Recent developments in Lipodystrophy

Purpose of review: Lipodystrophy syndromes have an estimated prevalence of 1.3–4.7 cases per million and as with other rare diseases conducting research can be challenging. The purpose of this review is to highlight recently published work that has provided important insights into the field of non-HIV associated lipodystrophy syndromes. Recent findings: Lipodystrophies are a heterogenous group of disorders and as such research is often focused on specific subtypes of the condition. The identification of children affected by LMNA mutations provided insights into the natural history of FPLD2, specifically that the adipose tissue phenotype predates the onset of puberty. Recent reports of heterozygous null variant carriers and the apparent absence of a lipodystrophy phenotype challenges our understanding of the molecular biology of perilipin 1 and its role in the pathogenesis of FPLD4. With a focus on therapeutics, studies delineating the differential responsiveness of PPAR gamma mutants to endogenous and synthetic ligands illustrated the potential for pharmacogenetics to inform therapeutic decisions in lipodystrophy due to PPARG mutations, while robust human studies have contributed important insights into the food independent metabolic effects of leptin in lipodystrophy. Finally, rare syndromes of lipodystrophy continue to serve as an exemplar for the contribution of genetically determined adipose tissue expandability to metabolic disease in the general population. Keywords: Lipodystrophy; LMNA; PLIN1; PPARG; Leptin

Diagnosis of insulin autoimmune syndrome using polyethylene glycol precipitation and gel filtration chromatography with ex vivo insulin exchange.

CONTEXT: Insulin-binding antibodies may produce severe dysglycaemia in insulin-naïve patients ('insulin autoimmune syndrome' (IAS) or Hirata disease), while rendering routine insulin assays unreliable. OBJECTIVE: To assess the performance of clinically used insulin assays and an optimal analytical approach in the context of IAS. DESIGN: Observational biochemical study of selected patients with hyperinsulinaemic hypoglycaemia. PATIENTS: Three patients without diabetes with recurrent spontaneous hyperinsulinaemic hypoglycaemia and 'positive' insulin antibodies. MEASUREMENTS: A panel of clinically used insulin assays (Siemens ADVIA® Centaur, Siemens Immulite® 2000, DiaSorin LIAISON® XL, PE AutoDELFIA® and the Beckman Coulter Access® 2) were used before and after plasma dilution or polyethylene glycol (PEG) precipitation. Anti-insulin IgG antibodies were measured by Isletest™ -IAA ELISA. Gel filtration chromatography (GFC) was undertaken with and without preincubation of plasma with exogenous insulin. RESULTS: Dilution of IAS plasma with assay-specific buffer increased insulin recovery, supporting negative immunoassay interference by antibodies. PEG precipitation of IAS plasma decreased insulin recovery using all assays except the Immulite® 2000. GFC discriminated high molecular weight and monomeric insulin, while ex vivo addition of exogenous insulin to plasma increased insulin bound to antibody, thereby improving the sensitivity of detection of insulin immunocomplexes. CONCLUSIONS: Immunoprecipitation with PEG must be used with caution in screening for insulin-antibody complexes as results are assay dependent. GFC with addition of exogenous insulin can identify significant insulin immunocomplexes with enhanced sensitivity, with attendant greater clinical utility and avoidance of radiolabelled reagents.Diabetes Research & Wellness Foundation Sutherland-Earl Clinical Fellowship (Grant ID: RG68554), Wellcome Trust (Grant ID: WT098498), Medical Research Council (Grant ID: MRC_MC_UU_12012/5), National Institute for Health Research (NIHR), Cambridge Biomedical Research CentreThis is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/cen.1317

The metabolic syndrome- associated small G protein ARL15 plays a role in adipocyte differentiation and adiponectin secretion.

Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis. In differentiated adipocytes GFP-tagged ARL15 localized predominantly to the Golgi with lower levels detected at the plasma membrane and intracellular vesicles, suggesting involvement in intracellular trafficking. Sequencing of ARL15 in 375 severely insulin resistant patients identified four rare heterozygous variants, including an early nonsense mutation in a proband with femorogluteal lipodystrophy and non classical congenital adrenal hyperplasia, and an essential splice site mutation in a proband with partial lipodystrophy and a history of childhood yolk sac tumour. No nonsense or essential splice site mutations were found in 2,479 controls, while five such variants were found in the ExAC database. These findings provide evidence that ARL15 plays a role in adipocyte differentiation and adiponectin secretion, and raise the possibility that human ARL15 haploinsufficiency predisposes to lipodystrophy

