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].

• Weakness

  The severity and pattern of muscle weakness varies, but most affected individuals show mildly delayed motor development, hypotonia, generalized muscle weakness, and weakness of the proximal limb muscles and neck muscles, resulting in difficulty running [diseaseinfosearch.org]

  On clinical examination, he had mild neck flexor and facial weakness, a high arched palate, and a pes cavus deformity; there were no cardiac symptoms. [annalsofian.org]

  The adult form may only present with weakness in the seventh decade. The course of nemaline myopathy may be static or progressive. Most patients have progressive weakness, although occasionally weakness improves over time. - CNM. [rrnursingschool.biz]

  There was bilateral facial weakness, as well as proximal and distal wasting and weakness in the arms and legs. Electromyography (EMG) showed a combination of myopathic and neurogenic changes. [researchgate.net]

• Feeding Difficulties

  Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management is warranted in most cases of congenital nemaline myopathy. [onlinelibrary.wiley.com]

  Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. [ncbi.nlm.nih.gov]

  Management and treatment A multidisciplinary approach is needed to handle respiratory insufficiency (permanent or intermittent use of mechanical ventilation and treatment of lower respiratory tract infections) and feeding difficulties (feeding techniques [orpha.net]

  Muscle weakness may also cause difficulty speaking (dysarthria) and swallowing resulting in feeding difficulties. Some infants with nemaline myopathy may require a feeding tube. [rarediseases.org]

• Rigor

  Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. [blueprintgenetics.com]

  The high mol. wt proteins titin and nebulin were highly sensitive to proteolysis during the rigor mortis period [5]. [wikigenes.org]

  Manstein and Stefan Raunser, Structure of the Rigor Actin-Tropomyosin-Myosin Complex, Cell, 10.1016/j.cell.2012.05.037, 150, 2, (327-338), (2012). P. B. Agrawal, M. Joshi, T. Savic, Z. Chen and A. H. [doi.org]

• Short Stature

  […] encephalopathy with microcephaly Severe neurodegenerative syndrome with lipodystrophy Short stature-intellectual disability-eye anomalies-cleft lip/palate syndrome Short stature-webbed neck-heart disease syndrome Short ulna-dysmorphism-hypotonia-intellectual [se-atlas.de]

  Cardiomyopathy and short stature associated with mitochondrial and/or lipid storage myopathy of skeletal muscle. Neuropaediatrie 1976;7: 196–208. 410. Williams ML, et al. Ichthyosis and neutral lipid storage disease. [slideshare.vn]

• El Salvador

  El Salvador : La Libertad, San Salvador, etc. Equatorial Guinea : Malabo, etc. Eritrea : Asmara, etc. Estonia : Haapsalu, Kuressaare, Narva, Pärnu, Saaremaa, Tallinn, Tartu, etc. Ethiopia : Addis Ababa, Bahir Dar, Gondar, etc. [maria-online.com]

• Dysphagia

  DEVELOPMENT: All the children presented dysphagia, with severe feeding problems during the first three years of life that nevertheless are somewhat mitigated as time goes by. [ncbi.nlm.nih.gov]

  Dysphagia was severe and a percutaneous gastrostomy was performed after he had lost 60 pounds. Eye and tongue movements were normal and his speech was clear. He could not raise his head if supine. [jamanetwork.com]

  Dysphagia, cardiomyopathy and ophtalmoplegia were not observed. [scielo.br]

  Myopathy of facial and neck muscles may lead to feeding difficulties, dysphagia, dysarthria and respiratory insufficiency. [symptoma.com]

• Diarrhea

  Pagina 54 - Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. ‎ Pagina 51 - Selective IgA deficiency: presentation of 30 cases and a review of the literature. ‎ [books.google.ro]

  In older infants or children, low plasma magnesium levels are encountered in malabsorption syndromes, prolonged diarrhea, rickets, protein energy malnutrition or other forms of chronic malnourishment, and hypoparathyroidism (117,123). [slideshare.vn]

• High Arched Palate

  Other common features include myopathic facies, high-arched palate, and scoliosis. Histologic findings on skeletal muscle biopsy are variable, even in patients with the same mutation. [diseaseinfosearch.org]

  Elongated faces and high arched palates and feet were also observed. On light microscopy, the nemaline bodies were observed in type 1 and 2 fibers. All patients showed type 1 predominance and atrophy. [ncbi.nlm.nih.gov]

