DiagnosisClinical DiagnosisDiagnosis of congenital fiber-type disproportion (CFTD), a genetically and clinically heterogeneous congenital myopathy, is based on a combination of the following [Brooke 1973, Clarke & North 2003, North 2004]: Clinical presentation consistent with congenital myopathyMorphologic features observed on skeletal muscle histology Most common clinical presentation. CFTD usually presents with hypotonia and varying degrees of skeletal muscle weakness that primarily affects the limbs, generally presenting at birth or within the first year of life and remaining stable over time or improving with age.Skeletal muscle histology (see Figure 1)FigureFigure 1. (A) H and E, (B) NADH, and (C) ATPase (pH 9.4) histochemical stains of a biopsy taken from the vastus lateralis of a six-month-old female with CFTD caused by a heterozygous TPM3 mutation. The type 1 fibers (dark staining on B. NADH; light staining (more...)The original criteria presented by Brooke in 1973 required that type 1 fibers be at least 12% smaller than the mean diameter of type 2A and/or type 2B fibers in the absence of other significant pathologic findings (e.g., many nemaline bodies, cores, or central nuclei; see Figure 1). In cases with type 2 fiber hypertrophy, type 1 fibers may have a normal diameter for age. More recent studies suggest that affected individuals with true congenital fiber size disproportion (i.e., those who do not have another defined neuromuscular condition such as myotonic dystrophy or Ullrich muscular dystrophy) have type 1 fibers that are generally at least 40% to over 80% smaller than type 2 fibers, particularly when the condition is associated with mutations in TPM3, RYR1, and ACTA1 [Laing et al 2004, Clarke et al 2008, Clarke et al 2010, Lawlor et al 2010]. Therefore, a 35%-40% degree of disproportion has been suggested as a better criterion for the diagnosis of CFTD [Clarke 2011]. However, cases of SEPN1-related CFTD may not meet this stricter criterion [Clarke 2011].
Note: Multiple males and at least one female without significant muscle weakness have been noted to have fiber-type disproportion on muscle biopsy that was performed in infancy, adolescence, or adulthood [Sobreira et al 2003; Author, personal observation]. Additional findings that may also be present:Type 1 fiber numerical predominance (Figure 1), not to be confused with fiber-type groupingDecreased presence of 2B/2X fibersOne type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)Less frequent abnormalities: central myonuclei, moth-eaten fibers, occasional nemaline rods [Brooke 1973], intramuscular hematopoiesis, infrequent central cores or multicores [Iannaccone et al 1987], and abnormal accumulation of endomysial adipocytesUltrastructural findings on electron microscopy (EM) are generally normal; however, fiber size variation may be present. Architectural abnormalities reported in some individuals include: infrequent multiminicores; nemaline bodies; and sub-sarcolemmal sarcomere disarray or glycogen accumulation.Pathologic findings may change over time, allowing the refinement of the diagnosis through a second biopsy at a later age. Some individuals with a diagnosis of CFTD on first biopsy are later found to have additional findings on second biopsies [De Paula et al 2009, Clarke 2011].Results of other medical testingSerum creatine phosphokinase (CK) concentration is generally normal or mildly elevated (i.e., no more than three times the upper limit of normal) [Clarke & North 2003, Laing et al 2004, Clarke et al 2008, Clarke et al 2010].Electromyography (EMG) is usually normal or myopathic, but neuropathic or mixed findings are also possible [Clarke et al 2008, Clarke et al 2010, Lawlor et al 2010].Nerve conduction studies are generally normal.Muscle imaging. Muscle ultrasound or MRI of the leg or whole body has been shown to be particularly useful in differentiating between congenital myopathies associated with certain genes (see Testing Strategy).Exclusion of other neuromuscular and non-neuromuscular conditions. The pathologic and clinical manifestations of CFTD overlap with other neuromuscular and non-neuromuscular diseases that must be excluded prior to making a diagnosis of CFTD. The majority of these diseases can be excluded based on a thorough physical examination, family history, and appropriate testing, potentially including serum creatine kinase concentration, EMG, muscle biopsy, and/or genetic testing. A comprehensive list of diseases that may present similarly to CFTD is included in Differential Diagnosis.Molecular Genetic TestingGenes. To date, the genetic basis of CFTD has been elucidated in only a portion of cases. Mutations have been identified in the following six genes: ACTA1, MYH7, RYR1, SEPN1, TPM2, and TPM3.Evidence for locus heterogeneity. CFTD was identified in an individual with an apparently balanced translocation t(10;17)(p11.2;q25) inherited from the mother, who had subtle findings of myopathy, suggesting a possible autosomal dominant mode of inheritance with variable expressivity [Gerdes et al 1994].In a kindred of seven males with severe congenital myopathy, biopsies in four of six were suggestive of CFTD. Linkage to the intervals Xp22.13 to Xp11.4 and Xq13.1 to Xq22.1 was found. Of note, Xq28, the locus of MTM1, the gene involved in X-linked myotubular myopathy, was excluded. All affected males had ptosis without ophthalmoplegia, low muscle tone, poor suck, and weakness of the facial and respiratory muscles with relatively normal strength in the limbs. Six of the seven died of respiratory failure within the first few months of life. One male walked at age 17 months and developed mild dilated cardiomyopathy at age 3.5 years. Some female carriers had mild myopathic signs [Clarke et al 2005].A Japanese girl with deletion 1p36, developmental delay, dysmorphic features, and hypotonia had CFTD on muscle biopsy, suggesting that a gene involved in CFTD may exist at this locus [Okamoto et al 2002] (see 1p36 Deletion Syndrome). SEPN1, the gene encoding selenoprotein N and implicated in CFTD and multiminicore disease, resides in this region; however, inheritance of the myopathy associated with SEPN1 alterations is