Monogenic Diabetes Not Caused By Mutations in Mody Genes: A Very Heterogenous Group of Diabetes

2017 ◽  
Vol 126 (10) ◽  
pp. 612-618 ◽  
Author(s):  
Zeynep Şıklar ◽  
Elisa de Franco ◽  
Matthew Johnson ◽  
Sarah Flanagan ◽  
Sian Ellard ◽  
...  
Keyword(s):  
Immune System ◽  
Beta Cells ◽  
Age Of Onset ◽  
Single Gene ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Pediatric Endocrinology ◽  
Immune System Dysfunction ◽  
Heterogenous Group ◽  
Type 1 Dm

AbstractMonogenic diabetes represents a heterogeneous group of disorders resulting from a single gene defect leading to disruption of insulin secretion or a reduction in the number of beta cells. Despite the classification of monogenic diabetes into neonatal diabetes or maturity onset diabetes of the young (MODY) according to age of onset, not every case can be classified into those 2 groups. We evaluated patients with monogenic diabetes diagnosed during the last 10 year period. Type 1 DM, MODY, and patients with negative autoantibodies and no mutation in a known gene were excluded from the study. Thirteen patients were diagnosed with monogenic diabetes in Department of Pediatric Endocrinology, Ankara University School of Medicine, Ankara, Turkey. Five of them were diagnosed after 6 months of age. Five had a KATP channel defect. Mutations in genes resulting in destruction of beta cells were detected in 7 patients, with 4 cases having a WFS, 2 an LRBA, and one a IL2RA mutation. Additional systemic findings were seen in 6/13 patients, with 5/6 having severe immune system dysfunction. Treatment with sulphonylurea was successful in two patients.. The other patients were given insulin in differing doses. Four patients died during follow-up, three of which had immune system dysfunction. Monogenic diabetes can be diagnosed after 6 months of age, even with positive autoantibodies. Immune dysfunction was a common feature in our cohort and should be investigated in all patients with early-onset monogenic diabetes. Mortality of patients with monogenic diabetes and additional autoimmunity was high in our cohort and is likely to reflect the multisystem nature of these diseases.

Neonatal Diabetes – From Gene Discovery yo Clinical Practice Changes

2013 ◽  
Vol 20 (3) ◽  
pp. 343-352
Author(s):  
Cristian Guja ◽  
Loreta Guja ◽  
Constantin Ionescu-Tîrgovişte
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Single Gene ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Special Focus ◽  
Sulphonylurea Treatment ◽  
The Common

Abstract Diabetes mellitus is one of the most common chronic diseases but also one of the most heterogeneous. Apart the common phenotypes of type 1 and type 2 diabetes, around 1-2% of all cases arise from a single gene mutation and are known as monogenic diabetes. Diabetes diagnosed within the first 6 months of life is known as neonatal diabetes and has been extensively studied during the last two decades. Unraveling the genetic cause and molecular mechanism of this rare diabetes phenotype led to a dramatic change in the treatment of these children who often can be switched from insulin to sulphonylurea treatment. The aim of this paper is to review the known genetic causes of neonatal diabetes and to highlight the most recent aspects of the disease caused by mutations in the KATP and insulin genes, with a special focus on the individualized treatment of these cases

scholarly journals Etiologic spectrum and clinical characteristics of pediatric diabetes among 276 children and adolescents with diabetes in a single academic center

2020 ◽  
Author(s):  
Ja Hye Kim ◽  
Yena Lee ◽  
Yunha Choi ◽  
Gu-Hwan Kim ◽  
Han-Wook Yoo ◽  
...  
Keyword(s):  
Clinical Features ◽  
Clinical Characteristics ◽  
Neonatal Diabetes ◽  
Wolfram Syndrome ◽  
Monogenic Diabetes ◽  
Molecular Characteristics ◽  
Pediatric Endocrinology ◽  
Academic Center ◽  
Pediatric Diabetes ◽  
Tertiary Center

