This study evaluates whether amino acid supplementation, combined with a structured diet and exercise program, improves body composition (increased muscle mass and reduced fat mass) and physical performance in individuals with facioscapulohumeral muscular dystrophy (FSHD). The study also compares responses to the intervention between individuals with FSHD and healthy individuals matched for age and sex.

Background and Rationale: Facioscapulohumeral muscular dystrophy (FSHD) is a rare disease (≈1:15,000-1:20,000) characterized by progressive muscle weakness, primarily affecting the face, shoulders, and upper body. The condition is associated with reduced strength, aerobic capacity, walking ability, and increased fatigue, leading to impaired quality of life. In the absence of a curative treatment, conservative strategies are essential. Exercise has demonstrated beneficial effects; however, the combined impact of exercise and amino acid supplementation-known to stimulate protein synthesis-has not been investigated in individuals with FSHD and may help counteract muscle loss. Objectives: The primary objective is to evaluate the effects of amino acid supplementation on body composition and physical performance in individuals with FSHD undergoing a standardized nutritional and exercise program.

The secondary objective is to compare these effects with those observed in healthy individuals matched for age and sex. Expected Outcomes: Amino acid supplementation is expected to result in greater improvements in lean mass, fat mass, aerobic fitness, muscle strength, walking performance, and daily physical activity compared to placebo. Improvements are expected in both groups; however, individuals with FSHD may exhibit smaller gains due to altered protein synthesis.

Study Population: The study will enroll 24 adults with genetically confirmed FSHD, aged 18-50 years, with mild to moderate disease severity and preserved walking ability. Participants will be recruited from the University of Pavia and the Italian National FSHD Registry. A control group of 24 healthy individuals, matched for age and sex, will be recruited through institutional channels.

Study Design: This is a randomized, double-blind, placebo-controlled crossover study. The intervention duration is 15 months per participant. Due to the rarity of the disease, total study completion is anticipated within approximately 36 months. Participants with FSHD will complete two 6-month intervention phases separated by a 3-month washout period, receiving both amino acid supplementation (essential amino acid mixture) and placebo (maltodextrins) in random order. Assessments will be conducted at baseline and at the end of each intervention phase. Healthy control participants will complete a single 6-month intervention phase. Intervention and Assessments: Participants will undergo evaluations including body composition, resting metabolic rate, handgrip strength, gait analysis, cardiopulmonary fitness (VO₂max), and daily physical activity measured via accelerometry. The intervention consists of a personalized dietary plan and a home-based exercise program including moderate-intensity aerobic training and resistance exercises targeting major muscle groups. Supplementation includes two daily doses of either amino acids or placebo, administered under blinded conditions. Risks and Safety: The study involves minimal risk. Potential risks are primarily related to minor injuries associated with home-based exercise. Risk mitigation strategies include participant instruction, monitoring, and the prescription of appropriate exercise protocols.

Inclusion Criteria:

1. Subjects of both sexes with a diagnosis of FSHD, confirmed by genetic testing.
2. Age between 18 and 50 years.
3. Belonging to clinical category A among the four defined in the Comprehensive Clinical Evaluation Form. These patients present the most characteristic signs of the disease: muscle weakness of the facial and scapular girdle.
4. Clinical score ranging from 2 to 5.
5. Preserved ability to walk at the time of enrollment.
6. Absence of central or peripheral nervous system involvement based on neurological history and physical examination.
7. Absence of scoliosis, limb contractures, and tendon retractions.

Exclusion Criteria:

1. Use of beta-blocker medications;
2. Psychological or psychiatric disorders;
3. Musculoskeletal injuries that impair the ability to perform physical exercise;
4. Recent medication adjustment, use of drugs that may affect fatigue, or use of fatigue-stimulating agents (e.g., Modafinil, amantadine);
5. Ongoing participation in another clinical investigation involving a medical device or drug, or participation in such a study completed less than 30 days prior;
6. Pregnant or breastfeeding women;
7. Patients unable to understand the purpose and conditions of the study and unable to provide informed consent;
8. Presence of additional diseases that may interfere with measurements;
9. Patients deprived of liberty or under legal guardianship.

Healthy participants will be age- and sex-matched adults without neuromuscular disease:

1. no chronic disease;
2. no neuromuscular disorders;
3. Same age range.

Risks for misinterpretation or misuse and risk of re-identifying participants dealing with a rare disease.