NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Nemaline Myopathy

Synonym: Nemaline Rod Myopathy. Includes: ACTA1-Related Nemaline Myopathy, CFL2-Related Nemaline Myopathy, KBTBD13-Related Nemaline Myopathy, NEB-Related Nemaline Myopathy, TNNT1-Related Nemaline Myopathy, TPM2-Related Nemaline Myopathy, TPM3-Related Nemaline Myopathy

, MD, MBBS, BSc, FRACP and , MBBS, M Med, FRACP.

Author Information
, MD, MBBS, BSc, FRACP
Professor, Faculty of Medicine
University of Sydney
Head, Institute for Neuroscience and Muscle Research
Children's Hospital at Westmead
Westmead, Australia
, MBBS, M Med, FRACP
Pediatric Neurologist, Royal Children's Hospital
Parkville, Australia

Initial Posting: ; Last Update: March 15, 2012.

Summary

Disease characteristics. Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. Six forms of NM exist, classified by onset and severity of motor and respiratory involvement:

  • Severe congenital (neonatal) (16% of all individuals with NM)
  • Amish NM
  • Intermediate congenital (20%)
  • Typical congenital (46%)
  • Childhood-onset (13%)
  • Adult-onset (late-onset) (4%)

Considerable overlap occurs among the forms. Significant differences in survival exist between individuals classified as having severe, intermediate, and typical congenital NM. Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life. Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk.

Diagnosis/testing. Diagnosis is based on clinical findings and the observation of characteristic rod-shaped structures (nemaline bodies) on muscle biopsy stained with Gomori trichrome. Disease-causing mutations have been identified in seven different genes, all of which encode protein components of the muscle thin filament.

Management. Treatment of manifestations: Monitoring of nutritional status, special feeding techniques, aggressive treatment of lower respiratory tract infections, ventilator use, physical and speech therapy, and standard care for gastroesophageal reflux.

Prevention of secondary complications: Mobility and physical therapy to help prevent joint contractures; preoperative assessment of pulmonary function to ensure optimal timing of surgical procedures and to minimize anesthetic risk.

Surveillance: Routine assessment for scoliosis, joint contractures, respiratory function, and the need for assistive devices.

Agents/circumstances to avoid: Neuromuscular blocking agents because of possible association with malignant hyperthermia susceptibility.

Genetic counseling. NM is inherited in an autosomal dominant or autosomal recessive manner. In one series, approximately 20% of cases were autosomal recessive, approximately 30% autosomal dominant, and approximately 50% simplex (i.e., single occurrences in a family) representing heterozygosity for de novo dominant mutations or homozygosity for autosomal recessive mutations. Accurate recurrence risk information requires determination of the mode of inheritance, if possible, through pedigree analysis and a combination of clinical evaluation, molecular genetic testing, and muscle biopsy of the parents. Carrier testing for at-risk relatives in families with autosomal recessive NM is possible if the disease-causing mutations in the family are known. Prenatal molecular genetic testing is possible for pregnancies at increased risk for NM if the disease-causing mutation(s) in the family are known.

Diagnosis

Clinical Diagnosis

The term nemaline myopathy (NM) refers to a group of genetically distinct disorders linked by common morphologic features observed on muscle histology.

The diagnosis of NM rests on the following clinical findings:

  • Weakness that is predominantly proximal, diffuse, or selective (scapuloperoneal, scapulohumeral, or distal), with or without facial weakness
  • Onset in infancy, childhood, or adulthood
  • Family history consistent with autosomal recessive or autosomal dominant inheritance, although many affected individuals represent simplex cases (i.e., a single occurrence in a family) attributable to autosomal recessive inheritance or a de novo dominant mutation

Electrophysiologic studies that may suggest a myopathic process but are of limited utility in making a specific diagnosis include the following:

  • Electromyography (EMG) may be normal in young individuals with NM and those who are mildly affected, but is usually myopathic in older individuals with NM. It shows polyphasia, small motor unit potentials with normal fiber density, and a full interference pattern with effort. In those with distal disease, 'neurogenic' abnormalities (large motor potentials with increased fiber density, discrete patterns on effort, and increased jitter on single-fiber EMG) are occasionally apparent.
  • Nerve conduction studies (NCV) are generally normal, although low-amplitude motor responses may be seen in those with marked loss of muscle bulk.

Muscle imaging studies

  • Muscle ultrasonography may demonstrate increased echogenicity resulting from increased fibrous content — changes useful in distinguishing between neurogenic and myogenic disorders.
  • Computed tomography (CT) reveals low density of muscle with preservation of volume (in contrast to neuropathies, in which atrophy is more marked).
  • Magnetic resonance imaging (MRI) commonly reveals patchy, fatty degeneration of muscle tissue and variable involvement of different muscle groups [Oishi & Mochizuki 1998, Wallgren-Pettersson & Laing 2001].

Serum creatine kinase concentration is usually normal or minimally elevated.

Muscle histology. A clinically affected muscle should be biopsied. Muscles with 'end-stage' weakness should be avoided. Consideration should be given to biopsying more than one muscle, as findings can vary in different muscle groups/limbs [Ryan et al 2003].

The diagnostic hallmark of NM is the presence of distinct rod-like inclusions (nemaline bodies) in the sarcoplasm of skeletal muscle fibers (see Figure 1).

Figure 1

Figure

Figure 1. Pathology of nemaline myopathy. Gomori trichrome staining of frozen muscle from an affected individual shows the nemaline bodies (rods) as dark blue/purple structures scattered throughout the muscle fibers (a: arrow, 60x magnification). The (more...)

The rods are often not visible on hematoxylin and eosin (H & E) staining, but appear as red or purple structures against the blue-green myofibrillar background with the modified Gomori trichrome stain. The distribution of rods within myofibers may be random, but they show a tendency to cluster under the sarcolemma and around nuclei. The proportion of fibers containing rods varies from one individual to another and from muscle to muscle. Although the number of rods appears to increase with age, no definitive correlation exists between number of rods and severity or age of onset of the myopathy [Ilkovski et al 2001, Ryan et al 2003]. In some individuals with NM, rods are not identified in the first muscle biopsy as a result of sampling; thus, the diagnosis is delayed until biopsy is repeated.

Pathologic changes of NM are much the same irrespective of the severity of the clinical manifestations or the age of onset.

Note: (1) Nemaline rods are not pathognomonic for NM. Nemaline rods observed on muscle biopsy in other neuromuscular disorders and unrelated conditions are considered a reflection of 'secondary' NM (see Differential Diagnosis). (2) Nemaline bodies are not usually present in heart muscle; however, rods have occasionally been observed in muscle of the diaphragm and heart [Ryan et al 2001]. (3) Whereas nemaline bodies typically occur in the sarcoplasm of the muscle fiber, intranuclear rods have been observed in muscle biopsies from those with severe neonatal myopathy, the 'typical' congenital onset form of NM [Sparrow et al 2003, Hutchinson et al 2006], and in some with adult-onset progressive myopathy. Intranuclear rods may be more common in individuals with NM related to ACTA1 (actin) mutations.

Muscle electron microscopy. Nemaline bodies are electron dense and measure 1-7 µm in length and 0.3-2 µm in width. The nemaline bodies are in structural continuity with Z-disks; their ultrastructure resembles the lattice pattern of the Z-disk. Focal disruption of the myofibrillar pattern and accumulation of thin filaments in areas devoid of sarcomeric structure are often observed. Rods are often associated with marked sarcomeric disorganization and loss of normal sarcomeric registration [Ilkovski et al 2001, Ryan et al 2003]. Not infrequently, however, areas of complete sarcomeric disarray abut relatively normal sarcomeres, a phenomenon that is poorly understood.

Rod composition. Consistent with their appearance as extensions of Z-lines, rods are largely made up of α-actinin. In addition, rods contain several other Z-line proteins including telethonin, filamin, myotilin, myozenin, and myopallidin. Although rods likely contain thin filament proteins such as tropomyosin and nebulin, antibodies to these proteins do not reveal any increase in fluorescence at the site of rods, presumably because their epitopes are inaccessible to staining.

Fiber typing. Predominance of type 1 fibers is a common feature of NM. In extreme cases, fiber typing by the ATPase reaction reveals a uniform reactivity of a pure population of type 1 fibers. Rods may be found equally in all fiber types or preferentially in either type 1 or type 2 fibers. Rod-containing fibers are often but not always hypotrophic. Fiber type 1 predominance and atrophy tend to become more prominent with age and are associated with abnormally high expression of fetal myosin (usually not expressed after age 6 months) and coexpression of fast and slow myosin in some muscle fibers [Ilkovski et al 2001, Ryan et al 2003]. Two studies have documented progressive conversion of type 2 to type 1 fibers [Gurgel-Giannetti et al 2003, Ryan et al 2003].