autosomal recessive.Vorwerk et al [1999] described two brothers with CFTD and insulin-resistant diabetes mellitus who were compound heterozygotes for alterations in the insulin receptor gene (IR; INSR). A third brother who did not inherit either INSR gene alteration did not develop symptoms of CFTD, suggesting a potential association between the mutations in INSR and CFTD [Vorwerk et al 1999].Clinical testingTable 1. Molecular Genetic Testing Used in Congenital Fiber-Type DisproportionView in own windowGene SymbolProportion of CFTD Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityACTA1<6%% ^{1Sequence analysis Sequence variants 2ClinicalUnknownDeletion / duplication analysis 3Unknown; none reported 4SEPN1Rare 5Sequence analysis Sequence variants 2ClinicalUnknownDeletion / duplication analysis 3Unknown; none reported 4TPM3~20%-40%Sequence analysis 6Sequence variants 2ClinicalUnknownDeletion / duplication analysis 3Unknown; none reported 4RYR110%-20% 7Likely commonSequence analysis 8Sequence variants 2ClinicalDeletion / duplication analysis 3Unknown; none reported 4TPM2RareSequence analysis 9Sequence variants 2ClinicalDeletion / duplication analysis 3Unknown; none reported 4MYH7Unknown 10Sequence analysis Sequence variants 2ClinicalUnknownDeletion / duplication analysis 3Unknown; none reported 41. Heterozygous missense mutations were observed in 6% of individuals with CFTD in one series [Laing et al 2004] and have been reported in at least seven families [Laing et al 2009].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.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.4. No large deletions or duplications that were causative of CFTD have been reported in ACTA1, RYR1, TPM2, or TPM3. 5. SEPN1 homozygous missense mutations have been reported in two sisters with CFTD [Clarke et al 2006]. 6. TPM3 heterozygous missense mutations have been reported in over ten families with CFTD, and homozygous mutations of the stop codon were reported in one family [Clarke et al 2008, Lawlor et al 2010, Munot et al 2010]. Clarke et al [2008] identified TPM3 alterations in four families from one CFTD cohort, representing approximately 20%-25% of their cases. Lawlor et al [2010] discovered TPM3 mutations in five of 13 families in another CFTD cohort, accounting for almost 40% of their cases.7. Clarke et al [2010] identified recessive RYR1 alterations in four of seven families with CFTD in whom ACTA1 and TPM3 mutations had been previously excluded, suggesting that RYR1 mutations are one of the two most common causes of CFTD, along with TPM3 alterations. They estimated that RYR1 alterations are responsible for 10%-20% of cases of CFTD.8. RYR1 compound heterozygous missense, nonsense, and/or splice site mutations were identified in four families (5 affected individuals) with CFTD in one study [Clarke et al 2010].9. A TPM2 heterozygous missense mutation was reported in a small number of families with CFTD [Brandis et al 2008, Clarke et al 2012].10. Heterozygous MYH7 mutations have been reported in at least three families (4 affected individuals) with CFTD. All of the families had other affected family members with muscle biopsies that contained additional morphologic features that did not fit the CFTD criteria [Muelas et al 2010, Ortolano et al 2011].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of CFTD is currently established by the combination of clinical presentation consistent with congenital myopathy and specific features on muscle biopsy.Molecular genetic testing can be used to confirm the diagnosis of CFTD in some individuals, but some individuals will have normal testing for all six currently associated genes.Muscle imaging, including ultrasound or MRI, may be helpful in guiding genetic testing, since some genes are associated with characteristic muscle involvement [Quijano-Roy et al 2012].Those with RYR1 mutations show particular involvement of the gluteus maximus muscle, adductor magnus, vastus lateralis, sartorius, and soleus muscle with sparing of the rectus femoris and gracilis muscles. Affected individuals with ACTA1 mutations show particular involvement of the gluteus maximus, medial muscles, tibial anterior and peroneal muscles, and posterior thigh, including the sartorius, adductor magnus, semitendinosus muscles, with sparing of the adductor longus, rectus femoris, and gracilis muscles.Those with SEPN1 mutations show involvement of the sartorius, posterior thigh, posterior tibial, and medial and lateral gastrocnemius muscles with sparing of the rectus femoris, adductor longus, and gracilis muscles. Those with mutations in MYH7 may show particular involvement of the tibial anterior and peroneal muscles, milder involvement of the soleus muscle, and sparing of the medial gastrocnemius muscle [Quijano-Roy et al 2012].Based on mutation frequency and gene size, it is recommended that sequence analysis be performed sequentially or in tiers of two to three genes at a time unless there are clinical/pathologic features or family history suggesting a different testing order. Sequential testing may be considered in the following order: TPM3, ACTA1, RYR1, MYH7, TPM2, SEPN1RYR1 mutations appear to be the most common cause of recessive CFTD, while TPM3 mutations seem to be the most common cause of autosomal dominant CFTD. Given the size of RYR1, testing can be more time consuming and costly than testing of the other genes, which may influence decisions about the order of testing. In individuals with ophthalmoplegia and/or a personal or family history of malignant hyperthermia, RYR1 screening could be considered first. MYH7}, TPM2, and particularly SEPN1 mutations appear to be rarer causes of CFTD and therefore could be considered for a second tier.In individuals with cardiomyopathy, MYH7 testing may be considered first.In individuals with spinal rigidity or early-onset scoliosis, SEPN1 testing may be considered first. To date, no large deletions or duplications in the six known genes have been identified to be causative of CFTD; however, disease-causing RYR1 and SEPN1 deletions have been identified in individuals with other related diagnoses. Therefore, there may be some clinical utility to pursuing deletion/duplication testing if sequencing is normal.