Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.

AIMS/HYPOTHESIS: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes. METHODS: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire. RESULTS: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day. CONCLUSIONS/INTERPRETATION: In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent. DATA AVAILABILITY: SLC19A2 mutation details have been deposited in the Decipher database ( https://decipher.sanger.ac.uk/ ).

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis.

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (-3.2 SD score vs. -2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.

Clinical profile and outcome of diabetic ketoacidosis in children.

UNLABELLED: BACKGROUND. There is little information on the clinical profile and outcome of children with diabetic ketoacidosis in India. We analysed the data of children managed by us at a tertiary care hospital. METHODS. We retrospectively analysed the case records of 21 children (13 boys and 8 girls) with diabetic ketoacidosis admitted to our hospital from January 2004 to August 2008. They were managed using a standard protocol including intravenous fluids and insulin infusion. Blood glucose, serum electrolytes, blood urea, arterial blood gases and urinary ketones were monitored at regular intervals. The outcomes were assessed. RESULTS: The median age at presentation was 8 years and 17 children (80%) were detected to have diabetes mellitus at the time of presentation. Twelve children (57%) presented with severe diabetic ketoacidosis. Polyuria with polydipsia was the commonest clinical presentation (17). All of them had elevated HbA1C levels. The average length of stay in the paediatric intensive care unit was 2.9 days. The median time for the arterial blood gases to become normal was 19 hours and for urinary ketones to become non-detectable was 28 hours. None of the children received bicarbonate and there were no complications or mortality. All the children were doing well on follow up at 3 months. CONCLUSION; The outcome of active management of diabetic ketoacidosis in children is rewarding. The use of a standard protocol for management was associated with no complications or mortality in our series.

Infantile-onset diabetes mellitus: a 1-year follow-up study.

This study evaluates the clinical profiles and outcomes of children with infantile-onset diabetes mellitus (IODM) (onset at <1 year). Twelve infants with IODM presenting to our hospital from January 2003 to December 2007 are analyzed. All undergo thorough history, clinical examination, and investigations and are managed as per hospital-approved protocol and periodically followed up. Of 12 infants (3 boys and 9 girls), 9 have a family history of DM. The median age at onset is 2.5 months. Six infants have features suggestive of Wolcott-Rallison syndrome (WRS), 4 infants have type 1 DM, and 1 infant each has Fanconi-Bickel syndrome and maturity-onset diabetes of young. None have pancreatic agenesis or calculi. Human leukocyte antigen (HLA) typing shows DQ3 and DR15 alleles predominating. Two children with WRS died; the rest are being followed up. The incidence of IODM is increasing, with multiple syndromic associations rather than a single perspective.

Neonatal Diabetes: A Case Series.

BACKGROUND: Neonatal diabetes mellitusis a rare disorder with an incidence of 1 in 2,60,000 live births. METHODS: Retrospective analysis of clinical and genetic profile of children admitted with neonatal diabetes mellitus in a tertiary-care hospital in Chennai, India over 11 years. RESULTS: Ten children were diagnosed with neonatal diabetes of whom 9 had permanent neonatal diabetes mellitus. The age range at onset was from 3 days- 5 months. Of the 9 children, KCNJ11 gene mutation was positive in one, and ABCC 8 and INS gene mutation in two children each. Children with KCNJ11 and ABCC 8 gene mutations were switched over to oral sulfonyl urea therapy. CONCLUSION: Few genotypes causing NDM can be managed effectively with oral sulfonyl ureas.

Hemophagocytic lymphohistiocytosis masking the diagnosis of lymphoma in an adolescent male.

Hemophagocytic lymphohistiocytosis (HLH) association with an underlying lymphoma is an uncommon entity in paediatrics. It may precede lymphoma diagnosis by several years or may occur at the time of remission or relapse of lymphoma. Simultaneous occurrence of HLH & lymphoma is rare. We here with report a case where HLH was the initial presentation which masked the diagnosis of lymphoma, however tissue biopsy revealed the underlying non-Hodgkin's lymphoma.

Kawasaki disease mimicking retropharyngeal abscess.

Kawasaki disease is an acute, self-limiting febrile mucocutaneous vasculitis of infants and young children. Retropharyngeal lymphadenopathy is a rare presentation of Kawasaki disease. We present a case of Kawasaki disease mimicking a retropharyngeal abscess, with upper airway obstruction resulting in delayed diagnosis.

Profile of typhoid fever in children from a tertiary care hospital in Chennai-South India.

AIM: To study the clinical profile and outcome of hospitalized children with typhoid fever. MATERIALS AND METHODS: A retrospective study was conducted in a private tertiary care children's hospital over a 3 year period. RESULTS: A total of 316 children (7 in every 1000 admissions) were diagnosed to have typhoid fever during this period. More than one third were aged between 5 and 10 years and most cases (38%) clustered around the months of January to April. Around 59% of children in our series were unimmunised against typhoid. Eosinopenia was seen in 72 %. There was a significant increase in NARST (p < 0.001). Predictors of severity in this study were increased AST levels, eosinopenia and isolation of NARST. CONCLUSION: Public health interventions to minimize human carrier contact, improved personal hygienic measures including health care behavior strategies, typhoid vaccination and rational antibiotic selection based on sensitivity pattern to prevent resistance will help to reduce the morbidity and mortality of this global health problem.

Thiamine responsive megaloblastic anemia syndrome.

Thiamine responsive megaloblastic anemia syndrome (TRMA) is a clinical triad characterized by thiamine-responsive anemia, diabetes mellitus and sensorineural deafness. We report a 4-year-old girl with TRMA whose anemia improved following administration of thiamine and this case report sensitizes the early diagnosis and treatment with thiamine in children presenting with anemia, diabetes and deafness.