Myopathy, Congenital, With Fiber-Type Disproportion

A number sign (#) is used with this entry because congenital fiber-type disproportion (CFTD) can be caused by mutation in the ACTA1 (102610), SEPN1 (606210), or TPM3 (191030) genes.

Mutations in the SEPN1 gene also cause rigid spine muscular dystrophy (RSMD1; 602771), which shows clinical overlap with CFTD.

See also CFTDX (300580), which has been mapped to chromosome Xq13.1-q22.1.

Description

Congenital fiber-type disproportion (CFTD) myopathy is a genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. Clarke and North (2003) stated that the diagnosis of 'congenital fiber-type disproportion' as a disease entity is one of exclusion. They also suggested that the nonspecific histologic findings should be termed 'fiber size disproportion,' thus reserving the term CFTD for those cases in which no secondary cause can be found.

Clinical Features

Brooke (1973) reported 12 cases and coined the term 'congenital fiber-type disproportion.' All patients had hypotrophy of type 1 muscle fibers, which were at least 12% smaller than either type 2A or type 2B fibers. Clinical features included congenital hypotonia, generalized weakness, and failure to thrive. Other features included long, thin face, scoliosis, high-arched palate, and multiple joint contractures. One patient had an affected parent.

Cavanagh et al. (1979) described 9 children with congenital fiber-type disproportion. Hypotonia, joint laxity, and congenital dislocation of the hip were the usual features. Muscle biopsies showed type 1 fibers that were smaller than the largest type 2 fibers by at least 13.5%. The natural history of the disorder was variable, with some children having fatal respiratory events. The parents in 1 case were second cousins. One mother was said to have weak legs in childhood, and another patient was said to have 2 affected paternal cousins.

Somer (1981) reported a 22-year-old man with muscle weakness and marfanoid features, including scoliosis. He had been a floppy infant. He worked as a television technician but could not lift TVs. Muscle biopsy showed type 1 fibers to be smaller than type 2 fibers. Type 2A fibers showed compensatory hypertrophy, and type 2B fibers were lacking.

Jaffe et al. (1988) described this disorder in a 12-year-old male and his infant sister. The parents were healthy and unrelated.

Vestergaard et al. (1995) reported a family in which of 2 of 3 sons had CFTD and insulin-resistant diabetes mellitus. The brothers, aged 15 and 8 at the time of the study, were born of nonconsanguineous healthy parents. Both had delayed milestones and muscle weakness. The diagnosis of CFTD was made in both probands at the age of 6 years. Muscle biopsy showed 74% small type 1 fibers of 16 micro m diameter and 26% type 2 fibers of 22 micro m diameter. No nemaline bodies were seen. Physical examination showed universal muscle hypotrophy and hirsutism. Glucosuria and postprandial hyperglycemia were discovered by chance at the age of 13 years in proband 1 and 6 years in proband 2; neither had been symptomatic. The father expressed a lesser degree of insulin resistance, and studies of muscle insulin receptor function showed a severe impairment of receptor kinase activity.

Clarke and North (2003) clarified the definition of CFTD through a comprehensive literature review and analysis. Of 218 reported cases of fiber size disproportion on muscle biopsy, they classified 67 cases as having CFTD, using inclusion criteria of (1) clinical muscle weakness and/or hypotonia, and (2) mean type 1 fiber diameter at least 12% smaller than mean type 2 fiber diameter. Exclusion criteria consisted of insufficient clinical information; a coexisting disorder of muscle or the nervous system; 2 or more syndromal features present; histologic features of a muscular dystrophy; and a coefficient of variation greater than 250 for type 2 fibers. In most cases, limb weakness was greatest in the limb girdle and proximal muscle groups, although many children had generalized muscle weakness. There was variable facial weakness (42% of patients), ophthalmoplegia (19%), and severe respiratory involvement (18%). Long face and high-arched palate were commonly reported. Reflexes were usually decreased or absent. Many patients had contractures, either at birth or developing later, of the ankles (10 cases), fingers (4 cases), hips (3 cases), elbows (3 cases), and knees (2 cases). Fifteen patients had scoliosis. Only 2 patients had cardiac involvement: dilated cardiomyopathy and atrial fibrillation, respectively (Banwell et al., 1999). Two patients had intellectual disability and 3 males had cryptorchidism. Fifty patients had type 1 fiber diameters that were 25% smaller than type 2, and these patients tended to have a more severe clinical phenotype. Family history was present in 43% of families, suggesting that genetics may play a role in a subset of patients.

Laing et al. (2004) identified 3 unrelated patients with severe CFTD from a muscle repository. The fiber size disproportion in these patients ranged from 45 to 54%, far exceeding the minimum level of 12%. Clinical records showed that all 3 had neonatal hypotonia with weak breathing, eventually requiring mechanical ventilation. There was also marked generalized proximal muscle and facial weakness. Two patients had a high-arched palate and a long, thin face, and 1 patient had scoliosis. None of the patients had ophthalmoplegia or cardiac involvement. Two patients died at ages 1.1 and 3.5 years, respectively, and the third was bedridden at age 3 years. Each patient carried a different heterozygous mutation in the ACTA1 gene (102610.0011-102610.0013).

