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Nemaline Myopathy


Nemaline myopathy is a genetic disorder characterized by skeletal muscle weakness. Clinical presentation varies largely and while some forms of nemaline myopathy are fatal in childhood, life expectancy is nearly normal in others.


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:

  • Severe congenital NM is associated with severe, generalized hypotonia and weakness of skeletal muscles. Nemaline bodies may also be detected in cardiac muscles [10]. Symptoms are present at birth and affected children have difficulties in suckling, swallowing and breathing. Spontaneous movements are restricted. Severe contractures may provoke fractures. Death in infancy is probable and is usually due to respiratory insufficiency or aspiration pneumonia.
  • Symptoms of intermediate congenital NM are similar but less severe. These children may develop the above described general symptoms of NM, that may not even be detectable in those infants suffering from severe congenital NM because of early death. This form of the disease may be fatal in infancy, but the average life expectancy is higher.
  • Patients diagnosed with typical congenital NM often demonstrate many of the aforementioned symptoms related to facial, neck and limb muscle weakness. Symptoms may improve over time, but patients may maintain an abnormal gait or even require a wheelchair.
  • Amish NM is characterized by episodes of tremor that start soon after birth. Tremor subsides slowly, but respiratory failure frequently leads to death in infancy.
  • Childhood-onset NM is usually diagnosed during the second decade of life. Early development of motor skills is unaltered, but progressive muscle weakness is noted during adolescence.
  • Adult-onset NM is rare. Age at symptom onset and symptoms themselves vary largely. They may not correspond in any way to those described for typical congenital NM [11].
  • Until the age of 17 years, she was asymptomatic except that her running speed was slow. The T1-weighted image of muscle MRI at the mid-thigh level showed hyperintensity of the quadriceps femoris muscle and relatively spared hamstring muscle.[ncbi.nlm.nih.gov]
  • The disease has a wide spectrum of phenotypes, ranging from forms with neonatal onset and fatal outcome to asymptomatic forms. The neonatal form is severe and usually fatal.[ncbi.nlm.nih.gov]
  • […] myopathy (NM) is a rare congenital myopathy characterized by muscle weakness, hypotonia and the presence in muscle fibers of inclusions known as nemaline bodies and a wide spectrum of clinical phenotypes, ranging from severe forms with neonatal onset to asymptomatic[ncbi.nlm.nih.gov]
  • Report of a family with symptomatic and asymptomatic members. Arch Neurol. 1978 Dec; 35 (12):823–826. [ PubMed ] [ Google Scholar ] Topaloglu H, Gögüs S, Yalaz K, Kücükali T, Serdaroglu A.[pubmedcentral.nih.gov]
  • […] disability-spasticity-ectrodactyly syndrome Intellectual disability-strabismus syndrome Intermediate DEND syndrome Intermediate nemaline myopathy Intermediate severe Salla disease Internal carotid agenesis Isolated Dandy-Walker malformation Isolated anencephaly/exencephaly Isolated asymptomatic[se-atlas.de]
Multiple Congenital Anomalies
  • Fatal neonatal nemaline myopathy with multiple congenital anomalies. J Pediatr. 1979 Jan; 94 (1):47–51. [ PubMed ] [ Google Scholar ] McMenamin JB, Curry B, Taylor GP, Becker LE, Murphy EG. Fatal nemaline myopathy in infancy.[pubmedcentral.nih.gov]
  • congenital anomalies-hypotonia-seizures syndrome Multiple congenital anomalies-hypotonia-seizures syndrome type 2 Multiple mitochondrial dysfunctions syndrome type 3 Multiple sulfatase deficiency Multiple system atrophy Multiple system atrophy, cerebellar[se-atlas.de]
Death in Infancy
  • Respiratory failure due to functional impairment of respiratory muscles or aspiration pneumonia usually leads to death in infancy.[symptoma.com]
