LGMD2I: Causes, Symptoms, and Diagnosis

Limb-girdle muscular dystrophy (LGMD) is a group of genetic disorders causing progressive weakness and wasting of the muscles around the shoulders and hips. Within this group, LGMD2I is a distinct subtype. Its name provides information: “LGMD” identifies the muscle group, “2” indicates recessive inheritance, and “I” signifies it was the ninth such form classified. This system helps distinguish it from dozens of other LGMD forms.

Genetic Basis of LGMD2I

LGMD2I is caused by a mutation in the fukutin-related protein gene (FKRP). This gene holds the instructions for producing a protein that participates in glycosylation, a process of adding sugar molecules to other proteins for proper muscle cell function. Specifically, this protein modifies alpha-dystroglycan, which connects a muscle fiber’s internal cytoskeleton to the supportive matrix outside the cell.

When the FKRP gene is mutated, the resulting protein is deficient, leading to incomplete glycosylation of alpha-dystroglycan. This defect weakens the connection between the muscle cell and its surroundings. This makes the muscle fibers fragile and susceptible to damage during contraction.

LGMD2I is inherited in an autosomal recessive pattern. This means an individual must inherit one mutated FKRP gene from each parent to develop the condition. A person who inherits only one mutated copy is a carrier who does not show symptoms but can pass the gene on to their children.

Recognizing the Symptoms

The primary symptom of LGMD2I is progressive weakness in the proximal muscles. This weakness appears gradually, manifesting in difficulties with everyday activities like climbing stairs, getting up from a seated position, or lifting objects overhead. A distinct waddling gait is also a common early sign as the hip muscles weaken.

The presentation of LGMD2I is variable. The age of onset can range widely, from early childhood to late teens or adulthood. The rate at which the muscle weakness progresses also differs from person to person, with some experiencing a slow decline and others a more rapid course.

Beyond the limb-girdle muscles, LGMD2I can affect other muscle groups. Weakness of the respiratory muscles can impair breathing, particularly during sleep, and may necessitate ventilatory support. The heart muscle can also be affected, leading to cardiomyopathy, where the heart becomes weakened and less efficient at pumping blood. This cardiac involvement requires monitoring and management.

The Diagnostic Process

The diagnostic process for LGMD2I begins with a clinical evaluation where a physician observes the characteristic pattern of muscle weakness. If proximal muscle weakness is identified, the next step is a blood test to measure the level of an enzyme called creatine kinase (CK). In muscular dystrophy, damaged muscle fibers release CK into the bloodstream, causing its levels to be elevated.

While high CK levels suggest muscle damage, they do not pinpoint the cause. The definitive diagnostic test for LGMD2I is genetic testing. A blood sample is analyzed for mutations in the FKRP gene, and identifying disease-causing mutations in both copies confirms the diagnosis.

Before genetic testing was widely available, a muscle biopsy was a more common tool. This procedure involves removing a small sample of muscle tissue for microscopic examination. In cases of LGMD2I, a biopsy reveals changes characteristic of muscular dystrophy and can be used to check for the abnormal glycosylation of alpha-dystroglycan. Today, genetic testing is the standard due to its accuracy and less invasive nature.

Managing the Condition

As there is currently no cure for LGMD2I, management focuses on a multidisciplinary approach to slow disease progression, manage symptoms, and maintain quality of life. Physical and occupational therapy are a main part of this strategy. Therapists design customized programs with gentle stretching to prevent joint stiffness and low-impact activities to help maintain muscle strength and function for as long as possible.

As muscle weakness advances, individuals may require assistive devices to maintain mobility. These can range from ankle-foot orthoses (braces) to improve walking stability to canes, walkers, or wheelchairs. Occupational therapists can also recommend adaptive equipment and modifications to the home and workplace to make daily tasks easier.

Regular monitoring of heart and lung function is a component of care. Cardiologists perform routine evaluations, such as electrocardiograms (ECGs) and echocardiograms, to detect cardiomyopathy early. Pulmonologists conduct breathing tests to monitor respiratory muscle strength. If breathing becomes compromised, interventions like non-invasive ventilation, often used at night, can provide support, improve sleep quality, and ease the work of the respiratory muscles.