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. However, the risk for malignant hyperthermia (MH) in individuals with a heterozygous mutation in RYR1 is not well understood. Therefore, it is recommended that individuals with a heterozygous mutation in RYR1 follow appropriate restrictions for MH.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-related myopathies. Heterozygous mutations in ACTA1 most commonly cause nemaline myopathy (NM). Homozygous mutations in ACTA1 have also been identified in a small number of individuals with NM [Laing et al 2009]. Nemaline myopathy is characterized by rod-like structures on muscle biopsy with clinical features similar to those seen in CFTD. Less frequently, ACTA1 mutations can also cause actin filament aggregate myopathy (characterized by accumulation of actin-contacting filaments), intranuclear rod myopathy (characterized by rod-like bodies in the nuclei), and congenital myopathy with core-like areas (without rods), as well as CFTD. A mixture of these pathologic findings can also be seen in a single individual.MYH7-related myopathies. Heterozygous mutations in MYH7 have been associated with isolated hypertrophic/dilated cardiomyopathy, Laing distal myopathy, and myosin storage myopathy (previously known as hyaline body myopathy) [Tajsharghi & Oldfors 2013]. Cardiac abnormalities have been reported in individuals with MYH7 mutations without a diagnosis of CFTD [Muelas et al 2010]. Laing early-onset distal myopathy generally presents with distal weakness, starting with weakness of the ankle dorsiflexors in childhood through early adulthood, and later progresses to include proximal limb muscle weakness. Muscle biopsy shows nonspecific findings, including type 1 predominance and hypotrophy [Tajsharghi & Oldfors 2013]. Myosin storage myopathy presents with variable proximal, distal, or scapuloperoneal weakness during early childhood to mid-to-late adulthood (4^th-6^th decade) [Goebel & Laing 2009, Tajsharghi & Oldfors 2013]. Inheritance is generally dominant, but recessive inheritance has been reported in at least one family with a more severe presentation that included cardiomyopathy. Muscle biopsy shows characteristic aggregation of unstructured material called hyaline bodies [Tajsharghi & Oldfors 2013]. RYR1-related myopathies. Heterozygous alterations in RYR1 cause central core disease (CCD), as well as core-rod myopathy and malignant hyperthermia without myopathy. All RYR1-related myopathies have clinical presentations that overlap with CFTD, with ophthalmoplegia often being a prominent feature [Treves et al 2005].Rare recessive RYR1 mutations have been associated with CCD [Treves et al 2005]. Homozygous or compound heterozygous alterations in RYR1 can cause other congenital myopathies, including congenital myopathies with central nuclei [Wilmshurst et al 2010], multiminicore disease [Treves et al 2005], and a form of congenital myopathy with internalized nuclei and myofibrillar disorganization [Bevilacqua et al 2011]. A large heterozygous deletion of RYR1 was reported in one individual with recessive multiminicore disease [Monnier et al 2009]. There has been one reported case of a heterozygous RYR1 mutation causing centronuclear myopathy [Jungbluth et al 2007]. SEPN1-related myopathies. Homozygous or compound heterozygous alterations in SEPN1 can also cause multiminicore disease (MmD) [Ferreiro et al 2002], rigid spine muscular dystrophy (RSMD) [Moghadaszadeh et al 2001], and desmin-related myopathy with Mallory body-like inclusions [Ferreiro et al 2004]. MmD is diagnosed based on the presence of multiple minicores on muscle biopsy. Clinical features generally include the onset of axial and proximal weakness and hypotonia at birth or in infancy. Scoliosis and respiratory involvement are also common. Most individuals with classic MmD develop spinal rigidity, and thus the classic form is believed to be synonymous with RSMD [Ferreiro et al 2002]. Desmin-related myopathy with Mallory body-like inclusions is defined histologically by the presence of hyaline plaques in approximately 10% of muscle fibers. Clinical features are similar to MmD/RSMD [Ferreiro et al 2004]. Deletions of approximately 90 to 100 base pairs have been reported to be associated with other SEPN1-related myopathies [Ferreiro et al 2004, Maiti et al 2009, Cagliani et al 2011]. TPM2-related myopathies and arthrogryposis. Heterozygous missense mutations in TPM2 are a rare cause of nemaline myopathy, characterized by nemaline rods [Donner et al 2002], and a common cause of cap disease/myopathy, characterized by cap-like structures composed of disorganized thin filaments that resemble a cap [Ohlsson et al 2008]. These myopathies have a clinical presentation that overlaps with CFTD [Donner et al 2002, Ohlsson et al 2008], but they differ from CFTD on muscle biopsy. Clarke et al [2012] described an individual whose initial muscle biopsy was consistent with CFTD, but electron microscopy identified cap structures, indicating that electron microscopy can be a useful tool in clarifying a diagnosis of CFTD. Cardiomyopathy has been reported in at least one individual with TPM2-associated cap myopathy [Clarke 2011]. Alterations in TPM2 can also cause distal arthrogryposis, including type 1 (DA1) and Sheldon-Hall syndrome (DA2B), both of which are characterized by prominence of distal contractures and lack of an obvious myopathic or neurogenic cause. Recessive TPM2 mutations have also been associated with Escobar syndrome with nemaline myopathy in at least one family. Affected individuals presented with hypotonia and multiple pterygium syndrome [Tajsharghi et al 2012].TPM3-related myopathies. Heterozygous, homozygous, and compound heterozygous mutations in TPM3 can cause nemaline myopathy with rod-like structures on biopsy and clinical features similar to those seen in CFTD [Pénisson-Besnier et al 2007]. A heterozygous TPM3 mutation has also been reported in one individual who had features of CFTD on first muscle biopsy, but on a later muscle biopsy had features consistent with cap myopathy (characterized by abnormally arranged myofibrils resembling a cap) [De Paula et al 2009].

