Clinical Diagnosis

Diagnosis of congenital fiber-type disproportion (CFTD), a genetically and clinically heterogeneous congenital myopathy, is based on a combination of clinical presentation and morphologic features observed on skeletal muscle histology [Brooke 1973, Clarke & North 2003, North 2004].

Most common clinical presentation. CFTD usually presents with hypotonia and varying degrees of skeletal muscle weakness that primarily affects the limbs, usually presenting at birth or within the first year of life and remaining stable over time or improving with age.

Skeletal muscle histology (see Figure)

Figure

Figure 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...)

• Type 1 fibers that are 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.

• Additional findings that may also be present:

  • Type 1 fiber numerical 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 hemopoiesis, 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 [Iannaccone et al 1987]; nemaline bodies; and sub-sarcolemmal sarcomere disarray or glycogen accumulation [Lenard & Goebel 1975].

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 were later found to have different conditions on second biopsies performed as little as one year or as much as 19 years later [Danon et al 1997, Ryan et al 2003, Camacho et al 2005].

Serum creatine phosphokinase (CK) concentration is generally normal or mildly elevated (i.e., no more than three times the upper limit of normal) [Torres & Moxley 1992].

Electromyography (EMG) is usually normal or myopathic [North 2004], but neuropathic or mixed findings are also possible.

Nerve conduction studies are generally normal.

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 ruled out 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 genetic testing. A comprehensive list of diseases that may present similarly to CFTD is included in the Differential Diagnosis section.

Molecular Genetic Testing

Genes. To date, the genetic basis of CFTD has been elucidated in only a minority of cases. Mutations have been identified in the following three genes:

• ACTA1 mutations were observed in 6% of individuals with CFTD in one series [Laing et al 2004].

• SEPN1 homozygous missense mutations have been observed in two sisters with CFTD [Clarke et al 2006].

• TPM3 heterozygous missense mutations were observed in six families with CFTD [Clarke et al 2008]

• TPM3 homozygous mutations have also been observed in individuals with CFTD [Author, unpublished data]

Other loci. 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]. 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 (IR; INSR) gene. 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 the INSR gene and CFTD [Vorwerk et al 1999].

Clinical uses

• Confirmatory diagnostic testing

• Carrier testing

• Prenatal diagnosis

Clinical testing

• Sequence analysis. Testing for ACTA1, SEPN1, and TPM3 mutations for CFTD is available on a clinical basis.

Table 1. Summary of Molecular Genetic Testing Used in Congenital Fiber-Type Disproportion

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Test Method	Mutations Detected	Mutation Detection Rate	Test Availability
Sequence analysis	ACTA1 sequence variants	Unknown (<6%) 1	Clinical
	SEPN1 sequence variants	Unknown	Clinical
	TPM3 sequence variants	Unknown (~20%-25%) 2	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Laing et al [2004] identified ACTA1 alterations in three patients representing approximately 6% of individuals with CFTD in a combined Australian and Japanese cohort.

2. Clarke et al [2008] identified TPM3 alterations in 4 families from one CFTD cohort, representing approximately 20%-25% of individuals with CFTD in the cohort.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy for a Proband

The diagnosis of CFTD is currently established by clinical presentation and muscle biopsy.

Molecular genetic testing can be used to confirm the diagnosis of CFTD in a limited number of individuals.

Based on mutation frequency, it is recommended that sequence analysis be performed sequentially –TPM3, ACTA1, SEPN1– unless there are clinical or pathologic features suggesting a different testing order. In individuals with spinal rigidity or early-onset scoliosis, it may be worthwhile to start with testing of SEPN1.

Genetically Related (Allelic) Disorders

ACTA1-related myopathies. Heterozygous mutations in ACTA1 can cause nemaline myopathy (NM) and congenital myopathy with excess thin filaments, also referred to as "actin myopathy." Nemaline myopathy is characterized by rod-like structures on biopsy with clinical features similar to those seen in CFTD. Actin myopathy shows subsarcolemmal accumulation of thin myofilaments with or without intranuclear rods [Nowak et al 1999]. Homozygous mutations in ACTA1 have also been identified in a small number of individuals with NM [Nowak et al 2007].

Heterozygous ACTA1 missense mutations also caused congenital myopathy with cores (without rods) in two unrelated families [Kaindl et al 2004].

SEPN1-related myopathies. Homozygote 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].