No definitive pathologic markers exist for the various genetic forms of NM. Detailed pathologic studies may provide morphologic clues to guide molecular genetic testing; however, the number of individuals with NM studied in detail is still too small to draw conclusions about the specificity of these findings:

Molecular Genetic Testing

Genes. Mutations in seven genes, encoding components of the sarcomeric thin filaments, have been identified as causing nemaline myopathy (NM) (Table 2). It is too early to determine the precise frequency of each of the genetic subgroups of NM, the proportion of de novo mutations, and the incidence of germline mosaicism:

  • ACTA1 encodes skeletal muscle alpha-actin.
  • NEB encodes nebulin.
  • TPM3 encodes slow alpha-tropomyosin, alpha-3 chain.
  • TPM2 encodes beta-tropomyosin.
  • TNNT1 encodes slow troponin T skeletal muscle.
  • CFL2 encodes cofilin2.
  • KBTBD13 encodes Kelch repeat and BTB domain-containing protein 13.

Evidence for locus heterogeneity

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Nemaline Myopathy

Gene SymbolProportion of NM Attributed to Mutations in This GeneTest MethodMutations Detected
ACTA115%-25% 1Sequence analysisSequence variants 2
Deletion / duplication analysis 3Exonic or whole-gene deletion; none reported
NEBUnknown 4Targeted mutation analysis 52502-nucleotide deletion spanning exon 55 6, 7
Sequence analysisSequence variants 3
Deletion / duplication analysis 3Exonic or whole-gene deletion 8
TPM32%-3% 9Sequence analysisSequence variants 3
Deletion / duplication analysis 3Exonic or whole-gene deletion; none reported
TPM2<1% 10Sequence analysisSequence variants 3
Deletion / duplication analysis 3Exonic or whole-gene deletion; none reported
TNNT1See footnote 11Sequence analysisSequence variants 3
Deletion / duplication analysis 3Exonic or whole-gene deletion; none reported
CFL2 Unknown 12 Sequence analysisSequence variants 3
KBTBD13UnknownSequence analysisSequence variants 3

1. ACTA1 mutations account for 15%-25% of all individuals with NM [Nowak et al 1999, Ilkovski et al 2001, Ryan et al 2001]. Of note, ACTA1 mutations may account for up to 50% of severe lethal congenital-onset forms of NM [Agrawal et al 2004].

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

4. It is likely that over half of nemaline myopathy cases are caused by NEB mutations; the exact proportion has yet to be conclusively determined.

5. Testing that employs a method to detect the specific 2502-nucleotide deletion spanning exon 55 (see Table 3)

6. The carrier frequency of this mutation in the Ashkenazi Jewish population is estimated to be 1:108. Its incidence in other populations is unknown.

7. The only known NEB mutation hotspot is a 2502 base-pair in-frame deletion of exon 55 (see Table 3) that was observed in five families of Ashkenazi Jewish ancestry [Anderson et al 2004]. This mutation may be a common cause of NM in the Ashkenazi Jewish population; its frequency in other populations is unknown.

8. Deletion/duplication analysis of NEB may employ any of a variety of techniques to detect not only deletion of exon 55, but also other deletions of an exon(s) or of the whole gene. Two such novel deletions have been reported [Lunkka-Hytonen et al 2008] (see Table A. Genes and Databases, HGMD].

9. 3/117 individuals screened [Ryan et al 2001, Wallgren-Pettersson & Laing 2003]

10. Dominant TPM2 mutations in 2/54 families with typical congenital-onset NM [Donner et al 2002]

11. Identified only in a genetically isolated group of Old Order Amish individuals with NM [Johnston et al 2000, Jin et al 2003]

12. Mutation of muscle-specific cofilin (CFL2) is a rare cause of nemaline myopathy, having been described in one family to date (see Molecular Genetics).

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Creatine kinase is generally checked early in the evaluation of individuals with suspected muscle weakness and is useful for distinguishing myopathies from muscular dystrophies. Muscle enzymes are usually normal in NM or may be mildly elevated [Ryan et al 2001].
  • Neurophysiologic testing in persons with suspected lower motor neuron disorders excludes neuropathy and may demonstrate 'myopathic' abnormalities (small, short-duration action potentials).
  • Electromyography is nonspecific, showing similar abnormalities in all congenital myopathies.
  • Muscle imaging is useful in distinguishing between neuropathic and myopathic processes, and can be used to identify an appropriate muscle to biopsy. Muscle MRI commonly reveals patchy, fatty degeneration of muscle tissue and variable involvement of different muscle groups [Oishi & Mochizuki 1998, Wallgren-Pettersson & Laing 2001]. These patterns of selective muscle involvement may guide genetic testing once the diagnosis of NM is made based on the pathologic findings [Jungbluth et al 2004]:
    • NM secondary to mutations in the nebulin gene (NEB) is reported to show a consistent pattern of selective muscle involvement corresponding to clinical severity. In mild cases, there may be complete sparing of thigh muscles and selective involvement of tibialis anterior and soleus muscles. In moderate cases, there is predominant involvement of rectus femoris, vastus lateralis, and hamstring muscles and diffuse involvement of anterior compartment and soleus muscles.
    • NM secondary to mutations in the skeletal muscle alpha-actin gene (ACTA1) may show diffuse involvement of thigh and leg muscles with relative sparing of the gastrocnemii.
  • Muscle biopsy demonstrating nemaline rods is necessary for definitive diagnosis.

Molecular genetic testing can be complex because of the number of genes responsible for NM. It is likely that over half of nemaline myopathy cases are the result of NEB mutations, though the exact proportion has yet to be conclusively proven. NEB genetic testing is expensive because of the large size of the gene (see Molecular Genetics). It is therefore worth considering testing other genes prior to analyzing NEB. It is acknowledged however, that molecular testing for congenital myopathies is in rapid evolution; recent advances in sequencing of multi-gene panels is likely to have considerable impact on genetic testing for these diseases.

The clinical presentation can be helpful in guiding the choice of genes to test. Alpha-skeletal actin (ACTA1) mutations cause 20%-25% of all nemaline myopathy, but 50% of severe nemaline myopathy. ACTA1 is small and relatively easy to analyze. Slow α-tropomyosin (TPM3) analysis should be considered particularly if nemaline rods are restricted to type 1 slow muscle fibers, or if fiber type disproportion is the only feature. Beta-tropomyosin (TPM2) analysis should be especially considered for mild dominant disease. Slow troponin T (TNNT1) mutations have been described to date only in the Old Order Amish population; though they may likely occur rarely in other populations. Mutation of muscle-specific cofilin (CFL2) is a rare cause of nemaline myopathy, having been described in one family to date. Mutations in KBTBD13 are associated with peculiarly slow voluntary movements and relative sparing of the facial and respiratory muscles.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Clinical Description

Natural History

The cardinal features of nemaline myopathy (NM) are weakness, hypotonia, and depressed or absent deep tendon reflexes; intrafamilial variation in course and outcome is considerable.

Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. In some individuals with NM, the distal muscles are involved. In congenital forms of NM, the face is often elongated and expressionless, with a tent-shaped mouth, high-arched palate, and retrognathia. Gross motor milestones are delayed, but most affected individuals are otherwise developmentally normal.

Dysarthria and feeding difficulties are common; approximately 25% of children with congenital-onset NM require gavage feeding or gastrostomy during the first few years of life.

Respiratory problems secondary to involvement of the diaphragm and intercostal muscles are common in congenital NM. The degree of skeletal muscle weakness does not necessarily reflect the degree of respiratory muscle involvement, particularly in older children and adults [Ryan et al 2001].

Many children with NM have hypermobility of joints in infancy and early childhood; contractures and deformities of the joints, including scoliosis, commonly develop with time.

The extraocular muscles are usually spared.

Cardiac contractility is usually normal.

Classification. The existing classification of NM into six forms is based on age of onset and severity of motor and respiratory involvement and includes the severe congenital (neonatal) form, Amish NM, intermediate congenital form, typical congenital form, childhood-onset form, and adult-onset (late-onset) form [Wallgren-Pettersson et al 1998].

Overlap among these groups is significant. It is also important to note that adults are sometimes diagnosed with NM in the course of investigation of other family members. Individuals in whom muscle involvement is relatively mild, despite onset in infancy or childhood, may be misclassified as having the adult-onset form.

In a review of 143 individuals with NM from Australia and North America, Ryan et al [2001] found that 23 (16%) had severe congenital NM, 29 (20%) had intermediate congenital NM, 66 (46%) had typical congenital NM, 19 (13%) had childhood-onset NM, and six (4%) had adult-onset NM. Children who crawled before age 12 months and walked before age 18 months were classified as having typical congenital NM. The distinction between the intermediate congenital and typical congenital forms of NM can often be made only in retrospect as no single parameter in infancy distinguishes between the two phenotypes.

Severe congenital (neonatal) NP presents at birth with severe hypotonia and muscle weakness, little spontaneous movement, difficulties with sucking and swallowing, gastroesophageal reflux, and respiratory insufficiency. Decreased fetal movements and polyhydramnios may complicate the pregnancy [Ryan et al 2001], and death in utero associated with fetal akinesia has been described. Uncommon findings include dilated cardiomyopathy and arthrogryposis multiplex congenita (i.e., multiple joint contractures) [Ryan et al 2001, Wallgren-Pettersson & Laing 2003]. Early mortality is common, usually resulting from respiratory insufficiency or aspiration pneumonia. However, occasional individuals with severe generalized weakness and inadequate respiration at birth survive long-term.