Natural HistoryClarke & North [2003], North & Goebel [2003], and North [2004] provide summaries of the natural history of congenital fiber-type disproportion (CFTD), while Sobrido et al [2005], Clarke et al [2008], Clarke et al [2010], and Lawlor et al [2010] present clinical data on the largest number of affected individuals with known mutations. Together, these citations are the primary references for the majority of this section. Findings are summarized in Table 2.Most children present with hypotonia, mild-to-severe generalized muscle weakness, and/or delayed motor milestones at birth or within the first year of life. Poor head control is also common. Limb weakness may be greatest in the limb girdle and proximal limb muscles, but weakness is not usually solely distal. Facial weakness is often present, resulting in a long face, high-arched palate, and tented upper lip. Ptosis, ophthalmoplegia, and bulbar weakness can be seen. Tendon reflexes are often decreased or absent.Motor milestones are often delayed. Although some individuals remain non-ambulatory throughout life, many eventually develop the ability to walk. In more than 90% of affected individuals, muscle weakness becomes static or shows improvement, and in 9% it is slowly progressive [Brooke 1973, Clarke & North 2003]. Progression may result in loss of independent ambulation in some individuals.Table 2. Clinical Features Seen in CFTD Based on Frequency of OccurrenceView in own windowFrequency of Occurrence
(% of Affected Individuals)Clinical FeaturesPrimary(>50%-75%)Hypotonia
Mild-to-severe generalized or proximal muscle weakness
Height and/or weight below the 3rd percentile
Decreased or absent deep tendon reflexes
Normal or mildly elevated CK levels
Normal or myopathic EMG
Normal intelligenceCommon(10%-50%)Facial weakness/myopathic facies: long face, high-arched palate, and tented upper lip
Mild-to-severe respiratory issues
Mild-to-severe feeding difficulties
Ophthalmoplegia
Joint contractures or arthrogryposis multiplex congenita
Congenital hip dislocation
Spinal abnormalities, including scoliosis, kyphoscoliosis, and lordosis
Joint laxityRarely reported(<10%)Cardiac involvement
Cognitive impairment
CryptorchidismAt least 30% of individuals with CFTD have mild-to-severe respiratory involvement, which may not develop until adulthood. The majority of severely affected children develop significant respiratory weakness; however, the severity of respiratory muscle weakness and limb muscle weakness do not always correlate. Respiratory failure may occur at any age with some affected children succumbing to respiratory failure during infancy or childhood. Respiratory failure can occur without evidence of respiratory distress. In more mildly affected individuals, respiratory insufficiency may manifest as nocturnal hypoxia, potentially resulting in frequent chest infections, morning headaches, daytime fatigue, decreased appetite, reduced weight gain, and/or sleep disturbances. Severe respiratory involvement in infancy does not always predict poor prognosis.Approximately 25% of individuals with CFTD show a more severe clinical course with significant and persistent weakness of limb or respiratory muscles at birth. The association in particular of ophthalmoplegia, ptosis, and facial and/or bulbar weakness with severe limb and respiratory weakness has previously been suggested to predict a poor prognosis.Mild-to-severe feeding difficulties occur in almost 30% of children with CFTD. Bulbar weakness may result in chewing and swallowing problems and aspiration of secretions. Infants with severe facial and bulbar weakness may have significant feeding issues and may require intervention (gavage feeding, and/or gastrostomy with or without fundoplication) if symptoms continue beyond the first few months of life. Milder feeding issues often resolve over time.Contractures of the ankles, fingers, hips, elbows, and knees occur in approximately 25% of affected children. Contractures may be present at birth or occur in older individuals who have decreased mobility secondary to severe weakness. Congenital hip dislocation and talipes equinovarus may also be present.Spinal deformities, including scoliosis, kyphoscoliosis, and lordosis, are seen in 25% or more of individuals. Spinal rigidity has also been reported. Contractures and spinal abnormalities are not necessarily associated with increased disease severity.Other. Most individuals have normal intelligence, but cognitive impairment has been reported in a few individuals.Cryptorchidism has been seen in a few males with CFTD.Dilated cardiomyopathy or other cardiac abnormalities have been identified in several individuals with CFTD:One required cardiac transplantation at age 12 years [Banwell et al 1999].A male with X-linked CFTD and dilated cardiomyopathy was medically stable during follow-up from age 3.5 years to age 5.5 years [Clarke et al 2005].One individual required a pacemaker for cardiomyopathy presenting with nocturnal and exertional dyspnea at age 28 years [Fujita et al 2005].A nine-month-old with CFTD had atrial fibrillation and an atrial septal defect [Banwell et al 1999].Dental crowding and high-arched palate, seen in other congenital myopathies, may be observed in CFTD.

Genotype-Phenotype CorrelationsSome genotype-phenotype correlations have been established. See Testing Strategy for more information on muscle imaging-related genotype-phenotype correlations. ACTA1. Laing et al [2004] reported three individuals with ACTA1-associated CFTD who did not have ophthalmoplegia, but did have severe disease with significant muscle weakness and respiratory insufficiency requiring ventilator support [Laing et al 2004]. ACTA1-associated myopathies have a variable phenotype ranging from severe infantile onset to milder weakness, but they appear to be more frequently associated with a more severe presentation. There is considerable phenotypic variability, even with the same mutation, making specific predictions difficult [Laing et al 2009]. MYH7. Only a few families with MYH7 mutations have been reported to have a muscle biopsy and clinical presentation consistent with CFTD. Individuals with MYH7-associated CFTD have a variable phenotype, with age of onset ranging from birth to adulthood. However, life expectancy is not significantly shortened, and the course is generally slowly progressive. Delayed motor milestones or abnormal gait are common presenting symptoms, but may not bring the individual to medical attention until adulthood [Sobrido et al 2005, Muelas et al 2010, Ortolano et al 2011]. Cardiac