TPM3-related myopathies. Heterozygous, homozygous, and compound heterozygous mutations in TPM3 can cause NM with rod-like structures on biopsy and clinical features similar to those seen in CFTD [Pénisson-Besnier et al 2007].

Natural History

Clarke and North [2003], North and Goebel [2003], and North [2004] provide summaries of the natural history of congenital fiber-type disproportion (CFTD) and are the primary references for the majority of this section. Findings are summarized in Table 2.

Most children present with hypotonia and mild-to-severe generalized muscle weakness at birth or within the first year of life. Limb weakness may be greatest in the limb girdle and proximal limb muscles, but weakness is never solely distal. Facial weakness is often present, resulting in a long face, high-arched palate, and tented upper lip. Ophthalmoplegia and bulbar weakness can be seen. Tendon reflexes are often decreased or absent.

Motor milestones may be delayed. Although some individuals remain non-ambulatory throughout life, many eventually develop the ability to walk [Brooke 1973, Akiyama & Nonaka 1996, Bartholomeus et al 2000]. 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 ambulation in some individuals [Akiyama & Nonaka 1996].

Approximately 30% of individuals with CFTD have mild-to-severe respiratory involvement. 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 [Sasaki et al 1990]. 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 [Khan et al 1996].

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 predict a poor prognosis [Torres & Moxley 1992].

Although respiratory failure suggests a poor prognosis, one hypotonic neonate with severe respiratory distress, bilateral talipes equinovarus, and facial and bulbar weakness without ophthalmoplegia was weaned off of ventilator support within the first month of life and walked at 24 months [Tsuji et al 1999].

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 [Torres & Moxley 1992]. Milder feeding issues often resolve over time.

Contractures of the ankles, fingers, hips, elbows, and knees occur in approximately 25% of affected children. Contractures are usually present at birth but may also 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 approximately 25% of individuals.

Contractures and spinal abnormalities are not 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 has 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 was medically stable during follow-up from age 3.5 years to age 5.5 years [Clarke et al 2005].

• One 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.

An adolescent male and an adult male presented with myalgia and muscle fatigue without significant muscle weakness. One also had mild hypotonia [Sobreira et al 2003].

Pregnancy. 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 [Rudnick-Schoneborn et al 1997, Sobrido et al 2005].

The pregnancy of a fetus with a congenital myopathy has an increased risk for complications such as polyhydramnios and reduced fetal movements and the delivery has an increased risk of breech presentation, fetal distress, failure to progress, and/or prematurity [North & Goebel 2003, North 2004].

Genotype-Phenotype Correlations

No consistent genotype-phenotype correlations have been established.

The three individuals found to have ACTA1 mutations did not have ophthalmoplegia, but did have severe disease with significant muscle weakness and respiratory insufficiency requiring ventilator support [Laing et al 2004].

The two sisters with homozygous SEPN1 missense mutations had CFTD and 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].

The ten individuals with CFTD caused by heterozygous missense mutations in TPM3 that have been described thus far generally presented with hypotonia and poor head control within the first year of life. Many of these individuals walked within the normal age range and had mild-to-moderate muscle weakness of proximal and/or distal muscles. Those individuals who had reached adulthood at the time of the study continued to be ambulatory. Respiratory difficulties during sleep were common and sometimes insidious, presenting in childhood or early adulthood. Abnormal spinal curvature (lordosis/kyphosis), weakness of neck flexion, foot drop, facial weakness, ptosis, and scapular winging were also common [Clarke et al 2008].

Prevalence

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

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

• 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

Treatment of Manifestations

It is recommended that care be provided by a multidisciplinary team that is 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. 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; therefore, precautions for malignant hyperthermia prior to anesthesia should be considered (see Malignant Hyperthermia Susceptibility.)

Preoperative assessment of pulmonary functioning is recommended to avoid respiratory 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

• Cardiac assessment to monitor for changes secondary to respiratory involvement

• 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].

Testing of Relatives at Risk

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

Therapies Under Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 three known cases of ACTA1-related CFTD have been the result of a de novo dominant mutation.

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

TPM3-related CFTD has been inherited in an autosomal dominant manner in two families and as a de novo dominant mutation in three individuals [Clarke et al 2008]. TPM3-related CFTD can also be inherited in an autosomal recessive manner [Author, unpublished data].

Risk to Family Members — Autosomal Dominant Inheritance

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 new gene mutation. The proportion of cases caused by de novo mutations is unknown.

