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Auer-Grumbach M.,Medical University of Graz | Olschewski A.,Medical University of Graz | Papi L.,Medical University of Graz | Kremer H.,Radboud University Nijmegen | And 21 more authors.
Nature Genetics | Year: 2010

Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families. Expression of mutant TRPV4 constructs in cells from the HeLa line revealed diminished surface localization of mutant proteins. In addition, TRPV4-regulated Ca 2+ influx was substantially reduced even after stimulation with 4αPDD, a TRPV4 channel-specific agonist, and with hypo-osmotic solution. In summary, we describe a new hereditary channelopathy caused by mutations in TRPV4 and present evidence that the resulting substitutions in the N-terminal ankyrin domain affect channel maturation, leading to reduced surface expression of functional TRPV4 channels. © 2010 Nature America, Inc. All rights reserved.


Reiner T.,University of Zagreb | Guardamagna O.,University of Turin | Nair D.,Royal Free Hospital NHS Foundation Trust | Soran H.,University of Manchester | And 8 more authors.
Atherosclerosis | Year: 2014

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme. © 2014 The Authors.


Ostergaard P.,St George's, University of London | Simpson M.A.,King's College London | Connell F.C.,Guys Hospital | Steward C.G.,Royal Hospital for Children | And 16 more authors.
Nature Genetics | Year: 2011

We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome. © 2011 Nature America, Inc. All rights reserved.


Le Goff C.,French Institute of Health and Medical Research | Mahaut C.,French Institute of Health and Medical Research | Abhyankar A.,Rockefeller University | Le Goff W.,University Pierre and Marie Curie | And 14 more authors.
Nature Genetics | Year: 2012

Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-β signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.


Smith B.,Yorkhill Hospital | Thomson J.,Leeds General Infirmary | Crossland D.,Freeman Hospital | Spence M.S.,Royal Victoria Hospital | Morgan G.J.,Evelina London Childrens Hospital
Catheterization and Cardiovascular Interventions | Year: 2014

Background Percutaneous closure of atrial defects (ASD) has evolved as the treatment of choice for the majority of defects and patent oval foramens. The Gore Septal Occluder (GSO) is an innovative device consisting mostly of a folded thin GoreTex tube for use in the closure of septal defects. Methods Reviewed is the multicenter UK experience of the first 22 ASD occlusions with the GSO TM device. All implantations were performed by consultant operators experienced in ASD device closure. The inclusion criterion was the presence of a hemodynamically significant secundum ASD with a diameter of <18 mm. Procedural data and acute and mid-term closure rates were retrospectively matched to a cohort of patients having defect closure using the Amplatzer Septal OccluderTM (ASOTM). Results Acute and 3-month follow-up closure rates for the GSOTM were 100% and 100% vs. 100% and 100% closure with the ASOTM implants. The difference in paired procedure times was not statistically significant (56 min: GSOTM; 42 min: ASOTM device P = ns), nor was the paired difference in fluoroscopic screening times (12 min: GSOTM vs. 8.4 min: ASOTM, P = ns). One GSO device embolized immediately after deployment and was successfully retrieved at the same procedure. There were no other significant complications in either group. Conclusions The GSOTM implant can achieve comparable closure rates to the ASOTM in small to moderate atrial septal defects after 3 months. Longer fluoroscopy and procedure times are a drawback; however these should improve with familiarity with the implant and deployment system. The larger sheath size was not associated with increased complications in our cohort. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.


Losekoot M.,Leiden University | Van Belzen M.J.,Leiden University | Seneca S.,Vrije Universiteit Brussel | Bauer P.,University of Tübingen | And 2 more authors.
European Journal of Human Genetics | Year: 2013

Huntington disease (HD) is caused by the expansion of an unstable polymorphic trinucleotide (CAG)n repeat in exon 1 of the HTT gene, which translates into an extended polyglutamine tract in the protein. Laboratory diagnosis of HD involves estimation of the number of CAG repeats. Molecular genetic testing for HD is offered in a wide range of laboratories both within and outside the European community. In order to measure the quality and raise the standard of molecular genetic testing in these laboratories, the European Molecular Genetics Quality Network has organized a yearly external quality assessment (EQA) scheme for molecular genetic testing of HD for over 10 years. EQA compares a laboratory's output with a fixed standard both for genotyping and reporting of the results to the referring physicians. In general, the standard of genotyping is very high but the clarity of interpretation and reporting of the test result varies more widely. This emphasizes the need for best practice guidelines for this disorder. We have therefore developed these best practice guidelines for genetic testing for HD to assist in testing and reporting of results. The analytical methods and the potential pitfalls of molecular genetic testing are highlighted and the implications of the different test outcomes for the consultand and his or her family members are discussed. © 2013 Macmillan Publishers Limited All rights reserved.


