LAMA2 Muscular Dystrophy

Clinical characteristics: The clinical manifestations of LAMA2 muscular dystrophy (LAMA2-MD) comprise a continuous spectrum ranging from severe congenital muscular dystrophy type 1A (MDC1A) to milder late-onset LAMA2-MD. MDC1A is typically characterized by neonatal profound hypotonia, poor spontaneous movements, and respiratory failure. Failure to thrive, gastroesophageal reflux, aspiration, and recurrent chest infections necessitating frequent hospitalizations are common. As disease progresses, facial muscle weakness, temporomandibular joint contractures, and macroglossia may further impair feeding and can affect speech.

In late-onset LAMA2-MD onset of manifestations range from early childhood to adulthood. Affected individuals may show muscle hypertrophy and develop a rigid spine syndrome with joint contractures, usually most prominent in the elbows. Progressive respiratory insufficiency, scoliosis, and cardiomyopathy can occur.

Diagnosis/testing: The diagnosis of LAMA2 muscular dystrophy is established in a proband with suggestive findings and biallelic (homozygous or compound heterozygous) pathogenic variants in LAMA2 identified by molecular genetic testing.

Management: Treatment of manifestations: It is recommended that multidisciplinary care be provided by specialists in neurology, gastroenterology, nutrition, orthopedics, occupational and physical therapy, speech and language therapy, education, psychiatry, pulmonary medicine, cardiology, ophthalmology, and social work.

Surveillance: Routine follow up of nutritional status and safety of oral intake, neurologic status, pulmonary function, developmental/educational progress, cognitive abilities, psychiatric issues, mobility and activities of daily living, cardiac status, vision, and social needs.

Agents/circumstances to avoid: Succinylcholine in induction of anesthesia because of risk of hyperkalemia and cardiac conduction abnormalities; statins, cholesterol-lowering medications, because of the risk of muscle damage.

Genetic counseling: LAMA2-MD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a LAMA2 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 LAMA2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.