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Sommerville, E.W.* ; Ng, Y.S.* ; Alston, C.L.* ; Dallabona, C.* ; Gilberti, M.* ; He, L.* ; Knowles, C.* ; Chin, S.L.* ; Schaefer, A.M.* ; Falkous, G.* ; Murdoch, D.* ; Longman, C.* ; de Visser, M.* ; Bindoff, L.A.* ; Rawles, J.M.* ; Dean, J.C.* ; Petty, R.K.* ; Farrugia, M.E.* ; Haack, T.B. ; Prokisch, H. ; McFarland, R.* ; Turnbull, D.M.* ; Donnini, C.* ; Taylor, R.W.* ; Gorman, G.S.*

Clinical features, molecular heterogeneity, and prognostic implications in YARS2-related mitochondrial myopathy.

JAMA Neurol. 74, 686-694 (2017)

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Importance: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. Objectives: To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. Design, Setting, and Participants: An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015. Main Outcome and Measures: The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants. Results: Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes. Conclusions and Relevance: The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder.

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