Congenital fiber-type disproportion myopathy (ORPHA:2020)
A rare genetic, congenital, non-dystrophic myopathy characterized by neonatal or infantile-onset hypotonia and mild to severe generalized muscle weakness.
Epidemiology
Prevalence is unknown.
Clinical description
Disease onset is typically 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. Approximately 30% of patients have mild to severe respiratory involvement and feeding difficulties. Contractures (ankles, fingers, hips, elbows, knees) and spinal deformities (scoliosis, kyphoscoliosis, lordosis) occur in approximately 25% of affected children. Congenital hip dislocation and talipes equinovarus may also be present. In rare cases, cardiac involvement, cognitive impairment and cryptorchidism may occur. Ophthalmoplegia, ptosis, and facial and/or bulbar weakness with severe limb/respiratory weakness predict a poor prognosis. Histologically, there is a characteristic (but not specific) reduction in the caliber of type 1 muscle fibers. Type 1 muscle fibers are predominant compared to type 2 fibers, which are either normal or hypertrophied.
Etiology
Causative mutations have been identified more frequently in 4 genes, ACTA1 (1q42.13), RYR1 (19q13.2), TPM3 (1q21.3), and SELENON (1p36.11).
Diagnostic methods
Diagnosis is based on a combination of clinical presentation and morphologic features observed on skeletal muscle histology. Molecular testing is clinically available for the causative genes.
Differential diagnosis
Differential diagnoses include other congenital myopathies (X-linked myotubular myopathy, multiminicore disease, nemaline myopathy) and neuromuscular disorders (congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy).
Antenatal diagnosis
Once the pathogenic variant(s) have been identified in the affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CFTD are possible.
Genetic counseling
For the majority of cases the pattern of inheritance is either autosomal recessive or autosomal dominant. The risk to siblings of inheriting the disease is therefore 50% in autosomal dominant forms and 25% in autosomal recessive forms. X-linked inheritance has been reported in one family, with a 50% risk of male siblings of an affected individual inheriting the disease; variable penetrance is seen in female carriers. The causative gene has not been identified.
Management and treatment
Management is directed towards treating the muscular weakness and contractures (through physical and occupational therapy, exercise, stretching), respiratory problems (breathing exercises, chest physiotherapy, ventilatory support), feeding difficulties (gavage or gastrostomy feedings). Regular orthopedic monitoring is needed and corrective surgery may be necessary.
Prognosis
Over time, the disease becomes static in more than 90% of patients or even shows improvement and, rarely, is slowly progressive.

                            Last update: 
                            May 2019


                            - Expert reviewer(s): 
                            Dr Luciano MERLINI