  The high arched palate, prognathic mandible, malocclusion and abnormal facies might complicate laryngeal intubation. [neurologyindia.com]

  arched palate (J Med Genet 1997;34:705) Diagnosis Clinicopathologic diagnosis Muscle biopsy Laboratory findings are typically nonspecific Treatment No proven effective therapy other than symptomatic treatment Symptomatic treatment has shown to be helpful [pathologyoutlines.com]

  On clinical examination, he had mild neck flexor and facial weakness, a high arched palate, and a pes cavus deformity; there were no cardiac symptoms. [annalsofian.org]

• Myopathy

  Nemaline myopathy due to mutations in α-tropomyosin SLOW was characterized by preferential rod formation in, and atrophy of, type 1 fibers. Light microscopic features of nemaline myopathy correlate poorly with disease course. [neurology.org]

  Keywords: Nemaline rods, myopathy, Z disc How to cite this article: Deepti A N, Gayathri N, Veerendra Kumar M, Shankar SK. Nemaline myopathy: A report of four cases. [annalsofian.org]

  DISEASE CHARACTERISTICS 1.1 Name of the disease (synonyms) Nemaline myopathy (NEM1 – NEM7) Includes nemaline myopathy with excess thin filaments/actin aggregates; nemaline myopathy with cores; nemaline myopathy with intranuclear rods; and Amish nemaline [nature.com]

  Term Name: nemaline myopathy Search Ontology: Synonyms: Nemaline body disease nemaline rod myopathy rod myopathy Definition: A congenital structural myopathy characterized by generally non-progressive muscle weakness of varying severity; certain muscle [zfin.org]

  Similar appearance & staining to: Cytoplasmic bodies Also see: Rods or Cytoplasmic bodies in target fibers Nemaline rod myopathy: Infantile No nemaline rods in quadriceps muscle from same child biopsied at 2 months of age Nemaline rod myopathy, Infantile [neuromuscular.wustl.edu]

• Psychomotor Retardation

  A case report is presented in which a 4-year-old male is diagnosed with hypertrophic cardiomyopathy, respiratory distress, muscle hypotonia, and psychomotor retardation. [ncbi.nlm.nih.gov]

  retardation syndrome Autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome Autosomal recessive cerebelloparenchymal disorder type 3 Autosomal recessive [se-atlas.de]

• Akinesia

  These observations demonstrate that nemaline myopathy can cause the fetal akinesia sequence, with onset of first symptoms as early as the beginning of the second trimester of pregnancy. [ncbi.nlm.nih.gov]

  KLHL40 mutation associated with severe nemaline myopathy, fetal akinesia, and cleft palate. [pediatricneurosciences.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. [medscape.com]

• Hyporeflexia

  Hyporeflexia was observed in most patients. Elongated faces and high arched palates and feet were also observed. On light microscopy, the nemaline bodies were observed in type 1 and 2 fibers. All patients showed type 1 predominance and atrophy. [ncbi.nlm.nih.gov]

  Diagnosis is made based upon clinical signs such as muscle weakness, absent or low deep tendon reflexes (hyporeflexia), and a high-arched palate, along with electron-dense aggregates, called nemaline rods, being observed at the microscopic level within [en.wikipedia.org]

  Since that time, other myopathies have been defined as congenital myopathies, which have the following characteristics: Onset in early life with hypotonia, hyporeflexia, generalized weakness that is more often proximal than distal, and poor muscle bulk [emedicine.medscape.com]

• Areflexia

  The disease caused additional neurological deficits (absent primitive reflexes, loose anal sphincter tone and areflexia of all extremities). [link.springer.com]

  […] syndrome Caudal appendage-deafness syndrome Caudal regression sequence Central bilateral macrogyria Central nervous system calcification-deafness-tubular acidosis-anemia syndrome Centronuclear myopathy Cerebellar ataxia, Cayman type Cerebellar ataxia-areflexia-pes [se-atlas.de]

• Stupor

  Making a diagnosis of postictal stupor is difficult after an unobserved convulsive attack unless one can elicit a history of a seizure disorder. [slideshare.vn]

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].

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.

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.

Causes

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.

Symptoms

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.

Diagnosis

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.

Treatment

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.
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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.