  • Cytogenet Cell Genet. 1995; 69 (1-2):15–17. [ PubMed ] [ Google Scholar ] Hunt CC, Eyre HJ, Akkari PA, Meredith C, Dorosz SM, Wilton SD, Callen DF, Laing NG, Baker E.[pubmedcentral.nih.gov]
  • L-tyrosine may prevent aspiration by reducing pharyngeal secretions and drooling. Most of the patients die from respiratory and cardiac failure. This article discusses a newborn infant who presented with generalized weakness and respiratory failure.[ncbi.nlm.nih.gov]
  • […] coloboma-cleft lip and palate-intellectual disability VACTERL with hydrocephalus Van den Bosch syndrome Variant of Guillain-Barré syndrome Vici syndrome Visceral neuropathy-brain anomalies-facial dysmorphism-developmental delay syndrome Vocal cord and pharyngeal[se-atlas.de]
Exertional Dyspnea
  • A twenty-year old male presented with diffuse limb muscle weakness and exertional dyspnea since childhood.[ncbi.nlm.nih.gov]
  • L-tyrosine may prevent aspiration by reducing pharyngeal secretions and drooling. Most of the patients die from respiratory and cardiac failure. This article discusses a newborn infant who presented with generalized weakness and respiratory failure.[ncbi.nlm.nih.gov]
  • Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family. myopathies, nemaline myopathy, nemaline nemaline body disease nemaline rod disease rod body disease rod-body myopathy rod myopathy Lehtokari[ghr.nlm.nih.gov]
  • Nemaline myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal myopathy.[ncbi.nlm.nih.gov]
  • It is the most common non-dystrophic myopathy."Myopathy" means muscle disease. Muscle fibers from a person with nemaline myopathy contains thread-like rods, sometimes called nemaline bodies.[en.wikipedia.org]
  • As such, the congenital myopathies can be divided into 6 pathologic categories. [1, 2] nemaline myopathy (subtypes: rod, core-rod, cap and zebra body myopathy); core myopathy (subtypes: central core and multiminicore myopathy); centronuclear myopathy[emedicine.medscape.com]
  • From Wikidata Jump to navigation Jump to search congenital structural myopathy characterized by generally non-progressive muscle weakness of varying severity nemaline rod myopathy rod myopathy nemaline body disease NEM NM edit English nemaline myopathy[wikidata.org]
Back Pain
  • She had chronic low back pain which had evolved over the preceding 10 years. Examination showed significant flexion of the thoracolumbar spine which was most prominent on standing and walking, improved on sitting and was relieved when supine.[em-consulte.com]
  • However, this patient suffered from chronic lower back pains radiating in the legs, which may explain the neurogenic changes on EMG in this patient. An additional peripheral neuropathy was excluded by nerve conduction studies in both patients.[ojrd.biomedcentral.com]
  • […] of Neuropathology, University Hospital RWTH Aachen, Aachen, Germany. 3 Department of Neurology, Medizinisches Zentrum StädteRegion Aachen, Würselen, Germany. 4 Reference Centre for Neuromuscular Diseases, Department of Neurology, University Hospital Angers[ncbi.nlm.nih.gov]
  • , Angers, France (5) Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany (6) Institute of Neuropathology, University Hospital Zürich, Zürich, Switzerland (7) Department of Neurology, University Hospitals Leuven, Leuven,[ojrd.biomedcentral.com]
Neonatal Hypotonia
  • RESULTS: Two patients had the typical congenital type, which exhibited neonatal hypotonia and delayed motor milestone, and five patients had the childhood onset type, which exhibited mild gait disturbance as a first symptom.[ncbi.nlm.nih.gov]
  • Diagnostic approach to neonatal hypotonia: retrospective study on 144 neonates. Eur J Pediatr. 2008 May. 167 (5):517-23. [Medline]. Birdi K, Prasad AN, Prasad C, Chodirker B, Chudley AE.[emedicine.medscape.com]
  • In a series of 250 infants with neonatal hypotonia described by Fardeau and Tome, muscle biopsy performed before age 2 months revealed that only 14% had a congenital myopathy.[emedicine.medscape.com]


