Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

Clinical characteristics.

Congenital fiber-type disproportion (CFTD) is usually characterized by hypotonia and mild-to-severe generalized muscle weakness at birth or within the first year of life. Although some individuals remain non-ambulatory throughout life, many eventually develop the ability to walk. In more than 90% of affected individuals, muscle weakness is static or improves; in the remainder it is usually slowly progressive. Mild-to-severe respiratory involvement is seen in approximately 30% of affected individuals; respiratory failure may occur at any age. Ophthalmoplegia, ptosis, and facial and/or bulbar weakness with severe limb/respiratory weakness may predict a poor prognosis. Mild-to-severe feeding difficulties occur in nearly 30% of children. Contractures of the hips, knees, ankles, elbows, and fingers occur in approximately 25% and may be present at birth or occur in older persons with decreased mobility secondary to severe weakness. Spinal deformities including scoliosis, kyphoscoliosis, and lordosis are seen in 25% or more of individuals.

Diagnosis/testing.

Diagnosis is based on a combination of clinical presentation and morphologic features observed on skeletal muscle histology. The pathologic and clinical manifestations of CFTD overlap with other neuromuscular and non-neuromuscular diseases that must be ruled out prior to making a diagnosis of CFTD. To date, pathogenic variants have been identified in six genes: ACTA1 (~6% of individuals with CFTD), MYH7 (unknown), RYR1 (~10%-20%), SELENON (SEPN1) (rare), TPM2 (rare), and TPM3 (~20%-25% of individuals with CFTD).

Management.

Treatment of manifestations: For weakness/contractures: physical therapy and occupational therapy (orthotics or splinting, serial casting, or walking supports/wheelchair); regular low-impact exercise, stretching, and submaximal strength training with sufficient rest to avoid exhaustion; for respiratory issues: breathing exercises, chest physiotherapy, seating assessment, immunizations, antibiotics for chest infections, tracheostomy, or ventilatory support; for feeding/swallowing difficulties: speech therapy, and gavage or gastrostomy feedings; orthopedic evaluation for foot deformities, joint contractures, and scoliosis; bracing or spinal fusion based on progression of the spinal curve and effect on pulmonary and motor function; treatment by a cardiologist as needed; orthodontia as needed.

Prevention of secondary complications: Consider precautions for malignant hyperthermia prior to anesthesia; preoperative assessment of pulmonary and cardiac function; consistent joint movement to prevent contractures.

Surveillance: Regular monitoring of motor abilities/weakness, pulmonary and cardiac function, and spine for scoliosis (especially in childhood and adolescence).

Agents/circumstances to avoid: Extended immobilization.

Genetic counseling.

CFTD is a genetically heterogeneous condition that can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner. To date, all identified cases of ACTA1, MYH7, and TPM2-related CFTD have been caused by autosomal dominant pathogenic variants while the SELENON and RYR1-related cases have been associated with autosomal recessive pathogenic variants. TPM3-related CFTD can be inherited in an autosomal dominant or autosomal recessive manner. ACTA1 and TPM3 pathogenic variants are often de novo dominant. A large portion of individuals with CFTD represent simplex cases (i.e., a single occurrence in a family). It can be difficult to determine inheritance pattern in the family of a simplex case when a pathogenic variant is not identified through testing of known genes. Prenatal testing for pregnancies at risk for CFTD is possible if the pathogenic variant(s) in a family are known.

Clinical Diagnosis

Diagnosis 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 myopathy
• Morphologic 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)

• 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 pathogenic variants 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 SELENON-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 numeric predominance (Figure 1), not to be confused with fiber-type grouping
  • Decreased presence of 2B/2X fibers
  • One 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 adipocytes

Ultrastructural 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 testing

• Serum 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 Testing

Genes. To date, the genetic basis of CFTD has been elucidated in only a portion of cases. Pathogenic variants have been identified in the following six genes: ACTA1, MYH7, RYR1, SELENON (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]. SELENON, the gene encoding selenoprotein N and implicated in CFTD and multiminicore disease, resides in this region; however, inheritance of the myopathy associated with SELENON 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 mutation of INSR and CFTD [Vorwerk et al 1999].

