Decreased Aerobic Capacity in ANO5-Muscular Dystrophy

Article type: Research Article

Authors: Ylikallio, Emil^{a; b; 1; *} | Auranen, Mari^{a; b; 1} | Mahjneh, Ibrahim^{c; d} | Lamminen, Antti^e | Kousi, Maria^f | Träskelin, Ann-Liz^f | Muurinen, Tiina^g | Löfberg, Mervi^b | Salmi, Tapani^h | Paetau, Andersⁱ | Lehesjoki, Anna-Elina^{a; f; j} | Piirilä, Päivi^g | Kiuru-Enari, Sari^b

Affiliations: [a] Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland | [b] Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Finland | [c] Division of Neurology, Pietarsaari District Hospital, Pietarsaari, Finland | [d] Department of Neurology, MRC Oulu, Oulu University Hospital and University of Oulu, Finland | [e] Department of Radiology, HUS Medical Imaging Center, Helsinki, Finland | [f] Folkhälsan Institute of Genetics, Helsinki, Finland | [g] Unit of Clinical Physiology, HUS Medical Imaging Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland | [h] Department of Clinical Neurophysiology, Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland | [i] Department of Pathology, HUSLAB and University of Helsinki, Helsinki, Finland | [j] Neuroscience Center, University of Helsinki, Finland

Correspondence: [*] Correspondence to: Emil Ylikallio, Biomedicum r.C526b, Haartmaninkatu 8, 00290 Helsinki, Finland. Tel.: +358 50 448 6380; Fax: +358 91 912 5610; E-mail: [email protected].

Note: [1] Equal contribution.

Abstract: Background: Anoctaminopathies are muscle diseases caused by recessive mutations in the ANO5 gene. The effects of anoctaminopathy on oxidative capacity have not previously been studied in a controlled setting. Objective: To characterize oxidative capacity in a clinically and genetically well-defined series of patients with anoctaminopathy. Methods: We sequenced the ANO5 gene in 111 Finnish patients with suspected LGMD2. Patients with positive findings underwent close clinical examination, including electromyography, muscle MRI, and, in selected cases, muscle biopsy. Oxidative capacity was analyzed using spiroergometry and compared to age-matched healthy controls. Results: We characterized 12 newly identified and 2 previously identified patients with ANO5 mutations from 11 families. Our material was genetically homogeneous with most patients homozygous for the Finnish founder variant c.2272C>T (p.Arg758Cys). In one family, we found a novel p.Met470Arg variant compound heterozygous with p.Arg758Cys. Lower limb muscle MRI revealed progressive fatty degeneration of specific posterior compartment muscles. Patients’ spiroergometric profiles showed that anoctaminopathy significantly impaired oxidative capacity with increasing ventilation. Conclusions: Our findings support earlier reports that anoctaminopathy progresses slowly and demonstrate that the disease impairs the capacity for aerobic exercise.

Keywords: Muscular dystrophies, limb-girdle, muscular diseases, inborn genetic diseases, aerobic exercise

DOI: 10.3233/JND-160186

Journal: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 475-485, 2016