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Timothy G Barrett

Publications and source records attributed to Timothy G Barrett.

6 recordsLinked to original sources
PubMed2006

Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families.

AIM: Thiamine-responsive megaloblastic anaemia syndrome (TRMA) is the association of diabetes mellitus, anaemia and deafness, due to mutations in SLC19A2, encoding a thiamine transporter protein. This is a unique monogenic form of vitamin-dependent diabetes for which there is limited long-term data. We aimed to study genotype-phenotype relationships and long-term follow-up in our cohort. METHODS: We have studied 13 patients from seven families and have follow-up data for a median of 9 y (2-30 y). RESULTS: All patients originated from Kashmir or Punjab, and presented with non-immune, insulin-deficient diabetes mellitus, sensorineural deafness and a variable anaemia in the first 5 y of life, the anaemia progressing to megaloblastic and sideroblastic changes in the bone marrow. The anaemia and diabetes mellitus responded to oral thiamine hydrochloride 25 mg/d, but during puberty thiamine supplements became ineffective, and almost all patients require insulin therapy and regular blood transfusions in adulthood. All patients are homozygous for mutations in the SLC19A2 gene. We have identified a novel missense mutation (T158R) that was excluded in 100 control alleles. CONCLUSION: Diabetes in this syndrome is due to an insulin insufficiency that initially responds to thiamine supplements; however, most patients become fully insulin dependent after puberty. A mutation screening strategy is feasible and likely to identify mutations in almost all cases.

Adolescent↗
PubMed2004

The emergence of type 2 diabetes in childhood.

Type 1 diabetes (with predominant insulin deficiency) was until recently assumed to be the diagnosis of almost all children presenting with glucose intolerance. This requires insulin treatment via subcutaneous injections, and most patients develop microvascular and macrovascular complications in adulthood. Advances in genetics in the 1990s identified a group of genetic disorders of pancreatic beta-cell function (maturity-onset diabetes of the young) for which the outlook is better than type 1, genetic testing is available, and oral medication is the preferred treatment. In 2000, the first cases of type 2 diabetes (predominant insulin resistance) were reported in UK children, reflecting a trend seen in North America over the last 20 years. Affected children are usually overweight or obese, often female, pubertal, predominantly of ethnic minority (South Asian) origin and have a family history of type 2 diabetes. The diagnosis is aided by demonstration of insulin resistance, and may include measurement of fasting insulin and C-peptide, markers of the metabolic syndrome (fasting lipids, sex hormone binding globulin) and absence of autoantibodies against beta-cell components (e.g. glutamic acid decarboxylase). Management is aimed towards weight stabilization in the growing child, education on healthy lifestyles and the treatment of hyperglycaemia with both insulin and insulin-sensitizing agents. The underlying cause of type 2 diabetes in children is likely to be related to the epidemic of childhood obesity. There is emerging evidence of an appalling outlook for these young people in terms of miscarriages and microvascular and cardiovascular complications, which are likely to present an enormous economic and health services burden over the next 20 years.

Child↗
PubMed2004

Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.

Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.

Adolescent↗
PubMedDate not supplied

Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation.

Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2.4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.

Child↗
PubMedDate not supplied

[Report of a Brazilian patient with Wolfram Syndrome].

OBJECTIVE: To report a case of a patient diagnosed with Wolfram Syndrome and brachydactyly type E. Wolfram Syndrome is characterized by the presence of diabetes mellitus, diabetes insipidus, atrophy of the optic nerve, alterations of the urinary tract, deafness and neurologic and psychiatric disorders. However, not all manifestations are present at diagnosis, indicating the necessity of long-term follow-up of these patients. This long-term follow-up should be extended to the patients' closest relatives, having in mind the increased risk of occurrence of psychiatric disorders and diabetes mellitus among the heterozygous carriers of Wolfram Syndrome. DESCRIPTION: Male, white patients, only child of non-consanguineous parents, was healthy until four years of age, when he presented with polydipsia and polyuria, being diagnosed with diabetes mellitus type I. Since then, he has needed regular insulin use, but has followed an inadequate diet due to socioeconomic problems. He was evaluated by the genetic service when he was 11 years old. Brachydactyly was observed on physical examination. In the course of the complementary investigation, bilateral atrophy of the optic nerve was observed; the visual evoked potential and the electroretinogram were compatible with extensive optic nerve injury. Both retinas were normal. The presence of insulin-dependent diabetes mellitus together with atrophy of the optic nerve is a sufficient criterion for the diagnosis of Wolfram Syndrome. The molecular investigation confirmed the diagnosis of Wolfram Syndrome. COMMENTS: The aim of the present report is to alert physicians about the association between diabetes mellitus and monogenic syndromes, such as Wolfram Syndrome.

English Abstract↗