abnormalities, including cardiomyopathy and rhythm abnormalities, have been reported in a small subset of individuals with MYH7 myopathy, including those who have one of the mutations known to be associated with CFTD [Muelas et al 2010]. In affected individuals with the recurrent p.Lys1729del mutation associated with myosin storage myopathy and CFTD, the anterior compartment of the lower leg is particularly affected, and weakness of the lower leg is sometimes the only identifiable muscle weakness [Muelas et al 2010].In a single large family with CFTD caused by a frameshift mutation in exon 39, weakness was primarily proximal [Sobrido et al 2005, Ortolano et al 2011]. Interestingly, this family had several members with a muscle biopsy consistent with CFTD, while at least one family member had a later biopsy consistent with myosin storage myopathy [Ortolano et al 2011].RYR1. Ophthalmoplegia appears to be particularly suggestive of underlying RYR1 mutations, although it can be subtle or absent, particularly in younger individuals or in individuals with milder disease [Clarke et al 2010].The five individuals reported with homozygous or compound heterozygous RYR1 mutations had the following findings: symptoms at birth or within the first two years of life with hypotonia, muscle weakness, or difficulty running; particularly weak axial muscles; variable requirements for feeding and breathing support from an early age; variable clinical course with death in infancy or early childhood from respiratory failure in some and retained ambulation for short distances into adulthood in others. Delayed motor milestones, respiratory weakness, ophthalmoplegia, ptosis, and facial weakness were all reported in multiple affected individuals; however, none were present in all five cases. SEPN1. The two sisters with CFTD caused by homozygous SEPN1 missense mutations had findings typical of SEPN1-related myopathy, including truncal hypotonia, neck weakness, progressive scoliosis, respiratory involvement, and relatively preserved strength in the extremities [Clarke et al 2006].TPM2. Thus far, TPM2 mutations have only been reported in a small number of families with onset ranging from severe hypotonia in infancy to difficulty running in childhood [Brandis et al 2008, Clarke et al 2012]. Unlike other cases of CFTD associated with mutations in other genes, one mother and son had two populations of type 1 fibers: one population that was hypotrophic and a second population that was relatively normal in size [Donner et al 2002, Brandis et al 2008]. TPM2 mutations can also cause CFTD with neonatal onset of severe hypotonia, weakness, respiratory weakness and arthrogryposis [Author, personal observation]. TPM3. TPM3-associated CFTD generally causes early onset of mild proximal and/or distal weakness, allowing for ambulation into adulthood without the need for invasive ventilation, and no ophthalmoplegia. Individuals with CFTD caused by heterozygous missense mutations in TPM3 who have been described thus far generally presented with hypotonia and/or delayed motor milestones within the first year of life [Clarke et al 2008, Lawlor et al 2010, Munot et al 2010]. A few affected individuals presented with difficulty running or keeping up with peers in childhood or adolescence [Lawlor et al 2010]. Many of these individuals walked within the normal age range and had mild-to-moderate muscle weakness of proximal and/or distal muscles. All individuals who had reached adulthood at the time of the studies were ambulatory. Respiratory difficulties during sleep were common and sometimes insidious, presenting in childhood or early adulthood, making respiratory monitoring particularly important for this subset of individuals [Clarke et al 2008, Lawlor et al 2010, Munot et al 2010, Clarke 2011]. Extraocular muscle weakness was not reported in this group of affected individuals [Clarke et al 2008, Lawlor et al 2010]. The single person with CFTD caused by homozygous TPM3 mutations had a more severe presentation: she never walked and required full-time respiratory and feeding support from early childhood [Lawlor et al 2010].

Differential DiagnosisCongenital myopathies. The primary differential diagnoses are other congenital myopathies, including centronuclear/X-linked myotubular myopathy, multiminicore disease, and nemaline myopathy [Clarke & North 2003].Since congenital myopathies often present similarly, congenital fiber-type disproportion (CFTD) cannot be distinguished from other congenital myopathies solely on clinical findings. Muscle biopsy can often help establish the appropriate diagnosis, since other congenital myopathies have specific associated histologic features, such as increased central nuclei, multiminicores, and nemaline bodies.Other neuromuscular disorders. Muscular dystrophies and diseases of the anterior horn cell may also present with fiber size disproportion and clinical findings similar to CFTD. The disorders that have been specifically associated with fiber size disproportion include the following:Type 1 spinal muscular atrophy (SMA)Congenital muscular dystrophy, including Ullrich muscular dystrophy [Schessel et al 2008]Emery-Dreifuss muscular dystrophyMyotonic dystrophy type 1, particularly the congenital formBecker muscular dystrophy, and rarely, Duchenne muscular dystrophy (see Dystrophinopathies)These dystrophies can be distinguished from CFTD based on physical examination, serum CK concentrations (often significantly increased), and muscle biopsy findings, including dystrophic changes (fiber degeneration and regeneration with necrosis and infiltration of fatty and connective tissue) and immunohistochemistry staining indicative of decreased protein expression [Kang & Kunkel 2006].Congenital myotonic dystrophy (DM1), and congenital muscular dystrophies in particular, may present very similarly to CFTD and appear indistinguishable on muscle biopsy. Furthermore, sensitive molecular genetic testing is not possible for all congenital muscular dystrophies.Molecular genetic testing detects a CTG expansion of DMPK in all individuals with DM1. Brain MRI and ophthalmologic examination may help to differentiate between CFTD and other types of congenital muscular dystrophy. Ullrich muscular dystrophy may be differentiated from CFTD based on the unique pattern of hyperlaxity of distal joints with contractures of more proximal joints, as well as immunohistochemical studies identifying abnormal amounts and/or localization of collagen VI.Spinal muscular atrophy (SMA) can often be differentiated from CFTD by physical examination, abnormal brain MRI, neurogenic EMG, and neurogenic muscle pathology displaying reinnervation and fiber type grouping. Molecular genetic testing using targeted mutation analysis and sequence analysis identifies two SMN1 mutations in virtually all individuals with SMA.Other conditions with fiber size disproportion. Fiber size disproportion of 12% or more may be a nonspecific finding on muscle biopsy, and secondary fiber size disproportion can be seen with various other neuromuscular and non-neuromuscular conditions. A more complete list of conditions associated with fiber size disproportion is provided by Iannaccone et al [1987], Imoto & Nonaka [2001], Clarke & North [2003], and North [2004].Fiber size disproportion has also been seen in healthy individuals, including healthy infants younger than age two months [Vogler & Bove 1985] and normal healthy young adult males [Staron et al 2000].