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 pathogenic variants 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 pathogenic variants show particular involvement of the gluteus maximus, medial muscles, tibial anterior and peroneal muscles, and posterior thigh, including the sartorius, adductor magnus, and semitendinosus muscles, with sparing of the adductor longus, rectus femoris, and gracilis muscles.
• Those with SELENON pathogenic variants 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 pathogenic variants 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 variant 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, SELENON
• RYR1 pathogenic variants appear to be the most common cause of recessive CFTD, while TPM3 pathogenic variants appear 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 SELENON pathogenic variants 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, SELENON 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 SELENON 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 pathogenic variants 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 pathogenic variant in RYR1 is not well understood. Therefore, it is recommended that individuals with a heterozygous pathogenic variant in RYR1 follow appropriate restrictions for MH.

Prenatal testing and preimplantation genetic testing for at-risk pregnancies require prior identification of the pathogenic variant(s) in the family.

Clinical Description

Clarke & 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 pathogenic variants. 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.

At 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 Correlations

Some 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 pathogenic variant, making specific predictions difficult [Laing et al 2009].

MYH7. Only a few families with MYH7 pathogenic variants 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 pathogenic variants known to be associated with CFTD [Muelas et al 2010].

• In affected individuals with the recurrent p.Lys1729del variant associated with myosin storage myopathy and CFTD, the anterior compartment of the lower leg is particularly involved, 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 variant 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 pathogenic variants, 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 pathogenic variants 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.

SELENON (SEPN1). The two sisters with CFTD caused by homozygous SELENON pathogenic missense variants had findings typical of SELENON-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 pathogenic variants have been reported in only 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 mutation of 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 pathogenic variants 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 pathogenic missense variants 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 pathogenic variants had a more severe presentation: she never walked and required full-time respiratory and feeding support from early childhood [Lawlor et al 2010].

Prevalence

CFTD is rare; prevalence is unknown. Studies suggest that CFTD is less common than nemaline myopathy [Wallgren-Pettersson et al 1990, Fardeau & Tomé 1994], which has an estimated incidence of 1:50,000 live births in Finland [Wallgren-Pettersson et al 1990].

Evaluations Following Initial Diagnosis

To 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:
  • Weakness
  • Hypotonia
  • Failure to thrive
  • Scoliosis
  • Contractures
• Comprehensive respiratory evaluation in individuals with and without respiratory symptoms including the following:
  • Respiratory rate
  • Signs of respiratory distress
  • History of recurrent chest infections
  • Ability to maintain oxygen saturation
  • Pulmonary function studies
  • Sleep 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 reflux
• Speech therapy assessment, particularly if dysarthria and/or hypernasal speech are present
• Cardiac evaluation for heart disease, including cor pulmonale and cardiomyopathy, particularly for those with pathogenic variants inTPM2 or MYH7 or those with an unknown genetic etiology. Evaluation should include echocardiogram and electrocardiogram.
• Physical therapy and occupational therapy assessment
• Screening for skeletal and orthopedic issues, including skeletal examination for scoliosis (after the child starts sitting), joint contractures, congenital hip dislocations, and foot deformities
• Examination by a general dentist with referral for orthodontic evaluation if dental crowding becomes apparent
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

It 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 clinical 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 Complications

Although 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.

Surveillance

The following are appropriate:

• Regular monitoring for scoliosis [North 2004], particularly in childhood and adolescence
• Regular 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 FVC
• After 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 pathogenic variants 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 wheelchairs

Agents/Circumstances to Avoid

Extended immobilization following surgery can exacerbate muscle weakness and thus should be avoided [North 2004].

Evaluation of Relatives at Risk

See 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 Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Congenital fiber-type disproportion (CFTD) is a genetically heterogeneous condition that can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.

To date, the majority of known cases of ACTA1-related CFTD have been the result of a de novo dominant pathogenic variant. A single CFTD-associated ACTA1 pathogenic variant has shown dominant inheritance in a father and son. The father did not report clinical symptoms but had a histopathologic diagnosis of CFTD based on muscle biopsy [Laing et al 2009].