“It just fits my needs better”: Autistic students and parents’ experiences of learning from home during the early phase of the COVID-19 pandemic

Background and aims: The COVID-19 pandemic has caused unprecedented disruption to people's lives, especially for families, whose children have been taken out of schools during lockdown restrictions and required to learn from home. Little is known, however, about the perceived impact of the lockdown restrictions on the educational experiences of autistic children and young people – a group whose conventional schooling experiences are already often challenging. In this study, we sought to (1) understand these experiences from the perspectives of autistic young people and their parents, and (2) identify the underlying sources of positive experiences at this challenging time, in order to inform the ways in which autistic children might flourish at school in more normal times. Methods: Ninety-one Australian participants, including 16 autistic young people aged 12–18 years, 32 autistic parents and 43 non-autistic parents of autistic young people aged 3–18 years, took part in semi-structured interviews about their experiences of life during the initial phase of the COVID-19 pandemic. The interviews were subjected to reflexive, thematic analysis to identify themes and subthemes for each research question. Results: Overall, our participants initially found the transition to learning from home extremely challenging, with parents reporting that the support received from schools was far from adequate. After that initial period of transition, however, many autistic children reported flourishing at home both educationally and personally. For these children and families, we identified three key ingredients essential to this flourishing, including: (i) the importance of connected, trusting relationships (‘people’); (ii) the sensory and social safety of home (‘place’); and (iii) the flexibility to pace and structure learning to suit the individual child (‘time’). Conclusions: While the initial COVID-19 lockdown presented many challenges to children learning at home, there were aspects of this otherwise-unsettling situation that enabled children to thrive and from which we can learn for the future. Implications: These findings have important implications for understanding how and when autistic children might thrive in institutional educational settings once the pandemic subsides, focusing on the relationships between teachers and students, the nature of the physical learning environment and the need for greater flexibility in planning the school day

“We’re stuck with what we’ve got”: The impact of lipodystrophy on body image.

Aims: To evaluate the impact of lipodystrophy on body image and how this affects patients’ daily lives. Background: Lipodystrophy refers to a group of rare conditions characterised by generalised or partial lack of body fat and is associated with severe metabolic problems e.g. severe insulin resistance, diabetes and pancreatitis. In addition to its metabolic effect, lack of adipose tissue may have a major impact on appearance and cause distressing physical changes. While global research has focused on diagnosis and management, there is no published work investigating the psychological effects of lipodystrophy on body image. Methods: Following ethical approval, participants with lipodystrophy were purposively sampled from the National Severe Insulin Resistance Service in Cambridge UK, and invited to take part in a semi-structured interview. Eleven (10 female, 1 male) interviews were conducted and digitally recorded. Data were analysed using an inductive thematic approach. Results: Four main themes were identified in the dataset; “Always feeling appearance was different”, “a better understanding of lipodystrophy is needed”, “feeling accepted”, and “there’s more to lipodystrophy than managing symptoms”. Participants spoke of distressing cosmetic effects related to lack of fat tissue and other changes related to lipodystrophy, contributing to negative body image. For some, negative body image led to feelings of worthlessness impacting daily life and adherence to treatment. Psychological support was lacking but desired by participants. Conclusion: Lipodystrophy contributes to negative body image affecting patients’ daily lives. Patients wanted psychological support alongside medical management. Further research is needed to determine how best to deliver psychological support and to evaluate its impact on wellbeing and metabolic management. Relevance to clinical practice: The effects of rare diseases such as lipodystrophy on appearance can be distressing for patients. Support beyond medical management is needed to improve patients’ daily lives and help them to live well with appearance-altering condition

"We're stuck with what we've got": The impact of lipodystrophy on body image.

