JOURNEY: A natural history study of limb-girdle muscular dystrophies R3–R5: baseline characteristics of study cohort
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Sarcoglycanopathies affect 1 in 178,000 people worldwide, accounting for 15%–20% of all limb-girdle muscular dystrophy (LGMD) cases. However, data on the clinical characteristics and natural history of LGMD are limited. Here, we describe the clinical phenotype and natural disease course of LGMD sarcoglycanopathies (2E/R4, 2D/R3, and 2C/R5).
Methods:
JOURNEY is a global, multicenter, prospective, longitudinal study of the natural history of participants with LGMD2E/R4, LGMD2D/R3, LGMD2C/R5, and LGMD2A/R1 (NCT04475926). Inclusion criteria required a clinical and genetic diagnosis of one of these subtypes, confirmed by either one homozygous or two heterozygous pathogenic or likely pathogenic mutations in the same sarcoglycan gene or the CAPN3 gene, as verified by a certified laboratory. This analysis includes patients with sarcoglycanopathy subtypes 2E/R4, 2D/R3, and 2C/R5; data for patients with LGMD2A/R1 are not shown. At enrollment, each subtype will be stratified by age (4–7y, 8–16y, and ≥17y) and ambulatory status (ambulatory and nonambulatory). Primary endpoints are North Star Assessment for Limb-Girdle–type Muscular Dystrophies (NSAD) score, Performance of Upper Limb (PUL) score, pulmonary function tests, and other timed function tests. Exploratory assessments include electrocardiogram (ECG), echocardiogram, magnetic resonance imaging, wearable device data, and patient/observer-reported outcomes. Functional assessments will be conducted every 6 months over a 3-year period.
Results:
A total of 137 participants are enrolled as of February 2024: 2E/R4, n=45; 2D/R3, n=49; and 2C/R5, n=43; age 4–7y, n=10; 8–16y, n=59; and ≥17y, n=68. 79/137 (58.0%) are female and 75/137 (54.7%) are ambulatory (2E/R4, n=25; 2D/R3, n=36; and 2C/R5, n=14). At baseline, 26.7% (2E/R4), 2.0% (2D/R3), and 16.3% (2C/R5) have cardiac disorders. Mean baseline NSAD total scores by subtype and age (4–7y, 8–16y, ≥17y) are (ambulatory) 2E/R4: 44.0, 40.6, 32.0; 2D/R3: 46.5, 34.3, 33.3; and 2C/R5: 47.0, 24.0, N/A; and (nonambulatory) 2E/R4: N/A, 1.5, 4.1; 2D/R3: N/A, 8.7, 1.5; and 2C/R5: N/A, 4.8, 2.5, respectively. Mean baseline PUL total scores by subtype and age (4–7y, 8–16y, ≥17y) are (ambulatory) 2E/R4: 36.8, 37.8, 36.6; 2D/R3: 33.5, 36.0, 34.3; and 2C/R5: 37.0, 30.3, N/A; and (nonambulatory) 2E/R4: N/A, 14.7, 16.9; 2D/R3: N/A, 29.3, 13.9; and 2C/R5: N/A, 17.1, 15.9, respectively. In ambulatory participants, physical functional assessments are generally worse in older patients across each subtype. Pulmonary functional assessments are generally worse in older nonambulatory patients (mean % forced expiratory volumes by subtype and age [4–7y, 8–16y, ≥17y] are 2E/R4: N/A, 75.86, 54.12; 2D/R3: N/A, 91.28, 56.71; and 2C/R5: N/A, 84.18, 55.72, respectively). Of the participants with ECG data available, 26.0% of ambulatory and 54.2% of nonambulatory participants have clinically insignificant ECG abnormalities; no ambulatory and 5.1% of nonambulatory participants have clinically significant ECG abnormalities.
Conclusion:
JOURNEY is a natural history study of LGMD, adding to the overall understanding of clinical characteristics and disease progression of individuals with subtypes 2E/R4, 2D/R3, and 2C/R5.