• 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 mutation first occurred, s/he may have somatic mosaicism for the mutation 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 failure by health care professionals to recognize the disorder and/or 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, 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 at least one family [Gerdes et al 1994].

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

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

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [Wallgren-Pettersson et al 1990], the possibility of mild manifestations in individuals who are carriers for a mutation causing CFTD cannot be excluded.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [Wallgren-Pettersson et al 1990], the possibility of mild manifestations in individuals who are carriers for a mutation causing CFTD cannot be excluded.

Offspring of a proband. The offspring of an individual with autosomal recessive CFTD are obligate heterozygotes (carriers) for a disease-causing mutation.

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

Carrier Detection

Carrier testing for family members at risk of carrying a SEPN1 mutation is available on a clinical basis once the mutations have been identified in the proband.

Risk to Family Members — X-Linked Inheritance

This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis.— ED.

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.

• If X-linked inheritance is established through pedigree analysis, the mother of an affected male is an obligate carrier. If X-linked inheritance cannot be established through pedigree analysis, a mother of more than one affected male may be a carrier or may have germline mosaicism. Although germline mosaicism has not been reported in X-linked CFTD, it has been reported in other X-linked congenital myopathies [Hane et al 1999].

• Female carriers of X-linked CFTD may have mild muscle weakness [Clarke et al 2005].

• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:

  • He has a de novo disease-causing mutation and his mother is not a carrier.

  • His mother has a de novo disease-causing mutation either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).

  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.

• If the mother of the proband is a carrier, the chance of transmitting the mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected. Female carriers of X-linked CFTD may have mild muscle weakness [Clarke et al 2005].

• If the mother of the only affected male in the family is not a carrier, the risk to sibs is low but greater than that of the general population because the possibility of germline mosaicism exists.

Offspring of a proband. Males with X-linked CFTD are not known to have reproduced [Clarke et al 2005].

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunts' offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing for X-linked CFTD is not clinically available.

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 X-linked recessive mutation. 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 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 between 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 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, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%, molecular genetic testing is available on a research basis only, or some of the genes in which disease-causing mutations occur have not been identified. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for ACTA1-related CFTD, SEPN1-related CFTD and TPM3-related CFTD is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing ACTA1, SEPN1, or TPM3 allele/s of an affected family member must be identified before prenatal testing can be performed.