Amish NM is a clinically distinct autosomal recessive form with neonatal onset and early childhood lethality. To date, it has been described in only a single genetic isolate of related Old Order Amish families [Johnston et al 2000]. It presents at birth with hypotonia, contractures and, remarkably, tremors that typically subside over the first two to three months of life. Progressive weakness associated with severe pectus carinatum, muscle atrophy, and contractures often leads to death resulting from respiratory insufficiency in the second year of life.

Intermediate congenital NM lies between the severe congenital form and typical congenital form in terms of disease severity at birth and long-term outcome. The early development of joint contractures is characteristic of this form of NM. Although individuals with this form of NM have anti-gravity movement and independent respiration at delivery, they are included in this subgroup if weakness prevents achievement of motor milestones or necessitates use of a wheelchair and/or ventilatory support by age 11 years. Distinction between intermediate congenital and typical congenital NM may therefore be possible only with increasing age.

Typical (mild) congenital NM usually presents in the neonatal period or first year of life with hypotonia, weakness, and feeding difficulties. The severity of muscle involvement is less than that seen in the severe congenital and intermediate congenital forms. Spontaneous anti-gravity movements are present and respiratory involvement is less prominent. Some weakness of the respiratory musculature is usual but may be subclinical, manifesting as insidious nocturnal hypoventilation or frequent lower respiratory tract infections. A minority of children present after age one year with delay of gross motor milestones, an abnormal waddling gait, or bulbar weakness manifesting as hypernasal speech or swallowing difficulties. Weakness is usually proximal at presentation, but late distal involvement evolves in a minority of individuals. Occasionally, individuals have both proximal and distal weakness early in life. Weakness is usually static or very slowly progressive and most individuals are able to lead independent, active lives [Wallgren-Pettersson et al 1998]. Cardiac involvement is rare.

Childhood-onset NM was first described by Laing et al [1992] in a large Australian kindred in which it was inherited in an autosomal dominant manner. Early motor development is normal. In the late first or early second decade, children experience the onset of symmetric weakness of ankle dorsiflexion with foot drop reminiscent of a peripheral neuropathy. Weakness is slowly progressive with eventual involvement of all ankle movement and more proximal limb musculature. Two older family members were wheelchair bound by age 40 years.

Van Engelen and colleagues [Pauw-Gommans et al 2006] reported a new phenotype in a Dutch pedigree with autosomal dominant NM and proximal muscle weakness with onset in childhood [Wallgren-Pettersson & Laing 2001, Gommans et al 2003]. Facial, respiratory, and cardiac muscles are normal. The remarkable feature is the complaint of muscle 'slowness'; individuals move in 'slow motion' and are unable to jump or run. Physiologic studies confirm slowing of muscle speed (as measured by force oscillation amplitude and maximal rate of force rise) and muscle relaxation time [Pauw-Gommans et al 2006].

Adult-onset (late-onset) NM varies in clinical presentation and disease progression. Most individuals with this phenotype develop generalized weakness between age 20 and 50 years without antecedent symptoms or family history. Myalgia may be prominent, and weakness may progress rapidly. Occasionally, individuals present with cardiomyopathy or the 'dropped head' syndrome, with severe weakness of neck extension with or without neck flexor weakness [Lomen-Hoerth et al 1999]. Respiratory or cardiac involvement is uncommon but, when present, often occurs in association with increasing weakness and physical disability.

Inflammatory changes on biopsy are not uncommon in adult-onset NM. A small number of affected individuals have developed a monoclonal gammopathy and paresthesiae in association with their myopathy. Comorbid monoclonal gammopathy may be a marker of poor prognosis in individuals with late-onset NM [Chahin et al 2005]. Based on the presence of additional and 'atypical' features on muscle biopsy in many individuals, the progressive nature of the weakness, and the absence of family history in the majority of individuals, the adult-onset variant of NM is likely to represent a different clinical entity from childhood NM.

Prognosis. In a review of 14 individuals with NM seen in London and 85 individuals with NM from the literature, Martinez & Lake [1987] identified neonatal hypotonia as the single most important prognostic sign in NM. However, their classification of children into severe congenital and mild congenital forms was retrospective and few details were given regarding the basis of their grouping.

In the 143 affected individuals reported by Ryan et al [2001], analysis of cumulative survival probabilities revealed significant differences in survival among those classified as having severe, intermediate, and typical congenital NM. In this series, hypotonia and severe weakness in infancy were not predictive of early mortality; however, very severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita were associated with death in the first year of life in all but one individual. Independent ambulation before age 18 months was predictive of survival. Seventeen of 23 children with severe congenital NM and 8/29 children with intermediate congenital NM died of respiratory failure, compared to 4/66 with typical congenital, 1/19 with childhood-onset, and 0/6 with adult-onset NM. In many individuals, a stormy early course with frequent respiratory tract infections was followed by clinical stabilization. Most children with typical congenital NM were eventually able to walk.

Pregnancy and delivery are relatively well tolerated by women with NM [Ryan et al 2001]. A high frequency of obstetric complications is associated with an affected fetus, including polyhydramnios, decreased fetal movements, and abnormal presentation or fetal distress [Ryan et al 2001].

Genotype-Phenotype Correlations

Genotype-phenotype correlation remains poorly defined in NM, largely because of the significant clinical overlap between differing forms of the disease (Table 2) and the significant proportion of cases for which the genetic basis remains unknown.

NM related to NEB (nebulin) mutations is more commonly associated with 'typical congenital' NM, and invariably inherited in an autosomal recessive fashion, while NM related to ACTA1 (actin) mutations is associated with variable presentations ranging from severe neonatal to adult onset.

Neonatal presentation of NM has been reported in those with autosomal recessive inheritance of mutations in NEB [Pelin et al 1999], TPM3 [Tan et al 1999], TNNT1 [Johnston et al 2000, Jin et al 2003], and ACTA1 [Sparrow et al 2003], and in those with autosomal dominant inheritance of mutations in ACTA1 [Nowak et al 1999].

'Childhood-onset' disease has been seen with autosomal dominant inheritance of mutations in TPM3 and ACTA1 [Nowak et al 1999, Ilkovski et al 2001].

Rare, distinctive phenotypes associated with NM include the Amish form of the disease [Johnston et al 2000, Jin et al 2003] and the form associated with peculiarly slow voluntary movements and relative sparing of the facial and respiratory muscles [Gommans et al 2002, Gommans et al 2003, Sambuughin et al 2010].

Genetic subtypes of nemaline myopathy. See Table 2.

Table 2. Phenotype Correlations with Mutated Genes

Mutated GeneMode of InheritancePhenotype
ACTA1AD/ARRange from severe congenital to childhood onset
NEBARTypical congenital (majority)
All other phenotypes (occasional)
TPM3AD/ARSevere congenital (AR)
Intermediate congenital
Childhood onset (AD)
TPM2AD Typical congenital
TNNT1ARAmish NM
CFL2 ARTypical congenital
KBTBD13AD Childhood onset, slowly progressive weakness with characteristic slowness of movements. Unstructured cores present on muscle biopsy, in addition to rods.

ACTA1 mutations have been identified in individuals with NM with varying clinical presentations and inheritance patterns [Nowak et al 1999, Ilkovski et al 2001, Ryan et al 2001]. The majority of individuals with NM have no family history (de novo dominant mutations). However, one family exhibited autosomal recessive inheritance with two affected children who were compound heterozygotes for mutations inherited from each parent. At least two families with autosomal dominant inheritance have been reported [Nowak et al 1999, Wallgren-Pettersson & Laing 2000].

Individuals with ACTA1 mutations exhibit marked clinical variability ranging from severe congenital weakness with death from respiratory failure in the first year of life to childhood-onset myopathy with survival into adulthood [Ryan et al 2001]. Marked variation in age of onset and clinical severity was observed in three affected members of the same family, suggesting that the ACTA1 genotype is not the sole determinant of phenotype [Ryan et al 2003].

NEB mutations identified to date have all been inherited in an autosomal recessive manner [Pelin et al 1999]. The majority of individuals with NM have the typical congenital form of NM, although recent follow-up studies have identified NEB mutations in individuals with wide-ranging phenotypes [Wallgren-Pettersson & Laing 2003].

TPM3 mutations may be inherited in a dominant or recessive manner [Tan et al 1999, Ryan et al 2001] and to date have been associated with severe- and intermediate-congenital as well as childhood-onset NM [Tan et al 1999, Durling et al 2002].

Penetrance

Data are insufficient to draw conclusions about penetrance in dominant (ACTA1, TPM3, TPM2, KBTBD13) forms of NM.

Nomenclature

Nemaline myopathy was first described in 1963 by investigators from the United States and Canada, and defined by a particular ultrastructural change on muscle biopsy: the finding of thread-shaped structures in muscle fibers, which are known as nemaline bodies, or rods (from the Greek nema, meaning thread). Prior to the identification of discrete forms of congenital myopathy, persons with these disorders were generally labeled as having ‘amyotonia congenita’, or benign congenital hypotonia.