MYH7-associated CFTD has been reported to be inherited in an autosomal dominant manner [Sobrido et al 2005, Muelas et al 2010, Ortolano et al 2011]. However, recessive and de novo dominant MYH7 pathogenic variants have been reported to be associated with other MYH7-diagnoses (see Genetically Related Disorders) and thus such inheritance may also occur with CFTD.

RYR1-associated CFTD has been reported to be inherited in an autosomal recessive manner.

SELENON (SEPN1)-related CFTD is inherited in an autosomal recessive manner.

TPM2-related CFTD can be inherited in an autosomal dominant manner or result from a de novo dominant pathogenic variant.

TPM3-related CFTD has been inherited in an autosomal dominant manner in at least three families and is the result of a de novo dominant pathogenic variant in at least eight individuals [Clarke et al 2008, Lawlor et al 2010]. TPM3-related CFTD has also been inherited in an autosomal recessive manner in a single family [Lawlor et al 2010].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Some individuals diagnosed with CFTD have an affected parent.
• A proband with CFTD may have the disorder as the result of a de novo pathogenic variant. The exact proportion of cases caused by de novo variants is unknown. However, de novo variants in TPM3 and ACTA1 appear to be a common cause of CFTD.
• Although some individuals diagnosed with CFTD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or decreased penetrance. In addition, if the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
• For probands with no apparent family history, parental disease status may be clarified through medical evaluation; i.e., physical examination and follow-up with appropriate studies (e.g., EMG, muscle biopsy) for any positive findings. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

• The risk to sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has a pathogenic variant in a gene associated with autosomal dominant CFTD, the risk to sibs is 50%.
• If both parents are clinically unaffected, the risk to sibs, while low, is greater than that in the general population because:
  • Although the incidence of germline mosaicism is unknown, it remains a possibility;
  • Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [Laing et al 2009, Lawlor et al 2010].

Offspring of a proband. Each child of an individual with autosomal dominant CFTD has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Autosomal Recessive Inheritance

X-Linked Inheritance

Related Genetic Counseling Issues

Determining the mode of inheritance

• A large proportion of individuals with CFTD represent simplex cases (i.e., a single occurrence in a family), most likely attributed to autosomal recessive inheritance, X-linked recessive inheritance, or a heterozygous de novo dominant or de novo X-linked recessive pathogenic variant. In a review of inheritance patterns of 39 individuals with CFTD [Clarke & North 2003], 22 of 39 individuals (56%) represented simplex cases, 11 of 39 individuals (28%) had a family history consistent with autosomal dominant inheritance, and six of 39 individuals (15%) had a family history consistent with autosomal recessive inheritance. Since publication of that review, a large kindred with X-linked inheritance of CFTD has also been reported [Clarke et al 2005].
• It can be difficult to determine an inheritance pattern in the family of an individual representing a simplex case (i.e., a single occurrence in a family). Detailed family history, medical history, and physical examination, EMG, and muscle biopsies of parents may or may not be helpful in differentiating among the various possibilities. For example, autosomal dominant inheritance with significant variable expressivity has been suggested in at least one family, in which the mother was clinically healthy but had subtle EMG and pathology findings suggestive of myopathy. The daughter had biopsy findings consistent with CFTD and muscle weakness, hypotonia, and joint contractures [Gerdes et al 1994]. Since the father was not evaluated, it is possible that the family had autosomal recessive CFTD and the mother's subclinical findings resulted from her heterozygous status. In another family, a child with ACTA1-associated CFTD had an asymptomatic father who carried an ACTA1 pathogenic variant and had histopathologic features of CFTD [Laing et al 2009].
• In some families with a simplex case, both parents have subtle myopathic findings clinically and/or on biopsy, indicating that heterozygotes of a recessive neuromuscular condition may have mild clinical or pathologic manifestations [Wallgren-Pettersson et al 1990]. Therefore, if only one parent is evaluated and found to have myopathic findings, it does not necessarily eliminate the possibility of autosomal recessive inheritance.
• If one parent is clinically healthy and has a normal muscle biopsy and the second parent has clinical signs of myopathy and/or myopathic findings on biopsy, inheritance is most likely autosomal dominant or X-linked (if no male-to-male transmission has occurred).
• If both parents are healthy without clinical or muscle biopsy findings suggestive of myopathy, inheritance may be autosomal recessive, de novo autosomal dominant, de novo X-linked recessive, or familial X-linked recessive.

