autosomal dominant limb-girdle muscular dystrophy type 1F

Autosomal dominant limb-girdle muscular dystrophy type 1F (LGMD1F) is a hereditary muscle disorder that primarily weakens the large muscles around the hips and shoulders. It is caused by disease-causing changes in the TNPO3 gene, which provides instructions for a protein involved in transporting molecules into the cell nucleus. Onset can occur in childhood, adolescence, or adulthood, and both males and females can be affected. The condition is considered very rare, affecting fewer than one person in a million worldwide. Over time, muscle weakness can progress and lead to mobility and respiratory challenges, but the rate and severity of progression differ widely between individuals.

LGMD1F chiefly presents with progressive weakness of the pelvic girdle muscles, particularly the iliopsoas, followed by the shoulder girdle muscles. Many individuals notice difficulty climbing stairs, rising from a seated position, or lifting objects overhead as early signs. Calf enlargement (hypertrophy) is frequently seen and may be mistaken for athletic muscle bulk. As the condition advances, weakness can extend to distal muscles of the hands and feet, producing an abnormal gait and reduced hand strength. Dysphagia (trouble swallowing), fatigue, exercise intolerance, and myalgia are common progressive features. Respiratory muscles may become involved in some people, leading to shortness of breath or nocturnal hypoventilation. Less common findings include spinal rigidity, finger contractures, arachnodactyly, ptosis, motor delays in childhood, and delayed independent walking. Cardiac conduction problems are not typical in this subtype, distinguishing it from several other limb-girdle muscular dystrophies. Not all individuals experience all features, and severity varies considerably. Even within the same family, some members may have mild difficulty walking while others eventually require mobility aids.

LGMD1F results from pathogenic variants in the TNPO3 gene. The TNPO3 protein helps shuttle specific proteins into the nucleus of muscle cells; when it does not work correctly, muscle fibers gradually weaken and waste away. The condition follows an autosomal dominant inheritance pattern, meaning one altered copy of TNPO3 is enough to cause symptoms. Each child of an affected individual has a 50% chance of inheriting the variant. Severity and exact symptoms can differ markedly among relatives who carry the same genetic change, a phenomenon known as variable expressivity. Families are encouraged to discuss genetic testing and counseling to clarify risks for other relatives and for future family planning.

Currently, management focuses on supportive care tailored to each person’s needs. A multidisciplinary team that may include neuromuscular specialists, physiatrists, physical and occupational therapists, speech-language pathologists, and respiratory therapists works together to maintain mobility, manage fatigue, and address swallowing or breathing difficulties. Regular surveillance for respiratory function helps detect declining lung capacity early so that non-invasive ventilation or breathing exercises can be introduced when needed. Customized exercise programs and stretching help preserve joint range of motion and delay contractures, while adaptive equipment such as ankle-foot orthoses or mobility aids can enhance independence. Genetic counseling provides important guidance for affected individuals and their families. No treatments are specifically approved for LGMD1F at this time. Individuals should talk with their healthcare team about symptomatic therapies, rehabilitation options, and emerging research opportunities.

The long-term outlook for LGMD1F varies. Some people retain the ability to walk for decades, while others experience faster progression and may need wheelchairs or respiratory support earlier in life. Severity and symptoms vary widely between individuals, even among close relatives. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with neuromuscular specialists and genetic counselors to understand expected changes, arrange appropriate monitoring, and explore supportive resources.

Clinical trials are underway exploring new treatment approaches for limb-girdle muscular dystrophies, including LGMD1F. Individuals interested in participating can search ClinicalTrials.gov or consult their care team about eligibility.