Phenotypic Spectrum of Myopathies with Recessive Anoctamin-5 Mutations

Article type: Research Article

Authors: Vázquez, José^{a; b; 1} | Lefeuvre, Claire^{b; 1} | Escobar, Rosa Elena^c | Luna Angulo, Alexandra Berenice^d | Miranda Duarte, Antonio^a | Delia Hernandez, Alma^e | Brisset, Marion^b | Carlier, Robert-Yves^f | Leturcq, France^g | Durand-Canard, Marie-Christine^h | Nicolas, Guillaume^b | Laforet, Pascal^b | Malfatti, Edoardo^{b; 1; *}

Affiliations: [a] Department of Medical Genetics, National Rehabilitation Institute, “Luis Guillermo Ibarra Ibarra”, México | [b] APHP, Department of Neurology, Raymond Poincaré Hospital, North-East-Ile-de-France Neuromuscular Pathology Reference Center, U 1179 INSERM, University Saint Quentin en Yvelines Versailles; Paris-Saclay, France | [c] Department of Electromyography and Muscle Dystrophies, National Rehabilitation Institute, “Luis Guillermo Ibarra Ibarra”, México | [d] Department of Neurosciences, National Rehabilitation Institute, “Luis Guillermobarra Ibarra”, México | [e] Department of Pathology, National Rehabilitation Institute, “Luis Guillermo Ibarra Ibarra”, México | [f] APHP, GH U. Paris Saclay, DMU Smart Imaging, Department of Radiology, Raymond Poincaré teaching Hospital, 104 Bld R. Poincaré, 92380 Garches, France; U 1179 INSERM, Université Paris-Saclay | [g] APHP, Department of Genetics, Cochin Hospital, Paris, France | [h] APHP, Service of Physiological Explorations Raymond Poincaré Hospital, 104 Bld Raymond Poincaré, 92380 Garches, France

Correspondence: [*] Correspondence to: Edoardo Malfatti MD, PhD, Service de Neurologie, Centre de Référence de Maladies Neuromusculaires Nord/Est/Ile-de-France, U1179 UVSQ-INSERM Handicap Neuromusculaire: Physiologie, Biothérapie et Pharmacologie appliquées, UFR Simone Veil-Santé, Université Versailles-Saint-Quentin-en-Yvelines, Pôle neuro-locomoteur, Hôpital Raymond Poincaré, 104 boulevard Raymond Poincaré, 92380 Garches, Tel.: +33 147107900; Fax: +33 171144993; E-mail: [email protected].

Note: [1] First co-authors, contributed equally to this study.

Abstract: Background:Biallelic variants in Anoctamin 5 (ANO5) gene are causative of limb-girdle muscular dystrophy (LGMD) R12 anoctamin5-related, non-dysferlin Miyoshi-like distal myopathy (MMD3), and asymptomatic hyperCKemia. Objective:To describe clinic, histologic, genetic and imaging features, of ANO5 mutated patients. Methods:Five patients, four from France (P1, P2, P3 and P4) and one from Mexico (P5), from four families were included. P1 and P2, belonging to group 1, had normal muscle strength; Group 2, P3, P4 and P5, presented with muscular weakness. Muscle strength was measured by manual muscle testing, Medical Research Council (MRC) grades 1/5 to 5/5. Laboratory exams included serum CK levels, nerve conduction studies (NCS)/needle electromyography (EMG), pulmonary function tests, EKG and cardiac ultrasound. ANO5 molecular screening was performed with different approaches. Results:Group 1 patients showed myalgias with hyperCKemia or isolated hyperCKemia. Group 2 patients presented with limb-girdle or proximo-distal muscular weakness. Serum CK levels ranged from 897 to 5000 UI/L. Muscle biopsy analysis in P4 and P5 showed subsarcolemmal mitochondrial aggregates. Electron microscopy confirmed mitochondrial proliferation and revealed discontinuity of the sarcolemmal membrane. Muscle MRI showed asymmetrical fibro-fatty substitution predominant in the lower limbs.P1 and P2 were compound heterozygous for c.191dupA (p.Asn64Lysfs*15) and c.1898 + G>A; P3 was homozygous for the c.692G>T. (p.Gly231Val); P4 harbored a novel biallelic homozygous exons 1–7 ANO5 gene deletion, and P5 was homozygous for a c.172 C > T (p.(Arg 58 Trp)) ANO5 pathogenic variant. Conclusions:Our cohort confirms the wide clinical variability and enlarge the genetic spectrum of ANO5-related myopathies.

DOI: 10.3233/JND-200515

Journal: Journal of Neuromuscular Diseases, vol. 7, no. 4, pp. 443-451, 2020