scholarly journals Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations

2020 ◽  
Vol 9 (1) ◽  
pp. 288
Author(s):  
Maria I. Alvelos ◽  
Catarina I. Gonçalves ◽  
Eduarda Coutinho ◽  
Joana T. Almeida ◽  
Margarida Bastos ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Bioinformatics Analysis ◽  
Clinical Presentation ◽  
Maturity Onset Diabetes ◽  
Portuguese Population ◽  
Clinical Criteria ◽  
Onset Diabetes ◽  
Insulin Dependence ◽  
Functional Consequences ◽  
Hnf1a Gene

Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, p = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.

scholarly journals Mutations in NOTCH3 Gene may Promote the Clinical Presentation of Spinocerebellar Ataxia Type 37 Caused by Mutations in DAB1 Gene

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhao-Wei Wang ◽  
Li-Ping Wang ◽  
Ye Du ◽  
Qi Liu
Keyword(s):  
Spinocerebellar Ataxia ◽  
Sanger Sequencing ◽  
Autosomal Dominant ◽  
Bioinformatics Analysis ◽  
Clinical Presentation ◽  
Cerebellar Atrophy ◽  
Gene Mutations ◽  
Brain Magnetic Resonance Imaging ◽  
Diagnostic Methods ◽  
Spinocerebellar Ataxia Type

Background: Autosomal dominant spinocerebellar ataxia type 37 (SCA37) and Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) result from DAB1 and NOTCH3 gene mutations, respectively.Methods: In addition to conventional diagnostic methods, next-generation sequencing (NGS) and Sanger sequencing were performed to define and confirm the DAB1 and NOTCH3 gene mutation for a Chinese pedigree. Bioinformatics analysis was also applied for the mutated DAB1 and NOTCH3 protein using available software tools.Results: Brain magnetic resonance imaging shows diffuse leukoencephalopathy and cerebellar atrophy in the proband. NGS and Sanger sequencing identified two novel heterozygous mutations: NM_021080:c.318T > G (p.H106Q) in the DAB1 gene and NM_000435:c.3298C > T (p.R1100C) in the NOTCH3 gene. Bioinformatics analysis suggested that the DAB1 and NOTCH3 gene mutations are disease-causing and may be responsible for the phenotypes.Conclusion: This is the first report of a pedigree with both SAC37 and CADASIL phenotypes carrying corresponding gene mutations. Mutations in the NOTCH3 gene may promote the clinical presentation of spinocerebellar ataxia type 37 caused by mutations in the DAB1 gene. In addition to general examinations, it is vital for physicians to apply molecular genetics to get an accurate diagnosis in the clinic, especially for rare diseases.

Maturity-Onset Diabetes of the Young (MODY): Genetic Causes, Clinical Characteristics, Considerations for Testing, and Treatment Options

Endocrines ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 485-501
Author(s):  
Zoltan Antal
Keyword(s):  
Clinical Presentation ◽  
Clinical Symptoms ◽  
Treatment Options ◽  
Maturity Onset Diabetes ◽  
Onset Diabetes ◽  
Inappropriate Treatment ◽  
Monogenic Forms Of Diabetes ◽  
Initial Description

Maturity Onset Diabetes of the Young (MODY) encompasses a group of rare monogenic forms of diabetes distinct in etiology and clinical presentation from the more common forms of Type 1 (autoimmune) and Type 2 diabetes. Since its initial description as a clinical entity nearly 50 years ago, the underlying genetic basis for the various forms of MODY has been increasingly better elucidated. Clinically, the diagnosis may be made in childhood or young adulthood and can present as overt hyperglycemia requiring insulin therapy or as a subtle form of slowly progressive glucose impairment. Due to the heterogeneity of clinical symptoms, patients with MODY may be misdiagnosed as possessing another form of diabetes, resulting in potentially inappropriate treatment and delays in screening of affected family members and associated comorbidities. In this review, we highlight the various known genetic mutations associated with MODY, clinical presentation, indications for testing, and the treatment options available.

scholarly journals Clinical Characteristics and Diagnostic Criteria of Maturity-Onset Diabetes Of The Young (MODY) due to Molecular Anomalies of the HNF1A Gene

2011 ◽  
Vol 96 (8) ◽  
pp. E1346-E1351 ◽  
Author(s):  
Christine Bellanné-Chantelot ◽  
David Joseph Lévy ◽  
Claire Carette ◽  
Cécile Saint-Martin ◽  
Jean-Pierre Riveline ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Clinical Characteristics ◽  
Maturity Onset Diabetes ◽  
Onset Diabetes ◽  
Hnf1a Gene

scholarly journals Monogenic diabetes: a new pathogenic variant of HNF1A gene

2021 ◽  
Vol 14 (1) ◽  
pp. e231837
Author(s):  
Raquel Vilela Oliveira ◽  
Teresa Bernardo ◽  
Sandrina Martins ◽  
Ana Sequeira
Keyword(s):  
Diabetes Mellitus ◽  
Genetic Test ◽  
Early Recognition ◽  
Single Gene ◽  
Signs And Symptoms ◽  
Oral Glucose ◽  
Maturity Onset Diabetes ◽  
Onset Diabetes ◽  
Fast Absorption ◽  
Hnf1a Gene

