Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

Objective: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). Subjects and methods: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. Results: A genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. Conclusions: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded

Fainting Fanconi syndrome clarified by proxy: a case report

BACKGROUND: Rare diseases may elude diagnosis due to unfamiliarity of the treating physicians with the specific disorder. Yet, advances in genetics have tremendously enhanced our ability to establish specific and sometimes surprising diagnoses. CASE PRESENTATION: We report a case of renal Fanconi syndrome associated with intermittent hypoglycemic episodes, the specific cause for which remained elusive for over 30 years, despite numerous investigations, including three kidney and one liver biopsy. The most recent kidney biopsy showed dysmorphic mitochondria, suggesting a mitochondrial disorder. When her son presented with hypoglycemia in the neonatal period, he underwent routine genetic testing for hyperinsulinemic hypoglycemia, which revealed a specific mutation in HNF4A. Subsequent testing of the mother confirmed the diagnosis also in her. CONCLUSION: Modern sequencing technologies that test multiple genes simultaneously enable specific diagnoses, even if the underlying disorder was not clinically suspected. The finding of mitochondrial dysmorphology provides a potential clue for the mechanism, by which the identified mutation causes renal Fanconi syndrome

Founder mutation in the PMM2 promotor causes hyperinsulinemic hypoglycaemia/polycystic kidney disease (HIPKD)

BACKGROUND: Polycystic kidney disease with hyperinsulinaemic hypoglycaemia (HIPKD) is a recently described disease caused by a single nucleotide variant, c.-167G>T, in the promoter region of PMM2 (encoding phosphomannomutase 2), either in homozygosity or compound heterozygosity with a pathogenic coding variant in trans. All patients identified so far are of European descent, suggesting a possible founder effect. METHODS: We generated high density genotyping data from 11 patients from seven unrelated families, and used this information to identify a common haplotype that included the promoter variant. We estimated the age of the promoter mutation with DMLE+ software, using demographic parameters corresponding to the European population. RESULTS: All patients shared a 0.312 Mb haplotype which was absent in 503 European controls available in the 1000 Genomes Project. The age of this mutation was estimated as 105-110 generations, indicating its occurrence around 600 BC, a time of intense migration, which might explain the presence of the same mutations in Europeans around the globe. CONCLUSION: The shared unique haplotype among seemingly unrelated patients is consistent with a founder effect in Europeans

Whole home exercise intervention for depression in older care home residents (the OPERA study) : a process evaluation

Background: The ‘Older People’s Exercise intervention in Residential and nursing Accommodation’ (OPERA) cluster randomised trial evaluated the impact of training for care home staff together with twice-weekly, physiotherapist-led exercise classes on depressive symptoms in care home residents, but found no effect. We report a process evaluation exploring potential explanations for the lack of effect. Methods: The OPERA trial included over 1,000 residents in 78 care homes in the UK. We used a mixed methods approach including quantitative data collected from all homes. In eight case study homes, we carried out repeated periods of observation and interviews with residents, care staff and managers. At the end of the intervention, we held focus groups with OPERA research staff. We reported our first findings before the trial outcome was known. Results: Homes showed large variations in activity at baseline and throughout the trial. Overall attendance rate at the group exercise sessions was low (50%). We considered two issues that might explain the negative outcome: whether the intervention changed the culture of the homes, and whether the residents engaged with the intervention. We found low levels of staff training, few home champions for the intervention and a culture that prioritised protecting residents from harm over encouraging activity. The trial team delivered 3,191 exercise groups but only 36% of participants attended at least 1 group per week and depressed residents attended significantly fewer groups than those who were not depressed. Residents were very frail and therefore most groups only included seated exercises. Conclusions: The intervention did not change the culture of the homes and, in the case study homes, activity levels did not change outside the exercise groups. Residents did not engage in the exercise groups at a sufficient level, and this was particularly true for those with depressive symptoms at baseline. The physical and mental frailty of care home residents may make it impossible to deliver a sufficiently intense exercise intervention to impact on depressive symptoms

