Clinical and genetic spectrum of a large cohort of patients with δ-sarcoglycan muscular dystrophy

Author:

Alonso-Pérez Jorge1,González-Quereda Lidia23,Bruno Claudio4,Panicucci Chiara4,Alavi Afagh5,Nafissi Shahriar6,Nilipour Yalda7,Zanoteli Edmar8,de Augusto Isihi Lucas Michielon8,Melegh Béla9,Hadzsiev Kinga9,Muelas Nuria31011,Vílchez Juan J211,Dourado Mario Emilio12,Kadem Naz13,Kutluk Gultekin13,Umair Muhammad1415,Younus Muhammad16,Pegorano Elena17,Bello Luca17,Crawford Thomas O18,Suárez-Calvet Xavier1,Töpf Ana19,Guglieri Michela19,Marini-Bettolo Chiara19,Gallano Pia23,Straub Volker19,Díaz-Manera Jordi1319

Affiliation:

1. Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Departament of Medicine, Barcelona, 08041, Spain

2. Genetics Department, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, 08041, Spain

3. Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Spain

4. Center of Translational and Experimental Myology, IRCSS Istituto Giannina Gaslini, Genova, 16147, Italy

5. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, 13871, Iran

6. Department of Neurology, Neuromuscular research center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, 14117, Iran

7. Pediatric Pathology Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, 14117, Iran

8. Department of Neurology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo, 05403, Brazil

9. Department of Medical Genetics, and Szentagothai Research Center, University of Pecs, School of Medicine, Pecs, 07522, Hungary

10. Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari I Politècnic La Fe, Neuromuscular Reference Centre, ERN-EURO-NMD, Valencia, 46026, Spain

11. Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, 46026, Spain

12. Department of Integrative Medicine, Federal University of Rio Grande do Norte, Campus Universitário Lagoa Nova, 59012-300 Natal, RN, Brazil

13. University of Health Sciences, Antalya Research and Training Hospital, Department of Paediatric Neurology, Antalya, 07100, Turkey

14. Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, 14611, Saudi Arabia

15. Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, 54770, Pakistan

16. State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing 100871, China

17. Department of Neuroscience, University of Padova, Padova, 35112, Italy

18. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

19. The John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 3BZ, UK

Abstract

Abstract Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict diseasés severity. This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies. We contacted 128 pediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty seven percent of the patients had consanguineous parents. Ninety one percent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in 5 patients (21.7%) and 4 patients (17.4%) required non-invasive ventilation. Sixty percent of patients were wheelchair-bound since early teens (median age of 12.0 years old). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression. This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy.

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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