Speakers
Rachel Carling
William J Griffiths
Stuart Moat
Parallel session
Chair: Rachel Carling
10.15 - 10.45 - Biochemistry of sterols, bile acids & oxysterols - William J Griffiths
Cholesterol is a key molecule in all human cells where it can make up 40 - 50 mole % of plasma membrane lipids. Disorders of cholesterol biosynthesis and metabolism lead to disease. These may present in infancy, but often in midlife. Many of the disorders of cholesterol biosynthesis/metabolism fall into the category of rare diseases which may be difficult to diagnose, with patients suffering the diagnostic odyssey. Here we present an LC-MS method incorporating simple derivatisation chemistry to assist in the diagnosis of multiple disorders related to cholesterol biosynthesis and metabolism. The method is applicable to measuring almost all cholesterol precursors from zymostenol and zymosterol, cholesterol itself, and its metabolites through the oxysterols to bile acids and their multiple conjugates. We will illustrate the method by looking at cases of patients where conventional methods have failed to uncover a definitive diagnosis.
10.45 - 11.15 - The Role of the Clinical Biochemist in the Syndrome Without a Name (SWAN) Clinic - Stuart Moat
One of the top priorities set out by the UK Rare Diseases Framework is to help patients get a diagnosis faster. There are approximately 3.5 million individuals in the UK with a rare disease and it is estimated that there are 7,000 rare diseases. Many of these patients experience the diagnostic odyssey, misdiagnosis or no diagnosis. Those patients in which there has been no diagnosis made are referred to as having a “Syndrome Without a Name” or SWAN. In Wales, a SWAN clinic was established in 2021. The use of whole genome sequencing (WGS) and expanded gene panels have significantly increased the identification of rare disorders. However, 70–75% of these patients are still left without a molecular diagnosis. The use of genomics has shown that a number of novel variants, variants of unknown significance (VUS) are detected along with known disease-causing variants. VUS are genetic changes without enough evidence to be definitively determined as either benign or pathogenic. With appropriate supporting biochemical evidence, a VUS can be reclassified as either pathogenic or benign. Metabolomics has consequently been used to complement WGS and gene panel testing to increase the diagnostic yield. The clinical biochemist is pivotal in gathering information from various investigations, literature and case reports to guide the clinical team on which metabolomic or functional assays are required to confirm / refute a disorder. Many of these metabolomic assays are not available in NHS laboratories and collaboration with experts in the UK academic metabolomic community is required to assist clinical biochemists translate knowledge and methods from academia to the clinical laboratory.
11.15 - 11.45 - Metabolomics and GCMS - Simon Eaton
Although most people familiar with metabolomics will be aware of metabolomics performed using either LCMS or NMR, the “old” technology of GCMS does have some advantages for metabolomics. The availability of libraries obtained using standardized derivatization, chromatography and ionization gives reassurance of compound identification, even on unit mass resolution mass spectrometers, for metabolites of central metabolic pathways. The analysis can be relatively rapidly developed from untargeted metabolomics analyses to targeted methods for identified compounds of interest. Unlike some other -omics analyses (genomics, transcriptomics), universal coverage of all metabolites is unlikely to be achieved using any platform, so to a certain extent choice of which area(s) of metabolism to obtain coverage over is implicit in deciding which metabolomics platform to choose. For example, lipidomics including complex lipids is much better served by techniques other than GCMS, but as most low-molecular weight metabolites are amenable to GCMS so there may yet be life in a very mature technology.
Rachel Carling graduated with a first class honours degree in Chemistry from Manchester University in 1996. She then gained a PhD in Analytical Chemistry before moving to Leeds and training as a Clinical Biochemist. She chose to specialise in metabolic biochemistry because of her interest in analytical techniques and became one of eight Higher Specialist Trainees in Metabolic Biochemistry, obtaining FRCPath in 2007. Rachel is now a Consultant Clinical Scientist at Guy’s & St Thomas’ Hospital where she is Director of South East Thames Regional Newborn Screening Laboratory, Scientific Head of Service and Clinical Lead for Biochemical Sciences. She is also Scientific Director for Viapath, GSTT site and Chair of the UK Metabolic Biochemistry Network.
Her main area of interest is inherited metabolic disease with a particular focus on the application of tandem mass spectrometry to the measurement of small molecules. She is passionate about science, an advocate of A3 thinking and committed to service improvement.
Bill received his BSc and PhD in Chemistry from University College, Cardiff. He was trained in biomedical mass spectrometry working with Professor Jan Sjövall at Karolinska Institutet in Stockholm. Bill has held academic positions in Kingston Jamaica, Stockholm Sweden and London. In 2007 Bill moved to Swansea University to take the Chair of Mass Spectrometry.
Bill’s research interests are in cholesterol biosynthesis and metabolism, particularly pathways of bile acid biosynthesis. Bill works closely with long term collaborator Professor Yuqin Wang, and the focus of their group’s work is on the involvement of oxysterols in biology, particularly inborn errors of metabolism, neurodegenerative disease and the immune system.
When living in the Caribbean, Bill played international rugby for Jamaica.
Simon Eaton received his PhD in Biochemistry and Metabolism in 1993 from University of Newcastle. Following this, he moved to UCL Great Ormond Street Institute of Child Health in London to the Paediatric Surgery Unit and developed an interest in paediatric metabolism and nutrition in neonatal and paediatric critical illness. He also is involved in tissue engineering for paediatric surgical conditions, and in mechanisms of dietary therapies for epilepsy. He runs a research laboratory which analyses a variety of metabolites and samples using GCMS, HPLC and isotope ratio mass spectrometry.