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Objectives Children with antibody positive type 1 diabetes mellitus (type 1 diabetes) are at an increased risk of developing celiac disease (CD) which suggests a common autoimmune basis with both high-risk human lymphocyte antigen (HLA) and non-HLA factors playing a role in the pathophysiology. We aim to describe the prevalence, immune profile, and clinical characteristics of children with CD who have type 1 diabetes mellitus in Qatar. Methods All children (aged 0–18 years) attending a regional diabetes clinic with antibody positive type 1 diabetes were screened for CD. Measurement of tissue transglutaminase IgA and IgG as well as anti-endomysial antibody, was done, clinical details about the birth history, family history of diabetes and CD, age of onset, and ethnicity were collected. Results Out of the 1,325 children with antibody positive type 1 diabetes, 54 were identified to have CD on screening and then confirmed on small bowel biopsy. The prevalence of CD in the type 1 diabetes childhood population in Qatar is 4.07%. CD and type 1 diabetes were more prevalent in the Qatari children (n=32) as compared to non-Qatari (n=22) and occurred mostly in the age group 6–10 years. The most common type 1 diabetes antibodies in children with CD were glutamic acid decarboxylase and insulin autoantibody. Twelve subjects were asymptomatic for CD symptoms and picked up only on screening. Conclusions The prevalence of CD in children with type 1 diabetes in Qatar is comparable to reports from around the world. Many children were asymptomatic and thus routine screening is recommended.

Context Idiopathic type 1 diabetes is characterized by the absence of autoantibodies and the underlying mechanisms are not clear. Objective We aimed to study the epidemiology, describe the clinical characteristics, and report results of genetic studies in pediatric patients with idiopathic type 1 diabetes. Methods This was a prospective study of type 1 diabetes patients attending Sidra Medicine from 2018 to 2020. Autoantibodies (GAD65, IAA, IA-2A, and ZnT8) were measured and genetic testing was undertaken in patients negative for autoantibodies to rule out monogenic diabetes. Demographic and clinical data of patients with idiopathic type 1 diabetes were compared with patients with autoimmune type 1 diabetes. Results Of 1157 patients with type 1 diabetes, 63 were antibody-negative. Upon genome sequencing, 4 had maturity onset diabetes of the young (MODY), 2 had Wolfram syndrome, 1 had H syndrome, and 3 had variants of uncertain significance in MODY genes; 53 patients had idiopathic type 1 diabetes. The most common age of diagnosis was 10 to 14 years. C-peptide level was low but detectable in 30 patients (56.6%) and normal in 23 patients (43.4%) The average body mass index was in the normal range and 33% of the patients had a history of diabetic ketoacidosis (DKA). Conclusion Four percent of the children had idiopathic type 1 diabetes. There were statistically significant differences in the C-peptide level and insulin requirement between the 2 groups. DKA was less common in the idiopathic group. Mutations in MODY genes suggest the importance of autoantibody testing and genetic screening for known causes of monogenic diabetes in idiopathic type 1 diabetes. The mechanism of idiopathic type 1 diabetes is unknown but could be due to defects in antibody production or due to autoantibodies that are not yet detectable or discovered.

Aims/Introduction Corneal confocal microscopy is a rapid, non‐invasive ophthalmic technique to identify subclinical neuropathy. The aim of this study was to quantify corneal nerve morphology in children with type 1 diabetes mellitus compared with age‐matched healthy controls using corneal confocal microscopy. Materials and Methods A total of 20 participants with type 1 diabetes mellitus (age 14 ± 2 years, diabetes duration 4.08 ± 2.91 years, glycated hemoglobin 9.3 ± 2.1%) without retinopathy or microalbuminuria and 20 healthy controls were recruited from outpatient clinics. Corneal confocal microscopy was undertaken, and corneal nerve fiber density (n/mm2), corneal nerve branch density (n/mm2), corneal nerve fiber length (mm/mm2), corneal nerve fiber tortuosity and inferior whorl length (mm/mm2) were quantified manually. Results Corneal nerve fiber density (22.73 ± 8.84 vs 32.92 ± 8.59; P, This is the first study showing significant corneal nerve loss in the central cornea and inferior whorl, indicative of early subclinical neuropathy in children with type 1 diabetes mellitus without microalbuminuria or retinopathy.

Objectives/design Comparative cross-sectional study to assess homocysteine and vitamin status in carriers of CBS gene mutations. Method Subjects included 34 parents (13 males, 21 females, age 27–59 years) of 30 patients with classical homocystinuria due to homozygous cystathionine β-synthase deficiency. Control subjects were matched for gender and age (13 males, 21 females, age 25–59 years). All subjects were of Qatari origin, had normal liver and renal function tests and had not taken drugs or vitamin supplements prior to the study. The concentrations of homocysteine, folic acid and vitamins B 6 and B 12 in blood were determined after an overnight fast. Results Heterozygous carriers had significantly increased fasting levels of homocysteine compared to controls (9.1 vs. 8.1μmol/l, P =0.012). Both folic acid (328 vs. 478pmol/l, P =0.002) and vitamin B 12 concentrations (232 vs. 287pmol/l, P =0.013) were reduced whilst there was no significant difference in vitamin B 6 levels between the two groups (5.8 vs. 6.44μg/l). Conclusions Increased homocysteine concentrations in CBS gene mutation carriers are associated with reduced concentrations of folic acid and vitamin B 12 in blood. In view of the adverse effects of mild hyperhomocysteinemia, routine testing of vitamin status in parents of homocystinuria patients may be warranted. The causal relationship and pathophysiological consequences are uncertain; it is likely that CBS gene mutation carriers need higher doses of dietary vitamins.

Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.

PubMedID: 25015100 Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severityduetocompensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibitedsevere kinetic defects (RAI ? 0.01). There was no correlation between CSG and RAI (r2 = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison ofCSGwith RSI detected a highly significant correlation (r2 = 0.74,P = 0.002).We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity. ©The Author 2014. 8Oxford University of Oxford: 2Institute UCLH Biomedical Research Centre Royal Devon and Exeter NHS Foundation Trust Wellcome Trust: 095101/Z/10/Z 1Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LE, UK, 2Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK, 3Macleod Diabetes and Endocrine Centre and, 4Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK, 5Department of Paediatric Endocrinology, Diyarbakir Children State Hospital, Diyarbakir 21100, Turkey, 6Division of Pediatric Endocrinology, Dr. Sadi Konuk Education and Research Hospital, Bakirkoy, Istanbul 34147, Turkey, 7Pediatric Endocrine Division, Queen Rania Al Abdullah Hospital for Children, King Hussein Medical Center, Royal Medical Services, Amman 11814, Jordan and 8Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK This work was supported by the Wellcome Trust (grant number 095101/Z/10/Z to A.L.G.). A.L.G. is a Wellcome Trust Senior Fellow in Basic and Biomedical Science. A.T.H. and S.E. are Wellcome Trust Senior Investigators. A.T.H. is a National Institute for Health Research (NIHR) Senior Investigator. A.T.H. is funded by the NIHR Exeter Clinical Research Facility. This article presents independent research supported by the NIHR Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.