Prevalence

NM is a rare disorder with an estimated incidence of 1:50,000 live births in one Finnish study and a more recent study in an American Ashkenazi Jewish population [Anderson et al 2004].

NM may be more common in some populations; Johnston et al [2000] suggested an incidence of 1:500 in the Amish community.

Differential Diagnosis

All congenital myopathies have a number of common clinical features: generalized weakness, hypotonia and hyporeflexia, poor muscle bulk, and dysmorphic features secondary to muscle weakness (e.g., pectus carinatum, scoliosis, foot deformities, a high arched palate, elongated facies). Therefore, the diagnosis of nemaline myopathy (NM) rests on the presence of the specific ultrastructural changes on muscle biopsy. In addition, marked clinical overlap exists between congenital myopathies including X-linked myotubular myopathy, central core disease and congenital fiber type disproportion; and other neuromuscular disorders including congenital muscular dystrophy, the limb-girdle muscular dystrophies, dystrophinopathies, metabolic myopathies, and spinal muscular atrophy.

In some individuals with congenital myopathy, cores and rods coexist (so-called 'core-rod' myopathy). Monnier et al [1997] and Scacheri et al [2000] reported different mutations in the C-terminal of the ryanodine receptor gene (RYR1) in two large families with core-rod myopathy, suggesting that the rods are a secondary feature of some cases of primary central core disease (CCD) [Scacheri et al 2000, von der Hagen et al 2008]. A second locus for core-rod myopathy has already been identified at 15q21-q23 [Gommans et al 2003] and further genetic heterogeneity is likely.

Another form of inherited myopathy with hyaline and nemaline bodies, for which no genetic locus has yet been identified, has been reported [Selcen et al 2002]. The affected siblings in this kindred had adult-onset muscle weakness that was greater distally than proximally, as well as respiratory insufficiency, cardiomyopathy, and cervical spine anomalies.

Secondary NM. Nemaline rods are not pathognomonic for NM. In humans, nemaline bodies have been seen on muscle biopsy in numerous other neuromuscular and unrelated conditions including mitochondrial myopathy [Lamont et al 2004], dermatomyositis, myotonic dystrophy type 1, and Hodgkin's disease, and in normal human extraocular muscle [Skyllouriotis et al 1999, Portlock et al 2003]. In NM secondary to other disease processes, clinical presentation and examination findings are usually consistent with the primary disease process. For example, in HIV myopathy, presentation is with a polymyositis-like illness characterized by progressive, painless proximal weakness possibly associated with dysphagia, muscle cramps, and paresthesia. Thus, rod formation likely represents a common pathophysiologic response of skeletal muscle to certain pathologic situations, and the diagnosis of 'primary' NM rests on both the finding of rod bodies on muscle biopsy and an appropriate clinical scenario.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with nemaline myopathy (NM), the following evaluations are recommended:

  • Thorough assessment of respiratory status, including pulmonary function studies and assessment for nocturnal hypoxia
  • For early-onset forms, assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux) and growth parameters to determine the need for feeding interventions such as gavage feeding or gastrostomy insertion
  • Physical examination to evaluate for joint contractures
  • Physical examination to evaluate for scoliosis, followed by spinal x-ray if scoliosis is suspected
  • Physical and occupational therapy evaluations relevant to the degree of weakness
  • Speech therapy evaluation if dysarthria and/or hypernasal speech is present
  • Orthodontic evaluation if palatal anomalies are present
  • Evaluation for the presence of dilated cardiomyopathy in those with the severe congenital form
  • Medical genetics consultation

Treatment of Manifestations

Consensus guidelines for management of congenital myopathies are currently in publication [Wang et al 2012].

A multidisciplinary approach to the clinical management of the individual greatly improves quality of life and can influence survival:

  • Assurance of adequate caloric intake and appropriate nutritional status, including special feeding techniques and high-calorie formulas and foods, if indicated
  • Aggressive treatment of lower respiratory tract infections
  • Evaluation at an early stage of the need for intermittent or permanent use of a mechanical ventilator to prevent insidious nocturnal hypoxia
  • Referral to an orthopedist for management of scoliosis and joint contractures, as in the general population
  • Physical therapy for maintenance/improvement of function and joint mobility
  • Speech therapy if dysarthria and/or hypernasal speech is present
  • Standard treatment of gastroesophageal reflux, if present
  • Assessment of cardiac status because of the risk (albeit low) of cardiomyopathy or cor pulmonale

Prevention of Primary Manifestations

Consensus guidelines for management of congenital myopathies are currently in publication [Wang et al 2012].

Prevention of Secondary Complications

Patient mobility and physical therapy help to control the development of joint contractures from disuse related to weakness.

Anesthetics are generally well tolerated in individuals with NM. Ryan et al [2001] reviewed the outcome of 130 affected individuals who underwent one or more surgical procedures. None developed malignant hyperthermia. However, five developed unexpected postoperative respiratory failure (following scoliosis repair in four individuals and fundoplication in one), necessitating prolonged ventilation in three individuals and resulting in the death of another. Preoperative assessment of pulmonary function is essential to ensure optimal timing of surgical procedures and to minimize anesthetic risk.

Surveillance

Consensus guidelines for management of congenital myopathies are currently in publication [Wang et al 2012].

Surveillance includes:

  • Routine assessment for scoliosis and joint contractures;
  • Regular formal assessment of respiratory function, including monitoring of sleep studies when significant respiratory impairment is identified;
  • Routine assessment of physical function and the need for mechanical assistance, such as a wheelchair.

Agents/Circumstances to Avoid

Malignant hyperthermia is a risk in congenital myopathies such as central core disease and in some muscular dystrophies. NM has not been definitively associated with malignant hyperthermia to date, although bradycardia and slight hyperthermia have been reported during cardiac surgery. It is advisable to avoid neuromuscular blocking agents when possible, especially given the reports of core-rod myopathies linking to genes for ryanodine receptor mutations [Monnier et al 2000, Scacheri et al 2000].

Prolonged periods of immobilization should be avoided after illness or surgery, as immobility may markedly exacerbate muscle weakness [Ryan et al 2001].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy and delivery are relatively well tolerated by women with NM [Ryan et al 2001]. A high frequency of obstetric complications is associated with an affected fetus, including polyhydramnios, decreased fetal movements, and abnormal presentation or fetal distress [Ryan et al 2001].

Therapies Under Investigation

L-tyrosine has been proposed as a potential therapy. A precursor of the neurotransmitters dopamine, norepinephrine, and epinephrine, L-tyrosine has been shown after oral administration in rats to increase catecholamine production and release, and to improve reaction and attention time and tolerance of physical stress. Two reports have shown subjectively improved muscle strength and clearance of oral secretions after oral tyrosine supplementation in individuals with NM. An international clinical trial was recently discontinued because of difficulties with participant recruitment and drug licensing, but subjective benefits from dietary supplementation with tyrosine have been reported in a small series of individuals with nemaline myopathy. L-tyrosine may be particularly effective in improving bulbar dysfunction and exercise tolerance in this condition [Ryan et al 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

In a mouse model, endurance exercise programs may overcome the increase in muscle weakness that follows prolonged periods of immobilization [Nair-Shalliker et al 2004]. Human data are lacking; however, the authors have cared for some individuals with typical congenital-onset NM who have demonstrated clinical improvement after a program of regular low-impact exercise (cycling and swimming).

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Nemaline myopathy (NM) is inherited in an autosomal dominant or autosomal recessive manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Some individuals diagnosed with NM have an affected parent.
  • A proband with NM may have the disorder as the result of a new gene mutation.
  • Most cases of ACTA1-related NM are simplex, but autosomal dominant and recessive inheritance are also seen, and two families with mosaicism for dominant mutations have been reported [Ryan et al 2003, Wallgren-Pettersson et al 2004].
  • If a proband has an identified ACTA1, TPM3, TPM2, or KBTBD13 mutation, the parents should be offered molecular genetic testing.
  • Recommendations for the evaluation of parents of an individual with no known family history of NM include evaluation of both parents for evidence of minor muscle weakness and possible muscle biopsy. The interpretation of abnormal muscle biopsy findings, however, can be difficult; therefore, biopsy should not be undertaken until other means of diagnosis (i.e., testing for ACTA1, TPM3, TPM2 or KBTBD13 mutations) have been attempted.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If a parent is affected and has a family history suggestive of AD inheritance or has an ACTA1, TPM3, TPM2 or KBTBD13 mutation, the risk is 50%.
  • If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner.
  • While no instances have been reported, germline mosaicism remains a possibility.

Offspring of a proband. Every child of an individual with autosomal dominant NM has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has an ACTA1, TPM3, or KBTBD13 mutation, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive NM are obligate heterozygotes (carriers) for a mutant allele causing NM.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Simplex cases. The majority of individuals with NM represent simplex cases (i.e., a single occurrence in a family), with heterozygosity for de novo dominant mutations or homozygosity for autosomal recessive mutations. In their review of 143 individuals from 110 kindreds, Ryan et al [2001] found that inheritance was autosomal recessive in 29 individuals from 15 kindreds (20%), autosomal dominant in 41 individuals from 22 kindreds (29%), and indeterminate in 73 individuals (50%).

