De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

Purpose This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. Conclusion Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients

Packages of Care for Dementia in Low- and Middle-Income Countries

In the fifth in a series of six articles on packages of care for mental disorders in low- and middle-income countries, Martin Prince and colleagues discuss the treatment of dementia

"The contribution of chronic diseases to the prevalence of dependence among older people in Latin America, China and India: a 10/66 Dementia Research Group population-based survey"

<p>Abstract</p> <p>Background</p> <p>The number of older people is set to increase dramatically worldwide. Demographic changes are likely to result in the rise of age-related chronic diseases which largely contribute to years lived with a disability and future dependence. However dependence is much less studied although intrinsically linked to disability. We investigated the prevalence and correlates of dependence among older people from middle income countries.</p> <p>Methods</p> <p>A one-phase cross-sectional survey was carried out at 11 sites in seven countries (urban sites in Cuba, Venezuela, and Dominican Republic, urban and rural sites in Peru, Mexico, China and India). All those aged 65 years and over living in geographically defined catchment areas were eligible. In all, 15,022 interviews were completed with an informant interview for each participant. The full 10/66 Dementia Research Group survey protocol was applied, including ascertainment of depression, dementia, physical impairments and self-reported diagnoses. Dependence was interviewer-rated based on a key informant's responses to a set of open-ended questions on the participant's needs for care. We estimated the prevalence of dependence and the independent contribution of underlying health conditions. Site-specific prevalence ratios were meta-analysed, and population attributable prevalence fractions (PAPF) calculated.</p> <p>Results</p> <p>The prevalence of dependence increased with age at all sites, with a tendency for the prevalence to be lower in men than in women. Age-standardised prevalence was lower in all sites than in the USA. Other than in rural China, dementia made the largest independent contribution to dependence, with a median PAPF of 34% (range 23%-59%). Other substantial contributors were limb impairment (9%, 1%-46%), stroke (8%, 2%-17%), and depression (8%, 1%-27%).</p> <p>Conclusion</p> <p>The demographic and health transitions will lead to large and rapid increases in the numbers of dependent older people particularly in middle income countries (MIC). The prevention and control of chronic neurological and neuropsychiatric diseases and the development of long-term care policies and plans should be urgent priorities.</p

Insulin signalling and the regulation of glucose and lipid metabolism

The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62568/1/414799a.pd

The protocols for the 10/66 dementia research group population-based research programme

BACKGROUND: Latin America, China and India are experiencing unprecedentedly rapid demographic ageing with an increasing number of people with dementia. The 10/66 Dementia Research Group's title refers to the 66% of people with dementia that live in developing countries and the less than one tenth of population-based research carried out in those settings. This paper describes the protocols for the 10/66 population-based and intervention studies that aim to redress this imbalance. METHODS/DESIGN: Cross-sectional comprehensive one phase surveys have been conducted of all residents aged 65 and over of geographically defined catchment areas in ten low and middle income countries (India, China, Nigeria, Cuba, Dominican Republic, Brazil, Venezuela, Mexico, Peru and Argentina), with a sample size of between 1000 and 3000 (generally 2000). Each of the studies uses the same core minimum data set with cross-culturally validated assessments (dementia diagnosis and subtypes, mental disorders, physical health, anthropometry, demographics, extensive non communicable disease risk factor questionnaires, disability/functioning, health service utilisation, care arrangements and caregiver strain). Nested within the population based studies is a randomised controlled trial of a caregiver intervention for people with dementia and their families (ISRCTN41039907; ISRCTN41062011; ISRCTN95135433; ISRCTN66355402; ISRCTN93378627; ISRCTN94921815). A follow up of 2.5 to 3.5 years will be conducted in 7 countries (China, Cuba, Dominican Republic, Venezuela, Mexico, Peru and Argentina) to assess risk factors for incident dementia, stroke and all cause and cause-specific mortality; verbal autopsy will be used to identify causes of death. DISCUSSION: The 10/66 DRG baseline population-based studies are nearly complete. The incidence phase will be completed in 2009. All investigators are committed to establish an anonymised file sharing archive with monitored public access. Our aim is to create an evidence base to empower advocacy, raise awareness about dementia, and ensure that the health and social care needs of older people are anticipated and met