Maturity-Onset Diabetes of the Young (MODY): Making the Right Diagnosis to Optimize Treatment

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Review

Maturity-Onset Diabetes of the Young (MODY): Making the Right Diagnosis to Optimize Treatment Shazhan Amed MD a,*, Richard Oram MD b,c a

Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom c Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 22 October 2015 Received in revised form 5 January 2016 Accepted 1 March 2016

Maturity onset diabetes of the young (MODY) is a rare but increasingly recognized cause of diabetes in young people. It is a monogenic disorder that typically presents at <25 years of age, is non-insulin dependent and is familial, with an autosomal dominant pattern of inheritance. The most common forms of MODY are caused by mutations in glucokinase and hepatic nuclear factor 1 alpha or 4 alpha genes and account for almost 80% of cases of MODY. MODY is commonly misdiagnosed as type 1 or type 2 diabetes and, as a result, patients are often inappropriately managed with insulin when they can be more effectively managed with oral sulfonylureas. Therefore, making the right diagnosis is critical for effective treatment as well as for genetic counselling and, more important, for patients’ quality of life. In this review, we aim to raise awareness about MODY among diabetes clinicians by describing key clinical and laboratory features of the most common forms of MODY, outlining features that might help to differentiate MODY from type 1 and type 2 diabetes and providing information about clinical tests and tools that might assist in identifying patients who are most likely to benefit from molecular genetic testing. © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Keywords: diabetes maturity onset diabetes of the young (MODY) monogenic glucokinase hepatic nuclear factor

r é s u m é Mots clés : diabète diabète de la maturité apparaissant chez le jeune (MODY) monogénique glucokinase facteur nucléaire hépatocytaire

Le diabète de la maturité apparaissant chez le jeune (MODY) est une cause rare, mais de plus en plus reconnue, de diabète chez les jeunes. Cette maladie monogénique qui se présente habituellement chez les jeunes de<25 ans est non insulinodépendante et familiale, et se transmet selon un mode autosomique dominant. Les formes les plus fréquentes de MODY sont causées par les mutations de la glucokinase et des gènes des facteurs nucléaires hépatocytaires HNF-1alpha et HNF-4alpha, et représentent près de 80 % des cas de MODY. On diagnostique souvent à tort le MODY comme étant un diabète de type 1 ou de type 2 et, par conséquent, on prend souvent en charge les patients de manière inappropriée par insuline alors qu’on peut les prendre en charge de manière plus efficace par les sulfamides hypoglycémiants par voie orale. Par conséquent, l’établissement d’un bon diagnostic est essentiel pour un traitement efficace ainsi que pour le conseil génétique, et plus important pour la qualité de vie des patients. Dans cette revue, nous avons pour objectif d’accroître la sensibilisation au MODY des cliniciens en diabète en décrivant les principales caractéristiques cliniques et biologiques des formes les plus fréquentes de MODY, en soulignant les caractéristiques qui aideraient à différencier le MODY du diabète de type 1 et de type 2 et en donnant des renseignements sur les examens et les outils cliniques qui aideraient à déterminer les patients qui sont plus susceptibles de bénéficier des tests de génétique moléculaire. © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Introduction The majority of cases of diabetes can be broadly classified into 2 categories: type 1 diabetes and type 2 diabetes, both of which are

* Address for correspondence: Shazhan Amed, MD, FRCPC, MSc, PH, Department of Pediatrics, British Columbia Children’s Hospital, SCOPE Initiative, 4480 Oak Street, ACB K4-206, Vancouver, British Columbia V6H 3V4, Canada. E-mail address: [email protected]

polygenic and result from interactions between genetic and environmental factors. In young people (<25 years of age), the most common subtype of diabetes is autoimmune type 1 diabetes (1). However, increasing rates of type 2 diabetes in youth and young adults and improved recognition of monogenic diabetes through advancements in the field of molecular genetics make the classification of diabetes subtype more complex. Accurate classification is very important because it determines treatment and impacts frequency of screening for diabetes-related complications and patients’