Understanding of the clinical characteristics and disease progression of LGMD may aid physicians with diagnosis and development of appropriate therapies.
Sarcoglycanopathies affect 1 in 178,000 people worldwide, accounting for 15%–20% of all limb-girdle muscular dystrophy (LGMD) cases. However, data on the clinical characteristics and natural history of LGMD are limited. Here, we describe the clinical phenotype and natural disease course of LGMD sarcoglycanopathies (2E/R4, 2D/R3, and 2C/R5).
Methods:
JOURNEY is a global, multicenter, prospective, longitudinal study of the natural history of participants with LGMD2E/R4, LGMD2D/R3, LGMD2C/R5, and LGMD2A/R1 (NCT04475926). Inclusion criteria required a clinical and genetic diagnosis of one of these subtypes, confirmed by either one homozygous or two heterozygous pathogenic or likely pathogenic mutations in the same sarcoglycan gene or the CAPN3 gene, as verified by a certified laboratory. This analysis includes patients with sarcoglycanopathy subtypes 2E/R4, 2D/R3, and 2C/R5; data for patients with LGMD2A/R1 are not shown. At enrollment, each subtype will be stratified by age (4–7y, 8–16y, and ≥17y) and ambulatory status (ambulatory and nonambulatory). Primary endpoints are North Star Assessment for Limb-Girdle–type Muscular Dystrophies (NSAD) score, Performance of Upper Limb (PUL) score, pulmonary function tests, and other timed function tests. Exploratory assessments include electrocardiogram (ECG), echocardiogram, magnetic resonance imaging, wearable device data, and patient/observer-reported outcomes. Functional assessments will be conducted every 6 months over a 3-year period.
Results:
A total of 137 participants are enrolled as of February 2024: 2E/R4, n=45; 2D/R3, n=49; and 2C/R5, n=43; age 4–7y, n=10; 8–16y, n=59; and ≥17y, n=68. 79/137 (58.0%) are female and 75/137 (54.7%) are ambulatory (2E/R4, n=25; 2D/R3, n=36; and 2C/R5, n=14). At baseline, 26.7% (2E/R4), 2.0% (2D/R3), and 16.3% (2C/R5) have cardiac disorders. Mean baseline NSAD total scores by subtype and age (4–7y, 8–16y, ≥17y) are (ambulatory) 2E/R4: 44.0, 40.6, 32.0; 2D/R3: 46.5, 34.3, 33.3; and 2C/R5: 47.0, 24.0, N/A; and (nonambulatory) 2E/R4: N/A, 1.5, 4.1; 2D/R3: N/A, 8.7, 1.5; and 2C/R5: N/A, 4.8, 2.5, respectively. Mean baseline PUL total scores by subtype and age (4–7y, 8–16y, ≥17y) are (ambulatory) 2E/R4: 36.8, 37.8, 36.6; 2D/R3: 33.5, 36.0, 34.3; and 2C/R5: 37.0, 30.3, N/A; and (nonambulatory) 2E/R4: N/A, 14.7, 16.9; 2D/R3: N/A, 29.3, 13.9; and 2C/R5: N/A, 17.1, 15.9, respectively. In ambulatory participants, physical functional assessments are generally worse in older patients across each subtype. Pulmonary functional assessments are generally worse in older nonambulatory patients (mean % forced expiratory volumes by subtype and age [4–7y, 8–16y, ≥17y] are 2E/R4: N/A, 75.86, 54.12; 2D/R3: N/A, 91.28, 56.71; and 2C/R5: N/A, 84.18, 55.72, respectively). Of the participants with ECG data available, 26.0% of ambulatory and 54.2% of nonambulatory participants have clinically insignificant ECG abnormalities; no ambulatory and 5.1% of nonambulatory participants have clinically significant ECG abnormalities.
Conclusion:
JOURNEY is a natural history study of LGMD, adding to the overall understanding of clinical characteristics and disease progression of individuals with subtypes 2E/R4, 2D/R3, and 2C/R5.
Understanding of the clinical characteristics and disease progression of LGMD may aid physicians with diagnosis and development of appropriate therapies.