29 research outputs found
Early onset non insulin dependent diabetes mellitus (NIDDM) - a link with paternal duplication of 6q24 and transient neonatal diabetes mellitus (TNDM).
No full textCentral precocious puberty in a girl with triple X syndrome and neonatal diabetes mellitus associated with paternal isodisomy of chromosome 6
No full textWe describe a girl with triple X syndrome and paternal isodisomy of chromosome 6 (UPD6), who developed neonatal diabetes mellitus (NDM) and precocious puberty. At birth she presented growth retardation and congenital anomalies (ventricular septal defect, macroglossia, umbilical hernia). Diabetes mellitus (DM) was diagnosed at 31 days of life and treated with insulin for 13 months. DM recurred at 4 years of age and since that time it required insulin, in spite of preserved beta-cell function. Tall stature was present from early childhood. At 7 years of age the girl presented central precocious puberty, height velocity further increased, but her near-final height was normal. This patient is unique in that precocious puberty has never been described in triple X females. Moreover it is a further example of paternal UPD6 causing NDM with a predisposition to type 2 DM in later life
Discrepant molecular and clinical diagnoses in Beckwith-Wiedemann and Silver-Russell syndromes
No full textAssessment of the role of genetic variation in the transient neonatal diabetes (TNDM) region on chromosome 6q24 in type 2 diabetes: a comparative genomic and haplotype approach
No full textBackground & Aims: Recent reports have supported the hypothesis that genes involved in monogenic forms of diabetes make excellent candidate genes for type 2 diabetes. Transient neonatal diabetes (TNDM) is a rare disorder associated with overexpression of genes at a paternally-expressed imprinted locus on chromosome 6q24, the key candidate gene being the transcription factor ZAC. Several type 2 diabetes linkage studies have indicated linkage to chromosome 6q22-25, in one case with evidence of over transmission of paternal alleles. We hypothesised that common genetic variation at this TNDM region could influence susceptibility to type 2 diabetes. Materials & Methods: Comparative genomic analysis was used to identify common variants within the ZAC region, from which its haplotype structurewas derived.Results: Seven SNPs with minor allele frequencies ranging from 15–46%, which captured the 5 most common haplotypes were genotyped in a large scale case-control (n=3643) and family based (n=520 families) study. This sample size had >80% power to detect odds ratios of >1.2 for all tagging SNPs. None of the 7 SNPs nor the haplotypes formed by these SNPs were associated with diabetes in our case control study (global p values for haplotype blocks 1 & 2 respectively = 0.81, 0.74). Nor did we find evidence for over transmission of any SNP or haplotype to affected offspring (global p values for blocks 1 & 2 = 0.09, 0.17), or for a parent of origin effect (p values ranged between 0.03–1 for the 7 SNPs).Conclusions: We conclude that common genetic variation at this locus is unlikely to influence susceptibility to Type 2 diabetes, although we cannot exclude a parent of origin effect with modest effect size.Support: Diabetes U
Loneliness in mid-life and older adults from ethnic minority communities in England and Wales: measure validation and prevalence estimates
No full text© 2020, The Author(s). We investigated the prevalence of loneliness among 1206 adults aged 40 + from six minority communities in England and Wales: Black Caribbean, Black African, Indian, Pakistani, Bangladeshi and Chinese. Replicating the approach from the previous studies, we demonstrate robust acceptability, reliability and validity for both the six-item De Jong Gierveld (DJG) and single-item loneliness scales in our six ethnic groups. The prevalence of loneliness using a single-item question (loneliness reported as often/always) ranges from 5% (Indian) to 14% (Chinese) compared with approximately 5% for the general population aged 40 + in Britain. Levels of loneliness are very much higher using the DJG scale. Using a loneliness threshold score of 5 +, the percentage ranged from 13% (Indian) to 36% (Chinese). We explored the importance of six established loneliness vulnerability factors for our sample using regression modelling. Three factors were not associated with loneliness—number of children, gender and health rating, and three factors were protective: younger age, being married and low financial strain. The addition of ethnicity did not change these relationships or enhance statistical power of our models. Being a member of the African Caribbean group was protective against loneliness but not for the other groups included in our study. We suggest that exposure to loneliness vulnerability factors rather than ethnicity per se or measurement artefact underpins differences in loneliness across ethnic groups
Loneliness in mid-life and older adults from ethnic minority communities in England and Wales: measure validation and prevalence estimates
