The Genetic Landscape of Mitochondrial Diseases in Spain: A Nationwide Call.

Marcello Bellusci,Eduardo Ruiz-Pesini,Rafael Artuch,Julio Montoya,Abraham J Paredes-Fuentes,Beatriz Gómez,Miguel A Martín

doi:10.3390/genes12101590

Abstract

The frequency of mitochondrial diseases (MD) has been scarcely documented, and only a few studies have reported data in certain specific geographical areas. In this study, we arranged a nationwide call in Spain to obtain a global estimate of the number of cases. A total of 3274 cases from 49 Spanish provinces were reported by 39 centres. Excluding duplicated and unsolved cases, 2761 patients harbouring pathogenic mutations in 140 genes were recruited between 1990 and 2020. A total of 508 patients exhibited mutations in nuclear DNA genes (75% paediatric patients) and 1105 in mitochondrial DNA genes (33% paediatric patients). A further 1148 cases harboured mutations in the MT-RNR1 gene (56% paediatric patients). The number of reported cases secondary to nuclear DNA mutations increased in 2014, owing to the implementation of next-generation sequencing technologies. Between 2014 and 2020, excepting MT-RNR1 cases, the incidence was 6.34 (95% CI: 5.71–6.97) cases per million inhabitants at the paediatric age and 1.36 (95% CI: 1.22–1.50) for adults. In conclusion, this is the first study to report nationwide epidemiological data for MD in Spain. The lack of identification of a remarkable number of mitochondrial genes necessitates the systematic application of high-throughput technologies in the routine diagnosis of MD.

Highlights

Mitochondrial diseases (MD) are caused by mutations in nuclear DNA or mitochondrial DNA genes
The general consensus is that MD frequency is greater than that previously expected, and the application of next-generation sequencing (NGS) techniques for diagnostic purposes has substantially increased the diagnostic yield, especially for MD caused by nDNA mutations
With the aim of describing the genetic landscape of MD in Spain, we called upon all the Spanish clinical units and diagnostic laboratories working in MD diagnosis to report for each case the following variables: affected gene, mode of inheritance, pathological variants reported as HGVS format, year and age of diagnosis, name of the clinician that requested the analysis, and genetic laboratory where diagnostic tests were performed

Summary

Introduction

Mitochondrial diseases (MD) are caused by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes. A prevalence of 1 in 4300 for nDNA and mtDNA mutations has been reported for adult populations in the north east of England [6]. In Spain, the incidence and prevalence of MD have been reported in paediatric and adult populations in certain geographical areas, but the number of cases were limited. The prevalence reported was 8 in 100,000 in the paediatric population and 5.7 in 100,000 in the general adult population in north-west Spain [9]. Other studies have reported the prevalence of some specific MD, such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS): 0.18 per 100,000 in the general population in Japan [12], or 18.4 in 100,000 in the paediatric population in a region of Finland [11]

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