Family planning

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

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

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CFTD are possible.

Literature Cited

• Banwell BL, Becker LE, Jay V, Taylor GP, Vajsar J. Cardiac manifestations of congenital fiber-type disproportion myopathy. J Child Neurol. 1999;14:83–7. [PubMed: 10073429]
• Bevilacqua JA, Monnier N, Bitoun M, Eymard B, Ferreiro A, Monges S, Lubieniecki F, Taratuto AL, Laquerrière A, Claeys KG, Marty I, Fardeau M, Guicheney P, Lunardi J, Romero NB. Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol. 2011;37:271–84. [PubMed: 21062345]
• Brandis A, Aronica E, Goebel HH. TPM2 mutation. Neuromuscul Disord. 2008;18:1005. [PubMed: 18789687]
• Brooke MH (1973) Congenital fiber type disproportion. In: Kakulas BA, ed. Clinical studies in myology. Proceedings of the 2nd International Congress on Muscle Diseases, held in Perth, Australia, Nov. 22-29, 1971. Experta Medica 147-59.
• Cagliani R, Fruguglietti ME, Berardinelli A, D'Angelo MG, Prelle A, Riva S, Napoli L, Gorni K, Orcesi S, Lamperti C, Pichiecchio A, Signaroldi E, Tupler R, Magri F, Govoni A, Corti S, Bresolin N, Moggio M, Comi GP. New molecular findings in congenital myopathies due to selenoprotein N gene mutations. J Neurol Sci. 2011;300:107–13. [PubMed: 20937510]
• Clarke NF. Congenital fiber-type disproportion. Semin Pediatr Neurol. 2011;18:264–71. [PubMed: 22172422]
• Clarke NF, Ilkovski B, Cooper S, Valova VA, Robinson PJ, Nonaka I, Feng JJ, Marston S, North K. The pathogenesis of ACTA1-related congenital fiber type disproportion. Ann Neurol. 2007;61:552–61. [PubMed: 17387733]
• Clarke NF, Kidson W, Quijano-Roy S, Estournet B, Ferreiro A, Guicheney P, Manson JI, Kornberg AJ, Shield LK, North KN. SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol. 2006;59:546–52. [PubMed: 16365872]
• Clarke NF, Kolski H, Dye D, Lim E, Smith R, Patel R, Fahey M, Bellance R, Romero N, Johnson E, Labarre-Vila A, Monnier N, Laing N, North K. Mutations in TPM3 are a common cause of congenital fiber type disproportion. Ann Neurol. 2008;63:329–37. [PubMed: 18300303]
• Clarke NF, North KN. Congenital fiber type disproportion--30 years on. J Neuropathol Exp Neurol. 2003;62:977–89. [PubMed: 14575234]
• Clarke NF, Smith RL, Bahlo M, North KN. A novel X-linked form of congenital fiber-type disproportion. Ann Neurol. 2005;58:767–72. [PubMed: 16173074]
• Clarke NF, Waddell LB, Cooper ST, Perry M, Smith RL, Kornberg AJ, Muntoni F, Lillis S, Straub V, Bushby K, Guglieri M, King MD, Farrell MA, Marty I, Lunardi J, Monnier N, North KN. Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. Hum Mutat. 2010;31:E1544–50. [PubMed: 20583297]
• Clarke NF, Waddell LB, Sie LT, van Bon BW, McLean C, Clark D, Kornberg A, Lammens M, North KN. Mutations in TPM2 and congenital fibre type disproportion. Neuromuscul Disord. 2012;22:955–8. [PubMed: 22832343]
• De Paula AM, Franques J, Fernandez C, Monnier N, Lunardi J, Pellissier JF, Figarella-Branger D, Pouget J. A TPM3 mutation causing cap myopathy. Neuromuscul Disord. 2009;19:685–8. [PubMed: 19553118]
• Donner K, Ollikainen M, Ridanpää M, Christen HJ, Goebel HH, de Visser M, Pelin K, Wallgren-Pettersson C. Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy. Neuromuscul Disord. 2002;12:151–8. [PubMed: 11738357]