Disease severity. Substantial variation in disease severity was observed within families with autosomal dominant inheritance and families with autosomal recessive inheritance, despite presumed genotypic homogeneity. To further complicate genetic counseling, asymptomatic parents can have pathologic changes of NM on muscle biopsy. It is unclear whether such individuals are manifesting heterozygotes of autosomal recessive NM or are subclinically affected with autosomal dominant NM.

Determination of inheritance pattern. When only one person in a family is affected by NM, determining the mode of inheritance can be problematic:

  • Inheritance is usually autosomal dominant as the result of either an inherited mutation or de novo mutation in a proband with an ACTA1, TPM3, TPM2, or KBTBD13 mutation.
  • In some families, both clinically healthy parents have shown abnormalities on muscle biopsy, suggesting a manifesting heterozygous state for a recessive gene mutation. Thus, if only one parent were to undergo muscle biopsy and show abnormalities, it cannot be determined if those changes are manifestations of a dominant gene mutation.
  • If one parent shows overt disease clinically and typical histologic abnormalities on muscle biopsy, and the other parent is healthy and shows normal findings on muscle biopsy, the likely mode of inheritance is autosomal dominant.
  • If both parents are clinically healthy and show no abnormality on muscle biopsy, dominant transmission from one of the parents is unlikely, leaving the possibility of a de novo dominant mutation (the proportion of which remains to be determined) in the child, germline mosaicism in one of the parents (the role of which has yet to be determined), or recessive inheritance.
  • As the molecular genetics of NM are clarified, some of these genetic counseling issues may be resolved.
  • In research studies in which disease-causing mutations can be identified, correlations can be made between the gene involved and the mode of inheritance.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • Congenital Muscle Disease International Registry (CMDIR)
    The CMD International Registry is a patient self-report registry with the goal to register the global congenital muscle disease population which includes congenital myopathy and congenital muscular dystrophy.
    1712 Pelican Avenue
    San Pedro CA 90732
    Phone: 800-363-2630
    Fax: 310-872-5374
    Email: counselor@cmdir.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Nemaline Myopathy (View All in OMIM)

102610ACTIN, ALPHA, SKELETAL MUSCLE 1; ACTA1
161650NEBULIN; NEB
161800NEMALINE MYOPATHY 3; NEM3
190990TROPOMYOSIN 2; TPM2
191030TROPOMYOSIN 3; TPM3
191041TROPONIN T1, SKELETAL, SLOW; TNNT1
256030NEMALINE MYOPATHY 2; NEM2
601443COFILIN 2; CFL2
605355NEMALINE MYOPATHY 5; NEM5
609273NEMALINE MYOPATHY 6; NEM6
609284NEMALINE MYOPATHY 1; NEM1
609285NEMALINE MYOPATHY 4; NEM4
610687NEMALINE MYOPATHY 7; NEM7
613727KELCH REPEAT AND BTB/POZ DOMAINS-CONTAINING PROTEIN 13; KBTBD13

Molecular Genetic Pathogenesis

Nemaline myopathy (NM) is a disorder of thin filament proteins, and thus it is necessary to understand the normal interactions of these proteins to understand the pathogenic mechanisms underlying NM.

Alpha-actinin, the major protein component of nemaline bodies, forms diagonal cross-connections between the thin filaments, which are anchored via a network of interactions between α-actinin, actin, nebulin, and other proteins. The myosin-containing thick filaments interdigitate with the thin filaments, which are made up of a double-stranded helix of globular actin monomers (e.g., F actin) associated with a single molecule of nebulin. At over 770 kd in size, nebulin ranks as one of the largest known proteins. The central portion contains up to 185 tandem repeats of 35 residues, each of which likely binds a single actin monomer. The carboxy terminus is unique and is embedded in the Z-lines. Along the length of the thin filaments, the tropomyosins and troponins together form a complex of proteins responsible for control of contraction by regulating the interactions of actin and myosin.

At rest, tropomyosin dimers lie along the actin filament in a potential myosin-binding site, sterically inhibiting myosin-actin interactions. Tropomyosin position and movement are controlled by the troponin complex consisting of three subunits: TN-I (inhibitory), TN-T (tropomyosin-binding), and TN-C (calcium-binding). When muscle is stimulated, intracellular calcium levels increase to a critical level and bind to TN-C. This releases the inhibitory effect of TN-I so that tropomyosin moves into the groove between actin helices, unmasking the myosin binding sites and triggering the contraction cycle.

Mutations in the genes encoding various components of the thin filament likely disrupt the orderly assembly of sarcomeric proteins and the functional interaction between the thin and thick filament during muscle contraction. Tissue culture studies of disease-causing mutations in ACTA1 suggest that mutant actin has a dominant negative effect on thin filament assembly and function and results in abnormal folding, altered polymerization, and aggregation of mutant actin isoforms [Ilkovski et al 2004]. Some of these effects are mutation-specific and likely result in variations in the severity of muscle weakness seen in individuals. A combination of these effects contributes to the common pathologic hallmarks of NM, namely intranuclear and cytoplasmic rod formation, accumulation of thin filaments, and myofibrillar disorganization.

The TPM3 c.26T>G (p.Met9Arg) mutation, associated with autosomal dominant childhood-onset NM, has been studied extensively in vitro and in vivo, providing initial insights into the pathogenesis of NM. This mutation occurs in the N-terminal structure of α-tropomyosin SLOW, which is implicated in binding actin, troponin T, and tropomodulin, and in head-tail interactions leading to the coiled-coil dimeric structure of tropomyosin. When expressed in rat adult cardiac myocytes, the mutant protein was incorporated into sarcomeres and the contractile response to Ca2+ was diminished; however, there was no rod formation [Michele et al 1999]. When expressed in Escherichia coli, the p.Met9Arg mutant had a 30- to 100-fold reduced affinity for actin binding and reduced activation of actomyosin S1 ATPase [Moraczewska et al 2000]. When the p.Met9Arg mutation was introduced into a transgenic mouse line, rod formation occurred in all muscles, with onset of weakness at age five to six months, mimicking late-childhood onset in humans [Corbett et al 2001]. The percentage of rods varied significantly between different muscle groups despite uniform expression of the mutant transgene, reflecting the same variability of muscle involvement seen in humans with NM. The mutant TPM3 is expressed, suggesting a dominant negative effect; an imbalance in other specific TPM isoform levels within NM muscle may contribute to disease pathogenesis [Corbett et al 2005]. Fiber-typing abnormalities in the mouse model appear to be related to a disruption in the developmental maturation of different muscle fiber types. Interestingly, the TPM3 nemaline mouse has compensatory hypertrophy of muscle fibers compared to wild type that may contribute to delayed onset of muscle weakness [Corbett et al 2001, Nair-Shalliker et al 2004]. Fiber hypertrophy occurs occasionally in individuals with NM and tends to correlate with a milder phenotype [North, unpublished observations], raising the possibility that exercise and hypertrophic agents may influence the course of the disease.

ACTA1

Normal allelic variants. ACTA1 consists of seven exons.

Pathologic allelic variants. More than 195 different mutations have now been identified in ACTA1 and are listed in the ACTA1 locus-specific database. The vast majority of these mutations are missense (see Table A, ACTA1 Locus Specific).

Normal gene product. Actin, alpha skeletal muscle has vital roles in cell integrity, structure, and motility. Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin. See Molecular Genetic Pathogenesis.

Abnormal gene product. See Molecular Genetic Pathogenesis. Both hemizygous and homozygous null mice show an increase in cardiac and vascular ACTA1 mRNA in skeletal muscle. No skeletal ACTA1 mRNA is present in null mice [Crawford et al 2002].

NEB

Normal allelic variants. NEB contains 183 exons in a 249-kb genomic region. Exon numbering varies in the literature because some exons are differentially expressed.

Pathologic allelic variants. See Table 3. To date, 64 different mutations in 55 families have been identified in NEB [Pelin et al 1999, Pelin et al 2002, Lehtokari et al 2006].

The majority of mutations are frameshifts caused by small deletions or insertions or point mutations causing premature stop codons or abnormal splicing. In addition, a 2502-bp deletion in NEB appears to be a common cause of NM in Ashkenazi Jewish families, with a carrier frequency of approximately 1:100 [Anderson et al 2004].

Table 3. Selected NEB Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.7622-2025_7727+372del2502
(exon 55 deletion)
p.Arg2478_Asp2512delNM_004543​.3
NP_004534​.2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Nebulin is a giant protein (600-900 kd) component of the cytoskeletal matrix.

Abnormal gene product. Most NEB mutations are predicted to result in truncated or internally deleted proteins. See Molecular Genetic Pathogenesis.

TPM3

Normal allelic variants. TPM3 contains 13 exons. Multiple transcript variants encoding different isoforms have been found for this gene.