1499-2671 © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjd.2016.03.002

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quality of life. Accurate diagnoses are most dramatic in patients treated with insulin who, when confirmed to have maturityonset diabetes of the young (MODY), can stop insulin after being transitioned to an oral sulfonylurea. Monogenic diabetes is the term used to describe all subtypes of diabetes caused by defects in single genes, and it includes neonatal diabetes, syndromic forms and, most commonly, MODY. More than 40 different genetic subtypes of monogenic diabetes have been identified, each with its own phenotype and pattern of inheritance (2). Clinical presentation of monogenic diabetes can vary from the most severe phenotype of pancreatic agenesis with neonatal diabetes and exocrine insufficiency to milder phenotypes in which diabetes onset occurs in adolescence or young adulthood (3). MODY is the most common type of monogenic diabetes and is the result of mutations in genes that are responsible for the development or function of beta cells. MODY is characterized by autosomal-dominant inheritance with a multigenerational family history of diabetes, onset before 25 years of age and the absence of pancreatic autoimmunity (typical in type 1 diabetes) and insulin resistance (typical in type 2 diabetes) (4). The clinical features of MODY, however, overlap with those of type 1 diabetes and type 2 diabetes and, therefore, misdiagnosis of MODY as type 1 or type 2 diabetes is common, and most cases of MODY are missed (5). This leads to inappropriate therapy with insulin and/or insulinsensitizing oral agents (6,7). Diagnosing MODY in patients with diabetes is key to providing accurate counselling about the predicted clinical outcomes, genetic counselling and subsequent identification of affected family members and, most important, appropriate management; in many cases, insulin can be stopped altogether after initiating treatment with an oral sulfonylurea (2). This article reviews the most common forms of MODY and their key clinical characteristics and provides an approach to diagnosis and management. The objective of this review is to raise awareness of the clinical tools, approaches and investigations that might help to identify patients with the most common forms of MODY and, as a result, prevent the misdiagnosis or lack of diagnosis of these patients. Rare forms of MODY are beyond the scope of this review but have been described elsewhere (4).

Epidemiology MODY is likely to account for 1% to 2% of all cases of diabetes in children and young adults, but accurate, population-based prevalence estimates of MODY are difficult to obtain because the majority of cases are misclassified as type 1 or type 2 diabetes. The United Kingdom reports a minimum prevalence of 108 cases per million population over the age of 1 year (5). Among young people in the United States, the minimum prevalence increases to 2.1 per 100,000 individuals <20 years of age (6). The frequency of clinical features suggestive of MODY (i.e. measurable C-peptide, diabetes onset before 25 years of age, negative pancreatic autoimmunity, positive family history of diabetes) in pediatric patients seen in a single diabetes centre is between 10% and 20% (7,8). There are few estimates of the incidence of MODY. In a Canadian study, the minimum incidence rate of MODY was 0.4 cases per 100,000 children and youth <18 years of age per year (9). Pathophysiology and clinical features of MODY MODY was recognized as a disease entity in the early 1920s and, since then, significant progress has been made in understanding its pathophysiology. A hereditary form of diabetes was first described in 1928 (10), and in 1975 (11) MODY was formally characterized as diabetes occurring as a result of a defect in the beta cells of individuals <25 years of age with autosomal-dominant patterns of

inheritance. Today, 13 different causal genes have been identified as being associated with distinct subtypes of MODY with varying phenotypes (12). The most common forms of MODY are mutations in hepatocyte nuclear factor 4 alpha (HNF4A, MODY-1), glucokinase (GCK, MODY-2) and hepatocyte nuclear factor 1 alpha (HNF1A, MODY-3), all of which result in functional defects in the beta cells but vary in terms of age of onset, associated clinical features and severity of hyperglycemia. GCK and HNF1A mutations account for roughly 70% of all cases of MODY (13). Some cases of MODY occur as a result of de novo gene mutations. In a recently published study from 2 national centres in Eastern Europe, de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of patients who had clinical findings consistent with MODY but did not have the typical multigeneration family history of diabetes. De novo mutations causing MODY represented 1.2% of all referrals for MODY testing (14). Glucokinase-MODY (MODY 2) Glucokinase (GCK) serves as the glucose sensor of pancreatic beta cells. GCK is responsible for catalyzing glucose in the blood that is taken up at the surface of the beta cell by the glucose transporter 2 (GLUT2) to glucose-6-phosphate. The activity of GCK is directly proportional to blood glucose concentration and, therefore, GCK has direct control over insulin secretion. More than 600 mutations of the GCK gene have been described, with the majority in people from the United Kingdom, France and Spain (15). A heterozygous lossof-function mutation of GCK leads to a shift in the insulin doseresponse curve where insulin release is regulated at a slightly higher set point because the beta cells are less sensitive to glucose due to decreased GCK activity. The result is mildly elevated fasting and postprandial blood sugar levels that generally do not exceed 6.7 and 8.6 mmol/L, respectively, and continue to be under tight homeostatic control. Rarely, a homozygous inactivating mutation of GCK results in severe neonatal diabetes requiring insulin therapy, and an activating mutation of GCK has the opposite effect, resulting in neonatal hyperinsulinemic hypoglycemia (15). GCK-MODY is usually asymptomatic and includes laboratory evidence of mild hyperglycemia that does not typically result in longterm diabetes-related complications. The population prevalence of GCK-MODY is estimated to be 1.1 in 1000 (16). GCK-MODY usually presents as incidental fasting hyperglycemia (≥5.5 mmol/L in 98% of patients) in an otherwise asymptomatic individual, and it is persistent and stable over a period of months to years (17). An oral glucose tolerance test (OGTT) demonstrates a modest rise in 2-hour glucose levels that is less than 3 mmol/L and 4.6 mmol/L in 70% (17) and 95% (4) of patients, respectively. It has been suggested that a glucose increment in OGTTs of less than 4.6 mmol/L can be used to prioritize patients for molecular genetic testing (13). Typically, the glycated hemoglobin (A1C) levels in patients with GCK-MODY are at the upper limit of normal and rarely exceed 7.5%. A history of well-controlled diabetes in a parent is often elicited and, if not, fasting blood sugar levels should be measured in both parents. GCKMODY is rarely associated with diabetes-related micro- or macrovascular complications, and affected patients do not require treatment (18). It is important to note, however, that these patients have the same risk as the general population for development of polygenic type 2 diabetes. GCK-MODY often presents during pregnancy, when there is routine screening for diabetes, so pregnancy presents an opportune time to diagnose accurately GCK-MODY. The impact of diagnosing GCK-MODY in pregnant women is significant because it can save the patients from unnecessary and sometimes lifelong treatments. The estimated prevalence of GCK-MODY is 9 in 1000 women with gestestional diabetes mellitus (GDM) (16). Differentiating GCKMODY as a cause for GDM from other more common subtypes of

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Table 1 Features of the most common forms of maturity-onset diabetes of the young MODY-1

MODY-2

MODY-3

Gene (chromosome) Characteristics

HNF4A (20q13.12) Typically nonobese, without evidence of pancreatic autoimmunity or features of insulin resistance

GCK (7p15.3-p15.1) Mild, long-lasting, stable fasting hyperglycemia; homozygous mutations cause permanent neonatal diabetes

Extrapancreatic features

• •

None

HNF1A (12q24.2) Typically nonobese, without evidence of pancreatic autoimmunity or features of insulin resistance; often normoglycemic in childhood • Raised cardiovascular risk (in excess of type 2 diabetes) • Glycosuria at BG <10 mmol/L • Low hs-CRP • Normal or ↑ HDL <5.5 mmol/L >5.0 mmol/L Common Sensitive to sulfonylureas; may require insulin

• Fasting BG 120 – 0 minute BG increment Microvascular complications Management

Macrosomia Diazoxide responsive hyperinsulinemic hypoglycemia in infancy ↓ HDL, ↓ TG, ↑ LDL

<5.5 mmol/L >5.0 mmol/L Common Sensitive to sulfonylureas; may require insulin

5.5–8.5 mmol/L <3.0 mmol/L Rare Pharmacologic treatment rarely needed; treatment during pregnancy common

BG, blood glucose level; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; MODY, maturity-onset diabetes of the young; TG, triglyceride level.

