Phenotypic variability in two siblings with monogenic diabetes due to the same
            <i>ABCC8</i>
            gene mutation

Cattoni, Alessandro; Jackson, Charlotte; Bain, Murray D.; Houghton, Jayne; Wei, Christina

doi:10.1111/pedi.12826

Cited by 12 publications

(4 citation statements)

References 21 publications

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“…This may or may not be accompanied by documented hyper‐ or hypoglycaemia in the neonatal period, either in the index case or a relative with the same mutation . There is also the possibility of a significant discordance in the correlation between genotype and phenotype ABCC8 mutation‐dependent diabetes that occurs within the same family . The mechanisms leading to this variable penetrance in the neonatal period are not fully understood and may differ according to whether the mutation is causing a gain or loss of channel function.…”

Section: Introductionmentioning

confidence: 99%

Phenotype, genotype and glycaemic variability in people with activating mutations in the ABCC8 gene: response to appropriate therapy

et al. 2019

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Aims To examine the phenotypic features of people identified with ABCC8-maturity-onset diabetes of the young (MODY) who were included in the adult 'Mater MODY' cohort and to establish their response to sulfonylurea therapy. Methods Ten participants with activating ABCC8 mutations were phenotyped in detail. A 2-hour oral glucose tolerance test was performed to establish glycaemic tolerance, with glucose, insulin and C-peptide measurements taken at baseline and 30-min intervals. Insulin was discontinued and sulfonylurea therapy initiated after genetic diagnosis of ABCC8-MODY. A blinded continuous glucose monitoring sensor was used to establish glycaemic control on insulin vs a sulfonylurea. ResultsThe mean age at diagnosis of diabetes was 33.8 AE 11.1 years, with fasting glucose of 18.9 AE 11.5 mmol/l and a mean (range) HbA 1c of 86 (51,126) mmol/mol [10.0 (6.8,13.7)%]. Following a genetic diagnosis of ABCC8-MODY three out of four participants discontinued insulin (mean duration 10.6 AE 1.69 years) and started sulfonylurea treatment. The mean (range) HbA 1c prior to genetic diagnosis was 52 (43,74) mmol/mol (6.9%) and the post-treatment change was 44 (30,57) mmol/mol (6.2%; P=0.16). Retinopathy was the most common microvascular complication in this cohort, occurring in five out of 10 participants.Conclusions Low-dose sulfonylurea therapy resulted in stable glycaemic control and the elimination of hypoglycaemic episodes attributable to insulin therapy. The use of appropriate therapy at the early stages of diabetes may decrease the incidence of complications and reduce the risks of hypoglycaemia associated with insulin therapy.

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Section: Introductionmentioning

confidence: 99%

Phenotype, genotype and glycaemic variability in people with activating mutations in the ABCC8 gene: response to appropriate therapy

et al. 2019

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“…In contrast, far fewer MODY families with heterozygous ABCC8 [ 44 , 45 , 46 ] and KCNJ11 [ 47 , 48 ] mutations have been described worldwide.…”

Section: Abcc8 and Kcnj11mentioning

confidence: 99%

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

Marucci

Rutigliano

Fini

et al. 2022

Genes

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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.

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“…Dominant missense gain-of-function mutations in the ABCC8 gene, coding for the sulfonylurea receptor 1 (SUR1) may cause MODY12 (a rare form of MODY that accounts for less than 1% of all MODY cases (Firdous et al, 2018) and transient or permanent neonatal diabetes mellitus (Gloyn et al, 2006, Mohan et al, 2018, Voevoda et al, 2016, Johnson et al, 2018, Fantes et al, 1995, Verkarre et al, 1998, Thornton et al, 2003, Henwood et al, 2005, Reis et al, 2000, Laukkanen et al, 2004, Meirhaeghe et al, 2001, Proks et al, 2006, Babenko et al, 2006, Shima et al, 2018, Cattoni et al, 2019. Recently, recessive ABCC8 gain-of-function mutations were also reported as causal of neonatal diabetes in two unrelated patients expanding the mode of inheritance of this pathology (Flanagan et al, 2017).…”

Section: Genetic Alteration and Clinical Phenotypementioning

confidence: 99%

Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes

Caballero

Gorgogietas

Arroyo

et al. 2021

International Review of Cell and Molecular Biology

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Monogenetic forms of diabetes represent 1% to 5% of all diabetes cases and are caused by mutations in a single gene. These mutations, affecting genes involved in pancreatic β-cell development, function and survival or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The abundance of each monogenic form of the disease and the severity of their symptoms depend on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, between others. The age of diabetes onset may also vary from neonatal presentations until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycaemic drugs e.g. sulfonylureas or glucagon like peptide 1 analogs to control their normoglycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired β-cell function and survival, and discuss the molecular mechanisms involved in β-cell demise.

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Phenotypic variability in two siblings with monogenic diabetes due to the same ABCC8 gene mutation

Cited by 12 publications

References 21 publications

Phenotype, genotype and glycaemic variability in people with activating mutations in the ABCC8 gene: response to appropriate therapy

Phenotype, genotype and glycaemic variability in people with activating mutations in the ABCC8 gene: response to appropriate therapy

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

Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes

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