Sobrido et al. (2005) reported a large Spanish family with CFTD inherited in an autosomal dominant pattern. Seven of 25 examined family members were affected. Onset of slowly progressive muscle weakness was in early childhood, manifest by clumsiness and difficulty running, climbing stairs, and getting up from the floor. As adults, all retained independent ambulation but demonstrated waddling gait, proximal upper and lower extremity weakness and atrophy, and hypo- or areflexia. Notably, none of the affected individuals had neonatal respiratory or sucking difficulties. MRI studies showed loss of volume and fatty infiltration of proximal muscles; EMG showed myopathic changes. Skeletal muscle biopsies of 2 affected individuals showed characteristic findings of CFTD without dystrophic changes. No mutations were identified in the coding sequence of the ACTA1 gene.

Clarke et al. (2006) reported 2 sisters, ages 32 and 30, respectively, with a diagnosis of congenital fiber-type disproportion. Skeletal muscle biopsies showed that type 1 fibers were at least 12% smaller than type 2 fibers, and there was no evidence of multiminicore disease or other findings typical of RSMD1. Clinically, the women had a severe congenital myopathy with truncal hypotonia in infancy, progressive scoliosis, progressive respiratory impairment, and osteopenia. One woman was wheelchair-bound and had had bilateral hip fractures in her twenties. Both patients had abnormal glucose tolerance tests and showed biochemical abnormalities suggesting insulin resistance.

Inheritance

Fardeau et al. (1975) reported a family with CFTD in which the father and 2 sisters were affected.

Curless and Nelson (1977) described this form of myopathy in identical twins. Although this occurrence in sibs and the parental consanguinity suggested autosomal recessive inheritance, parental involvement pointing to an autosomal dominant mode was reported by Kula et al. (1980) and Sulaiman et al. (1983).

Cytogenetics

Gerdes et al. (1994) reported a child with congenital fiber-type disproportion who was born with arthrogryposis multiplex congenita, dislocation of the hips, and mild scoliosis. By age 5 years, she had developed marked muscle weakness. Cytogenetic analysis identified a balanced chromosomal translocation, t(10;17)(p11.2;q25), transmitted by the clinically healthy mother. Maternal uniparental disomy for loci on either chromosome 10 or chromosome 17 was excluded. Although the mother had normal muscle strength and mass, muscle biopsy showed type 1 fiber predominance and EMG showed myopathic changes. Gerdes et al. (1994) suggested that congenital fiber-type disproportion in this family was dominantly inherited with variable expressivity, and that the translocation breakpoints may represent candidate gene regions.

The chromosome 1p36 deletion syndrome (607872) is characterized by hypotonia, moderate to severe developmental and growth retardation, and characteristic craniofacial dysmorphism (Shapira et al., 1997; Slavotinek et al., 1999). Muscle hypotonia and delayed motor development are almost constant features of the syndrome. Colmenares et al. (2002) suggested that the SKI protooncogene (164780) may contribute to phenotypes common in 1p36 deletion syndrome, particularly to facial clefting; Ski -/- mice showed features reminiscent of the syndrome. Okamoto et al. (2002) described a patient with the 1p36 deletion syndrome in whom FISH demonstrated that the SKI gene was deleted. The patient was a 4-year-old Japanese girl in whom dysmorphic features were evident at birth and right congenital hip dislocation necessitated surgical treatment. Dilated cardiomyopathy was recognized at the age of 7 months. A diagnosis of congenital fiber-type disproportion myopathy was made on muscle biopsy.

Molecular Genetics

In 3 unrelated patients with severe CFTD myopathy, Laing et al. (2004) identified 3 different mutations in the ACTA1 gene (D292V, 102610.0011; L221P, 102610.0012; P332S, 102610.0013). The authors reported that ACTA1 mutations accounted for approximately 6% of cases in their cohort, indicating genetic heterogeneity.

In 2 women with CFTD, Clarke et al. (2006) identified a homozygous mutation in the SEPN1 gene (G315S; 606210.0008). This mutation had previously been reported in patients with RSMD1.

Clarke et al. (2008) identified 5 different heterozygous TPM3 mutations (see, e.g., 191030.0005; 191030.0007; 191030.0008), in affected members of 6 unrelated families with congenital myopathy with fiber-type disproportion on skeletal muscle biopsy. The mutations were identified among 23 unrelated probands, making TPM3 the most common cause of CFTD to date.

Associations Pending Confirmation

For discussion of a possible association between CFTD and variation in the PTPLA gene, see 610467.0001.

Pathogenesis

Using mass spectrometry and gel electrophoresis to examine patient skeletal muscle, Clarke et al. (2007) determined that D292V- and P332S-actin accounted for 50% and 25 to 30% of total sarcomeric actin, respectively. In vitro assays showed that D292V-actin resulted in decreased motility due to abnormal interactions between actin and tropomyosin, with tropomyosin stabilized in the 'off' position. However, similar findings were not observed with P332S-actin, suggesting that tropomyosin dysfunction may not be a common mechanism in CFTD. Cellular transfection studies demonstrated that the mutant proteins incorporated into actin filaments and did not result in increased actin aggregation or disruption of the sarcomere. Clarke et al. (2007) concluded that ACTA1 mutations resulting in CFTD cause weakness by interfering with sarcomeric function rather than structure.