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Chronic granulomatous disease is a rare but very serious inherited disorder of the immune system that leaves sufferers vulnerable to potentially fatal bacterial and fungal infections. Researchers at Newcastle University demonstrated very high survival and cure rates following bone marrow transplantation for the disease and good quality of life for successfully transplanted patients. This led to a change in national clinical policy, and doctors at both specialist disease centres in the UK now recommend transplantation to families where previously they would not have done so. In the five years prior to 2008 there were only 11 transplants for chronic granulomatous disease in the UK and in the following five years, 36 transplants. 32 children are alive and cured of the disease.
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.
Lung transplants represent the last hope for cystic fibrosis patients with end-stage lung disease. However, since the mid-1990s, other than in large research centres, some cystic fibrosis patients were not offered this treatment because of the variable and often poor outcome of surgery. This patient group carried a difficult to treat bacterial infection caused by the Burkholderia genus. In 2001 researchers in Newcastle published findings that demonstrated that one particular species, Burkholderia cenocepacia, was responsible for the poor outcomes and that other species of Burkholderia were not as dangerous. This finding was incorporated into international guidelines and since 2008 most transplant centres worldwide have adopted a risk stratification approach to listing patients for transplant. Consequently, more than 30 people per year worldwide now get transplants that would otherwise have been denied.
Neuroblastoma is a paediatric cancer that arises from the sympathetic nervous system. The average age at diagnosis is 18 months and the disease accounts for approximately 15% of all childhood cancer-related deaths. Determining optimal treatment for individual patients is crucial for increasing chances of survival and for reducing side effects of chemotherapy and radiotherapy. Newcastle-led research identified unbalanced 17q gain as the most common segmental chromosomal abnormality (SCA) in patients with neuroblastoma; this was present in more than 50% of patients. Gain of 17q is now one of the key SCAs used to determine treatment for patients in a European neuroblastoma trial and in UK treatment centres. Newcastle research also led to the development of a simple diagnostic test for the detection of the main SCAs in neuroblastoma.
Basic molecular genetic research undertaken over the last 20 years by UCL Cardiovascular Genetics has had a significant impact on the identification and treatment of patients with familial hypercholesterolaemia (FH). We have developed DNA testing methods in the three genes currently known to cause FH and have established DNA diagnostic protocols which are now in wide use throughout the UK. As a direct consequence of our work, we estimate that up to 3,000 FH patients in the UK have had their diagnosis of FH confirmed by a DNA test. Our work led to the National Institute of Health and Clinical Excellence (NICE) in 2008 strongly recommending DNA and cascade testing and early treatment with high intensity statins, and furthermore, the inclusion of FH checks in the NHS's Vascular Checks programme.
Dialysis has revolutionised the management of End Stage Kidney Disease (ESKD), but the benefits of this invasive, demanding treatment may not be clear-cut for elderly, frail patients with other serious comorbidities. University of Hertfordshire and East and North Hertfordshire NHS Trust researchers have led the development of Conservative Management, an alternative to dialysis for some patients, providing multidisciplinary support and careful symptomatic management until death. The research shows that quality of life is maintained, survival may not be significantly compromised, and preferred place of death is more often achieved than for counterparts on dialysis. Conservative Management programmes have been adopted across the UK and elsewhere, influencing the care of many patients.
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.
Research from the University of Nottingham on aminoglycoside antibiotics in cystic fibrosis (CF) has changed clinical practice and improved patient safety internationally. There are over 70,000 people with CF worldwide. Most require frequent and prolonged intravenous courses of aminoglycoside antibiotics (which can cause kidney damage) to treat chronic lung infection with Pseudomonas aeruginosa. This infection may lead to respiratory failure and death. Our research has influenced national and international guidelines, and changed practice, such that once-daily aminoglycosides (less toxic to the kidneys) are now used. We have also stopped the use of gentamicin, in favour of less toxic aminoglycosides.
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.
Research conducted by Professor TM Cox has led to several advances in the management of lysosomal storage disorders; i) development of miglustat (Zavesca®); now available throughout the world (EMA and FDA approved) for adult patients with Gaucher's disease and throughout the European Union and five other countries worldwide for adult and pediatric patients with Niemann- Pick type C disease, ii) development of the potential successor eliglustat; now in Phase 3 clinical trials, iii) identification of a biomarker for Gaucher's: CCL18/PARC, now incorporated into NHS standard operating procedures for monitoring therapeutic intervention. His pre-clinical research into gene therapy for Tay-Sachs disease also helped establish the NIH-funded Gene Therapy Consortium and gain the FDA's pre-IND approval for clinical trials in 2013, which together have raised public awareness of this disease.