Pathologic allelic variants. See Table 4. Laing et al [1995] identified a p.Met9Arg substitution in the N-terminal end of tropomyosinSLOW in a kindred with dominantly inherited NM. Wattanasirichaigoon et al [2002] reported a person who was compound heterozygous for a point mutation and splice site mutation. A further example of recessive TPM3-related NM was documented by Tan et al [1999], who identified a homozygous p.Gln32* nonsense mutation in an infant with extremely delayed motor development.

Table 4. Selected TPM3 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.26T>Gp.Met9ArgNM_152263​.2
NP_689476​.2
c.94C>Tp.Gln312*
(Gln31X)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Tropomyosin alpha-3 chain is expressed mostly in slow, type 1 muscle fibers. Tropomyosin isoforms are components of the thin filaments of the sarcomere, acting to mediate the effect of calcium on actin-myosin interaction.

Abnormal gene product. In terms of understanding disease pathogenesis in NM, the best characterized is tropomyosin NM. Tissue culture and animal models have been developed for the p.Met9Arg mutation in TPM3 identified by Laing et al [1995]. This mutation was predicted to affect the N-terminal structure of the α-tropomyosin, which is implicated in binding actin and troponin T and for head-tail interactions leading to the coiled-coil dimeric structure of tropomyosin, which polymerizes along the entire length of the thin filament. In vitro studies suggest that the mutant TPM3 exerts a dominant negative effect and alters the Ca2+-activated force production, hastening relaxation of mutant tropomyosin and shifting the force-frequency relationship in skeletal muscle [Michele et al 1999, Michele et al 2002]. In addition, the p.Met9Arg mutation reduced the affinity of the mutant tropomyosin for actin, destabilized the tropomyosin coiled-coil, and would be expected to impair end-to-end association between tropomyosins in the thin filament [Moraczewska et al 2000].

Corbett and colleagues introduced the p.Met9Arg mutation into a transgenic mouse line, resulting in rod formation in all muscles and a late-onset (age five to six months) skeletal muscle weakness [Corbett et al 2001]. The percentage of rods varied significantly among different muscle groups despite uniform expression of the mutant transgene, reflecting the variability of muscle involvement seen in humans with NM. Preliminary studies in the mouse confirm that the mutant TPM3 is expressed and that there is an imbalance in other specific TPM isoform levels within NM muscle that may contribute to disease pathogenesis. Fiber typing abnormalities in the mouse model appear to be related to a disruption in the developmental progression of the different muscle fiber types.

TPM2

Normal allelic variants. TPM2 contains ten exons.

Pathologic allelic variants. Donner et al [2002] identified two different heterozygous missense mutations in TPM2.

Normal gene product. Tropomyosins are actin-filament-binding proteins expressed in skeletal, cardiac, and smooth muscle that act to regulate the calcium-sensitive interaction of actin and myosin during muscle contraction.

Abnormal gene product. The two missense mutations identified to date in TPM2 are speculated to affect the actin-binding properties of tropomyosin beta chain.

TNNT1

Normal allelic variants. The gene encoding troponin T, slow skeletal muscle consists of 14 exons.

Pathologic allelic variants. See Table 5. Johnston et al [2000] identified a homozygous stop codon mutation, predicted to truncate the protein at amino acid 180, in infants with the Amish form of NM.

Table 5. Selected TNNT1 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequence
c.538G>Tp.Glu180*NM_003283​.4

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The tropomyosin-troponin complex regulates the calcium sensitivity of the contractile apparatus of the sarcomere, linking excitation to contraction in skeletal muscle. The troponin T part of the troponin complex regulates its binding to tropomyosin.

Abnormal gene product. In the Amish form of NM, which is caused by a homozygous p.Glu180* nonsense mutation in TNNT1, troponin T (TnT), slow skeletal muscle, slow TnT is completely absent from slow fibers. Slow TnT confers greater calcium sensitivity than does fast TnT in single fiber contractility assays. Despite the lack of slow TnT, individuals with Amish NM have normal muscle strength at birth. The postnatal onset and infantile progression of Amish NM correspond to a down-regulation of cardiac and embryonic splice variants of fast TnT in normal developing human skeletal muscle, suggesting that the fetal TnT isoforms complement slow TnT.

CFL2

Normal allelic variants. The gene encoding the muscle isoform of cofilin (CFL2) on chromosome 14q12 consists of five exons [Thirion et al 2001].

Pathologic allelic variants. See Table 6. CFL2 has been directly implicated in human disease in only one family to date [Agrawal et al 2007]. A homozygous missense change (c.103C>A) was found in two sisters from a consanguineous family of Middle Eastern origin. While the possibility remains that this is a chance association, there is good supportive evidence that this change is pathogenic. The associated LOD score in the family was 1.9, the change was not found in over 200 healthy individuals (almost half of whom were ethnically matched) and reduced cofilin 2 levels were found in patient muscle biopsies by Western blot and immunohistochemistry. Both children had typical clinical features of a congenital myopathy that included congenital hypotonia, delayed early milestones, frequent falls and an inability to run. Nemaline bodies were seen on muscle biopsy at age two years in one child, together with occasional minicore lesions and actin filament accumulations. A muscle biopsy of the older child at age four years showed nonspecific abnormalities.

Agrawal et al [2007] directly sequenced CFL2 in 113 unrelated patients with nemaline myopathy of unknown genetic basis and 58 patients with other muscle pathologies. They found disease-associated mutations in only the single family reported above and concluded that CFL2 is a rare cause of nemaline myopathy, accounting for fewer than 1% of patients.

Table 6. CFL2 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.103C>Ap.Ala35ThrNM_021914​.6
NP_068733​.1

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The cofilins, together with actin depolymerization factor (ADF), form a group of proteins that catalyze the depolymerization of actin filaments in a pH-dependent manner. CFL2 encodes the muscle isoform of cofilin. CFL2 was considered a good candidate for nemaline myopathy because of its role in actin filament turnover in muscle.

Abnormal gene product. The c.103C>A change is predicted to substitute threonine in place of a highly conserved alanine 35 residue. In addition the mutant protein tended to precipitate abnormally when expressed in bacterial cells, suggesting that the mutation causes protein misfolding. Molecular modeling has suggested that the mutation may disrupt a beta sheet directly adjacent to the nuclear localization signal.

KBTBD13

Normal allelic variants. KBTBD13 has a single exon and the predicted open reading frame comprises 1374 nucleotides

Pathologic allelic variants. Three identified disease-associated mutations (p.Arg248Ser, p.Lys390Asn, and p.Arg408Cys) (see Table 7) are located in conserved domains of Kelch repeats [Sambuughin et al 2010].

Table 7. KBTBD13 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.742C>Ap.Arg248SerNM_001101362​.2 NP_001094832​.1
c.1170G>Cp.Lys390Asn
c.1222C>Tp.Arg408Cys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The gene encodes a protein, KBTBD13, of 458 amino acids with a molecular mass of 49 kd. The KBTBD13 protein contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. Previously identified BTB/POZ/Kelch domain-containing proteins have been implicated in a broad variety of biologic processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of the KBTBD13 protein in skeletal muscle is not yet known.

Abnormal gene product. The identified mutations are predicted to disrupt the molecule’s structure (beta-propeller blades); the effects on protein function are not yet known.

References

Published Guidelines/Consensus Statements

  1. Wang CH, Dowling JJ, North KN, Schroth MK, Sejersen T, Shapiro F, Bellini J, Weiss H, Guillet M, Amburgey K, Apkon S, Bertini E, Bonnemann C, Clarke N, Connolly AM, Estournet-Mathiaud B, Fitzgerald D, Florence JM, Gee R, Gurgel-Giannetti J, Glanzman AM, Hofmeister B, Jungbluth H, Koumbourlis AC, Laing NG, Main M, Morrison LA, Munns C, Rose K, Schuler PM, Sewry C, Storhaug K, Vainzof M, Yuan N. Consensus statement on standard of care for congenital myopathies. J Child Neurol. 2012;27:363–82. [PubMed: 22431881]