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.


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.


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 [2]. Few NM patients don't present any mutation described so far [3]. 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:

  • NEB, a gene located at 2q22, is necessary for expression of nebulin, a sarcomeric protein that stabilizes actin. Many NEB mutations have been described and all are inherited with an autosomal recessive trait. Particularly high prevalence rates of nearly 1% have been reported for the Ashkenazi Jewish population [4]. About half of all NM cases are triggered by NEB mutations.
  • ACTA1, ubicated at 1q42, encodes for skeletal muscle α-actin, a major component of myofibrils. Similar to NEB, many distinct mutations of the ACTA1 gene have been described, the majority of which are inherited with a dominant trait. Dominant inheritance of NM-associated mutations implies mild symptoms. Of note, although the overall number of distinct ACTA1 mutations that are inherited recessively is lower, they are more frequently found. Thus, ACTA1 defects are commonly associated with severe forms of NM [5].
  • TPM2, a gene to be found at 9p13, encodes for β-tropomyosin, an essential protein for regulation of muscle contraction.
  • TPM3, located at 1q21, encodes for α-tropomyosin, a protein fulfilling a regulatory role in slow twitch muscle fibers. Both TPM2 and TPM3 mutations are mostly inherited with a dominant trait. Symptoms caused by the latter are generally more severe [6].
  • TNNT1 is a gene ubicated at position 19q13 and mutations related with NM have classically been related with Amish NM. However, one Dutch and nine Palestinian patients have recently been diagnosed with TNNT1-mediated NM [7] [8]. This gene encodes for slow skeletal troponin T1, a protein which regulates actin-myosin-binding.

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 [9]. Highest prevalence rates have been reported for Ashkenazi Jews. Here, one out of 108 individuals carries a defective copy of NEB [4].

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 [1].

Sex distribution
Age distribution


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:

  • Troponin mediates conformational changes in tropomyosin.
  • The latter allows for binding of actin to myosin.
  • Active tilting of myosin heads results in a power stroke and shortening of the sarcomer by a few nanometers.
  • Actin-myosin binding is loosened and the cycle can start anew.

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.


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 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 [1]. 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:

  • Severe congenital NM is the most severe form of the disease. Respiratory failure due to functional impairment of respiratory muscles or aspiration pneumonia usually leads to death in infancy.
  • Intermediate congenital NM is still considered a severe form of NM, but affected individuals have a higher life expectancy than those suffering from severe congenital NM. Motor development is delayed and children may need respiratory support
  • Typical congenital NM is the most common type of NM. Motor deficits as described above may improve throughout life and patients may be able to live an independent life.
  • Amish NM is a severe form of NM caused by gene defects that have mainly been encountered in Amish children. Tremor, a symptom not characteristic for other forms of NM, is often seen here. Death during infancy is likely.
  • Childhood-onset NM is characterized by progressive muscle weakness that typically becomes apparent during the second decade of life.
  • Adult-onset NM is another progressive form of NM. Symptom onset may occur at any time during adulthood.

Patient Information

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.



  1. North KN, Ryan MM. Nemaline Myopathy. 1993.
  2. Sztal TE, Zhao M, Williams C, et al. Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function. Acta Neuropathol. 2015; 130(3):389-406.
  3. Keller CE, Hays AP, Rowland LP, Moghadaszadeh B, Beggs AH, Bhagat G. Adult-onset nemaline myopathy and monoclonal gammopathy. Arch Neurol. 2006; 63(1):132-134.
  4. Anderson SL, Ekstein J, Donnelly MC, et al. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet. 2004; 115(3):185-190.
  5. Laing NG, Dye DE, Wallgren-Pettersson C, et al. Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1). Hum Mutat. 2009; 30(9):1267-1277.
  6. Marttila M, Lehtokari VL, Marston S, et al. Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies. Hum Mutat. 2014; 35(7):779-790.
  7. van der Pol WL, Leijenaar JF, Spliet WG, et al. Nemaline myopathy caused byTNNT1 mutations in a Dutch pedigree. Mol Genet Genomic Med. 2014; 2(2):134-137.
  8. Abdulhaq UN, Daana M, Dor T, et al. Nemaline body myopathy caused by a novel mutation in troponin T1 (TNNT1). Muscle Nerve. 2016; 53(4):564-569.
  9. Yamamoto DL, Vitiello C, Zhang J, et al. The nebulin SH3 domain is dispensable for normal skeletal muscle structure but is required for effective active load bearing in mouse. J Cell Sci. 2013; 126(Pt 23):5477-5489.
  10. Buonocore G, Balestri P, Toti P, Bagnoli F. A new case of severe congenital nemaline myopathy. Acta Paediatr. 1993; 82(12):1082-1084.
  11. Taglia A, D'Ambrosio P, Palladino A, Politano L. On a case of respiratory failure due to diaphragmatic paralysis and dilated cardiomyopathy in a patient with nemaline myopathy. Acta Myol. 2012; 31(3):201-203.

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Last updated: 2019-07-11 21:36