Abstract Background The prevalence of monogenic diabetes is estimated to be 1–5% of patients with diabetes mellitus (DM). The overlapping clinical features of various forms of diabetes make differential diagnosis challenging. Therefore, this study investigated the etiologic distribution and clinical characteristics of pediatric diabetes, including monogenic diabetes, in a single tertiary center over the last 20 years. Methods This study included 276 consecutive patients with DM diagnosed before 18 years of age from January 2000 to December 2019. Clinical features, biochemical findings, β-cell autoantibodies, and molecular characteristics were reviewed retrospectively. Results Of the 276 patients, 206 patients (74.6%), 49 patients (17.8%), and 21 patients (7.6%) were diagnosed with type 1 DM, type 2 DM, and clinically suspected monogenic diabetes, respectively. Among 21 patients with suspected monogenic diabetes, 8 patients had clinical maturity-onset diabetes of the young (MODY), and the remaining 13 patients had other types of monogenic diabetes. Among them, genetic etiologies were identified in 14 patients (5.1%) from 13 families, which included MODY 5, transient neonatal DM, developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, Wolfram syndrome, Donohue syndrome, IPEX syndrome, Fanconi-Bickel syndrome, Wolcott-Rallison syndrome, cystic fibrosis-related diabetes, and maternally inherited diabetes and deafness. Conclusions Genetically confirmed monogenic diabetes accounts for 5.1% of patients referred to pediatric endocrinology clinics. The frequency of mutations in the major genes of MODY is low among pediatric patients in Korea. Identification of the genetic cause of DM is critical to provide appropriate therapeutic options and genetic counseling.

scholarly journals Monogenic Diabetes due to ABCC8/KCNJ11 Mutation: Case Study and Review of Literature

2020 ◽  
Author(s):  
Gul Bano
Keyword(s):  
Single Gene ◽  
Adult Population ◽  
Early Adulthood ◽  
Gene Mutations ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Effective Manner ◽  
Kcnj11 Gene ◽  
Mitochondrial Diabetes ◽  
The Family

Monogenic diabetes arises due to mutation in a single-gene and is recognized by their striking familial inheritance pattern. This form of diabetes is inherited in an autosomal dominant or recessive fashion, unlike polygenic Type 1 (autoimmune) or type 2 diabetes caused by the combined action of more than one gene [1-11]. Monogenic diabetes is classified into three main groups: Neonatal diabetes mostly presents in the first six months of birth, maturity onset diabetes of the young (MODY) and maternally inherited mitochondrial diabetes. These mutations run in the family and have a predictable course. Most of the monogenic diabetes is treated with oral medications like sulfonylurea rather than insulin. ABCC8/KCNJ11 gene mutations also cause monogenic diabetes. This gene mutation has been found in ~50% of congenital hyperinsulinemia (CHI) patients. In such cases diabetes commonly presents in the neonatal period (transient or permanent) or at adolescence / early adulthood [1]. We present a 58-year-old diabetic lady, who was detected with ABCC8 mutation during the cascade testing [8]. She was diagnosed with diabetes at the age of 12 [8]. Her son had history of neonatal hypoglycaemia and developed diabetes at the age of 15. He was the index case who was found to have ABCC8 mutation. The family has several other members diagnosed with diabetes. The aim of the article is to increase awareness and understanding of monogenic diabetes among the medical practitioners in adult population with diabetes so that the genetic testing can be offered in a cost effective manner.

scholarly journals Monogenic diabetes mellitus and clinical implications of genetic diagnosis

2021 ◽  
Vol 5 (3) ◽  
pp. 106-116
Author(s):  
Eungu Kang ◽  
Lindsey Yoojin Chung ◽  
Yu Jin Kim ◽  
Kyung Eun Oh ◽  
Young-Jun Rhie
Keyword(s):  
Diabetes Mellitus ◽  
Cell Function ◽  
Single Gene ◽  
Genetic Diagnosis ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Clinical Implications ◽  
High Dose ◽  
Activating Mutations ◽  
Β Cell Function

Monogenic diabetes mellitus, which is diabetes caused by a defect in a single gene that is associated with β cell function or insulin action, accounts for 1% to 6% of all pediatric diabetes cases. Accurate diagnosis is important, as the effective treatment differs according to genetic etiology in some types of monogenic diabetes: high-dose sulfonylurea treatment in neonatal diabetes caused by activating mutations in KCNJ11 or ABCC8; low-dose sulfonylurea treatment in HNF1A/HNF4A-diabetes; and no treatment in GCK diabetes. Monogenic diabetes should be suspected by clinicians for certain combinations of clinical features and laboratory results, and approximately 80% of monogenic diabetes cases are misdiagnosed as type 1 diabetes or type 2 diabetes. Here, we outline the types of monogenic diabetes and the clinical implications of genetic diagnosis.

scholarly journals Molecular and clinical characteristics of monogenic diabetes mellitus in southern Chinese children with onset before 3 years of age

2020 ◽  
Vol 8 (1) ◽  
pp. e001345
Author(s):  
Yunting Lin ◽  
Huiying Sheng ◽  
Tzer Hwu Ting ◽  
Aijing Xu ◽  
Xi Yin ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Genetic Testing ◽  
Age Of Onset ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Chinese Patients ◽  
Combination Strategy ◽  
Southern Chinese ◽  
Whole Exome ◽  
Design And Methods

IntroductionA specific molecular diagnosis of monogenic diabetes mellitus (MDM) will help to predict the clinical course and guide management. This study aims to identify the causative genes implicated in Chinese patients with MDM with onset before 3 years of age.Research design and methods71 children with diabetes mellitus (43 diagnosed before 6 months of age, and 28 diagnosed between 6 months and 3 years of age who were negative for diabetes-associated autoantibodies) underwent genetic testing with a combination strategy of Sanger sequencing, chromosome microarray analysis and whole exome sequencing. They were categorized into four groups according to the age of onset of diabetes (at or less than 6 months, 6 to 12 months, 1 to 2 years, 2 to 3 years) to investigate the correlation between genotype and phenotype.ResultsGenetic abnormalities were identified in 39 of 71 patients (54.93%), namely KCNJ11 (22), ABCC8 (3), GCK (3), INS (3), BSCL2 (1) and chromosome abnormalities (7). The majority (81.40%, 35/43) of neonatal diabetes diagnosed less than 6 months of age and 33.33% (3/9) of infantile cases diagnosed between 6 and 12 months of age had a genetic cause identified. Only 11.11% (1/9) of cases diagnosed between 2 and 3 years of age were found to have a genetic cause, and none of the 10 patients diagnosed between 1 and 2 years had a positive result in the genetic analysis. Vast majority or 90.48% (19/21) of patients with KCNJ11 (19) or ABCC8 (2) variants had successful switch trial from insulin to oral sulfonylurea.ConclusionsThis study suggests that genetic testing should be given priority in diabetes cases diagnosed before 6 months of age, as well as those diagnosed between 6 and 12 months of age who were negative for diabetes-associated autoantibodies. This study also indicates significant impact on therapy with genetic cause confirmation.

scholarly journals A RARE CASE OF A YOUNG INFANT WITH MONOGENIC DIABETES MELLITUS AND CENTRAL VENOUS SINUS THROMBOSIS

2020 ◽  
pp. 32-33
Author(s):  
Payal Patil ◽  
Rajesh Kulkarni ◽  
Aarti Kinikar
Keyword(s):  
Diabetes Mellitus ◽  
Autosomal Dominant ◽  
Sinus Thrombosis ◽  
Single Gene ◽  
Young Infant ◽  
Neonatal Diabetes ◽  
Female Child ◽  
Monogenic Diabetes ◽  
Permanent Neonatal Diabetes ◽  
Glucose Levels

