Muscle biopsy and mitochondrial disease criteria as diagnostic tools for paediatric patients presenting with neuromuscular phenotypes: highlighting the role of secondary mitochondrial dysfunction.

This study evaluated the diagnostic utility of muscle biopsy and the performance of the Nijmegen and modified Walker criteria in a real-life paediatric cohort with neuromuscular symptoms. A retrospective review at Oulu University Hospital included 220 paediatric patients with unexplained neuromuscular symptoms who underwent muscle biopsy between 1990 and 2024. Clinical data were collected, and patients were classified using both criteria. A genetic diagnosis was confirmed in 58 patients (26 %): 12 with primary mitochondrial diseases (21 %), 17 with secondary mitochondrial dysfunction (29 %), and 29 with other neuromuscular disorders (50 %). OXPHOS activities were measured in 189 patients (86 %); 49 (26 %) showed decreased activity, including 13 with genetic confirmation. Electron microscopy (n=175) showed mitochondrial abnormalities in 49 patients (28 %); 75 % of these had mitochondrial disease. The modified Walker criteria outperformed the Nijmegen (sensitivity 75 % vs 50 %; specificity 100 % vs 98 %). Mean Nijmegen scores were significantly higher in primary mitochondrial disease (p<0.05), also compared with patients with secondary dysfunction. In conclusion, muscle biopsy and mitochondrial disease criteria remain valuable tools distinguishing primary mitochondrial diseases. This study highlights the role of secondary mitochondrial dysfunction in non-mitochondrial genetic conditions and metabolic diseases with undefined genetic aetiologies waiting to be identified in the future.