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 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 six genes: ACTA1 (~6% of individuals with CFTD), MYH7 (unknown), RYR1 (~10%-20%), SEPN1 (rare), TPM2 (rare) and TPM3 (~20%-25% of individuals with CFTD).
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 mutations while the SEPN1 and RYR1-related cases have been associated with autosomal recessive mutations. TPM3-related CFTD can be inherited in an autosomal dominant or autosomal recessive manner. ACTA1 and TPM3 mutations 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 disease-causing mutation is not identified through testing of known genes. Prenatal testing for pregnancies at risk for CFTD is possible if the disease-causing mutation(s) in a family are known.