Fukuyama Congenital Muscular Dystrophy

Excerpt

Clinical characteristics: Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and brain malformations including, classically, cobblestone lissencephaly with cerebral and cerebellar dysplasia. There is a spectrum of severity and mild, typical, and severe phenotypes are recognized. Disease onset typically occurs in early infancy with poor suck/swallow, weak cry, and floppiness. Serum creatine kinase (CK) levels are usually in the thousands (10-60 times higher than normal). Motor development peaks at around age five to six years and thereafter regresses as muscle atrophy progresses. In the typical case, sitting without support or sliding along the floor on the buttocks may be the peak motor function. Deep tendon reflexes are diminished or absent after early infancy. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later-onset features include a myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech delays, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement after age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death.

Diagnosis/testing: The diagnosis of FCMD is established in a proband with biallelic pathogenic variants in FKTN identified by molecular genetic testing.

Management: Treatment of manifestations: Physical therapy and stretching exercises, treatment of orthopedic complications; mobility assistance devices such as long leg braces and wheelchairs; use of noninvasive respiratory aids or tracheostomy; prompt treatment of respiratory tract infections; anti-seizure medications; medical and/or surgical treatment for gastroesophageal reflux; gastrostomy tube placement when indicated to assure adequate caloric intake; cardiomyopathy treatment per cardiologist.

Surveillance: Monitor gastrointestinal function and for signs/symptoms of gastroesophageal reflux; for orthopedic complications including foot deformities and scoliosis; for myocardial involvement by chest radiography, EKG, and echocardiography in individuals older than age ten years; and respiratory function in individuals with advanced disease.

Genetic counseling: FCMD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FKTN pathogenic variant, each sib of an affected individual has at conception 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 the FKTN pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.