• Fardeau M, Tomé FM. Ultrastructure of muscle and neuromuscular junction: an historical survey of the early French contributions. Biol Cell. 1994;80:115–7. [PubMed: 8087060]
• Ferreiro A, Ceuterick-de Groote C, Marks JJ, Goemans N, Schreiber G, Hanefeld F, Fardeau M, Martin JJ, Goebel HH, Richard P, Guicheney P, Bonnemann CG. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol. 2004;55:676–86. [PubMed: 15122708]
• Ferreiro A, Quijano-Roy S, Pichereau C, Moghadaszadeh B, Goemans N, Bonnemann C, Jungbluth H, Straub V, Villanova M, Leroy JP, Romero NB, Martin JJ, Muntoni F, Voit T, Estournet B, Richard P, Fardeau M, Guicheney P. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet. 2002;71:739–49. [PMC free article: PMC378532] [PubMed: 12192640]
• Fujita K, Nakano S, Yamamoto H, Ito H, Ito H, Goto Y, Kusaka H. Rinsho Shinkeigaku. 2005;45:380–2. [An adult case of congenital fiber type disproportion (CFTD) with cardiomyopathy] [PubMed: 15960177]
• Gerdes AM, Petersen MB, Schrøder HD, Wulff K, Brøndum-Nielsen K. Congenital myopathy with fiber type disproportion: a family with a chromosomal translocation t(10;17) may indicate candidate gene regions. Clin Genet. 1994;45:11–6. [PubMed: 7908614]
• Goebel HH, Laing NG. Actionopathies and myosinopathies. Brain Pathol. 2009;19:516–22. [PMC free article: PMC8094766] [PubMed: 19563543]
• Häne BG, Rogers RC, Schwartz CE. Germline mosaicism in X-linked myotubular myopathy. Clin Genet. 1999;56:77–81. [PubMed: 10466421]
• Iannaccone ST, Bove KE, Vogler CA, Buchino JJ. Type 1 fiber size disproportion: morphometric data from 37 children with myopathic, neuropathic, or idiopathic hypotonia. Pediatr Pathol. 1987;7:395–419. [PubMed: 2451237]
• Imoto C, Nonaka I. The significance of type 1 fiber atrophy (hypotrophy) in childhood neuromuscular disorders. Brain Dev. 2001;23:298–302. [PubMed: 11504599]
• Jungbluth H, Zhou H, Sewry CA, Robb S, Treves S, Bitoun M, Guicheney P, Buj-Bello A, Bönnemann C, Muntoni F. Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2007;17:338–45. [PubMed: 17376685]
• Kang PB, Kunkel LM (2014) Muscular dystrophies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 216.
• Laing NG, Clarke NF, Dye DE, Liyanage K, Walker KR, Kobayashi Y, Shimakawa S, Hagiwara T, Ouvrier R, Sparrow JC, Nishino I, North KN, Nonaka I. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol. 2004;56:689–94. [PubMed: 15468086]
• Laing NG, Dye DE, Wallgren-Pettersson C, Richard G, Monnier N, Lillis S, Winder TL, Lochmüller H, Graziano C, Mitrani-Rosenbaum S, Twomey D, Sparrow JC, Beggs AH, Nowak KJ. Mutations and polymorphisms of the skeletal muscle α-actin gene (ACTA1). Hum Mutat. 2009;30:1267–77. [PMC free article: PMC2784950] [PubMed: 19562689]
• Laing NG, Wilton SD, Akkari PA, Dorosz S, Boundy K, Kneebone C, Blumbergs P, White S, Watkins H, Love DR, et al. A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nat Genet. 1995;9:75–9. [PubMed: 7704029]
• Lawlor MW, Dechene ET, Roumm E, Geggel AS, Moghadaszadeh B, Beggs AH. Mutations of tropomyosin 3 (TPM3) are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion. Hum Mutat. 2010;31:176–83. [PMC free article: PMC2815199] [PubMed: 19953533]
