Multi-centre collaboration improves understanding of mitochondrial disease

A national cohort study has provided a better understanding of mitochondrial disease caused by mutations in a mitochondrial gene.  This will lead to more rapid diagnosis, improved clinical care and a wider range of reproductive options for those who carry these mutations.

A team of clinicians from the across the UK, led by the Wellcome Centre for Mitochondrial Research at Newcastle University, were able to use the mitochondrial patient cohort to identify 125 individuals from 60 families who carried mutations in a gene called MT-ATP6.  This demonstrates the importance and value of a well‐characterised, large patient cohort, such as the one run from Newcastle University by Chief Investigator Prof Robert McFarland.

The study, published last month in Annals of Neurology, revealed a range of clinical features in patients with nine previously reported pathogenic mutations in the MT-ATP6 gene. The most common neurological findings were cerebellar ataxia, axonal neuropathy and learning disability.  Over 50% of the patients did not present with classic mitochondrial syndromes associated with mutations in this gene, such as Leigh syndrome and NARP (neuropathy, ataxia and retinitis pigmentosa). Moreover, five of the mutations accounted for >90% of MT-ATP6 related mitochondrial disease. Taken together, these findings will help clinicians recognise mitochondrial disease caused by mutations in this gene, and guide the diagnostic pathway in genetic ataxia and neuropathy.

Dr Yi Shiau Ng, Clinical Lecturer in Neurology, and Dr Grainne Gorman, Consultant Neurologist, said ”This study highlights the importance of collaboration and would not have been possible without the combined efforts of the NHS Highly Specialised Service for Rare Mitochondrial Disorders and referring clinicians in the UK. It has taken nearly 4 years to identify all the individuals included in the study but has resulted in the largest and most comprehensive evaluation of MT-ATP6 related mitochondrial disease to date. This will benefit many patients who carry these mutations, both now and in the future.”

The MT-ATP6 gene is located in the small piece of DNA within the mitochondria, known as mitochondrial DNA (mtDNA).  mtDNA is found in multiple copies within most cells of the body but mutations within the mtDNA, such as those identified in MT-ATP6, may not be present in every copy. There is often a mix of healthy and faulty mtDNA within a patient, known as heteroplasmy, and the level of faulty mtDNA must exceed a critical level before symptoms of mitochondrial disease occur.

Interestingly, the study revealed that the level of faulty mitochondrial DNA resulting in mitochondrial disease differed depending on the particular mutation that was present within the MT-ATP6 gene. These findings have important implications for those who carry these mutations but do not have any symptoms of mitochondrial disease, and will help couples make more informed reproductive choices if they wish to start a family.

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