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Oxford, United Kingdom

Hayee B.,University College London | Antonopoulos A.,Imperial College London | Murphy E.J.,University College London | Rahman F.Z.,University College London | And 18 more authors.
Glycobiology | Year: 2011

Glucose-6-phosphatase, an enzyme localized in the endoplasmic reticulum (ER), catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate. In humans, there are three differentially expressed glucose-6-phosphatase catabolic genes (G6PC1-3). Recently, it has been shown that mutations in the G6PC3 gene result in a syndrome associating congenital neutropenia and various organ malformations. The enzymatic function of G6PC3 is dependent on G6P transport into the ER, mediated by G6P translocase (G6PT). Mutations in the gene encoding G6PT result in glycogen storage disease type-1b (GSD-1b). Interestingly, GSD-1b patients exhibit a similar neutrophil dysfunction to that observed in G6PC3-deficient patients. To better understand the causes of neutrophil dysfunction in both diseases, we have studied the neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of patients with G6PC3 and G6PT syndromes. Unexpectedly, sodium dodecyl sulfate-polyacrylamide gel electrophoresis experiments indicated hypo-glycosylation of gp91phox, the electron-transporting component of the NADPH oxidase, in all of these patients. Rigorous mass spectrometric glycomic profiling showed that most of the complex-type antennae which characterize the neutrophil N-glycome of healthy individuals were severely truncated in the patients' neutrophils. A comparable truncation of the core 2 antenna of the O-glycans was also observed. This aberrant neutrophil glycosylation is predicted to have profound effects on the neutrophil function and merit designation of both syndromes as a new class of congenital disorders of glycosylation. © 2011 The Author.

Collopy L.C.,Queen Mary, University of London | Walne A.J.,Queen Mary, University of London | Cardoso S.,Queen Mary, University of London | De La Fuente J.,Imperial College London | And 9 more authors.
Blood | Year: 2015

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n 5 15), (2) uncertain status (n 5 6), and (3) bystanders (n 5 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution. (Blood. 2015;126(2):176-184) © 2015 by The American Society of Hematology.

Geel J.A.,Paediatric Haematology Oncology Unit | Bennett K.G.,University of Witwatersrand | Rigby J.M.,University of Witwatersrand | Poole J.E.,Paediatric Haematology Oncology Unit
SAJCH South African Journal of Child Health | Year: 2011

Naevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is an autosomal dominant syndrome of developmental anomalies associated with an increased risk of malignancies. Patients have multiple lesions, which may be subtle, and the diagnosis can easily be missed, leading to sub-optimal follow-up. Despite its infrequency clinicians may benefit from familiarity with the syndrome, as these patients are hypersensitive to radiation and prone to develop multiple malignancies. Patients can present to paediatricians, oncologists, maxillofacial surgeons, radiation oncologists and dermatologists, and it will be to the benefit of the patient with this syndrome for these specialists to have a working knowledge of this rare but fascinating disorder.

Shankar A.,University College London | Hall G.W.,Paediatric Haematology Oncology Unit | Gorde-Grosjean S.,Reims University Hospital Center | Hasenclever D.,Institute For Medizinische Informatik | And 11 more authors.
European Journal of Cancer | Year: 2012

Purpose: To examine whether three cycles of a low-intensity chemotherapy consisting of cyclophosphamide [500 mg/m 2 - day 1], vinblastine [6 mg/m 2 - days 1 and 8] and prednisolone [40 mg/m 2 - days 1-7] (CVP) is safe and therapeutically effective in children and adolescents with early stage nodular lymphocyte predominant Hodgkin lymphoma [nLPHL]. Patients and methods: Fifty-five children and adolescents with early stage nLPHL [median age 13 years, range 4-17 years] diagnosed between June 2005 and October 2010 in the UK and France are the subjects of this report. Staging investigations included conventional cross sectional as well as 18 fluro-deoxyglucose [FDG] PET imaging. Histology was confirmed as nLPHL by an expert pathology panel. Results: Of the 45 patients, who received CVP as first line treatment, 36 [80%, 95% Confidence Interval [CI]: (68; 92)] either achieved a complete remission [CR] or CR unconfirmed [CRu], the remaining nine patients achieved a partial response. All nine subsequently achieved CR with salvage chemotherapy [n = 7] or radiotherapy [n = 2]. Ten patients received CVP at relapse after primary treatment that consisted of surgery alone and all achieved CR. To date, only three patients have relapsed after CVP chemotherapy and all had received CVP as first line treatment at initial diagnosis. The 40-month freedom from treatment failure and overall survival for the entire cohort were 75.4% (SE ± 6%) and 100%, respectively. No significant early toxicity was observed. Conclusions: Our results show that CVP is an effective chemotherapy regimen in children and adolescents with early stage nLPHL that is well tolerated with minimal acute toxicity. © 2011 Elsevier Ltd. All rights reserved.

Muda Z.,Paediatric Haematology Oncology Unit | Ibrahim H.,Paediatric Haematology Oncology Unit | Abdul Rahman E.J.,Paediatric Haematology Oncology Unit | Othman I.S.,Paediatric Haematology Oncology Unit | And 3 more authors.
Medical Journal of Malaysia | Year: 2014

Spontaneous intracranial haemorrhage (ICH) is a rare complication of chronic immune thrombocytopenic purpura (ITP) in children. We report four patients with cITP who developed ICH. The latency between onset of ITP and ICH varied from 1-8 years. All our patients were profoundly thrombocytopenic (platelet count of <10 x 109/l) at the time of their intracranial bleed. The presenting features and management are discussed. All patients survived, three had complete neurological recovery while one had a minimal residual neurological deficit. © 2014, Malaysian Medical Association. All rights reserved.

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