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

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Literature Cited

1. Akiyama C, Nonaka I. A follow-up study of congenital non-progressive myopathies. Brain Dev. 1996;18:404–8. [PubMed: 8891237]
2. 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]
3. Bartholomeus MG, Gabreels FJ, ter Laak HJ, van Engelen BG. Congenital fibre type disproportion a time-locked diagnosis: a clinical and morphological follow-up study. Clin Neurol Neurosurg. 2000;102:97–101. [PubMed: 10817896]
4. 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.
5. Camacho A, Villarejo A, Simon R, Mateos F, Cabello A. Clinical and histologic changes in the follow-up of a congenital myopathy. Pediatr Neurol. 2005;33:139–41. [PubMed: 16087062]
6. Clarke NF, North KN. Congenital fiber type disproportion--30 years on. J Neuropathol Exp Neurol. 2003;62:977–89. [PubMed: 14575234]
7. 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]
8. Clarke N, 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;63:329–337. [PubMed: 18300303]
9. 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]
10. Danon MJ, Giometti CS, Manaligod JR, Swisher C. Sequential muscle biopsy changes in a case of congenital myopathy. Muscle Nerve. 1997;20:561–9. [PubMed: 9140362]
11. Fardeau M, Tome FMS (1994) Congenital myopathies. In: Engel AG, Franzini-Armstrong C (eds) Myology, 2 ed. McGraw-Hill, New York, pp 1487-532.
12. 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]
13. 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]
14. Fujita K, Nakano S, Yamamoto H, Ito H, Ito H, Goto Y, Kusaka H. Rinsho Shinkeigaku. 2005;45:380–2. [PubMed: 15960177]
15. Gerdes AM, Petersen MB, Schroder HD, Wulff K, Brondum-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]
16. Hane BG, Rogers RC, Schwartz CE. Germline mosaicism in X-linked myotubular myopathy. Clin Genet. 1999;56:77–81. [PubMed: 10466421]
17. 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]
18. Imoto C, Nonaka I. The significance of type 1 fiber atrophy (hypotrophy) in childhood neuromuscular disorders. Brain Dev. 2001;23:298–302. [PubMed: 11504599]
19. Kaindl AM, Ruschendorf F, Krause S, Goebel HH, Koehler K, Becker C, Pongratz D, Muller-Hocker J, Nurnberg P, Stoltenburg-Didinger G, Lochmuller H, Huebner A. Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet. 2004;41:842–8. [PMC free article: PMC1735626] [PubMed: 15520409]
20. Kang PB, Kunkel LM (2006) Muscular dystrophies. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York, Chap 216.
21. Khan Y, Heckmatt JZ, Dubowitz V. Sleep studies and supportive ventilatory treatment in patients with congenital muscle disorders. Arch Dis Child. 1996;74:195–200. [PMC free article: PMC1511397] [PubMed: 8787421]
22. Laing NG, Clarke NF, Dye DE, Liyanage K, Walker KR, Kobayashi Y, Shimakawa S, Hagiwara T, Ouvrier R, Sparrow JC, Nishino I, North KN, Nonaka I. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol. 2004;56:689–94. [PubMed: 15468086]
23. Laing NG, Wilton SD, Akkari PA, Dorosz S, Boundy K, Kneebone C, Blumbergs P, White S, Watkins H, Love DR, Haan E. A mutation in the α tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nat Genet. 1995;9:75–9. [PubMed: 7704029]
24. Lenard HG, Goebel HH. Congenital fibre type disproportion. Neuropadiatrie. 1975;6:220–31.
25. 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]
26. North K (2004) Congenital myopathies. In: Engel AG, Franzini-Armstrong C (eds) Myology, 3 ed. McGraw-Hill, New York, pp 1473-533.
27. North K, Goebel HH (2003) Congenital myopathies. In: Jones HR, DeVivo DC, Darras BT (eds) Neuromuscular Disorders in Infancy, Childhood and Adolescence: A Clinician's Approach. Butterworth-Heinemann, Woburn, MA, pp 601-32.
28. Nowak KJ, Sewry CA, Navarro C, Squier W, Reina C, Ricoy JR, Jayawant SS, Childs AM, Dobbie JA, Appleton RE, Mountford RC, Walker KR, Clement S, Barois A, Muntoni F, Romero NB, Laing NG. Nemaline myopathy caused by absence of alpha-skeletal muscle actin. Ann Neurol. 2007;61:175–84. [PubMed: 17187373]
29. Nowak KJ, Wattanasirichaigoon D, Goebel HH, Wilce M, Pelin K, Donner K, Jacob RL, Hubner C, Oexle K, Anderson JR, Verity CM, North KN, Iannaccone ST, Muller CR, Nurnberg P, Muntoni F, Sewry C, Hughes I, Sutphen R, Lacson AG, Swoboda KJ, Vigneron J, Wallgren-Pettersson C, Beggs AH, Laing NG. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet. 1999;23:208–12. [PubMed: 10508519]
30. 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]
31. 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. Neuromusc Dis. 2007;17:330–7. [PubMed: 17376686]
32. Rudnick-Schoneborn S, Glauner B, Rohrig 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]
33. Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, Houston R, Muirhead D, Dennett X, Shield LK, De Girolami U, Iannaccone ST, Laing NG, North KN, Beggs AH. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology. 2003;60:665–73. [PubMed: 12601110]
34. Sasaki M, Yoneyama H, Nonaka I. Respiratory muscle involvement in nemaline myopathy. Pediatr Neurol. 1990;6:425–7. [PubMed: 1963532]
35. Sobreira C, Marques W, 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]
36. 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]
37. 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]
38. Torres CF, Moxley RT. Early predictors of poor outcome in congenital fiber-type disproportion myopathy. Arch Neurol. 1992;49:855–6. [PubMed: 1524518]
39. Tsuji M, Higuchi Y, Shiraishi K, Mitsuyoshi I, Hattori H. Congenital fiber type disproportion: severe form with marked improvement. Pediatr Neurol. 1999;21:658–60. [PubMed: 10513694]
40. 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]
41. 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]
42. Wallgren-Pettersson C (1990) Congenital nemaline myopathy: a longitudinal study. Commentationes Physico-Mathematicae 111/1990, Dissertationes No 30, University of Finland.
43. Wallgren-Pettersson C, Kaariainen H, Rapola J, Salmi T, Jaaskelainen 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]

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Author Notes

Dr. Beggs’ Web site: www.childrenshospital.org/research/beggs

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

• 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 to live Web site

• 12 April 2006 (et) Original submission