Dr Charlotte Alston
Associate Clinical Lecturer
Mitochondrial diseases are common genetic disorders caused by defective energy production. They affect numerous organs and due to the clinical and genetic heterogeneity, obtaining a genetic diagnosis is often difficult yet crucial for the counselling of patients and their families. There are no cures but establishing a genetic diagnosis enables patients and their families’ access to genetic and reproductive counselling.
After undertaking my Undergraduate studies – BSc (Hons) Genetics (Immunology) – at the University of Aberdeen, I completed my Clinical Scientist training in Medical Genetics at the North of Scotland Regional Genetics Laboratory. I moved to Newcastle to join the Highly Specialised Service for Rare Mitochondrial Disorders in 2007.
I was awarded a personal Fellowship from NIHR in 2013 to undertake my PhD studies (NIHR-HCS-D12-03-04) which I completed in 2017. My research focused upon improving the diagnostic pathway for paediatric patients with a biochemical diagnosis of isolated complex I deficiency using next-generation sequencing in the form of our recently acquired Ion Torrent PGM.
With the genomics reconfiguration within the NHS, the Highly Specialised Service for Rare Mitochondrial Disorders is now part of the North East and Yorkshire Genomics Laboratory Hub (GLH), of which I am the Genomics Service Lead for Mitochondrial Diseases. Our laboratory now provides Specialist mitochondrial genetic testing for the ‘North’ geographic region, which in fact reaches as far as Cambridge to the South, Manchester in the West and Newcastle in the North.
I remain passionate about uncovering the genetic variants that cause paediatric mitochondrial disease. Establishing a genetic diagnosis means that we can tell families what is wrong with their poorly son or daughter, and offer reproductive options such as prenatal testing or preimplantation genetic testing to help them minimise the risk of having poorly children in future.
Is muscle biopsy necessary for the diagnosis of paediatric mitochondrial disease?
I am currently a NIHR Post-Doctoral Research Fellow and Chief Investigator of the research study “Diagnosis of Mitochondrial Disease without Muscle” (IRAS 655610; REC: 20/NE/0272) which is a multi-site study that uses trio whole exome sequencing and RNA analysis from blood to obtain a genetic diagnosis.
Although muscle biopsy was always very important to help us choose the most appropriate genes to analyse, whole exome sequencing lets us look at all the genes so we don’t have to choose anymore. This means we don’t need muscle biopsy from about half our patients to make a genetic diagnosis. There are some cases where muscle or skin biopsy is really helpful – for example where we aren’t sure what the gene does, or where we need to know what the variant does to the protein. These are what we call ‘variants of uncertain pathological significance’ (VUS). These are often identified in patients with no clear genetic diagnosis and evolving molecular biology tools, such as CRISPR /Cas9 gene editing, and functional studies such as western blotting, could be used to prove pathogenicity (the cause of the symptoms) or confirm they are not causative. This type of analysis is often beyond the NHS scope but my group aims to develop a pipeline to bring these cutting edge technologies into diagnostics. The implications of this will be crucial as the NHS adopts whole genome sequencing in first line diagnostic testing, and the availability of these techniques will be vital for establishing the genetic diagnosis for patients with many types of rare disease, both within the NHS and further afield.
Sponsor/funder: National Institute for Health Research (NIHR)