Childhood-onset mitochondrial diseases: A 30-year population-based study highlighting the role of secondary mitochondrial dysfunction

This doctoral thesis shows that in children with neuromuscular symptoms secondary mitochondrial dysfunction is a common finding. The study highlights the central role of genetic testing in diagnostics while showing that muscle biopsy remains an important tool in selected patients, especially when genetic findings are inconclusive.

Childhood-onset mitochondrial diseases are rare genetic disorders that usually affect multiple organ systems. Diagnosis is challenging because of the highly variable clinical presentation, and not all patients receive a genetic diagnosis despite advances in diagnostic methods in recent years. This 30-year population-based study investigated paediatric patients with suspected mitochondrial disease. The study focused on the molecular genetic background of the symptoms, the occurrence of mitochondrial DNA (mtDNA) depletion and deletions, and the diagnostic value of muscle biopsy, respiratory chain enzyme analyses and established mitochondrial disease criteria.

In a cohort of 220 children who underwent muscle biopsy, a genetic diagnosis was established in 58 (26%): 12 with primary mitochondrial diseases, 17 with secondary mitochondrial dysfunction and 29 with other neuromuscular disorders. Decreased respiratory chain enzyme activity was found in 26% and ultrastructural mitochondrial abnormalities in 28%. The study also showed that diagnostic criteria are still useful in suspected mitochondrial disease.

In addition, muscle biopsy samples from 104 paediatric patients were analysed for mtDNA content and deletions. MtDNA depletion was identified in three patients and mtDNA deletions in two patients. In one patient, mtDNA depletion was shown to be secondary to muscular dystrophy. The study also identified a novel DHX16 gene variant in a patient with severe neurological and ophthalmological symptoms. Functional studies confirmed the pathogenicity of the variant and demonstrated that mitochondrial dysfunction was also secondary in this case.
Overall, the thesis highlights the difficulty of distinguishing primary mitochondrial disease from secondary mitochondrial dysfunction. The findings support the importance of genetic testing together with muscle biopsy and other functional studies in selected cases. These results improve understanding of mitochondrial dysfunction in childhood and may help develop more accurate diagnostic approaches in the future.