DiagnosisClinical DiagnosisThe 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 weaknessOnset in infancy, childhood, or adulthoodFamily 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 mutationElectrophysiologic 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 studiesMuscle 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).FigureFigure 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: TPM3 is expressed only in type 1 (slow) fibers, and fiber atrophy and nemaline bodies in individuals with the TPM3 mutation occur preferentially in type 1 fibers [Wallgren-Pettersson et al 1998, Tan et al 1999, Ryan et al 2003].Very numerous rods, abnormal accumulation of glycogen and actin filaments, and marked sarcomeric disruption have been observed in individuals with ACTA1 mutations [Ilkovski et al 2001, Ryan et al 2003].In the Amish form of NM, complete loss of troponin T, slow skeletal muscle causes selective atrophy of type 1 fibers [Jin et al 2003].Nebulin immunocytochemistry is normal in the majority of individuals with NEB mutations. Abnormal staining in a small proportion of individuals can serve as a guide for molecular genetic testing [Wallgren-Pettersson & Laing 2000].Molecular Genetic TestingGenes. 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 Additional individuals with NM do not link to any of the seven loci identified at the time of publication, suggesting further genetic heterogeneity [Wallgren-Pettersson et al 1999, Wallgren-Pettersson & Laing 2003, Jeannet et al 2007].Clinical testingSequence analysis of ACTA1, CFL2, KBTBD13, NEB, TPM3, TPM2, and TNNT1. Results of linkage analyses suggest that NEB mutations are likely to be a relatively common cause of NM; however, sequence analysis is hampered by the large size of the gene and the large number of repetitive sequences [Pelin et al 1999, Wallgren-Pettersson et al 1999] (see Molecular Genetics). Table 1. Summary of Molecular Genetic Testing Used in Nemaline MyopathyView in own windowGene SymbolProportion of NM Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityACTA115%-25% ^{1Sequence analysisSequence variants 2ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletion; none reportedNEBUnknown 4Targeted mutation analysis 52502-nucleotide deletion spanning exon 55 6, 7 ClinicalSequence analysisSequence variants 3Deletion / duplication analysis 3Exonic or whole-gene deletion 8TPM32%-3% 9Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletion; none reportedTPM2<1% 10Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletion; none reportedTNNT1See footnote 11Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletion; none reportedCFL2 Unknown 12 Sequence analysisSequence variants 3ClinicalKBTBD13UnknownSequence analysisSequence variants 3Clinical1. 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.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, 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).Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandCreatine 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.Genetically Related (Allelic) DisordersACTA1. Goebel et al [1997] reported three individuals with congenital myopathy and excess accumulation of thin filaments that stained positive for skeletal muscle α-actin. Two of these individuals also had nemaline bodies. Mutations were subsequently identified in ACTA1 [Nowak et al 1999]. Therefore, mutations in this gene may present with the pathologic finding of accumulation of thin filaments in the absence of nemaline bodies [Wallgren-Pettersson & Laing 2003].Heterozygous missense mutations in ACTA1 have also been identified in individuals with the histologic picture of congenital fiber-type disproportion (CFTD), characterized by selective hypotrophy of type 1 fibers in the absence of other abnormalities on light or electron microscopy. All three individuals with CFTD with ACTA1 mutations had severe congenital weakness and respiratory failure without ophthalmoplegia, and were clinically indistinguishable from individuals with ACTA1 mutations and severe congenital-onset NM [Laing et al 2004]. Jungbluth et al [2001] described an individual with mild NM and sleep hypoventilation in whom an ACTA1 mutation was identified. Cores were also noted in the muscle biopsy, suggesting that cores may also occur as a secondary feature in primary NM. The cores were predominantly in type 2 fibers, as distinct from typical central core disease (CCD) and the core-rod myopathy found in the family described by Scacheri et al [2000], in which the cores occurred predominantly in type 1 fibers. The identification of a novel ryanodine receptor gene mutation causing a form of central core disease with associated rod formation suggests that core-rod myopathy may exist as a separate disease entity [Monnier et al 2000, Scacheri et al 2000].NEB. Mutations in NEB are not known to be associated with any other phenotypes.TPM3. Mutations in TPM3 have been associated with congenital fiber type disproportion.TPM2. Mutations in TPM2 have been associated with distal arthrogryposis multiplex congenita type I and with cap disease, a congenital myopathy with a nonspecific clinical phenotype defined by the finding on muscle biopsy of enlarged Z-discs and cap-like structures containing disorganized thin filaments at the periphery of muscle fibers [Tajsharghi et al 2007].TNNT1. Mutations in TNNT1 are not known to be associated with any other phenotypes.CFL2. Mutations in CFL2 are not known to be associated with any other phenotypes.KBTBD13. Mutations in KBTBD13 are not known to be associated with any other phenotypes.}

