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.

Aix Marseille University INSERM MMG Marseille France

AP HP UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire Centre de Génétique Moléculaire et Chromosomique GH Pitié Salpêtrière Paris France

APHM Laboratoire de Génétique Moléculaire Hôpital TIMONE Enfants

APHP GH Université Paris Saclay DMU Smart Imaging Medical Imaging Department Raymond Poincaré Teaching Hospital Garches France

APHP GH Université Paris Saclay Neuromuscular Center Child Neurology and ICU Department Raymond Poincare Hospital Garches France

APHP Neuromuscular Reference Center Pitié Salpêtrière Hospital Institute of Myology Paris France

Centre de Référence de Pathologie Neuromusculaire Paris Est GHU Pitié Salpêtrière Assistance Publique Hôpitaux de Paris Paris France

Centre of Molecular Biology and Genetics University Hospital Brno Brno Czech Republic

CHU de Rouen Service de Néonatologie Réanimation pédiatrique Neuropédiatrie et Éducation Fonctionnelle de L'enfant INSERM U 1245 ED497 76000 Rouen France

Department of Neurology Faculdade de Medicina da Universidade de São Paulo São Paulo Brazil

Department of Neurology Rigshospitalet University of Copenhagen Copenhagen Denmark

Department of Paediatric Neurology Motol University Hospital Prague Czech Republic

Department of Pediatric Neurology and Reference Center for Neuromuscular Diseases AOC CHU Montpellier Montpellier France

Department of Radiology Motol University Hospital Prague Czech Republic

Diagnostic Imaging Service Clinica Las Condes Santiago de Chile Chile

Instituto Nacional de Rehabilitación Pedro Aguirre Cerda Santiago de Chile Chile

Nord Est Ile de France Neuromuscular Reference Center PHENIX FHU Hôpital Raymond Poincaré AP HP INSERM U1179 Garches France

Pediatric Neurology Department Clinica Las Condes Santiago de Chile Chile

Pediatric Neurology Vall d'Hebron Institut de Recerca Hospital Universitari Vall d'Hebron Vall d'Hebron Barcelona Hospital Campus Barcelona Spain Passeig de la Vall d'Hebron 119 129 08035

Pediatric Neuroradiology Radiology Department Hospital Universitari Vall d'Hebron Vall d'Hebron Barcelona Hospital Campus Barcelona Spain

PhyMedExp University of Montpellier INSERM CNRS Montpellier France

Radiology Department CHU Montpellier Montpellier France

Sorbonne Université Inserm UMRS974 Centre de Recherche en Myologie GH Pitié Salpêtrière Paris France

Sorbonne Université Myology Institute Neuromuscular Morphology Unit Center for Research in Myology GH Pitié Salpêtrière Paris France

Unit for Neuromuscular and Neurodegenerative Disorders Bambino Gesù Children's Hospital Rome Italy

Unità Operativa Complessa Di Neurologia Fondazione Policlinico Universitario A Gemelli IRCCS Roma Italia

Univ Grenoble Alpes Inserm U1216 CHU Grenoble Alpes GIN Grenoble France

Univ Paris Est UPE INSERM U955 IMRB APHP Centre de Référence de Pathologie Neuromusculaire Nord Est Ile de France Hôpital Henri Mondor Créteil France

Université de Versailles U1179 INSERM UVSQ Versailles France

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$a Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort / $c S. Quijano-Roy, J. Haberlova, C. Castiglioni, J. Vissing, F. Munell, F. Rivier, T. Stojkovic, E. Malfatti, M. Gómez García de la Banda, G. Tasca, L. Costa Comellas, A. Benezit, H. Amthor, I. Dabaj, C. Gontijo Camelo, P. Laforêt, J. Rendu, NB. Romero, E. Cavassa, F. Fattori, C. Beroud, J. Zídková, N. Leboucq, N. Løkken, Á. Sanchez-Montañez, X. Ortega, M. Kynčl, C. Metay, D. Gómez-Andrés, RY. Carlier

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$a 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.

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$a Haberlova, Jana $u Department of Paediatric Neurology, Motol University Hospital, Prague, Czech Republic

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$a Castiglioni, Claudia $u Pediatric Neurology Department, Clinica Las Condes, Santiago de Chile, Chile $u Instituto Nacional de Rehabilitación Pedro Aguirre Cerda, Santiago de Chile, Chile

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$a Rivier, François $u Department of Pediatric Neurology and Reference Center for Neuromuscular Diseases AOC, CHU Montpellier, Montpellier, France $u PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France

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$a Stojkovic, Tanya $u APHP, Neuromuscular Reference Center, Pitié-Salpêtrière Hospital, Institute of Myology, Paris, France

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700    1_

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$a Benezit, Audrey $u APHP, GH Université Paris-Saclay, Neuromuscular Center, Child Neurology and ICU Department, Raymond Poincare Hospital, Garches, France

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$a Amthor, Helge $u APHP, GH Université Paris-Saclay, Neuromuscular Center, Child Neurology and ICU Department, Raymond Poincare Hospital, Garches, France $u Université de Versailles, U1179 INSERM-UVSQ, Versailles, France

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$a Dabaj, Ivana $u APHP, GH Université Paris-Saclay, Neuromuscular Center, Child Neurology and ICU Department, Raymond Poincare Hospital, Garches, France $u CHU de Rouen, Service de Néonatologie, Réanimation pédiatrique, Neuropédiatrie et Éducation Fonctionnelle de L'enfant, INSERM U 1245, ED497, 76000, Rouen, France

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700    1_

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700    1_

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$a Gómez-Andrés, David $u 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 $1 https://orcid.org/0000000156547791

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