Ramsden S.C.,Saint Marys Hospital | Clayton-Smith J.,St Marys Hospital | Birch R.,Yorkhill Hospital | Buiting K.,Universitatsklinikum Essen
BMC Medical Genetics | Year: 2010

Background: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct neurodevelopmental genetic disorders that map to 15q11-q13. The primary phenotypes are attributable to loss of expression of imprinted genes within this region which can arise by means of a number of mechanisms. The most sensitive single approach to diagnosing both PWS and AS is to study methylation patterns within 15q11-q13; however many techniques exist for this purpose. Given the diversity of techniques available, there is a need for consensus testing and reporting guidelines.Methods: Testing and reporting guidelines have been drawn up and agreed in accordance with the procedures of the UK Clinical Molecular Genetics Society and the European Molecular Genetics Quality Network.Results: A practical set of molecular genetic testing and reporting guidelines has been developed for these two disorders. In addition, advice is given on appropriate reporting policies, including advice on test sensitivity and recurrence risks. In considering test sensitivity, the possibility of differential diagnoses is discussed.Conclusion: An agreed set of practice guidelines has been developed for the diagnostic molecular genetic testing of PWS and AS. © 2010 Ramsden et al; licensee BioMed Central Ltd.


Fitzgerald M.P.,Yorkhill Hospital | Armstrong L.,Crosshouse Hospital | Hague R.,Yorkhill Hospital | Russell R.K.,Yorkhill Hospital
Journal of Crohn's and Colitis | Year: 2013

We report a case of Epstein-Barr virus infection with the subsequent development of haemophagocytic lymphohistiocytosis in a teenage Crohn's disease patient treated with azathioprine. We found that the early introduction of the anti-B cell monoclonal antibody rituximab precipitated a rapid fall in circulating B-cells and EBV viral load, resulting in a prompt and sustained recovery from what is a potentially fatal complication of azathioprine therapy in Crohn's disease patients. © 2012 European Crohn's and Colitis Organisation.


Alexander C.L.,Stobhill Hospital | Shankland G.S.,Yorkhill Hospital | Carman W.,Gartnavel General Hospital | Williams C.,Stobhill Hospital
British Journal of Dermatology | Year: 2011

Background: Dermatophytes are the major cause of superficial mycoses in samples submitted to Clinical Mycology, Glasgow. The most prevalent species is Trichophyton rubrum as identified classically by microscopy and culture. Recent advances in polymerase chain reaction (PCR) technology were examined for the feasibility of introducing a T. rubrum real-time PCR assay into a routine diagnostic service. Objective: To improve the diagnostic mycology service by the introduction of a real-time PCR test for T. rubrum. Methods: The DNA from 4972 nail and skin samples was obtained using the Qiagen QIAsymphony automated extractor. This DNA was subjected to real-time PCR using T. rubrum-specific primers and a probe. Results: During phase 1 of the study, 862 samples were analysed; 446 of 470 specimens that grew T. rubrum were detected by PCR. Out of 4110 samples analysed during phase 2, 753 T. rubrum infections were diagnosed and reported within 72 h. A total of 3357 samples were negative for a fungal infection by PCR and microscopy; these were also reported within 72 h. Conclusions: A vast reduction in the turnaround times can be achieved using this technique as opposed to classical methods. Samples which are PCR negative but microscopy positive are still subjected to culture. Screening samples for their suitability for PCR prior to processing eliminates the application of PCR for T. rubrum on inappropriate samples such those from the scalp or pityriasis versicolor. © 2011 British Association of Dermatologists.


Hamilton J.,Yorkhill Hospital | Jones I.,Yorkhill Hospital | Srivastava R.,Yorkhill Hospital | Galloway P.,Yorkhill Hospital
Clinica Chimica Acta | Year: 2012

Background: Cholesterol ester storage disease (CESD) and Wolman Disease (WD) are due to deficiency of lysosomal acid lipase (LAL). A new method is described for the measurement of LAL in dried blood spots (DBS) using Lalistat 2 an inhibitor of LAL. Methods: LAL activity in DBS extracts was measured using the substrate 4-methylumbelliferyl palmitate. LAL activity was determined by measuring total lipase activity and lipase activity in the presence of Lalistat 2. The specificity of Lalistat 2 was investigated using human recombinant LAL (hrLAL) and human pancreatic lipase (hPL). Results: Lalistat 2 inhibited hrLAL with 1% residual activity at 1μM inhibitor but had no effect on hPL up to 10μM. LAL activity in DBS samples obtained from normal controls (n=140) was 0.50-2.30. nmol/punch/h and in patients with CESD was < 0.03 nmol/punch/h (n=11). Activity in carriers showed intermediate activity: 0.15-0.40. nmol/punch/h (n=15). Conclusions: Measurement of LAL using DBS is made difficult by the presence of other lipases in whole blood. Lalistat 2 is a specific inhibitor of LAL which allows the determination of LAL in DBS. Results show the method differentiates clearly between normal controls, carriers and affected cases. © 2012 Elsevier B.V.

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