Diabetes mellitus is a metabolic disease characterised by chronically high glucose levels. Genetic factors have been implicated in the etiology following mutations in a single gene. An extremely rare form of diabetes mellitus is monogenic diabetes, a subset of which is permanent neonatal diabetes which is usually suspected in a child less than 6 months presenting with hyperglycaemia. We are reporting case of a 40 days old female child with an autosomal dominant INS gene mutation which results in permanent neonatal diabetes in infants requiring lifelong insulin therapy.

Monogenic forms of diabetes resulting from β‎ cell dysfunction

2011 ◽  
pp. 1754-1759
Author(s):  
Rachel Besser ◽  
Andrew Hattersley
Keyword(s):  
Clinical Phenotype ◽  
Single Gene ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Maturity Onset Diabetes ◽  
Monogenic Disorders ◽  
Cell Dysfunction ◽  
Onset Diabetes ◽  
Monogenic Forms Of Diabetes ◽  
Clinical Category

Monogenic diabetes refers to diabetes resulting from mutations in a single gene. This chapter discusses monogenic disorders causing β‎ cell dysfunction, which accounts for the majority of cases of monogenic diabetes. Patients can usually be divided into three clinical categories: maturity-onset diabetes of the young (MODY), which is dominantly inherited familial diabetes; neonatal diabetes, diagnosed under the age of 6 months; and monogenic diabetes syndromes, which are characterized by multiple nonpancreatic features. In each clinical category, there are several aetiological genes that usually result in a discrete clinical phenotype.

scholarly journals Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 117
Author(s):  
Antonella Marucci ◽  
Irene Rutigliano ◽  
Grazia Fini ◽  
Serena Pezzilli ◽  
Claudia Menzaghi ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Precision Medicine ◽  
Genetic Disorder ◽  
Single Gene ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Maturity Onset Diabetes ◽  
Patients With Diabetes ◽  
Clinical Strategy

Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1–5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions (“actionable genes”). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in “actionable genes”, including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.

Monogenic Diabetes: Genetics and Relevance on Diabetes Mellitus Personalized Medicine

2020 ◽  
Vol 16 (8) ◽  
pp. 807-819 ◽  
Author(s):  
Madalena Sousa ◽  
Jácome Bruges-Armas
Keyword(s):  
Diabetes Mellitus ◽  
Complex Disease ◽  
Clinical Manifestations ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Diabetes Genetics ◽  
Individualize Treatment

Background: Diabetes mellitus (DM) is a complex disease with significant impression in today's world. Aside from the most common types recognized over the years, such as type 1 diabetes (T1DM) and type 2 diabetes (T2DM), recent studies have emphasized the crucial role of genetics in DM, allowing the distinction of monogenic diabetes. Methods: Authors did a literature search with the purpose of highlighting and clarifying the subtypes of monogenic diabetes, as well as the accredited genetic entities responsible for such phenotypes. Results: The following subtypes were included in this literature review: maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM) and maternally inherited diabetes and deafness (MIDD). So far, 14 subtypes of MODY have been identified, while three subtypes have been identified in NDM - transient, permanent, and syndromic. Discussion: Despite being estimated to affect approximately 2% of all the T2DM patients in Europe, the exact prevalence of MODY is still unknown, accentuating the need for research focused on biomarkers. Consequently, due to its impact in the course of treatment, follow-up of associated complications, and genetic implications for siblings and offspring of affected individuals, it is imperative to diagnose the monogenic forms of DM accurately. Conclusion: Currently, advances in the genetics field allowed the recognition of new DM subtypes, which until now, were considered slight variations of the typical forms. Thus, it is imperative to act in the close interaction between genetics and clinical manifestations, to facilitate diagnosis and individualize treatment.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

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