Literature Cited

  1. Agrawal PB, Greenleaf RS, Tomczak KK. Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2. Am J Hum Genet. 2007;80:162–7. [PMC free article: PMC1785312] [PubMed: 17160903]
  2. Agrawal PB, Strickland CD, Midgett C, Morales A, Newburger DE, Poulos MA, Tomczak KK, Ryan MM, Iannaccone ST, Crawford TO, Laing NG, Beggs AH. Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol. 2004;56:86–96. [PubMed: 15236405]
  3. Anderson SL, Ekstein J, Donnelly MC, Keefe EM, Toto NR, LeVoci LA, Rubin BY. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet. 2004;115:185–90. [PubMed: 15221447]
  4. Chahin N, Selcen D, Engel AG. Sporadic late onset nemaline myopathy. Neurology. 2005;65:1158–64. [PubMed: 16148261]
  5. Corbett MA, Akkari PA, Domazetovska A, Cooper ST, North KN, Laing NG, Gunning PW, Hardeman EC. An alphaTropomyosin mutation alters dimer preference in nemaline myopathy. Ann Neurol. 2005;57:42–9. [PubMed: 15562513]
  6. Corbett MA, Robinson CS, Dunglison GF, Yang N, Joya JE, Stewart AW, Schnell C, Gunning PW, North KN, Hardeman EC. A mutation in alpha-tropomyosin (slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy. Hum Mol Genet. 2001;10:317–28. [PubMed: 11157795]
  7. Crawford K, Flick R, Close L, Shelly D, Paul R, Bove K, Kumar A, Lessard J. Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period. Mol Cell Biol. 2002;22:5887–96. [PMC free article: PMC133984] [PubMed: 12138199]
  8. Donner K, Ollikainen M, Ridanpaa M, Christen HJ, Goebel HH, de Visser M, Pelin K, Wallgren-Pettersson C. Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy. Neuromuscul Disord. 2002;12:151–8. [PubMed: 11738357]
  9. Durling HJ, Reilich P, Muller-Hocker J, Mendel B, Pongratz D, Wallgren-Pettersson C, Gunning P, Lochmuller H, Laing NG. De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy. Neuromuscul Disord. 2002;12:947–51. [PubMed: 12467750]
  10. Goebel HH, Anderson JR, Hubner C, Oexle K, Warlo I. Congenital myopathy with excess of thin myofilaments. Neuromuscul Disord. 1997;7:160–8. [PubMed: 9185179]
  11. Gommans IM, Davis M, Saar K, Lammens M, Mastaglia F, Lamont P, van Duijnhoven G, ter Laak HJ, Reis A, Vogels OJ, Laing N, van Engelen BG, Kremer H. A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions. Brain. 2003;126:1545–51. [PubMed: 12805120]
  12. Gommans IM, van Engelen BG, ter Laak HJ, Brunner HG, Kremer H, Lammens M, Vogels OJ. A new phenotype of autosomal dominant nemaline myopathy. Neuromuscul Disord. 2002;12:13–8. [PubMed: 11731279]
  13. Gurgel-Giannetti J, Reed UC, Marie SK, Zanoteli E, Fireman MA, Oliveira AS, Werneck LC, Beggs AH, Zatz M, Vainzof M. Rod distribution and muscle fiber type modification in the progression of nemaline myopathy. J Child Neurol. 2003;18:235–40. [PubMed: 12731651]
  14. Hutchinson DO, Charlton A, Laing NG, Ilkovski B, North KN. Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred. Neuromuscul Disord. 2006;16:113–21. [PubMed: 16427282]
  15. Ilkovski B, Cooper ST, Nowak K, Ryan MM, Yang N, Schnell C, Durling HJ, Roddick LG, Wilkinson I, Kornberg AJ, Collins KJ, Wallace G, Gunning P, Hardeman EC, Laing NG, North KN. Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene. Am J Hum Genet. 2001;68:1333–43. [PMC free article: PMC1226120] [PubMed: 11333380]
  16. Ilkovski B, Nowak KJ, Domazetovska A, Maxwell AL, Clement S, Davies KE, Laing NG, North KN, Cooper ST. Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms. Hum Mol Genet. 2004;13:1727–43. [PubMed: 15198992]
  17. Jeannet PY, Mittaz L, Dunand M, Lobrinus JA, Bonafe L, Kuntzer T. Autosomal dominant nemaline myopathy: a new phenotype unlinked to previously known genetic loci. Neuromuscul Disord. 2007;17:6–12. [PubMed: 17157023]
  18. Jin JP, Brotto MA, Hossain MM, Huang QQ, Brotto LS, Nosek TM, Morton DH, Crawford TO. Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy. J Biol Chem. 2003;278:26159–65. [PubMed: 12732643]
  19. Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, Koch T, Schaffer AA, Francomano CA, Biesecker LG. A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet. 2000;67:814–21. [PMC free article: PMC1287886] [PubMed: 10952871]
  20. Jungbluth H, Sewry CA, Brown SC, Nowak KJ, Laing NG, Wallgren-Pettersson C, Pelin K, Manzur AY, Mercuri E, Dubowitz V, Muntoni F. Mild phenotype of nemaline myopathy with sleep hypoventilation due to a mutation in the skeletal muscle alpha-actin (ACTA1) gene. Neuromuscul Disord. 2001;11:35–40. [PubMed: 11166164]
  21. Jungbluth H, Sewry CA, Counsell S, Allsop J, Chattopadhyay A, Mercuri E, North K, Laing N, Bydder G, Pelin K, Wallgren-Pettersson C, Muntoni F. Magnetic resonance imaging of muscle in nemaline myopathy. Neuromuscul Disord. 2004;14:779–84. [PubMed: 15564032]
  22. Laing NG, Clarke NF, Dye DE, Liyanage K, Walker KR, Kobayashi Y, Shimakawa S, Hagiwara T, Ouvrier R, Sparrow JC, Nishino I, North KN, Nonaka I. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol. 2004;56:689–94. [PubMed: 15468086]
  23. Laing NG, Majda BT, Akkari PA, Layton MG, Mulley JC, Phillips H, Haan EA, White SJ, Beggs AH, Kunkel LM. et al. Assignment of a gene (NEMI) for autosomal dominant nemaline myopathy to chromosome I. Am J Hum Genet. 1992;50:576–83. [PMC free article: PMC1684287] [PubMed: 1347195]
  24. Laing NG, Wilton SD, Akkari PA, Dorosz S, Boundy K, Kneebone C, Blumbergs P, White S, Watkins H, Love DR. A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy NEM1. Nat Genet. 1995;10:249. [PubMed: 7663526]
  25. Lamont PJ, Thorburn DR, Fabian V, Vajsar J, Hawkins C, Saada Reisch A, Durling H, Laing NG, Nevo Y. Nemaline rods and complex I deficiency in three infants with hypotonia, motor delay and failure to thrive. Neuropediatrics. 2004;35:302–6. [PubMed: 15534765]
  26. Lehtokari VL, Pelin K, Sandbacka M, Ranta S, Donner K, Muntoni F, Sewry C, Angelini C, Bushby K, Van den Bergh P, Iannaccone S, Laing NG, Wallgren-Pettersson C. Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Hum Mutat. 2006;27:946–56. [PubMed: 16917880]
  27. Lomen-Hoerth C, Simmons ML, Dearmond SJ, Layzer RB. Adult-onset nemaline myopathy: another cause of dropped head. Muscle Nerve. 1999;22:1146–50. [PubMed: 10417802]
  28. Lunkka-Hytonen M, Lehtokari VL, Pelin K, Brudzewsky D, Wallgren-Pettersson C. Development of the multiplex ligation-dependent probe amplification (MLPA) method for identifying large scale mutations in the nebulin gene. Neuromuscul Disord. 2008;18:787.
  29. Martinez BA, Lake BD. Childhood nemaline myopathy: a review of clinical presentation in relation to prognosis. Dev Med Child Neurol. 1987;29:815–20. [PubMed: 2826280]
  30. Michele DE, Albayya FP, Metzger JM. A nemaline myopathy mutation in alpha-tropomyosin causes defective regulation of striated muscle force production. J Clin Invest. 1999;104:1575–81. [PMC free article: PMC409864] [PubMed: 10587521]
  31. Michele DE, Coutu P, Metzger JM. Divergent abnormal muscle relaxation by hypertrophic cardiomyopathy and nemaline myopathy mutant tropomyosins. Physiol Genomics. 2002;9:103–11. [PubMed: 12006676]
  32. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet. 1997;60:1316–25. [PMC free article: PMC1716149] [PubMed: 9199552]
  33. Monnier N, Romero NB, Lerale J, Nivoche Y, Qi D, MacLennan DH, Fardeau M, Lunardi J. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet. 2000;9:2599–608. [PubMed: 11063719]
  34. Moraczewska J, Greenfield NJ, Liu Y, Hitchcock-DeGregori SE. Alteration of tropomyosin function and folding by a nemaline myopathy-causing mutation. Biophys J. 2000;79:3217–25. [PMC free article: PMC1301196] [PubMed: 11106625]
  35. Nair-Shalliker V, Kee AJ, Joya JE, Lucas CA, Hoh JF, Hardeman EC. Myofiber adaptational response to exercise in a mouse model of nemaline myopathy. Muscle Nerve. 2004;30:470–80. [PubMed: 15372535]
  36. Nowak KJ, Wattanasirichaigoon D, Goebel HH, Wilce M, Pelin K, Donner K, Jacob RL, Hubner C, Oexle K, Anderson JR, Verity CM, North KN, Iannaccone ST, Muller CR, Nurnberg P, Muntoni F, Sewry C, Hughes I, Sutphen R, Lacson AG, Swoboda KJ, Vigneron J, Wallgren-Pettersson C, Beggs AH, Laing NG. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet. 1999;23:208–12. [PubMed: 10508519]
  37. Oishi M, Mochizuki Y. Magnetic resonance imaging findings of the skeletal muscle of a patient with nemaline myopathy. Intern Med. 1998;37:776–9. [PubMed: 9804088]
  38. Pauw-Gommans IM, Gerrits KH, de Haan A, van Engelen BG. Muscle slowness in a family with nemaline myopathy. Neuromuscul Disord. 2006;16:477–80. [PubMed: 16793268]
  39. Pelin K, Donner K, Holmberg M, Jungbluth H, Muntoni F, Wallgren-Pettersson C. Nebulin mutations in autosomal recessive nemaline myopathy: an update. Neuromuscul Disord. 2002;12:680–6. [PubMed: 12207938]
  40. Pelin K, Hilpela P, Donner K, Sewry C, Akkari PA, Wilton SD, Wattanasirichaigoon D, Bang ML, Centner T, Hanefeld F, Odent S, Fardeau M, Urtizberea JA, Muntoni F, Dubowitz V, Beggs AH, Laing NG, Labeit S, de la Chapelle A, Wallgren-Pettersson C. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci U S A. 1999;96:2305–10. [PMC free article: PMC26779] [PubMed: 10051637]
  41. Portlock CS, Boland P, Hays AP, Antonescu CR, Rosenblum MK. Nemaline myopathy: a possible late complication of Hodgkin's disease therapy. Hum Pathol. 2003;34:816–8. [PubMed: 14506646]
  42. Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, Houston R, Muirhead D, Dennett X, Shield LK, De Girolami U, Iannaccone ST, Laing NG, North KN, Beggs AH. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology. 2003;60:665–73. [PubMed: 12601110]
  43. Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, Laing NG, Beggs AH, North KN. Nemaline myopathy: a clinical study of 143 cases. Ann Neurol. 2001;50:312–20. [PubMed: 11558787]
  44. Ryan MM, Sy C, Rudge S, Ellaway C, Ketteridge D, Roddick LG, Iannaccone ST, Kornberg AJ, North KN. Dietary L-tyrosine supplementation in nemaline myopathy. J Child Neurol. 2008;23:609–13. [PubMed: 18079309]
  45. Sambuughin N, Yau KS, Olivé M, Duff RM, Bayarsaikhan M, Lu S, Gonzalez-Mera L, Sivadorai P, Nowak KJ, Ravenscroft G, Mastaglia FL, North KN, Ilkovski B, Kremer H, Lammens M, van Engelen BG, Fabian V, Lamont P, Davis MR, Laing NG, Goldfarb LG. Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. Am J Hum Genet. 2010;87:842–7. [PMC free article: PMC2997379] [PubMed: 21109227]
  46. Scacheri PC, Hoffman EP, Fratkin JD, Semino-Mora C, Senchak A, Davis MR, Laing NG, Vedanarayanan V, Subramony SH. A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology. 2000;55:1689–96. [PubMed: 11113224]
  47. Selcen D, Krueger BR, Engel AG. Familial cardioneuromyopathy with hyaline masses and nemaline rods: a novel phenotype. Ann Neurol. 2002;51:224–34. [PubMed: 11835379]
  48. Skyllouriotis ML, Marx M, Skyllouriotis P, Bittner R, Wimmer M. Nemaline myopathy and cardiomyopathy. Pediatr Neurol. 1999;20:319–21. [PubMed: 10328285]
  49. Sparrow JC, Nowak KJ, Durling HJ, Beggs AH, Wallgren-Pettersson C, Romero N, Nonaka I, Laing NG. Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul Disord. 2003;13:519–31. [PubMed: 12921789]
  50. Tajsharghi H, Ohlsson M, Lindberg C, Oldfors A. Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2). Arch Neurol. 2007;64:1334–8. [PubMed: 17846275]
  51. Tan P, Briner J, Boltshauser E, Davis MR, Wilton SD, North K, Wallgren-Pettersson C, Laing NG. Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy. Neuromuscul Disord. 1999;9:573–9. [PubMed: 10619715]
  52. Thirion C, Stucka R, Mendel B, Gruhler A, Jaksch M, Nowak KJ, Binz N, Laing NG, Lochmüller H. Characterization of human muscle type cofilin (CFL2) in normal and regenerating muscle. Eur J Biochem. 2001;268:3473–82. [PubMed: 11422377]
  53. von der Hagen M, Kress W, Hahn G, Brocke KS, Mitzscherling P, Huebner A, Müller-Reible C, Stoltenburg-Didinger G, Kaindl AM. Novel RYR1 missense mutation causes core rod myopathy. Eur J Neurol. 2008;15:e31–2. [PubMed: 18312400]
  54. Wallgren-Pettersson C, Beggs AH, Laing NG. 51st ENMC International Workshop: Nemaline Myopathy. 13-15 June 1997, Naarden, The Netherlands. Neuromuscul Disord. 1998;8:53–6. [PubMed: 9565992]
  55. Wallgren-Pettersson C, Laing NG. Report of the 70th ENMC International Workshop: nemaline myopathy, 11-13 June 1999, Naarden, The Netherlands. Neuromuscul Disord. 2000;10:299–306. [PubMed: 10838258]
  56. Wallgren-Pettersson C, Laing NG. Report of the 83rd ENMC International Workshop: 4th workshop on nemaline myopathy, 22-24 September 2000, Naarden, The Netherlands. Neuromuscul Disord. 2001;11:589–95. [PubMed: 11525890]
  57. Wallgren-Pettersson C, Laing NG. 109th ENMC International Workshop: 5th workshop on nemaline myopathy, 11th-13th October 2002, Naarden, The Netherlands. Neuromuscul Disord. 2003;13:501–7. [PubMed: 12899878]
  58. Wallgren-Pettersson C, Pelin K, Hilpela P, Donner K, Porfirio B, Graziano C, Swoboda KJ, Fardeau M, Urtizberea JA, Muntoni F, Sewry C, Dubowitz V, Iannaccone S, Minetti C, Pedemonte M, Seri M, Cusano R, Lammens M, Castagna-Sloane A, Beggs AH, Laing NG, de la Chapelle A. Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy. Neuromuscul Disord. 1999;9:564–72. [PubMed: 10619714]
  59. Wallgren-Pettersson C, Pelin K, Nowak KJ, Muntoni F, Romero NB, Goebel HH, North KN, Beggs AH, Laing NG. Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. Neuromuscul Disord. 2004;14:461–70. [PubMed: 15336686]
  60. Wang CH, Dowling JJ, North KN, Schroth MK, Sejersen T, Shapiro F, Bellini J, Weiss H, Guillet M, Amburgey K, Apkon S, Bertini E, Bonnemann C, Clarke N, Connolly AM, Estournet-Mathiaud B, Fitzgerald D, Florence JM, Gee R, Gurgel-Giannetti J, Glanzman AM, Hofmeister B, Jungbluth H, Koumbourlis AC, Laing NG, Main M, Morrison LA, Munns C, Rose K, Schuler PM, Sewry C, Storhaug K, Vainzof M, Yuan N. Consensus statement on standard of care for congenital myopathies. J Child Neurol. 2012;27:363–82. [PubMed: 22431881]
  61. Wattanasirichaigoon D, Swoboda KJ, Takada F, Tong HQ, Lip V, Iannaccone ST, Wallgren-Pettersson C, Laing NG, Beggs AH. Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy. Neurology. 2002;59:613–7. [PubMed: 12196661]

