Mitochondrial disease in children : from clinical presentation to genetic background

Sammanfattning: Mitochondrial disorders are amongst the most common groups of inborn errors of metabolism. They are caused by deficiencies in the final pathway of the cellular energy production, the mitochondrial respiratory chain. The disorders are clinically and genetically heterogeneous and the aetiology can be found in the mitochondrial, or in the nuclear genome. This thesis describes children with mitochondrial disorders, with focus on clinical symptoms, disease courses, biochemical abnormalities and genetic causes of disease. The research aimed to increase the understanding of the clinical phenotypes and pathophysiological mechanisms. We also aimed to identify novel disease-causing variants in mitochondrial (mtDNA), as well as nuclear, DNA in order to generate better tools for genetic counselling. In a study of patients with deficiencies of complex I of the mitochondrial respiratory chain, we observed a variety of clinical presentations. Early-onset of disease and muscle weakness were features in common. Developmental retardation and failure to thrive were seen in a majority of the patients. Causative variants in mtDNA were identified in six of the 11 patients. Leigh syndrome (LS) is a severe, neurodegenerative disease of early childhood. The genetic aetiology is heterogeneous. In a study of 25 children with LS, we observed early onset of disease, in 80% before six months of age. A subset of patients had a rapidly progressive disease and early death, 60% survived beyond the age of five years. Eight of the patients had a disease causing variant in mtDNA. The age ofonset, clinical symptoms or prognosis did not differ significantly between patients with mitochondrial and nuclear mutations in this cohort. A defect in the POLG gene was detected in a patient with Alpers syndrome. He had a heterozygous variant on one allele, the other allele being entirely deleted. The patient had rapid disease progression and died in a valproate induced liver failure. Massively parallel sequencing of the entire human genome and its implementation in clinical use is a diagnostic leap in the field of mitochondrial disorders. In a cohort of patients with combined deficiencies of the mitochondrial respiratory chain, 31 patients were subjected to whole genome/exome sequencing. A genetic diagnosis was established in 16 of these (52%), so far. Two novel gene defects were identified; SLC25A26 and COQ7. The latter gene encodes an enzyme of the Coenzyme Q (CoQ) biosynthesis. These disorders are responsive to CoQ10 treatment. We demonstrated a new mechanism of treatment using 2,4- dihydroxybenzoic acid in order to bypass the deficient step. In conclusion, paediatric mitochondrial disorders are severe, progressive and usually multisystemic. The most common symptoms are often non-specific and the diagnostic procedure is a challenge. The genetic aetiology is heterogeneous, a substantial proportion of the causative variants are found in mtDNA. The phenotype-genotype correlation is poor, making whole genome sequencing an excellent diagnostic tool.