Susana Quijano-Roy1,2, Jana Haberlova3, Claudia Castiglioni4,5, John Vissing6, Francina Munell7, François Rivier8,9, Tanya Stojkovic10, Edoardo Malfatti11, Marta Gómez García de la Banda1, Giorgio Tasca12, Laura Costa Comellas7, Audrey Benezit1, Helge Amthor1,2, Ivana Dabaj1,13, Clara Gontijo Camelo14, Pascal Laforêt15, John Rendu16, Norma B Romero17,18, Eliana Cavassa1, Fabiana Fattori19, Christophe Beroud20, Jana Zídková21, Nicolas Leboucq22, Nicoline Løkken6, Ángel Sanchez-Montañez23, Ximena Ortega24, Martin Kynčl25, Corinne Metay26,27, David Gómez-Andrés28, Robert Y Carlier29. 1. APHP, GH Université Paris-Saclay, Neuromuscular Center, Child Neurology and ICU Department, Raymond Poincare Hospital, Garches, France. 2. Université de Versailles, U1179 INSERM-UVSQ, Versailles, France. 3. Department of Paediatric Neurology, Motol University Hospital, Prague, Czech Republic. 4. Pediatric Neurology Department, Clinica Las Condes, Santiago de Chile, Chile. 5. Instituto Nacional de Rehabilitación Pedro Aguirre Cerda, Santiago de Chile, Chile. 6. Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 7. Pediatric Neurology, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain, Passeig de la Vall d'Hebron 119-129, 08035. 8. Department of Pediatric Neurology and Reference Center for Neuromuscular Diseases AOC, CHU Montpellier, Montpellier, France. 9. PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France. 10. APHP, Neuromuscular Reference Center, Pitié-Salpêtrière Hospital, Institute of Myology, Paris, France. 11. Univ Paris Est UPE, INSERM, U955 IMRB, APHP, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Hôpital Henri Mondor, Créteil, France. 12. Unità Operativa Complessa Di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia. 13. CHU de Rouen, Service de Néonatologie, Réanimation pédiatrique, Neuropédiatrie et Éducation Fonctionnelle de L'enfant, INSERM U 1245, ED497, 76000, Rouen, France. 14. Department of Neurology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil. 15. Nord/Est/Ile de France Neuromuscular Reference Center, PHENIX FHU, Hôpital Raymond-Poincaré, AP-HP. INSERM U1179, Garches, France. 16. Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, GIN, Grenoble, France. 17. Sorbonne Université, Myology Institute, Neuromuscular Morphology Unit, Center for Research in Myology, GH Pitié-Salpêtrière, Paris, France. 18. Centre de Référence de Pathologie Neuromusculaire Paris-Est, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 19. Unit for Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, Rome, Italy. 20. APHM, Laboratoire de Génétique Moléculaire, Hôpital TIMONE Enfants; Aix Marseille University, INSERM, MMG, Marseille, France. 21. Centre of Molecular Biology and Genetics, University Hospital Brno, Brno, Czech Republic. 22. Radiology Department, CHU Montpellier, Montpellier, France. 23. Pediatric Neuroradiology, Radiology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. 24. Diagnostic Imaging Service, Clinica Las Condes, Santiago de Chile, Chile. 25. Department of Radiology, Motol University Hospital, Prague, Czech Republic. 26. AP-HP, UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Centre de Génétique Moléculaire et Chromosomique, GH Pitié Salpêtrière, Paris, France. 27. Sorbonne Université - Inserm UMRS974, Centre de Recherche en Myologie, GH Pitié-Salpêtrière, Paris, France. 28. Pediatric Neurology, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain, Passeig de la Vall d'Hebron 119-129, 08035. david_gomez@vhebron.net. 29. APHP, GH Université Paris-Saclay, DMU Smart Imaging, Medical Imaging Department, Raymond Poincaré Teaching Hospital, Garches, France.
Abstract
BACKGROUND: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. OBJECTIVE: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). RESULTS: 27 patients (2-62 years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. CONCLUSION: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.
BACKGROUND: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. OBJECTIVE: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). RESULTS: 27 patients (2-62 years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. CONCLUSION: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.