HNF1B mutations are associated with a Gitelman-like tubulopathy that develops during childhood

Mutations in the transcription factor hepatocyte nuclear factor 1B (HNF1B) are the most common inherited cause of renal malformations, yet also associated with renal tubular dysfunction, most prominently magnesium wasting with hypomagnesemia. The presence of hypomagnesemia has been proposed to help select appropriate patients for genetic testing. Yet, in a large cohort, hypomagnesemia was discriminatory only in adult, but not in pediatric patients. We therefore investigated whether hypomagnesemia and other biochemical changes develop with age.This article is freely available via Open Access. Click on the Additional Link to access full-text

The OPERA trial : a protocol for the process evaluation of a randomised trial of an exercise intervention for older people in residential and nursing accommodation

Background: The OPERA trial is large cluster randomised trial testing a physical activity intervention to address depression amongst people living in nursing and residential homes for older people. A process evaluation was commissioned alongside the trial and we report the protocol for this process evaluation. Challenges included the cognitive and physical ability of the participants, the need to respect the privacy of all home residents, including study non-participants, and the physical structure of the homes. Evaluation activity had to be organised around the structured timetable of homes, leaving limited opportunities for data collection. The aims of this process evaluation are to provide findings that will assist in the interpretation of the clinical trial results, and to inform potential implementation of the physical activity intervention on a wider scale. Methods/design: Quantitative data on recruitment of homes and individuals is being collected. For homes in the intervention arm, data on dose and fidelity of the intervention delivered; including individual rates of participation in exercise classes are collected. In the control homes, uptake and delivery of depression awareness training is monitored. These data will be combined with qualitative data from an in-depth study of a purposive sample of eight homes (six intervention and two control). Discussion: Although process evaluations are increasingly funded alongside trials, it is still rare to see the findings published, and even rarer to see the protocol for such an evaluation published. Process evaluations have the potential to assist in interpreting and understanding trial results as well as informing future roll-outs of interventions. If such evaluations are funded they should also be reported and reviewed in a similar way to the trial outcome evaluation

Falha de resposta à glibenclamida em criança brasileira com diabetes melito neonatal permanente e síndrome DEND devido a mutação C166Y no gene KCNJ11 (Kir6.2)

Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (PNDM) and several cases have been successfully treated with oral sulfonylureas. We report on the attempted transfer of insulin therapy to glibenclamide in a 4-year old child with PNDM and DEND syndrome, bearing a C166Y mutation in KCNJ11. An inpatient transition from subcutaneous NPH insulin (0.2 units/kg/d) to oral glibenclamide (1 mg/kg/d and 1.5 mg/kg/d) was performed. Glucose and C-peptide responses stimulated by oral glucose tolerance test (OGTT), hemoglobin A1c levels, the 8-point self-measured blood glucose (SMBG) profile and the frequency of hypoglycemia episodes were analyzed, before and during treatment with glibenclamide. Neither diabetes control nor neurological improvements were observed. We concluded that C166Y mutation was associated with a form of PNDM insensitive to glibenclamide.As mutações ativadoras, heterozigóticas do gene KCNJ11 (Kir6.2) são a causa mais freqüente de diabetes melito neonatal permanente (DMNP) e a terapêutica oral com sulfoniluréias tem sido bem sucedida em muitos destes casos. Relatamos o processo de substituição da insulinoterapia convencional para o tratamento oral com glibenclamida em uma paciente de 4 anos, portadora de DMNP e síndrome DEND devido a uma mutação C166Y no gene KCNJ11. A insulina NPH (0,2 U/kg/dia) foi substituída pela glibenclamida (1 mg/kg/dia e 1,5 mg/kg/dia) durante internação hospitalar. As respostas de glicose e peptídeo-C no teste de tolerância oral à glicose (OGTT), os níveis de hemoglobina glicada, o perfil de glicemias capilares de 8 pontos e a freqüência de hipoglicemias foram comparados antes e durante o tratamento com glibenclamida. Não houve melhora no controle glicêmico, nem no quadro neurológico. Concluímos que a mutação C166Y associa-se a uma forma de DMNP insensível à glibenclamida

