autosomal recessive limb-girdle muscular dystrophy type 2U

Autosomal recessive limb-girdle muscular dystrophy type 2U is a very rare inherited muscle disorder that mainly weakens the large muscles of the hips and shoulders. It is caused by harmful changes in the ISPD gene, which interfere with adding sugar chains to the protein alpha-dystroglycan, a process that keeps muscle cells stable and connected. Symptoms often start in childhood or the teen years with trouble running, climbing stairs, or lifting objects, and both boys and girls can be affected. The severity and specific features can vary considerably from person to person, with some individuals needing a wheelchair early while others stay mobile into adulthood. Fewer than one in a million people worldwide are thought to have this condition.

Severity and symptoms vary widely between individuals. Musculoskeletal system: The hallmark is progressive weakness of the limb-girdle muscles, often first noticed as difficulty running, climbing stairs, or rising from the floor. Calf muscles may appear unusually large or firm (true or pseudo-hypertrophy) even as strength declines. Many individuals experience exercise-induced muscle pain, and some develop visible shoulder-blade protrusion (scapular winging). Over time a subset lose independent ambulation. Respiratory system: Reduced vital capacity is common, and some people require nighttime ventilation support as respiratory muscles weaken. Cardiovascular system: About one-third of individuals show heart involvement, which can range from mild rhythm changes to cardiomyopathy that needs specialist management. Laboratory features: Blood tests consistently reveal markedly elevated creatine kinase levels, reflecting ongoing muscle damage. Muscle biopsy, when performed, often demonstrates hypoglycosylation of alpha-dystroglycan, a key diagnostic clue. Not all individuals experience all features, and the rate of progression differs considerably, even among siblings.

The condition is caused by pathogenic variants in the CRPPA gene. CRPPA encodes an enzyme that helps build a special sugar molecule added to alpha-dystroglycan; without this modification, muscle fibers become fragile and prone to damage during normal activity. It is inherited in an autosomal recessive pattern, meaning a child must receive an altered copy of CRPPA from both parents to be affected. Parents who each carry a single variant (carriers) are typically healthy but have a 25 percent chance with each pregnancy of having an affected child. This condition is more common when parents share a common ancestor because relatives are more likely to carry the same rare variant. Genetic counseling can explain carrier testing options for family members and discuss implications for future pregnancies. Even within the same family, the severity and specific symptoms can vary considerably (variable expressivity).

Currently, management focuses on supportive care and symptom management. A multidisciplinary care team that may include neuromuscular specialists, physical and occupational therapists, pulmonologists, and cardiologists tailors interventions to each individual’s needs. Foundational approaches include individualized physiotherapy and stretching programs to maintain joint flexibility, assistive devices to optimize mobility, and pain management strategies for muscle discomfort. Respiratory monitoring is essential, with consideration of non-invasive ventilation if nighttime breathing becomes shallow. Cardiac evaluations help detect rhythm changes or cardiomyopathy early so that appropriate medications or other interventions can be started. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Discussions with a genetic counselor and ongoing coordination among specialists ensure that treatment remains personalized as needs change over time.

Outcomes depend on many factors, including age at symptom onset, rate of progression, and access to specialized care. Some individuals retain independent walking ability for decades, while others require wheelchairs or respiratory support in adolescence or early adulthood. Heart and breathing complications can affect overall health, but proactive monitoring and modern supportive therapies have improved quality of life and survival for many people. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with neuromuscular specialists and patient support networks, and genetic counseling provides guidance for family planning and carrier testing.

Clinical trials are underway exploring new treatment approaches, including therapies aimed at enhancing alpha-dystroglycan glycosylation or stabilizing muscle fibers. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.