Limb-Girdle Muscular Dystrophy Type 2I/R9

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Synonyms

LGMD2I/R9, LGMD2I, FKRP-related limb-girdle muscular dystrophy R9, muscular dystrophy-dystroglycanopathy type C, LGMD due to FKRP deficiency, autosomal recessive limb-girdle muscular dystrophy type 2I,

Overview

LGMD2I/R9 is a rare, genetic disorder causing progressive weakness and wasting of the arm and leg muscles, leading to a gradual loss of functional independence. It is caused by mutations in the FKRP gene, which impairs the glycosylation of alpha-dystroglycan, a protein crucial for muscle cell stability. Symptoms typically emerge in childhood or adulthood, and the condition can also affect heart and lung function, with management focused on symptom control and physical therapy. 

Symptoms

Symptoms of limb-girdle muscular dystrophy type 2I/R9 include progressive weakness and wasting in the shoulders, hips, and legs, leading to a waddling gait, difficulty running, climbing stairs, and getting up from a sitting position. Other symptoms can include frequent falls, muscle contractures, and potential heart and respiratory complications. 

Causes

Limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9) is caused by mutations in the fukutin-related protein (FKRP) gene. These mutations lead to a deficiency in the fukutin-related protein, which is crucial for properly “sugaring” another protein called alpha-dystroglycan. This loss of sugar (hypoglycosylation) weakens the connection between the muscle cell membrane and the surrounding connective tissue, causing muscle damage and progressive weakness. This is an autosomal recessive disorder, meaning an individual must inherit a faulty copy of the gene from both parents to develop the condition. 

Prevention

There is no way to prevent Limb-Girdle Muscular Dystrophy (LGMD) Type 2I/R9 as it is a genetic disorder, but management focuses on slowing progression and managing symptoms. Strategies include regular physical and occupational therapy to maintain flexibility and strength, avoiding high-intensity exercise, maintaining a healthy weight, and managing other health concerns like cardiovascular and respiratory health. Researchers are also actively developing gene therapies and other treatments to target the underlying cause of the disease.

Diagnosis

Diagnosis of Limb-Girdle Muscular Dystrophy type 2I/R9 starts with clinical symptoms like muscle weakness, often in the shoulders and hips, and is confirmed by genetic testing for mutations in the FKRP gene. Other diagnostic steps include a blood test for high creatine kinase (CK) levels, and sometimes a muscle biopsy or electromyography (EMG). 

Prognosis

The prognosis for limb-girdle muscular dystrophy type 2I/R9 is a progressive decline in muscle function, leading to a wheelchair for mobility typically within 23-26 years after symptom onset. The disease can also lead to impaired heart and lung function over time. However, with good supportive care, life expectancy can extend into adulthood, with one case reaching the seventh decade. The severity can vary depending on the specific genetic mutation. 

Treatment

There is no cure for LGMD2I/R9, so management focuses on supportive therapies and symptom relief. Treatments include physical therapy to maintain muscle strength and flexibility, respiratory support, and occupational therapy for daily activities. Gene therapy is an investigational treatment option, with clinical trials currently evaluating its safety and efficacy in the United States and Europe.