• Maiti B, Arbogast S, Allamand V, Moyle MW, Anderson CB, Richard P, Guicheney P, Ferreiro A, Flanigan KM, Howard MT. A mutation in the SEPN1 selenocysteine redefinition element (SRE) reduces selenocysteine incorporation and leads to SEPN1-related myopathy. Hum Mutat. 2009;30:411–6. [PMC free article: PMC2909032] [PubMed: 19067361]
• Moghadaszadeh B, Petit N, Jaillard C, Brockington M, Roy SQ, Merlini L, Romero N, Estournet B, Desguerre I, Chaigne D, Muntoni F, Topaloglu H, Guicheney P. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet. 2001;29:17–8. [PubMed: 11528383]
• Monnier N, Laquerrière A, Marret S, Goldenberg A, Marty I, Nivoche Y, Lunardi J. First genomic rearrangement of the RYR1 gene associated with an atypical presentation of lethal neonatal hypotonia. Neuromuscul Disord. 2009;19:680–4. [PubMed: 19734047]
• Muelas N, Hackman P, Luque H, Garcés-Sánchez M, Azorín I, Suominen T, Sevilla T, Mayordomo F, Gómez L, Martí P, María Millán J, Udd B, Vílchez JJ. MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy. Neurology. 2010;75:732–41. [PubMed: 20733148]
• Munot P, Lashley D, Jungbluth H, Feng L, Pitt M, Robb SA, Palace J, Jayawant S, Kennet R, Beeson D, Cullup T, Abbs S, Laing N, Sewry C, Muntoni F. Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia. Neuromuscul Disord. 2010;20:796–800. [PubMed: 20951040]
• North K (2004) Congenital myopathies. In: Engel AG, Franzini-Armstrong C, eds. Myology. 3 ed. New York, NY: McGraw-Hill; 2004:1473-533.
• North K, Goebel HH. Congenital myopathies. In: Jones HR, DeVivo DC, Darras BT, eds. Neuromuscular Disorders in Infancy, Childhood and Adolescence: A Clinician's Approach. Woburn, MA: Butterworth-Heinemann; 2003:601-32.
• Ohlsson M, Quijano-Roy S, Darin N, Brochier G, Lacène E, Avila-Smirnow D, Fardeau M, Oldfors A, Tajsharghi H. New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations. Neurology. 2008;71:1896–901. [PubMed: 19047562]
• Okamoto N, Toribe Y, Nakajima T, Okinaga T, Kurosawa K, Nonaka I, Shimokawa O, Matsumoto N. A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy. J Hum Genet. 2002;47:556–9. [PubMed: 12376748]
• Ortolano S, Tarrío R, Blanco-Arias P, Teijeira S, Rodríguez-Trelles F, García-Murias M, Delague V, Lévy N, Fernández JM, Quintáns B, Millán BS, Carracedo A, Navarro C, Sobrido MJ. A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy. Neuromuscul Disord. 2011;21:254–62. [PubMed: 21288719]
• Pénisson-Besnier I, Monnier N, Toutain A, Dubas F, Laing N. A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: A clinical and pathological study. Neuromuscul Disord. 2007;17:330–7. [PubMed: 17376686]
• Quijano-Roy S, Avila-Smirnow D, Carlier RY. WB-MRI muscle study group. Whole body muscle MRI protocol: pattern recognition in early onset NM disorders. Neuromuscul Disord. 2012;22 Suppl 2:S68–84. [PubMed: 22980770]
• Robinson RL, Brooks C, Brown SL, Ellis FR, Halsall PJ, Quinnell RJ, Shaw MA, Hopkins PM. RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Hum Mutat. 2002;20:88–97. [PubMed: 12124989]
• Rudnik-Schöneborn S, Glauner B, Röhrig D, Zerres K. Obstetric aspects in women with facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, and congenital myopathies. Arch Neurol. 1997;54:888–94. [PubMed: 9236578]
• Schessl J, Goemans NM, Magold A, Zou Y, Hu Y, Kirschner J, Sciot R, Bonnemann CG. Predominant fiber atrophy and fiber type disproportion in early Ullrich disease. Muscle Nerve. 2008;38:1184–91. [PubMed: 18720506]
