New clinical signs and genotypes of known mitochondrial disorders

Abstract

Objective: Mitochondrial disorders present a heterogeneous group of inherited disorders with wide clinical manifestations including neurological symptoms. As age of onset and symptoms considerably vary, NGS technologies become the main diagnostic approach for searching a genetic cause of mitochondrial pathology and could be effective to expand knowledge about phenotypic spectrum in this group of diseases. Methods: We've applied a target sequencing of 62 mitochondrial nuclear genes using NGS technology on IonTorrent PGM to define a molecular defect in our patients. Main including criteria were clinical phenotype, brain MRI abnormalities, PEO signs, high FGF21 blood level. Results: We present two interesting cases. 1. Two affected sibs (13-year-old boy, 7-year-old girl) of healthy non-consagenious parents were thought to have just cerebral palsy. They were born in time, had development delay, sleep and feeding problems since birth, epileptic seizures (since 2 y.o.), dystonic movements, bulbar syndrome. Brain MRI in both cases revealed diffuse symmetric atrophy of cerebral cortex. The boy had cataract since 11.5-y.o. They had no abnormalities in blood acylcarnitines, lysosomal enzymes activities and urine organic acids level. NCL1/2 and gangliosidosis were excluded. Mitochondrial disease was suspected. Genetic testing detected two compound heterozygous substitutions in DNA2 gene c.C1078A:p.Q360K/ c.C1795T:p.R599C. Both have high predicted scores of pathogenicity and low frequency of occurrence. Parents were confirmed to be heterozygous carriers. High score of mtDNA depletion was measured. It became the first description of this disease in children. 2. A girl of consagenious parents was born with hypertrophic cardiomyopathy, high lactate level in blood (6–8 mmol/l) and urine, severe muscle hypotonia and respiratory insufficiency. Blood acylcarnitines level was normal. Mitochondrial disease was suspected. NGS analysis revealed a new homozygous mutation c.C1037T:p.S346L in COX10 gene. Conclusion: Our results show that NGS tool is essential and effective approach as routine molecular diagnostic for inherited neurologic pediatric disorders.