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 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 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 are usually present at birth, but may occur in older persons with decreased mobility secondary to severe weakness. Spinal deformities including scoliosis, kyphoscoliosis, and lordosis are seen in approximately 25% of individuals.
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, mutations have been identified in three genes, ACTA1 (~6% of individuals with CFTD), SEPN1 (rare), and TPM3 (~20% -25% of individuals with CFTD). Testing is clinically available for all three genes.
CFTD is a genetically heterogenous condition that can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner. To date, all identified cases of ACTA1-related CFTD have been caused by autosomal dominant mutations while the SEPN1-related cases have been associated with autosomal recessive mutations. Mutations in TPM3 are inherited in an autosomal dominant or autosomal recessive manner. 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 mutations in ACTA1, SEPN1 or TPM3 are not identified. Prenatal testing for pregnancies at risk for ACTA1-related CFTD, SEPN1-related CFTD and TPM3-related CFTD is available clinically if the disease-causing mutations in a family are known.