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Over the past decade our research findings have impacted on the diagnosis and treatment of patients with inherited cardiomyopathies. Our work on risk stratification in patients with hypertrophic cardiomyopathy forms the basis for international guidelines on the use of implantable cardioverter defibrillators. Our research in patients with arrhythmogenic right ventricular cardiomyopathy has led to the development of a new international standard for the diagnosis of disease in patients and relatives. We have contributed to national and European guidelines on genetic testing in these conditions. We have also been influential in changing national policies, service design, and provision of care for inherited heart muscle disease.
Research conducted by Professor Tim Goodship and co-workers at Newcastle has had a profound effect on the prognosis for patients with atypical haemolytic uraemic syndrome (aHUS). By engaging in research on the genetic factors underlying the disease they developed an understanding of the molecular mechanisms responsible. Identifying that the majority of patients with aHUS have either acquired or inherited abnormalities of the regulation of complement (part of the immune system) led to the establishment of a UK national service for genetic screening and treatment with the complement inhibitor eculizumab. As eculizumab is now available to patients in England, the progression to end-stage renal failure can be prevented and patients already on dialysis will soon be successfully transplanted.
A routine service for genetic diagnosis of familial hypercholesterolaemia (FH) was developed and commissioned by the Northern Ireland Department of Health, based on the identification by the Queen's team of a series of mutations causing this condition. The team then developed novel diagnostic strategies that led to over 900 affected individuals being identified so that treatment could be delivered to them. Samples are received for diagnosis from the UK and Ireland and the work of the Centre helped to inform recent NICE guidance. The laboratory is recognised as an expert laboratory for the diagnosis of inherited lipid disorders by the International Federation for Clinical Chemistry and Laboratory Medicine.
Ataxia telangiectasia (A-T) is an inherited disease affecting multiple systems in the body, causing severe disability and death. Work led by Professor Malcolm Taylor at the University of Birmingham has been central to the biological and clinical understanding of this disease, from the identification of the gene responsible to the clarification of related conditions with different underlying causes. As a result of this work, within the 2008-13 period, his laboratory has been designated the national laboratory for clinical diagnosis of A-T — a service also offered internationally — and has also changed national screening policy for breast cancer, following his confirmation of the increased risks of A-T patients and those who carry a single copy of the gene for this type of tumour. Furthermore, he has contributed in a major way to patient support for this condition.
Individuals with Xeroderma pigmentosum (XP) are extremely susceptible to sunlight-induced skin cancers and, in some cases, develop neurological problems. Alan Lehmann has developed a cellular diagnostic test for this disorder. This test is now conducted as an integral part of a multi-disciplinary XP specialist clinic in London, which was established as a direct result of Alan Lehmann's research in Sussex and which has led to the improved diagnosis and management of the disorder and an improved quality of life for affected individuals.
Congenital myasthenic syndromes (CMS) are inherited neuromuscular disorders caused by defects at neuromuscular junctions, which are often a result of acetylcholine receptor gene mutations. A subset of CMS patients (around 14% in the US and Europe) have limb-girdle myasthenia (LGM). This disease can be highly disabling with symptoms including increasing weakness of skeletal muscles. As a result of collaborative work between Newcastle and Oxford, it was determined that many LGM patients have a mutation of the Dok-7 gene (unrelated to the acetylholine receptor), and do not, therefore, respond to standard CMS treatments. Since then, a number of additional mutations have been discovered, and genetic testing is now available for the majority of known LGM-causative genes. Crucially, Dok-7 patients, and those with other non-receptor related mutations, can now be diagnosed accurately and treated effectively, with ephedrine and salbutamol (in the US, albuterol). This significantly improves these patients' quality of life by enabling them to walk and breathe unassisted.
Sudden cardiac death causes 4.5 million deaths worldwide each year many of which could be prevented by implantable cardioverter defibrillators (ICDs), but these also carry risks. Research in the groups of Huang and Grace has led to diagnostic assays offering three times the predictive accuracy of current approaches in guiding cardiologists concerning indications for ICD implantation. The assay has been clinically trialled; since 2008, through the trial, the lives of three patients identified by the assay as at high risk were saved. Further work led by Grace and colleagues provided an improved, subcutaneous ICD (SICD); Grace also participated in a US-based clinical trial (NCT00399217) providing the evidence required for FDA approval supporting also later inclusion into NICE guidance. Since 2008 the SICD has been implanted in over 2500 patients in 16 countries.
The diagnosis and treatment of patients with Maturity Onset Diabetes of the Young (MODY) has been revolutionised by the research of Professors Andrew Hattersley (FRS) and Sian Ellard at Exeter. Prior to this research, up to 90% of patients with MODY were misdiagnosed as having type 1 or type 2 diabetes. To address this, the team developed new tests and integrated these into routine diagnosis. They showed that patients could be stratified to achieve delivery of the most appropriate therapy and, as a result, as many as 15000 patients worldwide have now gained a better quality of life.
Research conducted at UCL/UCLH over the last 20 years has enabled the identification of adults with acute leukaemia who are most likely to benefit from the use of stem cell transplantation, i.e. those with acute leukaemia in first remission. The treatment is highly intensive, potentially toxic and expensive high-dose chemotherapy followed by haemopoietic stem cell transplantation, and is inappropriate for some patients. The work has made a major contribution to the development of guidelines worldwide for the treatment of this disease. Improved patient selection for transplantation results in improved survival, less toxicity with improved overall quality of life, and a more appropriate use of NHS resources.
Research at the University of Nottingham has defined the clinical phenotype and management of lymphangioleiomyomatosis, a rare and often fatal multisystem disease affecting 1 in 200,000 women worldwide. The group has led the development and evaluation of new therapies and diagnostic strategies which are now part of routine clinical care. The research has underpinned the transformation of this previously under recognised and untreatable disease into a condition recognised by respiratory physicians, with international clinical guidelines, patient registries, clinical trials, specific treatments and a UK specialist clinical service.