No full text© 2021, The Author(s). We investigated the prevalence of loneliness among 1206 adults aged 40 + from six minority communities in England and Wales: Black Caribbean, Black African, Indian, Pakistani, Bangladeshi and Chinese. Replicating the approach from the previous studies, we demonstrate robust acceptability, reliability and validity for both the six-item De Jong Gierveld (DJG) and single-item loneliness scales in our six ethnic groups. The prevalence of loneliness using a single-item question (loneliness reported as often/always) ranges from 5% (Indian) to 14% (Chinese) compared with approximately 5% for the general population aged 40 + in Britain. Levels of loneliness are very much higher using the DJG scale. Using a loneliness threshold score of 5 +, the percentage ranged from 13% (Indian) to 36% (Chinese). We explored the importance of six established loneliness vulnerability factors for our sample using regression modelling. Three factors were not associated with loneliness—number of children, gender and health rating, and three factors were protective: younger age, being married and low financial strain. The addition of ethnicity did not change these relationships or enhance statistical power of our models. Being a member of the African Caribbean group was protective against loneliness but not for the other groups included in our study. We suggest that exposure to loneliness vulnerability factors rather than ethnicity per se or measurement artefact underpins differences in loneliness across ethnic groups.Leverhulme Trust (F/00275/Q); National Institute of Social Care and Health Research (SCRA/10/02)
Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood
No full textTransient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For approximately 50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K+ channel (K(ATP) channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic beta-cell K(ATP) channel, were sequenced. K(ATP) channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted earlier (all P < 0.001). K(ATP) channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). K(ATP) channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes
Beckwith-Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1
No full textThe imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. DNA methylation defects involving ICR1 result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith-Wiedemann syndrome (maternal ICR1 hypermethylation in 10% of BWS cases) and a growth retardation disorder, the Silver-Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). In familial BWS, hypermethylation of ICR1 has been found in association with microdeletion of repetitive DNA motifs within ICR1 that bind the zinc finger protein CTCF; but more recently, ICR1 point mutations were described in BWS pedigrees. We present a case report of two brothers with BWS and prolonged post-pubertal growth resulting in very large stature. A maternally inherited point mutation was identified in ICR1 in both brothers, which altered binding of OCT transcription factors. The same mutation was present on the paternally inherited allele of their unaffected mother. This is a second report of a point mutation causing ICR1 hypermethylation by altering an OCT-binding motif. The atypical growth phenotype of the brothers may be connected to the unusual underlying cause of their BWS. European Journal of Human Genetics (2012) 20, 240-243; doi:10.1038/ejhg.2011.166; published online 24 August 201
Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood
No full textBackground Silver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%–10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS.Methods A retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped.Results The median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤−2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS.Conclusion Historical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases
Comparing species and ecosystem-based estimates of fisheries yields
No full textAuthor Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Fisheries Research 111 (2011): 139-144, doi:10.1016/j.fishres.2011.07.009.Three methods are described to estimate potential yields of commercial fish species: (i) single-species calculation of maximum sustainable yields, and two ecosystem-based methods derived from published results for (ii) energy flow and for (iii) community structure. The requirements imposed by food-web fluxes, and by patterns of relative abundance, provide constraints on individual species. These constraints are used to set limits to ecosystem-based yields (EBY); these limits, in turn, provide a comparison with the usual estimates of maximum sustainable yields (MSY). We use data on cod and haddock production from Georges Bank for the decade 1993-2002 to demonstrate these methods. We show that comparisons among the three approaches can be used to demonstrate that ecosystem based estimates of yields complement, rather than supersede, the single-species estimates. The former specify the significant changes required in the rest of the ecosystem to achieve a return to maximum sustainable levels for severely depleted commercial fish stocks. The overall conclusion is that MSY defines changes required in particular stocks, whereas EBY determines the changes required in the rest of the ecosystem to realize these yields. Species specific MSY only has meaning in the context of the prey, predators and competitors that surround it.We acknowledge NSF awards OCE081459 (to DJG) and OCE0814474 (to JHS)
