Balkan Journal of Medical Genetics

CLINICAL EXPERIENCE OF NEUROLOGICAL MITOCHONDRIAL DISEASES IN CHILDREN AND ADULTS: A SINGLE-CENTER STUDY
Rogac M, Neubauer D, Leonardis L, Pecaric N, Meznaric M, Maver A, Sperl W, Garavaglia BM, Lamantea E, Peterlin B
*Corresponding Author: Mihael Rogac, M.D., Ph.D., Clinical Institute of Genomic Medicine, University Medical Center Ljubljana, Slajmerjeva 4, 1000 Ljubljana, Slovenia. Tel: +386-1-522-6078. Fax: +386-1-540-1137. E-mail: mihael.rogac@kclj.si
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INTRODUCTION

It is still a challange to diagnose a primary mitochondrial disease (MD) in a clinical setting. In general, MDs are characterized as a dysfunction of oxidative phosphorylation (OXPHOS) and/or enzymes involved in the mitochondrial role in the oxidation of sugars, amino acids and fats to water and carbon dioxide. Primary MD is a genetic and/or a biochemical defect of OXPHOS. Mitochondrial diseases are the most commonly inherited metabolic diseases in neurology, both in children and in adults. The minimum prevalence rate for mitochondrial DNA (mtDNA), mutations was one in 5000 (20 per 100,000) and for nuclear mutations was 2.9 per 100,000 adults in Northeast England [1]. Childhood MD prevalence has been estimated at 3.0-6.2 per 100,000 with a point prevalence in Sweden of mitochondrial encephalomyopathies in children of 4.8 per 100,000 [2]. The clinical, biochemical and genetic heterogeneity is shaping the right diagnostic approach, one which is changing rapidly with next-generation sequencing (NGS) methods [3]. Mitochondria is now recognized as able to perform multiple essential functions involved in cellular homeostasis and cellular energetics [4]. Oxidative phosphorylation is a very sophisticated mitochondrial mechanism being able to produce chemical energy in a form of adenosine triphosphate (ATP). Glucose, glutamin and branched chain amino acids are the main micronutrients that are the substrates of the chain of reactions, where a pool of acetyl coenzyme A (acetyl-CoA) and Krebs cycle intermediates in a mitochondrial matrix is filled by three key-enzymes: pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex and branched chain alpha-keto acid dehydrogenase complex with a thiamine, flavin adenine dinucleotide (FAD) and Mg2+ as essential cofactors in all three enzymatic complexes. The Krebs cycle produces reduced equivalents in a form of NADH2 and FADH2, which push the respiratory chain enzymes to create a proton gradient that promotes ATP synthesis. Mitopathogenic mechanisms are recognized in a number of medical disciplines [5]. A muscle biopsy has been the gold standard used to set a diagnosis of primary MD in the pre genomic era. Nevertheless, the procedure has been invasive, costly, and usually requires general anesthesia in children. In order to evaluate the probability of underlying MD according to scoring of the clinical picture, Nijmegen MD Criteria (MDC) was developed [6,7]. Recent reanalysis of the MDC revealed that they are still useful in the clinical diagnosis of MD, both in children and adults, interpreting whole-exome results, as well as in deciding whether muscle biopsy needs to be performed [8]. In the last few years, NGS methods of leucocyte-derived DNA with yield of 40.0% have reversed the diagnostic approach from a “function to gene” to a “gene to function” approach and decreased the need for muscle biopsy [9]. Nevertheless, a muscle biopsy remains the method of choice for enabling diagnosis in selected clinical cases, where a confirmatory diagnostics is required. In this paper, we describe the clinical characteristics and the results of imaging and laboratory investigations [muscle histology, histochemistry, electron microscopy (EM), respiratory chain enzymes (RCEs), pyruvate dehydrogenase complex (PDHc) activities, and/or molecular genetics] in a cohort of Slovenian neurological mitochondrial patients, of whom 26 are children and 36 are adults. Use of MDC, new NGS methods and repositioning of a muscle biopsy in the genomic era is emphasized. The study outlines the clinical experience of neurological mitochondrial diseases in Slovenia, a European country of 2 million people. It is important to improve early recognition and noninvasive diagnostics of MDs due to its devastating character and current unsatisfactory treatment options.

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