R Guimarães-Costa1, G Fernández-Eulate1, K Wahbi1, F Leturcq2, E Malfatti3, A Behin1, S Leonard-Louis1, I Desguerre4, C Barnerias4, M C Nougues5, A Isapof5, B Estournet-Mathiaud6, S Quijano-Roy6, A Fayssoil7, D Orlikowski8, B Fauroux9, I Richard10, C Semplicini11, N B Romero12, G Querin1, B Eymard1, P Laforêt13, T Stojkovic1. 1. Nord-Est/Ile-de-France Neuromuscular Reference Center, Myology Institute, Pitié-Salpêtrière Hospital, Paris, France. 2. Department of Biochemistry and Molecular Genetics, Cochin Hospital, Paris, France. 3. Department of Neurology, APHP, Raymond Poincaré Hospital, Nord-Est/Ile-de-France Neuromuscular Reference Center, Versailles Paris-Saclay, U 1179 INSERM, Versailles Saint-Quentin-en-Yvelines University, Saint-Aubin, France. 4. Developmental Diseases Clinic, Necker-Enfants Malades Hospital, Paris, France. 5. Department of Neuropediatrics, Nord-Est/Ile-de-France Neuromuscular Reference Center, Armand-Trousseau Children's Hospital, Paris, France. 6. Neuromuscular Unit, Pediatric Neurology and ICU Department, Raymond Poincaré Hospital, APHP Paris-Saclay. UVSQ U1179 INSERM, Garches, France. 7. Pneumology Intensive Care Unit, Raymond Poincaré Hospital, Paris, France. 8. Resuscitation Department and Domiciliary Ventilation Unit, Raymond Poincaré Hospital, Paris, France. 9. Pneumology Department, Armand-Trousseau Children's Hospital, Paris, France. 10. INTEGRARE, Genethon, Inserm, Evry University, Paris-Saclay University, Evry, France. 11. Department of Neurosciences, University of Padua, Padua, Italy. 12. Neuromuscular Morphology Unit, Nord-Est/Ile-de-France Neuromuscular Reference Center, Myology Institute, Pitié-Salpêtrière Hospital, Paris, France. 13. Nord-Est/Ile-de-France Neuromuscular Reference Center, Neurology Department, Raymond-Poincaré Hospital, Garches, France.
Abstract
BACKGROUND AND PURPOSE: To describe a large series of patients with α, β, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 β-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and β-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% β-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.
BACKGROUND AND PURPOSE: To describe a large series of patients with α, β, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 β-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and β-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% β-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.