Standards of diagnosis and care for the Sarcoglycanopathies

Organisers: Jordi Diaz-Manera, Tanya Stojkovic, Linda Lowes, Elena Pegoraro

Location: Hoofddorp

Date: 8-10 November 2024

Online Preparatory Meetings: 25^th July 2024, 4^th September 2024, 16^th September 2024

Participants: Claudio Bruno (Italy), Laura Cárdenas (Spain), Kristl Claeys (Belgium), Marta de Antonio Ferrer (Spain), Filipe Di Pace (Brazil), Meredith James (UK), Nicholas Johnson (USA), Lea Leonardis (Slovenia), Leonela Luce (UK), Najoua Miladi (Tunisia), Andre Muller-York (Germany), Isabelle Richard (France), Carles Sánchez (Italy), Dorianna Sandona (Italy), Beril Talim (Turkey), Giorgio Tasca (UK), Suji Vasu (USA), Conrad Weihl (USA), Stephan Wenninger (Germany)

In the Early-Career Programme: Megan Iammarino (USA), Jorge Alonso-Perez (Spain)
Patient Representatives: Carles Sánchez, Laura Cárdenas, Jessica Martin
Patient Advocacy: Suji Vasu, Aleksandra Leijenhorst Le Belle
Organisation and Support: Holly Borland

Translations:
Dutch by Aleksandra Leijenhorst- le Belle
French by Isabelle Richard
German by Stephan Wenninger
Italian by Claudio Bruno
Slovenian by Lea Leonardis
Spanish by Carles Sanchez
Tunesian by Najoua Miladi
Turkish by Beril Talim

Workshop Aims and Objectives

Limb Girdle Muscular Dystrophy (LGMD) R3-6 (sarcoglycanopathies) are a group of 4 slowly progressive muscular dystrophies. They are caused by a mistake (variant) in a gene that usually helps the muscles grow and work. These diseases cause weakness of the muscles around the pelvis and shoulders. They usually start during childhood and worsen over time. A large number of patients lose the ability to walk before the age of twenty. However, some patients have a milder disease which starts later and progresses more slowly. Some patients can develop problems with their heart and/or breathing. There are similarities and differences between patients depending on which gene is affected or the way their gene is different. Even though the genes involved in these diseases were described thirty years ago, a lot is still unknown about how the disease progresses over time. There are currently no standardised guidelines on how to diagnose and follow up patients in clinic over time. There are also no guidelines about how to care for these patients.

The main aim of this workshop was to develop diagnostic and care guidelines tailored to the needs of patients with sarcoglycanopathies. Participants in this meeting reviewed the existing literature available on the progression, diagnosis, and management of the disease. They then presented the main findings on virtual meetings that took place before the face-to-face workshop, to prepare the discussions.

Objectives of the workshop:

• Develop an algorithm for the diagnosis of sarcoglycanopathies for clinicians, experts, and non-experts in neuromuscular diseases.
• Agree on recommendations for the follow-up, care, and management of the disease based on published literature and expert opinions.

Activities and Workshop

There were 30 participants from 12 different countries, including 3 patient representatives and 2 patient advocates. The countries represented were France, Germany, Spain, Italy, UK, USA, Brazil, Belgium, Netherlands, Slovenia, Turkey, and Tunisia (representing North Africa). The workshop included experts in the fields of neuromuscular disease, cardiology, respiratory management, physiotherapy, and genetics.

Three virtual meetings were held prior to the face-to-face workshop. During these meetings, the participants reviewed the current literature and created a list of considerations to address at the workshop. They also developed a draft of the algorithm for the diagnosis of sarcoglycanopathies to be reviewed and discussed at the workshop. The topics of conversation focused on:

• Diagnostics and genetics
• Common clinical features of sarcoglycanopathies
• Motor function and exercise
• Cardiac, respiratory, and bone health
• State of the art therapeutic strategies for sarcoglycanopathies

The workshop was held on 8-10^h November 2024. Each participant shared their experience of the disease, whether it be through personal, clinical, or research experience.

Patient representatives and advocates shared their personal difficulties of having and/or supporting people with sarcoglycanopathies. Patients reported experiencing long delays before receiving their diagnosis and challenges with receiving clear expectations about the future and tailored care. They expressed that these can have a significant mental health impact on patients and their families. The patient representatives reported a lack of psychological support for families. All patients agreed that because there is no curative treatment for the disease currently, involvement of a multidisciplinary team of specialists, including a neuromuscular clinician, is key for successful management. They also highlighted the need of having international agreed standards on the diagnosis and care of patients with sarcoglycanopathies.

Clinicians and researchers discussed the signs and symptoms experienced by patients that help in the diagnosis. Sarcoglycanopathies are generally severe muscle diseases that start early in life, during childhood, and progress over time, meaning that muscle weakness worsens over time. This ultimately results in needing walking aids or a wheelchair by the second or third decade of life. Patients with the disease may also develop tight or stiff tendons (contractures), curving of the spine (scoliosis), and problems with the shoulder blades. Heart and breathing problems are common, especially once patients can no longer walk by themselves. The group reviewed the existing differences based on the country of origin in terms of symptoms experienced by patients and on the diagnosis protocol.

Once the clinicians had discussed the typical presentation of the disease, the group agreed on the best way to diagnose and care for patients with sarcoglycanopathies. Various methods help doctors diagnose a patient with sarcoglycanopathy. These include the typical clinical presentation, genetic testing, muscle biopsy analysis using antibody testing (e.g., immunohistochemistry), and muscle imaging scans (MRI). The group agreed that a confirmed diagnosis can only be established using genetic testing showing two pathogenic variants found in the gene affected. Management of the disease includes review by a specialist multidisciplinary team of healthcare professionals, including physicians, physiotherapists, occupational therapists, and nutritionists with experience in neuromuscular diseases. Due to the relatively high number of patients who develop heart and breathing complications, specialised doctors in heart and breathing functions should be included in the care of patients as soon as possible. There are no drugs that can slow down the disease currently. Therefore, the experts recommended physiotherapy, occupational therapy, exercise guidance, nutrition advice, and cardiac and respiratory care as key for the management of patients. The experts also discussed recommendations about use of anaesthesia, emergency care, and the transition from paediatric to adult care. Attention was also paid to the therapeutic interventions for sarcoglycanopathies. The discussion focused on the gene therapy studies currently in clinical trials or about to enter clinical trials, as well as on the pharmacological strategy based on the repurposing of the correctors of the cystic fibrosis transmembrane conductance regulator (CFTR). Intermittent steroid treatment at a low dosage requires further research to understand its effectiveness.

A full report will be published in Neuromuscular Disorders (PDF).