Non-autoimmune Insulin-dependent Diabetes Research Articles

Wolcott-Rallison syndrome, A rare paediatric case report

Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive, neonatal or infancy onset disease that is non-autoimmune insulin-dependent diabetes and is associated with skeletal dysplasia and liver failure. It results in the death of the patient, mainly due to multi-organ failure. Less than 60 cases have been described in the literature so far. Here, we present a very rare case of WRS, which was diagnosed by genetic testing for EIF2AK3 mutations with typical findings of the disease, except skeletal dysplasia, which eventually died due to multi-organ failure. To the best of our knowledge, this is the first case report of WRS in Pakistan.

Wolfram syndrome type 1: a case series

BackgroundWolfram syndrome (WS) is a rare autosomal recessive multisystem neurodegenerative disease characterized by non-autoimmune insulin-dependent diabetes mellitus, optic atrophy, sensorineural deafness, and diabetes as the main features. Owing to clinical phenotypic heterogeneity, the misdiagnosis rate is high. However, early accurate diagnosis and comprehensive management are key to improving quality of life and prolonging life.ResultsEleven patients from seven WS pedigrees with 10 mutation sites (c.1314_1317delCTTT, c.C529T, c.C529A, c.G2105A, c.C1885T, c.1859_1860del, c.G2020A, c.C529A, c.G2105A, and c.G1393C) in the WFS1 gene were included. We conducted further expert department analysis to clarify the diagnosis and analyze the correlation between genes and phenotypes.ConclusionsThe genotypes of these patients were closely associated with their phenotypes. The clinical data of the patients were analyzed to provide a basis for the diagnosis and clinical management of the disease.

Wolfram Syndrome 1: A Pediatrician's and Pediatric Endocrinologist's Perspective.

Wolfram syndrome 1 (WS1) is a rare autosomal recessive neurodegenerative disease caused by mutations in WFS1 and WFS2 genes that produce wolframin, a protein involved in endoplasmic reticulum calcium homeostasis and cellular apoptosis. Its main clinical features are diabetes insipidus (DI), early-onset non-autoimmune insulin-dependent diabetes mellitus (DM), gradual loss of vision due to optic atrophy (OA) and deafness (D), hence the acronym DIDMOAD. Several other features from different systems have been reported such as urinary tract, neurological, and psychiatric abnormalities. In addition, endocrine disorders that can appear during childhood and adolescence include primary gonadal atrophy and hypergonadotropic hypogonadism in males and menstrual cycle abnormalities in females. Further, anterior pituitary dysfunction with deficient GH and/or ACTH production have been described. Despite the lack of specific treatment for the disease and its poor life expectancy, early diagnosis and supportive care is important for timely identifying and adequately managing its progressive symptoms. The current narrative review focuses on the pathophysiology and the clinical features of the disease, with a special emphasis on its endocrine abnormalities that appear during childhood and adolescence. Further, therapeutic interventions that have been proven to be effective in the management of WS1 endocrine complications are discussed.

A case report of a child with Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder. It is characterized by neonatal/ early onset non-autoimmune insulin dependent diabetes (permanent neonatal diabetes mellitus-PNDM) associated with spondyloepiphyseal dysplasia, tendency to skeletal fractures and growth retardation. We report a child with features of WRS, born to consanguineous parents and with an older sister having similar clinical features.

β Cell Replacement after Gene Editing of a Neonatal Diabetes-Causing Mutation at the Insulin Locus.

SummaryPermanent neonatal diabetes mellitus (PNDM) can be caused by insulin mutations. We generated induced pluripotent stem cells from fibroblasts of a patient with PNDM and undetectable insulin at birth due to a homozygous mutation in the translation start site of the insulin gene. Differentiation of mutant cells resulted in insulin-negative endocrine stem cells expressing MAFA, NKX6.1, and chromogranin A. Correction of the mutation in stem cells and differentiation to pancreatic endocrine cells restored insulin production and insulin secretion to levels comparable to those of wild-type cells. Grafting of corrected cells into mice, followed by ablating mouse β cells using streptozotocin, resulted in normal glucose homeostasis, including at night, and the stem cell-derived grafts adapted insulin secretion to metabolic changes. Our study provides proof of principle for the generation of genetically corrected cells autologous to a patient with non-autoimmune insulin-dependent diabetes. These cases should be readily amenable to autologous cell therapy.

Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome

Mutations in SLC29A3 lead to pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy plus syndrome. We report a new association of PHID syndrome with severe systemic inflammation, scleroderma-like changes, and cardiomyopathy. A 12-year-old girl with PHID syndrome presented with shortness of breath, hepatosplenomegaly, and raised erythrocyte sedimentation rate and C-reactive protein. An echocardiogram showed biventricular myocardial hypertrophy, and cardiac magnetic resonance imaging showed circumferential late gadolinium enhancement of the myocardium. No systemic amyloid deposits were observed on a whole-body serum amyloid P scintigraphy scan. Abdominal ultrasound revealed intra-abdominal fat surrounding the solid organs, suggesting a possibility of evolving lipodystrophy with visceral adiposity. PHID syndrome is a novel monogenic autoinflammatory syndrome (AIS) associated with severe elevation of serum amyloid. Lipodystrophy, cutaneous sclerodermatous changes, and cardiomyopathy were also present in this case. In contrast to other AIS, blockade of interleukin-1 and tumor necrosis-α was ineffective.

Major Histocompatibility Complex Class I-Deficient NOD-B2mnull Mice are Diabetes and Insulitis Resistant

Specific allelic combinations within the class II region of the major histocompatibility complex (MHC) represent a major genetic component for susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in humans. We produced and used a stock of NOD/Lt mice congenic for a functionally inactivated beta 2-microglobulin (B2mnull) locus to assess whether there was an absolute requirement for MHC class I expression and/or CD8+ T-cells in diabetogenesis. These NOD-B2mnull mice do not express cell surface MHC class I molecules or produce detectable levels of CD8+ T-cells and are diabetes and insulitis resistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic beta-cell function and can result in the development of nonautoimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molecules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect plasma insulin levels in either NOD/Lt mice or in those of a mixed 129 and C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia (> 1,500 pM) independent of the disrupted B2m locus, suggesting that these mice could conceivably develop insulin-resistant diabetes. However, none of these mice became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoimmune diabetes in NOD/Lt mice, without engendering a separate, distinct form of glucose intolerance.