM) is a rare genetic disorder characterized by extensive muscle weakness. Severe forms are often lethal in early childhood, but the most typical form of NM is associated with a normal life expectancy.
To date, ten gene defects have been identified as possible triggers of NM. All these genes encode for proteins that play important roles in regulation and execution of muscle contraction. If any of those proteins malfunctions, the muscle is unable to contract in a normal manner. Affected muscles are hypotonic and weak, the patient is unable to exert significant forces with them.
In most cases, symptoms are already present at birth or develop within a short period of time afterwards. NM typically affects muscles of face, neck and limbs. Infants carrying any of the above mentioned gene mutations thus present an altered facial expression, difficulties to breathe, feed, swallow and speak. Motor development is delayed and children suffering from NM usually lift their heads, sit, stand and walk later than their peers.
If family history or clinical examination imply NM, a muscle biopsy needs to be obtained and analyzed for characteristic alterations of muscle cells. If these are found, a genetic screening should be carried out to identify the precise mutation that triggered myopathy in that particular case. This information is of particular importance to evaluate inheritance patterns and to advise adult patients that may wish to have children.
Causative treatment is not available; supportive therapy is adjusted to the needs of every individual patient. Infants may require a feeding tube to assure proper nutrition. Respiratory assistance may be necessary to avoid respiratory failure. Stretching, low-intensity exercise and massages may help to relieve muscle complaints. However, even orthopedic measures can't guarantee that a patient suffering from NM may not require a wheelchair at some point in their lives.