Maturity onset diabetes of the young defines a diabetes mellitus subtype, with no insulin resistance or autoimmune pancreatic β-cells dysfunction, that occurs by mutation in a single gene. A 13-year-old girl hospitalised due to hyperglycemia plus glycosuria without ketosis, and with normal glycated haemoglobin of 6.8%. She started a sugar-free fast-absorption diet and no insulin therapy was required. Fasting glucose was normal, but 2 hours after lunch she presented hyperglycemia as after 2 hours of an oral glucose tolerance test, with 217 mg/dL. Family history was positive for type 2 diabetes mellitus with an autosomal dominant pattern. She was discharged with fast-absorption sugar-free diet and low-dose of sulfonylurea. A genetic test was performed detecting a mutation in heterozygosity of HNF1A gene, compatible with the diagnosis of maturity onset diabetes of the young 3 (MODY3), not reported in the literature. Early recognition of signs and symptoms increase awareness of MODY. Genetic test allows confirmation and leads to optimised treatment.

scholarly journals Novel glucokinase mutation in a boy with maturity-onset diabetes of the young

2008 ◽  
Vol 136 (9-10) ◽  
pp. 542-544 ◽  
Author(s):  
Tatjana Milenkovic ◽  
Dragan Zdravkovic ◽  
Katarina Mitrovic
Keyword(s):  
Autosomal Dominant ◽  
Molecular Level ◽  
Dominant Mode ◽  
Maturity Onset Diabetes ◽  
Primary Defect ◽  
Glucokinase Gene ◽  
Onset Diabetes ◽  
Heterogenous Group ◽  
Glucokinase Mutation ◽  
Mode Of Inheritance

INTRODUCTION Maturity-onset diabetes of the young (MODY) is a heterogenous group of disorders characterized by an early onset of insulin-independent diabetes mellitus, an autosomal dominant mode of inheritance and a primary defect in beta-cell. There are six subtypes of MODY. MODY2 and MODY3 are the most frequent. CASE OUTLINE We present a nine-year-old boy with intermittent hyperglycaemia. According to family history, the diagnosis of MODY2 was suspected. Molecular analysis revealed novel missense mutation R250c in exon 7 of glucokinase gene. Mutation (c.748 C>T) is the result of substitution of aminoacid cysteine by arginine (p.Arg250Cys). This is the first pediatric patient with MODY2 in Serbia whose diagnosis is established at molecular level. CONCLUSION Molecular diagnosis of MODY has important consequences in terms of prognosis, therapy and family screening of the disorder. Investigation of other patients with MODY2 in our country is important to establish prevalence and nature of mutations in glucokinase gene.

scholarly journals Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

2021 ◽  
Vol 12 ◽  
Author(s):  
Mariam Moalla ◽  
Wajdi Safi ◽  
Maab Babiker Mansour ◽  
Mohamed Hadj Kacem ◽  
Mona Mahfood ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Clinical Investigation ◽  
Direct Sequencing ◽  
Short Review ◽  
Tunisian Population ◽  
Maturity Onset Diabetes ◽  
Clinical Criteria ◽  
Pathogenic Variants ◽  
Onset Diabetes ◽  
And Function

Introduction/AimsMaturity-Onset Diabetes of the Young (MODY) is a monogenic non-autoimmune diabetes with 14 different genetic forms. MODY-related mutations are rarely found in the Tunisian population. Here, we explored MODY related genes sequences among seventeen unrelated Tunisian probands qualifying the MODY clinical criteria.Materials and MethodsThe GCK and HNF1A genes were systematically analyzed by direct sequencing in all probands. Then, clinical exome sequencing of 4,813 genes was performed on three unrelated patients. Among them, 130 genes have been reported to be involved in the regulation of glucose metabolism, β-cell development, differentiation and function. All identified variants were analyzed according to their frequencies in the GnomAD database and validated by direct sequencing.ResultsWe identified the previously reported GCK mutation (rs1085307455) in one patient. The clinical features of the MODY2 proband were similar to previous reports. In this study, we revealed rare and novel alterations in GCK (rs780806456) and ABCC8 (rs201499958) genes with uncertain significance. We also found two likely benign alterations in HNF1A (rs1800574) and KLF11 (rs35927125) genes with minor allele frequencies similar to those depicted in public databases. No pathogenic variants have been identified through clinical exome analysis.ConclusionsThe most appropriate patients were selected, following a strict clinical screening approach, for genetic testing. However, the known MODY1-13 genes could not explain most of the Tunisian MODY cases, suggesting the involvement of unidentified genes in the majority of Tunisian affected families.

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