Natural HistoryThe 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 CorrelationsGenotype-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 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 GenesView in own windowMutated GeneMode of InheritancePhenotypeACTA1AD/ARRange from severe congenital to childhood onsetNEBARTypical congenital (majority)
All other phenotypes (occasional)TPM3AD/ARSevere congenital (AR)
Intermediate congenital
Childhood onset (AD)TPM2AD Typical congenitalTNNT1ARAmish NMCFL2 ARTypical congenitalKBTBD13AD 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].

Differential DiagnosisAll 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Severe congenital (neonatal) NMAmish NMIntermediate congenital NMTypical congenital NMChildhood-onset NMAdult-onset (late-onset) NM

ManagementEvaluations Following Initial DiagnosisTo 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 hypoxiaFor 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 insertionPhysical examination to evaluate for joint contracturesPhysical examination to evaluate for scoliosis, followed by spinal x-ray if scoliosis is suspectedPhysical and occupational therapy evaluations relevant to the degree of weaknessSpeech therapy evaluation if dysarthria and/or hypernasal speech is presentOrthodontic evaluation if palatal anomalies are presentEvaluation for the presence of dilated cardiomyopathy in those with the severe congenital formMedical genetics consultationTreatment of ManifestationsConsensus 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 indicatedAggressive treatment of lower respiratory tract infectionsEvaluation at an early stage of the need for intermittent or permanent use of a mechanical ventilator to prevent insidious nocturnal hypoxiaReferral to an orthopedist for management of scoliosis and joint contractures, as in the general populationPhysical therapy for maintenance/improvement of function and joint mobilitySpeech therapy if dysarthria and/or hypernasal speech is presentStandard treatment of gastroesophageal reflux, if presentAssessment of cardiac status because of the risk (albeit low) of cardiomyopathy or cor pulmonalePrevention of Primary ManifestationsConsensus guidelines for management of congenital myopathies are currently in publication [Wang et al 2012]. Prevention of Secondary ComplicationsPatient 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.SurveillanceConsensus 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 AvoidMalignant 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementPregnancy 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 InvestigationL-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.OtherIn 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).

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Nemaline Myopathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTPM31q21​.3Tropomyosin alpha-3 chainTPM3 homepage - Leiden Muscular Dystrophy pagesTPM3NEB2q23​.3Nebulin NEBACTA11q42​.13Actin, alpha skeletal muscleACTA1 homepage - Leiden Muscular Dystrophy pagesACTA1TNNT119q13​.42Troponin T, slow skeletal muscleTNNT1 homepage - Leiden Muscular Dystrophy pagesTNNT1TPM29p13​.3Tropomyosin beta chainTPM2 homepage - Leiden Muscular Dystrophy pagesTPM2CFL214q13​.1Cofilin-2 CFL2KBTBD1315q22​.31Kelch repeat and BTB domain-containing protein 13KBTBD13 homepage - Leiden Muscular Dystrophy pagesKBTBD13Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Nemaline Myopathy (View All in OMIM) View in own window 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: KBTBD13Molecular Genetic PathogenesisNemaline 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.ACTA1Normal 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].NEBNormal 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 View in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequences c.7622-2025_7727+372del2502
(exon 55 deletion)p.Arg2478_Asp2512delNM_004543​.3
NP_004534​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal 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.TPM3Normal 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 tropomyosin_SLOW 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.Gln32X nonsense mutation in an infant with extremely delayed motor development.Table 4. Selected TPM3 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid Change
(Alias ¹)Reference Sequencesc.26T>Gp.Met9ArgNM_152263​.2
NP_689476​.2 c.94C>Tp.Gln312X
(Gln31X)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal 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.TPM2Normal 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.TNNT1Normal 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 VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencec.538G>Tp.Glu180XNM_003283​.4See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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.Glu180X 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.CFL2Normal 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 GeneReviewView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences c.103C>Ap.Ala35ThrNM_021914​.6
NP_068733​.1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 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 nucleotidesPathologic 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 GeneReviewView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences c.742C>Ap.Arg248SerNM_001101362​.2 NP_001094832​.1c.1170G>Cp.Lys390Asnc.1222C>Tp.Arg408CysSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 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 biological 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.