Clinical Presentation, Genetic Etiology, and Coenzyme Q10 Levels in 55 Children with Combined Enzyme Deficiencies of the Mitochondrial Respiratory Chain

Objectives To evaluate the clinical symptoms and biochemical findings and establish the genetic etiology in a cohort of pediatric patients with combined deficiencies of the mitochondrial respiratory chain complexes. Study design Clinical and biochemical data were collected from 55 children. All patients were subjected to sequence analysis of the entire mitochondrial genome, except when the causative mutations had been identified based on the clinical picture. Whole exome sequencing/whole genome sequencing (WES/WGS) was performed in 32 patients. Results Onset of disease was generally early in life (median age, 6 weeks). The most common symptoms were muscle weakness, hypotonia, and developmental delay/intellectual disability. Nonneurologic symptoms were frequent. Disease causing mutations were found in 20 different nuclear genes, and 7 patients had mutations in mitochondrial DNA. Causative variants were found in 18 of the 32 patients subjected to WES/WGS. Interestingly, many patients had low levels of coenzyme Q10 in muscle, irrespective of genetic cause. Conclusions Children with combined enzyme defects display a diversity of clinical symptoms with varying age of presentation. We established the genetic diagnosis in 35 of the 55 patients (64%). The high diagnostic yield was achieved by the introduction of massive parallel sequencing, which also revealed novel genes and enabled elucidation of new disease mechanisms.

Automated summary

In this study, clinical and biochemical data from 55 pediatric patients with combined deficiencies of mitochondrial respiratory chain complexes were evaluated to establish genetic etiology. Disease onset was early in life, with common symptoms including muscle weakness, hypotonia, and developmental delay. Variants were found in 20 different nuclear genes and in mitochondrial DNA among the patients.