Diabetes monogênico: Diabetes tipo MODY, Diabetes  Neontal / Monogenic diabetes: MODY Diabetes, Neonatal Diabetes

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.

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The use of glimepiride for the treatment of neonatal diabetes mellitus caused by a novel mutation of the ABCC8 gene

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0030 ◽

2020 ◽

Vol 33 (12) ◽

pp. 1605-1608

Author(s):

Xiao Qin ◽

Jingzi Zhong ◽

Dan Lan

Keyword(s):

Diabetes Mellitus ◽

Novel Mutation ◽

Male Infant ◽

Neonatal Diabetes ◽

Monogenic Diabetes ◽

Neonatal Diabetes Mellitus ◽

Rare Form ◽

Case Presentation ◽

Abcc8 Gene

AbstractObjectivesNeonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that is usually diagnosed in the first six months of life.Case presentationWe report on a male infant with neonatal diabetes who presented with diabetic ketoacidosis at two months and 16 days. A novel homozygous missense mutation (c.259T>G) was identified in the ABCC8 gene. In this case, insulin was replaced with glimepiride at a dosage of 0.49 mg/kg/day at five months, and this achieved metabolic control and satisfactory growth as observed at follow-up.ConclusionsThis report improves our understanding of the mutational spectrum of ABCC8, which is normally associated with NDM, and shows that the treatment regimen for this condition can be successfully switched from insulin therapy to the use of sulfonylurea.

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Neonatal Diabetes – From Gene Discovery yo Clinical Practice Changes

Romanian Journal of Diabetes Nutrition and Metabolic Diseases ◽

10.2478/rjdnmd-2013-0034 ◽

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

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

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0043-120571 ◽

2017 ◽

Vol 126 (10) ◽

pp. 612-618 ◽

Cited By ~ 3

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.

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

10.21203/rs.3.rs-76758/v1 ◽

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.

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

Journal of Endocrinology and Metabolism Research ◽

10.37191/mapsci-2582-7960-1(1)-006 ◽

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.

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Monogenic diabetes mellitus in Norway

Norsk Epidemiologi ◽

10.5324/nje.v23i1.1603 ◽

2013 ◽

Vol 23 (1) ◽

Cited By ~ 1

Author(s):

Oddmund Søvika ◽

Henrik Underthun Irgens ◽

Janne Molnes ◽

Jørn V. Sagena ◽

Lise Bjørkhaug ◽

...

Keyword(s):

Diabetes Mellitus ◽

Genetic Testing ◽

Correct Diagnosis ◽

Molecular Genetic ◽

Neonatal Diabetes ◽

Monogenic Diabetes ◽

University Hospital ◽

Diagnosis And Prognosis ◽

Hnf1a Gene ◽

Choice Of Therapy

Here, we review data on monogenic diabetes mellitus in Norway based on the Norwegian MODY Registry at Haukeland University Hospital, Bergen. This registry comprises established or suspected cases of maturity-onset diabetes of the young (MODY) referred to our laboratory for genetic testing. We also present data on neonatal diabetes, another group of monogenic diabetes. To date, we have genetically diagnosed nearly 500 MODY cases in Norway. Mutations in the HNF1A gene (MODY3) were detected in about 50% of families with clinical MODY. GCK-MODY (MODY2) was the second most prevalent type, but may be underreported. We have also found mutations in the monogenic genes ABCC8, CEL, HNF1B, HNF4A, INS, KCNJ11 and NEUROD1. Based on genetic screening in the Norwegian MODY Registry and HUNT2, we estimate the number of MODY cases in Norway to be at least 2500-5000. Founder effects may determine the geographical distribution of MODY mutations in Norway. The molecular genetic testing of MODY and neonatal diabetes is mandatory for correct diagnosis and prognosis as well as choice of therapy

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Monogenic diabetes mellitus and clinical implications of genetic diagnosis

Precision and Future Medicine ◽

10.23838/pfm.2021.00100 ◽

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.

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Monogenic Diabetes Mellitus: Neonatal Diabetes and Maturity-Onset Diabetes of the Young

Sperling Pediatric Endocrinology ◽

10.1016/b978-0-323-62520-3.00010-5 ◽

2021 ◽

pp. 279-298

Author(s):

Siri Atma W. Greeley ◽

Mary K. McCauley ◽

Louis H. Philipson ◽

Mark A. Sperling

Keyword(s):

Diabetes Mellitus ◽

Neonatal Diabetes ◽

Monogenic Diabetes ◽

Maturity Onset Diabetes ◽

Onset Diabetes

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

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001345 ◽

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.

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