Mitochondrial disease

A 14-year-old girl is referred for investigation of progressive external ophthalmoplegia, bilateral ptosis, and a recent syncopal episode. Her mother has diabetes and sensorineural deafness. Fundoscopy reveals pigmentary retinopathy. An ECG shows first-degree heart block. **Discuss:** (1) the recognised clinical syndrome and its genetic basis, including the inheritance pattern and its implications for the family; (2) the dual-genome logic — why mitochondrial disease can arise from either mtDNA or nDNA and why most paediatric disease is nuclear; (3) the threshold effect and heteroplasmy, and how they explain variability within a family; (4) the specific cardiac complication that can cause sudden death and the surveillance that prevents it; (5) the pharmacological contraindications in suspected mitochondrial disease.