AIMS AND OBJECTIVES: To evaluate the impact of lipodystrophy on body image and how this affects patients' daily lives. BACKGROUND: Lipodystrophy refers to a group of rare conditions characterised by generalised or partial lack of body fat and is associated with severe metabolic problems, for example, severe insulin resistance, diabetes and pancreatitis. In addition to its metabolic effect, lack of adipose tissue may have a major impact on appearance and cause distressing physical changes. While global research has focused on diagnosis and management, there is no published work investigating the psychological effects of lipodystrophy on body image. METHODS: Following ethical approval, participants with lipodystrophy were purposively sampled from the National Severe Insulin Resistance Service in Cambridge, UK, and invited to take part in a semi-structured interview. Eleven (10 female, one male) interviews were conducted and digitally recorded. Data were analysed using an inductive thematic approach. RESULTS: Four main themes were identified in the data set; "Always feeling appearance was different," "a better understanding of lipodystrophy is needed," "feeling accepted" and "there's more to lipodystrophy than managing symptoms." Participants spoke of distressing cosmetic effects related to lack of fat tissue and other changes related to lipodystrophy, contributing to negative body image. For some, negative body image led to feelings of worthlessness impacting daily life and adherence to treatment. Psychological support was lacking but desired by participants. CONCLUSION: Lipodystrophy contributes to negative body image affecting patients' daily lives. Patients wanted psychological support alongside medical management. Further research is needed to determine how best to deliver psychological support and to evaluate its impact on well-being and metabolic management. RELEVANCE TO CLINICAL PRACTICE: The effects of rare diseases such as lipodystrophy on appearance can be distressing for patients. Support beyond medical management is needed to improve patients' daily lives and help them to live well with appearance-altering conditions

COVID-19: A Crisis of Borders

ABSTRACT The public health crisis of COVID-19 has compounded preexisting crises of democratic stability and effective governance, spurring debate about the ability of developed democracies to respond effectively to emergencies confronting their citizens. These crises, much discussed in recent political science, are joined by a further crisis which complicates and reinforces them: A migration crisis. Widespread travel and immigration restrictions instigated the largest and fastest decline in global human mobility in modern history, and COVID-19 may fundamentally change immigration over the longer term. The migration crisis heightens three crucial and preexisting concerns within immigration policy: the role of visa design; the status of undocumented migrants and other migrants without recourse to public funds; and the interaction of immigration and the labor market policy. It could reinforce a rising tide of nationalism and anti-immigrant sentiment, protectionist sentiment within labor-market policy debates, and a K-shaped recovery in migration patterns

Describing the natural history of clinical, biochemical and radiological outcomes of children with familial partial lipodystrophy type 2 (FPLD2) from the UK: a retrospective case series.

CONTEXT: Familial partial lipodystrophy type 2 (FPLD2) results from autosomal dominant mutations in the LMNA gene, causing lack of subcutaneous fat deposition and excess ectopic fat accumulation, leading to metabolic complications and reduced life expectancy. The rarity of the condition means that the natural history of FPLD2 throughout childhood is not well understood. We report outcomes in a cohort of 12 [5M] children with a genetic diagnosis of FPLD2, under the care of the UK National Severe Insulin Resistance Service [NSIRS] which offers multidisciplinary input including dietetic, in addition to screening for co-morbidities. OBJECTIVE: To describe the natural history of clinical, biochemical, and radiological outcomes of children with FPLD2. DESIGN: A retrospective case note review of children with a genetic diagnosis of FPLD2 who had been seen in the paediatric NSIRS was performed. PATIENTS: 12 [5M] individuals diagnosed with FPLD2 via genetic testing before age 18 and who attended the NSIRS clinic were included. MEASUREMENTS: Relationships between metabolic variables (HbA1c, triglycerides, fasting insulin, fasting glucose and ALT) across time, from first visit, to most recent, were explored using a multivariate model, adjusted for age and gender. Age of development of co-morbidities was recorded. RESULTS: 3 patients (all female) developed diabetes between 12 and 19yrs and were treated with Metformin. 1 female has hypertrophic cardiomyopathy and 4 [1M] patients developed mild hepatic steatosis at a median [range] age of 14[12-15]yrs. 3 [1M] patients reported mental health problems related to lipodystrophy. There were no relationships between biochemical results and age. Patients with diabetes had higher concentrations of ALT than patients who did not have diabetes, adjusted for age, gender and BMI SDS. CONCLUSIONS: Despite dietetic input, some patients, more commonly females, developed co-morbidities after the age of 10. The absence of relationships with biochemical results and age likely reflects the small cohort size. We propose that, whilst clinical review and dietetic support are beneficial for children with FPLD2, formal screening for co-morbidities before age 10 may not be of benefit. Clinical input from an MDT including dietician, psychologist, and clinician should be offered from diagnosis. This article is protected by copyright. All rights reserved.D.B.S (WT 219417) and S.O. are supported by the Wellcome Trust (WT 214274), the MRC Metabolic Disease Unit (MC_UU_00014/1), and the NIHR Cambridge Biomedical Research Centre and NIHR Rare Disease Translational Research Collaboratio