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).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with congenital fiber-type disproportion, the following evaluations are recommended:Medical history and physical examination with particular attention to the following:WeaknessHypotoniaFailure to thriveScoliosisContracturesComprehensive respiratory evaluation in individuals with and without respiratory symptoms including the following:Respiratory rateSigns of respiratory distressHistory of recurrent chest infectionsAbility to maintain oxygen saturationPulmonary function studiesSleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.Feeding evaluation including assessment of suck and swallow and gastroesophageal refluxSpeech therapy assessment, particularly if dysarthria and/or hypernasal speech are presentCardiac evaluation for heart disease, including cor pulmonale and cardiomyopathy, particularly for those with mutations inTPM2 or MYH7 or those with an unknown genetic etiology. Evaluation should include echocardiogram and electrocardiogram.Physical therapy and occupational therapy assessmentScreening for skeletal and orthopedic issues, including skeletal examination for scoliosis (after the child starts sitting), joint contractures, congenital hip dislocations, and foot deformitiesExamination by a general dentist with referral for orthodontic evaluation if dental crowding becomes apparentMedical genetics consultationTreatment of ManifestationsIt is recommended that care be provided by a multidisciplinary team coordinated by a clinician familiar with treatment of neuromuscular conditions [North & Goebel 2003, North 2004]. Teams often include a pulmonologist, neurologist, physical therapist and/or rehabilitation medicine specialist, orthopedist, and medical geneticist.Hypotonia, weakness, and joint contractures may benefit from physical therapy, occupational therapy, and/or orthopedic intervention. Interventions may include exercise and stretching programs, orthotics or splinting, serial casting, or walking supports/wheelchairs [North 2004]. Regular low-impact exercise, stretching, and submaximal strength training may be helpful. These activities should be balanced with sufficient rest time to avoid exhaustion [North 2004].Respiratory issues may benefit from breathing exercises, chest physiotherapy for handling secretions, seating assessment, immunization against influenza and other respiratory infections, antibiotics for chest infections, tracheostomy, or ventilatory support [North 2004].Feeding and swallowing difficulties may benefit from speech therapy, diet supplementation, and feeding by gavage or gastrostomy. Gastrostomy and fundoplication should be considered if feeding issues continue beyond a few months of age [North 2004].Referral to an orthopedist for evaluation of scoliosis and joint contractures is recommended. If scoliosis is present, serial x-rays can be used to define and monitor the degree of curve. The need for bracing or corrective (spinal fusion) surgery is based on the progression of the curve, the effect on pulmonary function, and the likelihood that surgery could affect motor function [North 2004].Foot deformities may benefit from physical therapy, splinting/casting, or corrective surgery by an orthopedic surgeon [North 2004].Cardiac involvement should be monitored by a cardiologist and treated as necessary [North 2004].Orthodontic evaluation and appropriate intervention may be necessary.Prevention of Secondary ComplicationsAlthough malignant hyperthermia has not been described in CFTD, it has been seen in other congenital myopathies, particularly RYR1-associated myopathies; therefore, precautions for malignant hyperthermia prior to anesthesia should be considered (see Malignant Hyperthermia Susceptibility.)Preoperative assessment of pulmonary and cardiac function is recommended to avoid complications.Prevention of scoliosis, respiratory and feeding issues, and cardiac disease may be possible with comprehensive early screening and regular monitoring as described in Treatment of Manifestations.Contractures may be avoided by consistent joint movement or therapy.SurveillanceThe following are appropriate:Regular monitoring for scoliosis [North 2004], particularly in childhood and adolescenceRegular pulmonary monitoring including assessment for evidence of decreased nocturnal ventilation, such as morning headaches, daytime drowsiness, and decreased appetite or school performance; sleep studies; and lung function tests, including FEV1 and FVCAfter an initial cardiac evaluation, consideration of ongoing cardiac monitoring on a case-by-case basis. Monitoring is advisable in those who have been found to have mutations in MYH7 and TPM2 and/or baseline cardiac abnormalities. Other subsets of individuals with CFTD may require cardiac monitoring in the future as more data are gathered regarding the incidence of cardiac complications in these people.Regular assessment of motor abilities to determine need for physical therapy, occupational therapy, and physical support, such as walkers or wheelchairsAgents/Circumstances to AvoidExtended immobilization following surgery can exacerbate muscle weakness and thus should be avoided [North 2004].Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Pregnancy has not been specifically studied in women or fetuses with CFTD. Women with congenital myopathies generally do not experience significant complications during pregnancy or delivery; however, gestation may lead to an increase in symptoms in some women with CFTD and other congenital myopathies, including exacerbation of fatigue and muscle weakness [Rudnik-Schöneborn et al 1997, Sobrido et al 2005].The pregnancy of a fetus with a congenital myopathy is at an increased risk for complications such as polyhydramnios and reduced fetal movements and the delivery is at an increased risk for breech presentation, fetal distress, failure to progress, and/or prematurity [North & Goebel 2003, North 2004].Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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. Congenital Fiber-Type Disproportion: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMYH714q11​.2Myosin-7MYH7 homepage - Leiden Muscular Dystrophy pagesMYH7TPM31q21​.3Tropomyosin alpha-3 chainTPM3 homepage - Leiden Muscular Dystrophy pagesTPM3ACTA11q42​.13Actin, alpha skeletal muscleACTA1 homepage - Leiden Muscular Dystrophy pagesACTA1TPM29p13​.3Tropomyosin beta chainTPM2 homepage - Leiden Muscular Dystrophy pagesTPM2RYR119q13​.2Ryanodine receptor 1RYR1 homepage - Leiden Muscular Dystrophy pagesRYR1SEPN11p36​.11Selenoprotein NSEPN1 homepage - Leiden Muscular Dystrophy pagesSEPN1Data 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 Congenital Fiber-Type Disproportion (View All in OMIM) View in own window 102610ACTIN, ALPHA, SKELETAL MUSCLE 1; ACTA1 160760MYOSIN, HEAVY CHAIN 7, CARDIAC MUSCLE, BETA; MYH7 180901RYANODINE RECEPTOR 1; RYR1 190990TROPOMYOSIN 2; TPM2 191030TROPOMYOSIN 3; TPM3 255310MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION; CFTD 606210SELENOPROTEIN N, 1; SEPN1ACTA1Normal allelic variants. ACTA1 comprises seven exons and is approximately 3.8 kb in length. Multiple normal allelic variants (single nucleotide polymorphisms SNPs) have been identified in ACTA1. Pathologic allelic variants. At least seven heterozygous mutations in ACTA1 have been associated with congenital fiber-type disproportion (CFTD) [Laing et al 2004], as shown in Table 3. Numerous other ACTA1 mutations causing nemaline or actin myopathy have also been reported [Laing et al 2009].Table 3. ACTA1 Pathologic Variants Associated with Congenital Fiber-Type Disproportion Discussed in This GeneReviewView in own windowNucleotide ChangeAmino Acid ChangeReference Sequencesc.16G>Ap.Glu6LysNM_001100​.3
NP_001091​.1c.143G>Ap.Gly48Aspc.621G>Cp.Glu207Aspc.668T>Cp.Leu223Proc.727G>Ap.Glu243Lysc.881A>Tp.Asp294Valc.1000C>Tp.Pro334SerSee 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. ACTA1 codes for the actin, alpha skeletal muscle protein (skeletal muscle α-actin). The resulting encoded 377-amino acid protein plays an important role in skeletal muscle contraction through interaction with myosin. The α-actin isoform is uniquely expressed in skeletal muscle. Abnormal gene product. The seven identified ACTA1 base changes associated with CFTD cause single amino acid substitutions. Most of these mutations are found on the same face of the actin protein, suggesting that they impact a specific protein interaction or similar muscle function [Laing et al 2009]. One hypothesis suggests that these mutations affect the ability of α-actin to interact with tropomyosin, most likely interfering with the relationship between the two proteins and affecting sarcomere function [Clarke et al 2007]. In contrast, heterozygous mutations in ACTA1 that are associated with nemaline myopathy act through a dominant-negative effect: the mutant α-actin hinders the normal role of the wild-type protein.MYH7Normal allelic variants. MYH7 comprises 39 exons (38 coding exons) [NM_000257.2] and is approximately 23 kb in length. Multiple single nucleotide polymorphisms (SNPs) have also been identified in MYH7. Pathologic allelic variants. At least two heterozygous mutations in MYH7 have been associated with congenital fiber-type disproportion (CFTD) [Muelas et al 2010, Ortolano et al 2011], as shown in Table 4. The p.Lys1729del mutation causes deletion of one out of three consecutive AAG triplet repeats. This mutation has also been associated with Laing distal myopathy and reported as a founder mutation in the Safor region of Spain [Muelas et al 2010]. Other MYH7 mutations have also been reported to cause Laing distal myopathy, myosin storage myopathy, and hypertrophic and dilated cardiomyopathy [Tajsharghi & Oldfors 2013].Table 4. MYH7 Pathologic Variants Associated with Congenital Fiber-Type Disproportion Discussed in This GeneReviewView in own windowNucleotide ChangeAmino Acid ChangeReference Sequencesc.5186_5188delAGAp.Lys1729delNM_000257​.2
NP_000248​.2c.5807A>Gp.*1936Trpext*31 ^{1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Asterisk indicates nucleotide(s) are 3' of the translation stop codon; “ext*#” is used to indicate the extension of a protein sequence until a new stop codon is reached at “#” amino acids downstream as a consequence of a variant changing the natural stop codon into an amino acid.Normal gene product. MYH7 codes for the beta-myosin heavy chain protein. The resulting 1935-amino acid protein plays an important role in cardiac and skeletal muscle contraction. It is expressed in slow, type 1 fibers and the ventricles of the heart. Abnormal gene product. Most previously identified mutations in MYH7 have been missense changes located in the globular myosin head (possibly impacting actin binding sites) or the rod region of the protein [Tajsharghi & Oldfors 2013]. Mutations in the tail of the myosin heavy chain, such as p.Lys1729del, affect the tail’s ability to form a coiled coil dimer or its interaction with other proteins [Goebel & Laing 2009]. The p.*1936Trpext*31 mutation is predicted to cause the stop codon to be replaced by a tryptophan resulting in the elongation of the protein tail by 31 amino acids [Ortolano et al 2011]. RYR1Normal allelic variants. RYR1 comprises 106 exons, and the cDNA is approximately 15,117 kb in length. Multiple normal allelic variants (single nucleotide polymorphisms) have been identified in RYR1 [Robinson et al 2002]. Pathologic allelic variants. Eight compound heterozygous mutations in RYR1 have been reported to be associated with CFTD [Clarke et al 2010], as shown in Table 5. Other recessive and/or dominant RYR1 mutations causing centronuclear myopathy, multiminicore myopathy, malignant hyperthermia, central core disease, and congenital myopathy with internalized nuclei and myofibrillar disorganization have also been reported [Treves et al 2005, Robinson et al 2002, Jungbluth et al 2007, Wilmshurst et al 2010, Bevilacqua et al 2011].Table 5. RYR1 Pathologic Variants Associated with Congenital Fiber-Type Disproportion Discussed in This GeneReviewView in own windowNucleotide ChangeAmino Acid ChangeReference Sequencesc.738T>Gp.Tyr246XNM_000540​.2
