Genetic causes of rare diseases with emphasis on metabolic disordersassociated with primary mitochondiopathies

Authors: Vibhuti Rambani 1    Miriam Kolnikova 2    Vladimir Bzduch 3    Martina Skopkova 1    Daniela Gasperikova 1   
1 Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia    2 Department of Neurology, Medical Faculty of Comenius University and National Institute of Children's Diseases, Bratislava, Slovakia    3 Department of Paediatrics, Medical Faculty of Comenius University and National Institute of Children's Diseases, Bratislava, Slovakia   
Year: 2020
Section: Cellular metabolism, physiology, molecular biology and genetics
Abstract No.: 2041
ISBN: 978-80-972360-6-9

Primary mitochondrial diseases (MTDs) form a clinically and genetically heterogeneous group of inherited disorders that arise as a result of a defect in mitochondrial energetic metabolism. The incidence of MTDs is estimated to 1:5000, which makes them one of the most recurrent groups of inherited disorders with an important burden for the society. MTDs are progressive with variable severity of a wide range of symptoms and can emerge congenitally or anytime in life. An MTD can be caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA genes. Mutations in the nuclear DNA resulting in MTDs were found in more than 210 genes and can be inherited in autosomal recessive, dominant, and X-linked pattern. The aim of this project is to identify the genetic cause of a disease in two patients with clinical suspicion on the mitochondrial disorder.

Methods: Whole-exome sequencing (WES) was performed on the DNA of both patients extracted from peripheral blood. Suspected variants were confirmed in patients and their parents by Sanger sequencing.

Results: Case 1 is a 20-year-old male. He is affected with early infantile-onset encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. WES revealed compound heterozygous known pathogenic variants (p.Arg482Trp and p.Arg206Ter) in the FBXL4 gene, which plays significant roles in mitochondrial bioenergetics, mitochondrial DNA maintenance, and mitochondrial dynamics.

Case 2 is a 9-year-old boy affected by delayed psychomotor development, increasing spasticity, cortical atrophy, and increased lactate. Brain MRI showed cerebellar atrophy, leukoencephalopathy, and reduced volume of basal ganglia. Using WES we have identified compound heterozygous likely pathogenic variants (p.Tyr241Ser and p.Met251Val) in the PMPCA gene that encodes α-mitochondrial processing peptidase (α-MPP), which helps in the processing of mitochondrial proteins.

Conclusion: Whole exome sequencing is a powerful tool for the identification of genetic causes in patients with clinical suspicion on primary mitochondriopathies. Most importantly, the knowledge of genetic reasons is crucial for the development of effective treatments for patients with mitochondrial diseases.

Supported by: APVV-17-0296, VEGA2-083/17.