‘Do you really want me to tell ya!’ critical learning in engaging young people in contact with the justice system as peer educators with social work students

This paper outlines and evaluates an active and experiential learning project, which gave young people involved with the justice system, a voice as peer educators engaging with social work students outside of the traditional educational institution. The project had two key interconnecting elements. Firstly, by engaging a hidden population of young people in a realistic and meaningful way, it enabled them to share their experiences, and allowed students to understand the complexity of what it means to be socially excluded. Secondly, through this active participation process the young people began to see education as a desirable goal. The project took place over three months and included 10 social work students and 13 young people involved with the justice system. Creative use of multimedia facilitated production of a learning resource to capture the young people’s lived experiences with statutory social work and justice systems. Young people were fundamentally challenged in their beliefs about themselves being involved in education to achieve a qualification. Students were challenged in their creativity and versatility responding to the task, when collaborating with ‘hard to reach’ young people. They were furthermore challenged in terms of their attitudes and assumptions in relation to offending and social justice

A qualitative process evaluation of training for non-physician clinicians/associate clinicians (NPCs/ACs) in emergency maternal, neonatal care and clinical leadership, impact on clinical services improvements in rural Tanzania: the ETATMBA project: Table 1

Objectives The Enhancing Human Resources and Use of Appropriate Training for Maternal and Perinatal Survival in sub-Saharan Africa (ETATMBA) project is training non-physician clinicians as advanced clinical leaders in emergency maternal and newborn care in Tanzania and Malawi. The main aims of this process evaluation were to explore the implementation of the programme of training in Tanzania, how it was received, how or if the training has been implemented into practice and the challenges faced along the way. Design Qualitative interviews with trainees, trainers, district officers and others exploring the application of the training into practice. Participants During late 2010 and 2011, 36 trainees including 19 assistant medical officers one senior clinical officer and 16 nurse midwives/nurses (anaesthesia) were recruited from districts across rural Tanzania and invited to join the ETATMBA training programme. Results Trainees (n=36) completed the training returning to 17 facilities, two left and one died shortly after training. Of the remaining trainees, 27 were interviewed at their health facility. Training was well received and knowledge and skills were increased. There were a number of challenges faced by trainees, not least that their new skills could not be practised because the facilities they returned to were not upgraded. Nonetheless, there is evidence that the training is having an effect locally on health outcomes, like maternal and neonatal mortality, and the trainees are sharing their new knowledge and skills with others. Conclusions The outcome of this evaluation is encouraging but highlights that there are many ongoing challenges relating to infrastructure (including appropriate facilities, electricity and water) and the availability of basic supplies and drugs. This cadre of workers is a dedicated and valuable resource that can make a difference, which with better support could make a greater contribution to healthcare in the country

De novo mutations in EIF2B1 affecting eIF2 signaling cause neonatal/early onset diabetes and transient hepatic dysfunction

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this recordData and resource availability. EIF2B1 mutation details have been deposited in the Decipher database (https://decipher.sanger.ac.uk/). All other data sets generated and/or analysed for this study are available from the corresponding author upon reasonable request.Permanent neonatal diabetes is caused by reduced β-cell number or impaired β-cell function. Understanding the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 permanent neonatal diabetes patients and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified 2 further patients with de novo EIF2B1 variants. In addition to diabetes, 4/5 patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation which occurs under stress conditions and triggers expression of stress-response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway.European Foundation for the Study of DiabetesDiabetes UKDiabetes Research and Wellness FoundationWellcome TrustNational Institute for Health Research (NIHR)Royal Societ