• Sobreira C, Marques W Jr, Barreira AA. Myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy. J Neurol Neurosurg Psychiatry. 2003;74:1317–9. [PMC free article: PMC1738650] [PubMed: 12933945]
• Sobrido MJ, Fernandez JM, Fontoira E, Perez-Sousa C, Cabello A, Castro M, Teijeira S, Alvarez S, Mederer S, Rivas E, Seijo-Martinez M, Navarro C. Autosomal dominant congenital fibre type disproportion: a clinicopathological and imaging study of a large family. Brain. 2005;128:1716–27. [PubMed: 15857933]
• Staron RS, Hagerman FC, Hikida RS, Murray TF, Hostler DP, Crill MT, Ragg KE, Toma K. Fiber type composition of the vastus lateralis muscle of young men and women. J Histochem Cytochem. 2000;48:623–9. [PubMed: 10769046]
• Tajsharghi H, Ohlsson M, Palm L, Oldfors A. Myopathies associated with β-tropomyosin mutations. Neuromuscul Disord. 2012;22:923–33. [PubMed: 22749895]
• Tajsharghi H, Oldfors A. Myosinopathies: pathology and mechanisms. Acta Neuropathol. 2013;125:3–18. [PMC free article: PMC3535372] [PubMed: 22918376]
• Treves S, Anderson AA, Ducreux S, Divet A, Bleunven C, Grasso C, Paesante S, Zorzato F. Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders. Neuromuscul Disord. 2005;15:577–87. [PubMed: 16084090]
• Vogler C, Bove KE. Morphology of skeletal muscle in children. An assessment of normal growth and differentiation. Arch Pathol Lab Med. 1985;109:238–42. [PubMed: 3838454]
• Vorwerk P, Christoffersen CT, Muller J, Vestergaard H, Pedersen O, De Meyts P. Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy). Horm Res. 1999;52:211–20. [PubMed: 10844410]
• Wallgren-Pettersson C, Kääriäinen H, Rapola J, Salmi T, Jääskeläinen J, Donner M. Genetics of congenital nemaline myopathy: a study of 10 families. J Med Genet. 1990;27:480–7. [PMC free article: PMC1017195] [PubMed: 2213842]
• Wang CL, Coluccio LM. New insights into the regulation of the actin cytoskeleton by tropomyosin. Int Rev Cell Mol Biol. 2010;281:91–128. [PMC free article: PMC2923581] [PubMed: 20460184]
• Wilmshurst JM, Lillis S, Zhou H, Pillay K, Henderson H, Kress W, Müller CR, Ndondo A, Cloke V, Cullup T, Bertini E, Boennemann C, Straub V, Quinlivan R, Dowling JJ, Al-Sarraj S, Treves S, Abbs S, Manzur AY, Sewry CA, Muntoni F, Jungbluth H. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol. 2010;68:717–26. [PubMed: 20839240]

Author Notes

Dr Beggs' website

Acknowledgments

We would like to acknowledge and thank all of those who aided in the writing of this review, including Pankaj Agrawal, MD, MMSc; Jessie Hastings, MS, CGC; Michael Lawlor, MD, PhD; and Christopher R Pierson, MD, PhD. In addition, the authors gratefully acknowledge the Lee and Penny Anderson Family Foundation, the Joshua Frase Foundation, the Muscular Dystrophy Association (USA), and the National Institutes of Health for their funding of our studies on congenital myopathies.

Revision History

• 18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 11 April 2013 (me) Comprehensive update posted live
• 23 October 2008 (cd) Revision: prenatal diagnosis for ACTA1 mutations available clinically
• 13 August 2008 (cd) Revision: sequence analysis and prenatal testing for TPM3 mutations as a cause of CFTD available clinically
• 12 January 2007 (me) Review posted live
• 12 April 2006 (et) Original submission