NP_000531​.2c.1205T>Cp.Met402Thrc.5333C>Ap.Ser1778Xc.6104A>Tp.His2035Leuc.9000+1G>TSplice sitec.9978C>Ap.Asn3326Lysc.10204T>Gp.Cys3402Glyc.13480G>Tp.Glu4494XSee 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. RYR1 codes for the skeletal muscle isoform ryanodine receptor protein. The resulting 5,038-amino acid protein plays an important role in excitation–contraction coupling and skeletal muscle calcium homeostasis. It is predominantly expressed in skeletal muscle [Treves et al 2005].Abnormal gene product. Nonsense mutations are predicted to cause lack of production of the full-length protein. The splice site mutation (c.9000+1G>T) eliminates a donor splice site, causing exon skipping and resulting in an out of frame transcript that is predicted to produce a truncated non-functional protein. The exact impact of the missense variants is unknown. SEPN1Normal allelic variants. SEPN1 comprises 13 exons and is approximately 18.5 kb in length. Selenoprotein N, like other selenoproteins, contains a selenocysteine encoded by UGA. Several SNPs have been identified in SEPN1. Current data are available in online databases (see Table A), such as the SNP database provided by the National Center for Biotechnology Information) NCBI.Pathologic allelic variants. Only one mutation in SEPN1 has been associated with CFTD in the literature [Clarke et al 2006] (see Table 6). This mutation has also been identified in two families from Belgium and the United Kingdom affected with multiminicore disease and rigid spine muscular dystrophy; a founder effect has been suggested. Numerous other SEPN1 mutations causing multiminicore disease and rigid spine muscular dystrophy have also been reported [Ferreiro et al 2002]. Table 6. SEPN1 Pathologic Variants Associated with Congenital Fiber-Type Disproportion Discussed in This GeneReviewView in own windowNucleotide ChangeAmino Acid ChangeReference Sequencesc.943G>Ap.Gly315SerNM_020451​.2
NP_065184​.2See 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. SEPN1 codes for selenoprotein N, a 590-amino acid protein that plays an important role in skeletal muscle [Moghadaszadeh et al 2001]. Two SEPN1 isoforms have been identified, both of which are widely expressed in many different tissues. Based on the structure of selenoprotein N and the enzymatic function of several other selenoproteins, it is hypothesized that selenoprotein N may also function as an enzyme, but its role is not yet known [Moghadaszadeh et al 2001]. The fiber size variation in cases of SEPN1-related CFTD is not as striking as the disproportion seen in most patients with CFTD associated with TPM3, ACTA1, or RYR1 mutations, perhaps accounting for the observation that SEPN1 mutations are not be a common cause of CFTD [Clarke 2011]. Abnormal gene product. The identified base change causes a substitution of an evolutionarily conserved amino acid [Ferreiro et al 2002], which does not affect the level of expression of the protein in skeletal muscle tissue [Clarke et al 2005].TPM2Normal allelic variants. TPM2 comprises 11 exons and is approximately 8-10 kb in length [Wang & Coluccio 2010]. Multiple single nucleotide polymorphisms (SNPs) have been identified in TPM2. Current data are available in online databases (see Table A), such as the SNP database provided by NCBI.Pathologic allelic variants. At least one heterozygous mutation in TPM2 has been associated with congenital fiber-type disproportion (CFTD) [Brandis et al 2008], as shown in Table 7. Other TPM2 mutations causing nemaline or cap myopathy, distal arthrogryposis, and Escobar syndrome have also been reported [Tajsharghi et al 2012].Table 7. TPM2 Pathologic Variants Associated with Congenital Fiber-Type Disproportion Discussed in This GeneReviewView in own windowNucleotide ChangeAmino Acid ChangeReference Sequencesc.349G>Ap.Glu117LysNM_003289​.3
NP_003280​.2See 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. TPM2 codes for β-tropomyosin, which is expressed in the sarcomere of striated muscle where it associates with α-actin in the thin filament. β-tropomyosin is primarily expressed in the slow type 1 muscle fibers but also has some expression in fast muscle fibers and cardiac muscle [Tajsharghi et al 2012]. Abnormal gene product. Mutations in TPM2 may influence the formation of the coiled-coil structure of the protein and/or its ability to interact with proteins in the thin filament [Tajsharghi et al 2012]. TPM3Normal allelic variants. TPM3 comprises 13 exons and is at least 42 kb in length. The gene produces multiple transcripts, one of which is muscle specific. The muscle-specific slow muscle α-tropomyosin is coded for by ten exons, producing a transcript 1.3 kb in length [Laing et al 1995]. The NM_152263.2 variant is transcribed from the distal promoter, and is predominantly expressed in slow-twitch skeletal muscle.Pathologic allelic variants. Ten different mutations in TPM3 have been reported to be associated with CFTD in the literature; at least two of these ten have also been associated with nemaline myopathy [Clarke et al 2008, Lawlor et al 2010]. Several other homozygous, heterozygous, and compound heterozygous TPM3 mutations have also been described as causative of nemaline myopathy [Pénisson-Besnier et al 2007].Table 8. TPM3 Pathologic Variants Associated with Congenital Fiber-Type Disproportion Discussed in This GeneReviewView in own windowNucleotide ChangeAmino Acid Change
(Alias 1)Reference Sequences c.11C>Tp.Ala4ValNM_152263​.2
NP_689476​.2 c.272G>Cp.Arg91Proc.298C>Ap.Leu100Metc.502C>Gp.Arg168Glyc.502C>Tp.Arg168Cysc.503G>Ap.Arg168Hisc.505A>Gp.Lys169Gluc.721G>Ap.Glu241Lysc.733A>Gp.Arg245Glyc.857A>Cp.*286Serext*57 2(X286Ser)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 conventions2. Asterisk indicates nucleotide(s) are 3' of the translation stop codon; “ext*#” is used to indicate the extension of a protein sequence until a new stop codon is reached at “#” amino acids downstream as a consequence of a variant changing the natural stop codon into an amino acid. Normal gene product. The muscle-specific slow muscle α-tropomyosin contains 285 amino acids, producing a protein that is solely expressed in the slow type 1 muscle fibers. The TPM3 protein is a component of the thin filament and plays a role in muscle contraction.Abnormal gene product. All dominant heterozygous mutations in TPM3 reported to date are missense mutations that are hypothesized to affect the protein’s ability to interact with other proteins in the muscle thin filament, including actin and β-tropomyosin, thus affecting the muscle’s ability to contract [Clarke et al 2008].}