Our mission is to discover the molecular and metabolic basis of inherited disorders, particularly those affecting the brain and/or liver, and thereby to find new treatments for these disorders. Of our 30,000 genes, 4,000 code for enzymes and transporters. Enzymes convert one chemical ("metabolite") to another and transporters move chemicals between cells and organelles. When an enzyme or transporter doesn't work properly we call this an "inborn error of metabolism". Inborn errors can present in many different ways. Those affecting the brain can cause epileptic fits, movement disorders (like Parkinson's disease or ataxia), paralysis and psychiatric symptoms such as autism. Those affecting the liver can produce liver failure or cirrhosis. Identification of a "new" inborn error as the cause of neurological disease or liver disease has traditionally relied on the development of new, more sensitive, more specific and more accurate techniques for the analysis of metabolites or enzymes. Mass spectrometry (MS) has played a very major part in these developments and, with a major contribution from Dr Kevin Mills, we have gradually built up from a single gas chromatograph - mass spectrometer to a state-of-the-art MS facility, run by Kevin, with capabilities for measuring a wide range of metabolites ("metabolomics"), lipids ("lipidomics"), proteins ("proteomics") and sugar chains attached to proteins ("glycomics"). The identification of specific abnormal metabolites/lipids/ proteins / glycans has led to the development of new tests for enzymes and transporters and to analysis of candidate genes. This aspect of our work has been led by Dr Philippa Mills.
More recently "new" disorders have been identified by analysis of the coding regions of panels of genes or all 30,000 genes - an "exome" analysis. In this work we have collaborated closely with GOSgene, and Prof Nick Lench and his colleagues in the DNA diagnostic laboratory. The identification of a potentially faulty gene by the DNA panel or exome analysis has led to targeted measurements of metabolites and enzymes to confirm that the gene really is faulty, again relying heavily on the skills of Kevin and Philippa.
We have also commenced an analysis of children with a susceptibility to a low blood sugar - "ketotic hypoglycaemia" - by whole genome sequencing which looks not just at the DNA that codes for proteins but also the regions that regulate gene expression. Again, we will need analysis of metabolites and enzymes to confirm we have found the DNA abnormality that is responsible for the child's metabolic disorder.
The detection of the known inborn errors of metabolism and of "new" disorders and the development of new treatments will continue to be heavily dependent on state-of-the-art methods for the analysis of metabolites ("metabolomics, lipidomics"), proteins ("proteomics") glycans ("glycomics") and DNA ("genomics"). Thus, it is very exciting to be in a unit that is constantly seeking to improve what these platforms can offer.
We have made significant contributions to the elucidation of the following inborn errors and their treatment (the numbers in brackets are the reference numbers in the Online Mendelian Inheritance in Man [OMIM] database, http://www.ncbi.nlm.nih.gov/omim)
Disorders of bile acid synthesis - some treatable by bile acid replacement therapy (607764, 604741, 213700, 604489, 261515, 603711)
Peroxisomal disorders (excluding disorders already mentioned) - biogenesis disorders (e.g. 603360), and disorders of plasmalogen synthesis (602744)
Disorders of monoamine neurotransmitter synthesis causing infantile Parkinsonism - treatable in some cases (608643, 191290)
Disorders of fatty acid oxidation - detectable by newborn screening with treatment available to prevent brain damage (201450) or as cause of hyperisulinism treatable with diazoxide (609975)
Disorders of cholesterol synthesis causing developmental delay and malformations (270400, 602398, 302960, 215140)
Disorders leading to phytosterol accumulation - both genetic (210520) and as a consequence of parenteral nutrition, the latter leading to severe liver disease and treatable by reduction of phytosterol intake.
Congenital disorders of glycosylation (212065, 608104, 611908)
Disorders affecting vitamin B6 metabolism causing B6-responsive epilepsy (610090, 107323)
Disorders of manganese transport causing dystonia / Parkinsonism and chronic liver disease (611146) - treatable with disodium calcium edetate and iron supplementation
Disorders of intermediary metabolism causing movement disorders e.g. pyruvate dehydrogenase E2 deficiency (245348) treatable with a ketogenic diet and hydroxyisobutyryl-CoA hydrolase deficiency (610690)
Grants (last 5 years/current)
Great Ormond Street Children's Charity
|2010 - 2012||W1228 Metabolic Research. £118,052|
|2011 - 2012||W1022 Vitamin B6 metabolism in neonates and the effect of feeding method. £86,442|
|2012 - 2014||W1216 Identification of children whose epilepsy can be controlled better by vitamin B6 than anti-epileptic drugs. £53,386|
|2012 - 2015||W1254 Inborn Errors of Metabolism / Other Novel Therapeutic Interventions. /3197,085|
Donation from Parents of a Child with a Metabolic Disorder
|2010 - 2011||Measurement of S2-carboxylpropylcysteamine in urine and use in treatment of 3-hydroxyisobutyryl-CoA hydrolase deficiency. £31,000|
Industry Sponsored Investigator Led Project
|2012 - 2015||Actelion UK Ltd. Tests for diagnosis and monitoring of Niemann-Pick C disease. £72,500|
NIHR Biomedical Research Centre
|2009 - 2012||Is pyridox(am)ine phosphate oxidase deficiency a common cause of epilepsy, infertility, miscarriage and premature birth? BRC Senior Postdoctoral Personal Fellowship for Dr P. Mills. £104,612|
|2012 - 2015||Innovative medicine initiative EU Consortium - Stem cells for biological assays of novel drugs and predictive toxicology (StemBANcc). 850,000 Euros|
|2013 - 2016||European Union SME Targetive collaborative. Health and the understanding of metabolism, aging and nutrition (HUMAN) project. 613,000 Euros|
Action Medical Research
|2012 - 2015||Investigation of manganese metabolism and treatment development for neurological childhood disorders associated with manganese accumulation using a zebrafish gene knockout model. Research Training Fellowship for Dr. Karin Tuschl. £200,000|