Title: Preventing death and long term institutional care by developing a newborn screening strategy to Identify Neonatal Diabetes
Funder: Health Education England

Abstract: Neonatal Diabetes Mellitus (NDM) is a rare form of diabetes diagnosed in the first 6 months of life. NDM is caused by mutations in a single gene that alter insulin production, leading to hyperglycaemia. A correct genetic diagnosis of NDM is important as it determines the most effective form of treatment, with many children successfully treated with sulphonylurea tablets instead of lifelong insulin injections. Most patients with NDM present with severe hyperglycaemia and diabetic ketoacidosis, associated with prolonged hospital admission and adverse outcomes including lifelong neurological damage or death. The prognosis is linked to the severity of the hyperglycaemia and ketoacidosis acidosis, and crucially, the speed with which the disease is recognised and treatment implemented. I hypothesise that detection of hyperglycaemia before the patient becomes symptomatic is possible by measuring blood glucose at day 5-7 of life, using a Guthrie card blood spot which is routinely collected from a heel prick for the National Newborn Screening Programme. I anticipate the blood glucose concentration of NDM patients will be significantly higher than those who are unaffected. I will determine if measurement of blood glucose from bloods spots is a viable method of detecting NDM by carrying out four distinct investigations: 1) I will establish and optimise a robust, high throughput blood spot glucose assay and determine the stability of blood glucose from Guthrie cards stored under different conditions 2) I will assess the diagnostic accuracy of blood spot glucose for detecting NDM by retrospectively measuring blood spot glucose from the Guthrie cards of patients diagnosed with NDM in our laboratory 3) I will test the screening strategy prospectively in German and French cohorts (access to approximately 800,000 Guthrie cards) and assess the diagnostic accuracy 4) In collaboration with University of Exeter Health Economics department, I will perform an exploratory economic analysis of a newborn screening programme for NDM. This result of this work will be submitted to the Newborn Screening Committee for consideration for implementation in the UK. The long-term health and economic benefits of identifying NDM patients before they present acutely and ensuring the correct genetic diagnosis and subsequent treatment are expected to be substantial.

Lay abstract: INTRODUCTION Neonatal Diabetes' is a rare condition in which babies are born with a genetic defect that means their blood sugar (glucose) rises from birth and they get increasingly severe diabetes. Babies who develop neonatal diabetes are not recognised as being ill until several weeks to months after birth when their glucose reaches a life threatening level and they start to vomit and lose consciousness. Many infants die, and those that do not may be left with life changing brain damage and needing to be in hospital or institutional care for life.In this research project, we will develop a test that will identify these babies before they get ill. All babies at days 5-7 of life have a blood spot taken from a prick of their heel to test for a number of rare diseases. The new test will measure blood glucose on this same blood spot to identify those with high blood glucose so the diabetes can be diagnosed and treated before life threatening illness develop.PROJECT PLANThe research will involve 4 parts.1. Develop an effective test that can measure the level of glucose on blood spots 2. Find out if glucose on the blood spots is clearly raised at day 5-7 in patients diagnosed with neonatal diabetes. 3. Assess if the new test correctly picks up babies with neonatal diabetes by adding it to a national screening programme in Germany and France testing over 800,000 babies. 4. Work out how cost-effective the test is to work out whether it should be adopted in the UK.OUTCOME OF PROJECT This work will provide the evidence for using the cheap and easy measurement of glucose on neonatal blood spot to prevent death and lifelong care that can follow delayed diagnosis of neonatal diabetes. The potential benefits are both dramatically improved health of children with this condition as well as national economic savings from prevention of more severe disease.PATIENT AND PUBLIC PARTICIPATION Patients and members of the public will assist with developing participant information resources, including letters to parents, to ensure that these are understandable and clear to participants. In addition, patients and members of the public will assist in producing summaries of our findings, including social media posts, to ensure these are clear and can have maximum impact.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE