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Clinical Implications of a Molecular Genetic Classification of Monogenic Beta-cell Diabetes

Authors: Rinki Murphy, MBChB ; Sian Ellard, PhD, MRCPath ; Andrew T Hattersley, BMBCh, MA, DM, FRCPFaculty and Disclosures


Summary and Introduction


Monogenic diabetes resulting from mutations that primarily reduce β-cell function accounts for 1-2% of diabetes cases, although it is often misdiagnosed as either type 1 or type 2 diabetes. Knowledge of the genetic etiology of diabetes enables more-appropriate treatment, better prediction of disease progression, screening of family members and genetic counseling. We propose that the old clinical classifications of maturity-onset diabetes of the young and neonatal diabetes are obsolete and that specific genetic etiologies should be sought in four broad clinical situations because of their specific treatment implications. Firstly, diabetes diagnosed before 6 months of age frequently results from mutation of genes that encode Kir6.2 (ATP-sensitive inward rectifier potassium channel) or sulfonylurea receptor 1 subunits of an ATP-sensitive potassium channel, and improved glycemic control can be achieved by treatment with high-dose sulfonylureas rather than insulin. Secondly, patients with stable, mild fasting hyperglycemia detected particularly when they are young could have a glucokinase mutation and might not require specific treatment. Thirdly, individuals with familial, young-onset diabetes that does not fit with either type 1 or type 2 diabetes might have mutations in the transcription factors HNF-1a (hepatocyte nuclear factor 1-α) or HNF-4α, and can be treated with low-dose sulfonylureas. Finally, extrapancreatic features, such as renal disease (caused by mutations in HNF-1β) or deafness (caused by a mitochondrial m.3243A>G mutation), usually require early treatment with insulin.


Since 1992, numerous genetic subtypes of diabetes have been described in which gene mutations result in diabetes primarily through β-cell dysfunction. This knowledge means that patients who were previously categorized clinically as having maturity-onset diabetes of the young (MODY), permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus (TNDM) can now usually be classified by genetic subgroup. Definition of the genetic subgroup can result in appropriate treatment, genetic counseling and prognostic information.

In this article we describe the challenge of identifying the minority of patients who have monogenic β-cell diabetes (1-2% of all diabetes cases) amongst the vast majority who have type 1 or 2 diabetes. First, we discuss why we think the term MODY might be outdated. Next, we describe how to differentiate monogenic diabetes from other types of diabetes. We then outline the monogenic β-cell forms of diabetes under the following four main phenotypic categories for clearer clinical identification: diabetes diagnosed before 6 months of age (which is usually associated with mutations in Kir6.2 or sulfonylurea receptor 1 [SUR1], or with abnormalities in chromosome 6q24); familial, mild fasting hyperglycemia (asso ciated with glucokinase mutation); familial, young-onset diabetes (associated with HNF1 homeobox A gene [HNF1A; previously termed TCF1] or HNF4 homeobox Agene [HNF4A]); and diabetes with extra pancreatic features (associated with HNF1 homeobox B gene [HNF1B; previously termed TCF2] or mitochondrial m.3243A>G mutation).

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