Chapter Notes

Author Notes

Web: www.inmr.com.au

Revision History

  • 15 March 2012 (me) Comprehensive update posted live
  • 21 October 2010 (cd) Revision: deletion/duplication analysis for NEB gene available
  • 17 August 2010 (me) Comprehensive update posted live
  • 2 April 2009 (me) Comprehensive update posted live
  • 16 October 2006 (me) Comprehensive update posted to live Web site
  • 17 June 2004 (me) Comprehensive update posted to live Web site
  • 25 November 2002 (kn) Revisions
  • 19 June 2002 (me) Review posted to live Web site
  • 24 February 2002 (kn) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1288PMID: 20301465
PubReader format: click here to try

Views

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

  • Congenital Fiber-Type Disproportion[GeneReviews<sup>®</sup>. 1993]
    Congenital Fiber-Type Disproportion
    DeChene ET, Kang PB, Beggs AH. GeneReviews<sup>®</sup>. 1993
  • Collagen Type VI-Related Disorders[GeneReviews<sup>®</sup>. 1993]
    Collagen Type VI-Related Disorders
    Lampe AK, Flanigan KM, Bushby KM, Hicks D. GeneReviews<sup>®</sup>. 1993
  • Central Core Disease[GeneReviews<sup>®</sup>. 1993]
    Central Core Disease
    Malicdan MCV, Nishino I. GeneReviews<sup>®</sup>. 1993
  • Congenital Muscular Dystrophy Overview[GeneReviews<sup>®</sup>. 1993]
    Congenital Muscular Dystrophy Overview
    Sparks S, Quijano-Roy S, Harper A, Rutkowski A, Gordon E, Hoffman EP, Pegoraro E. GeneReviews<sup>®</sup>. 1993
  • Review Nemaline myopathy: a clinical study of 143 cases.[Ann Neurol. 2001]
    Review Nemaline myopathy: a clinical study of 143 cases.
    Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, Laing NG, Beggs AH, North KN. Ann Neurol. 2001 Sep; 50(3):312-20.
See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...