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Wedatilake Y.,University College London | Brown R.M.,University of Oxford | McFarland R.,Northumbria University | Yaplito-Lee J.,Murdoch Childrens Research Institute | And 17 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Background: SURF1 deficiency, a monogenic mitochondrial disorder, is the most frequent cause of cytochrome c oxidase (COX) deficient Leigh syndrome (LS). We report the first natural history study of SURF1 deficiency. Methods. We conducted a multi-centre case notes review of 44 SURF1-deficient patients from ten different UK centres and two Australian centres. Survival data for LRPPRC-deficient LS and nuclear-encoded complex I-deficient LS patients were obtained from previous publications. The survival of SURF1-deficient patients was compared with these two groups using Kaplan-Meier survival analysis and logrank test. Results: The majority of patients (32/44, 73%) presented in infancy (median 9.5 months). Frequent symptoms were poor weight gain (95%, median age 10 months), hypotonia (93%, median age 14 months), poor feeding/vomiting (89%, median age 10 months), developmental delay (88%, median age 14 months), developmental regression (71%, median age 19 months), movement disorder (52%, median age 24 months), oculomotor involvement (52%, median age 29 months) and central respiratory failure (78%, median age 31 months). Hypertrichosis (41%), optic atrophy (23%), encephalopathy (20%), seizures (14%) and cardiomyopathy (2%) were observed less frequently.Lactate was elevated in CSF (mean 4.3 mmol/L) in all patients (30/30) and in blood (mean 4.4 mmol/L) in 31/38 (81%). Fibroblast COX activity was universally decreased (25/25). Normal COX histochemistry was noted in 30% of biopsies, whereas muscle COX activity was reduced in 96% (25/26). Neuroimaging demonstrated lesions characteristic of LS in 28/33 (85%) and atypical findings in 3/33 (9%). Peripheral neuropathy was present in 13/16 (81%) (demyelinating 7/16, axonal 2/16). Kaplan-Meier analysis demonstrated that SURF1-deficient patients experience longer survival (median 5.4 years, p < 0.001) compared to LRPPRC deficiency (median 1.8 years) and nuclear-encoded complex I-deficient LS (median 1.6 years). Survival >10 years was observed in 7 patients, 6 of these patients did not experience neurological regression. The most frequent mutation was c.312-320del10insAT. Five novel mutations (c.468-469delTC, c.799-800delCT, c.575G>A (p.Arg192Gln), c.751+5G>A and c.752-2A>G) were identified. Conclusions: SURF1-deficient patients have a homogeneous clinical and biochemical phenotype. Early recognition is essential to expedite diagnosis and enable prenatal diagnosis. © 2013 Wedatilake et al.; licensee BioMed Central Ltd.

Sheridan E.,Royal Infirmary | Sheridan E.,St Jamess Hospital | Wright J.,Royal Infirmary | Small N.,University of Bradford | And 8 more authors.
The Lancet | Year: 2013

Background Congenital anomalies are a leading cause of infant death and disability and their incidence varies between ethnic groups in the UK. Rates of infant death are highest in children of Pakistani origin, and congenital anomalies are the most common cause of death in children younger than 12 in this ethnic group. We investigated the incidence of congenital anomalies in a large multiethnic birth cohort to identify the causes of the excess of congenital anomalies in this community. Methods We obtained questionnaire data from the mothers of children with one or more anomalies from the Born in Bradford study, a prospective birth cohort study of 13 776 babies and their families in which recruitment was undertaken between 2007 and 2011. Details of anomalies were prospectively reported to the study and we cross checked these details against medical records. We linked data for anomalies to maternal questionnaire and clinical data gathered as part of the Born in Bradford study. We calculated univariate and multivariate risk ratios (RRs) with 95% CIs for various maternal risk factors. Findings Of 11 396 babies for whom questionnaire data were available, 386 (3%) had a congenital anomaly. Rates for congenital anomaly were 305.74 per 10 000 livebirths, compared with a national rate of 165.90 per 10 000. The risk was greater for mothers of Pakistani origin than for those of white British origin (univariate RR 1.96, 95% CI 1.56-2.46). Overall, 2013 (18%) babies were the off spring of fi rst-cousin unions. These babies were mainly of Pakistani origin - 1922 (37%) of 5127 babies of Pakistani origin had parents in fi rst-cousin unions. Consanguinity was associated with a doubling of risk for congenital anomaly (multivariate RR 2.19, 95% CI 1.67-2.85); we noted no association with increasing deprivation. 31% of all anomalies in children of Pakistani origin could be attributed to consanguinity. We noted a similar increase in risk for mothers of white British origin older than 34 years (multivariate RR 1.83, 95% CI 1.14-3.00). Maternal education to degree level was protective (0.53, 95% CI 0.38-0.75), irrespective of ethnic origin. Interpretation Consanguinity is a major risk factor for congenital anomaly. The risk remains even after adjustment for deprivation, and accounts for almost a third of anomalies in babies of Pakistani origin. High levels of educational attainment are associated with reduced risk in all ethnic groups. Our fi ndings will be valuable in health promotion and public health, and to those commissioning antenatal, paediatric, and clinical genetic services. Sensitive advice about the risks should be provided to communities at increased risk, and to couples in consanguineous unions, to assist in reproductive decision making.

