| Summary: | Mitochondrial disease is the most commonly inherited neurometabolic disease in childhood with an estimated birth prevalence of 1 in 7634. This heterogeneous disease group can be caused by primary mitochondrial DNA mutations or secondary to nuclear gene mutations and have a variable disease onset and progression. My studies aimed to detail the multi-system phenotypic spectrum of children with mitochondrial disease and correlate their disease burden with the underlying causative mutation to assist the diagnostic process for clinicians and develop clinical guidelines. The Medical Research Council Centre for Translational Research in Neuromuscular Disorders Mitochondrial Disease Patient Cohort Study UK formed the core component of my methodology. This national project, based at Newcastle University, is the largest database of confirmed mitochondrial patients globally offering a unique resource. My primary study was in children with mtDNA disease. There is a significant delay between onset of symptoms and time to diagnosis. Hearing impairment is an early feature, although may not be recognized as part of an underlying genetic condition. Developmental delay and/or regression, short stature and constipation are very common in children with mtDNA mutations. Cardiac disease, as recognised in other studies, increases the associated mortality of mtDNA disease, particularly with the m.3243A>G mutation. Mitochondrial disease is a major cause of cardiac failure. An audit of children presenting to a tertiary cardiothoracic centre with cardiomyopathy identified that mitochondrial disease was responsible for at least 8% of cases. Mitochondrial disease can also cause sudden death in infancy and childhood. A one year prospective study analyzing cardiac tissue samples from children requiring surgical intervention for end-stage cardiac failure demonstrated 21% were due to mitochondrial disease, of which 80% had not previously been known. Children with mitochondrial disease who have had cardiac transplantation have good cardiac outcomes with subjective reports of improved quality of life. Children affected by mitochondrial disease are more likely to be born smaller, have slower linear growth, end up shorter and have a lower body mass index than their unaffected peers.
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