Tubeuf S.,University of Leeds | Willis T.A.,University of Leeds | Potrata B.,University of Leeds | Grant H.,University of Leeds | And 4 more authors.
European Journal of Human Genetics | Year: 2015

This paper investigates the willingness of adults with inherited retinal disease to undergo and pay for diagnostic genetic testing in three hypothetical scenarios and to explore the factors that influence decision making. Fifty patients were presented with three scenarios whereby genetic testing provided increasing information: confirming the diagnosis and inheritance pattern alone, providing additional information on future visual function, and identifying in addition a new treatment which could stabilise their condition. Willingness to pay (WTP) was elicited using an iterative bidding game. Regression analysis was used to investigate the probability of agreeing to and paying for testing. Qualitative data were also reviewed to provide a comprehensive understanding of WTP and decision making. The majority of participants agreed to undergo genetic testing in each of the three scenarios. Scenario 2 was the least acceptable with 78% of participants agreeing to genetic testing. The probability of agreeing to genetic testing decreased with age. Between 72 and 96% of participants reported a WTP for genetic testing. Average WTP was £539, £1516, and £6895 for scenarios 1, 2, and 3 respectively. Older participants and participants with higher incomes were willing to pay more for testing. Qualitative data provided additional detail about the rationale behind participants' decisions. The study suggests that patients with inherited retinal disease were willing to undergo and to pay for diagnostic genetic testing, suggesting that they valued the information it may provide. However, several patients preferred not to receive prognostic information and were less willing to pay for genetic testing that yielded such detail. © 2015 Macmillan Publishers Limited All rights reserved.

Higham L.,University of Leeds | Ahmed S.,University of Leeds | Ahmed M.,Yorkshire Regional Genetics Service
Journal of Genetic Counseling | Year: 2013

This study aimed to explore the hopes and fears of young adults with cystic fibrosis (CF). Fifteen young adults with CF, aged 18-29, were interviewed about their hopes and fears using a grounded theory approach. Five themes were identified during the analysis: perceptions of living with unpredictable health and fear of death and dying; hopes for normality; hopes for a normal relationship and/or marriage; hopes for having children; and hopes for a normal work life. Participants feared the unpredictable nature of CF and the suffering that they believed they would have to endure due to ill health before premature death. Despite their fears, participants hoped to live a "normal" life by achieving their hopes of having long-lasting relationships, having children and pursuing a career. The findings highlight the need to help alleviate the fears of young adults with CF and to enable them to plan to achieve their hopes, hence giving them a sense of control over their condition. © 2012 National Society of Genetic Counselors, Inc.

Petit F.,Service de Genetique Clinique | Petit F.,University of Lille Nord de France | Plessis G.,Caen University Hospital Center | Decamp M.,Laboratoire Of Genetique Medicale | And 4 more authors.
European Journal of Medical Genetics | Year: 2015

Here we report three patients affected with neurodevelopmental disorders and harbouring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment. © 2014 Elsevier Masson SAS.

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