GDM is important because each is managed differently; the mother does not have increased risk for type 2 diabetes postpregnancy, does not need treatment beyond pregnancy and is not at risk for diabetesrelated complications. Identifying GCK-MODY in pregnant women with GDM requires clinical criteria to guide referral for genetic testing, given that universal testing is neither practical nor feasible. Chakera et al, in a population-based study, compared pregnant women with GCK-MODY to those with GDM and found that fasting blood glucose levels and body mass indexes (BMIs) were predictors of GCK-MODY, whereas family history was nondiscriminatory. The authors suggest testing all pregnant women with normal prepregnancy BMIs and fasting blood glucose levels ≥5.5 mmol/L, which would detect almost 70% of patients and would require testing 2.7 patients to identify 1 true case (16). Fetal insulin secretion in response to maternal hyperglycemia plays a key role in fetal growth. The effects of GCK-MODY on the fetus depend on whether the fetus is affected. For example, babies without the mutation are exposed to maternal hyperglycemia and, as a result, are at risk for macrosomia and have an estimated 700 grams of excess body weight at birth. Babies with the mutation inherited from their mothers have similar homeostatic glucose set points and, therefore, are born with normal weights. However, if the mutation is inherited from the fathers, the babies are at risk of being born with low birth weights (19,20). In a comparison of adult offspring (mean age 40 years) born to mothers as opposed to fathers affected by GCK-MODY, although those born to affected mothers had higher birth weights by 450 grams (p<0.001), there was no difference or deterioration in glucose tolerance or beta cell function in adulthood (21). HNF1A-MODY (MODY 3) and HNF4A-MODY (MODY 1) HNF1A and HNF4A, in conjunction with a network of transcription factors, coordinate gene expression during embryonic development and, in the mature beta cell, regulate the expression of insulin as well as beta-cell development, proliferation and apoptosis. A mutation in the HNF1A or HNF4A gene results in an alteration of gene expression of proteins that are involved in glucose transport and glucose metabolism and also increases apoptosis of the beta cell (4). The progressive decline in beta-cell function that is often seen in these patients is likely to be the result of decreased beta-cell proliferation and increased beta-cell apoptosis. HNF1A MODY is 10 times more common than HNF4A MODY and is the most common cause of symptomatic familial diabetes (22). HNF1A mutations demonstrate high penetrance, in which 63% of mutation carriers develop diabetes before 25 years of age, 79% before 35 years and 96% before 55 years (23). Age at diagnosis is

partially dependent on the location of the mutation within the gene, where mutations affecting terminal exons 8 to 10 result in a clinical presentation that is, on average, 8 years later than mutations on exons 1 to 6 (24). HNF4A MODY accounts for only 3% to 5% of cases of MODY, and the penetrance of mutations is variable; most carriers develop diabetes before 25 years of age, but some do not develop diabetes until the fourth decade of life (4). HNF1A and HNF4A MODY present similarly but have some distinct clinical features. Both typically present during adolescence or young adulthood when beta-cell function has declined to the point of causing dysglycemia. A large glucose increment of >5 mmol/L is observed on OGTTs, but in the early stages of the disease, fasting blood glucose levels are commonly normal because of sufficient insulin secretory capacity to achieve fasting euglycemia. Patients are at similar risk for micro- and macrovascular complications as those with type 1 or type 2 diabetes, and glycemic control plays a critical role (4). Distinctive to HNF1A-MODY are extra-pancreatic features that might help differentiate it from other diabetes subtypes. HNF1AMODY mutations are associated with reduced expression of the sodium-glucose cotransporter 2 and reduced glucose reabsorption in the proximal tubule, resulting in low renal thresholds for glucose and glycosuria at blood glucose levels of <10 mmol/L (25). Also, these patients have higher than normal high-density lipoprotein (HDL) cholesterol concentrations (26); however, their risk for cardiovascular disease is not lowered but, rather, is reported to be higher than in patients with type 1 or type 2 diabetes (27). HNF4A-MODY also has unique extrapancreatic features, including reduced levels of HDL cholesterol, low triglyceride levels and high low-density lipoprotein (LDL) cholesterol levels. Also, 50% of patients are macrosomic at birth (28), and 15% of patients with HNF4A have histories of diazoxide-responsive neonatal hyperinsulinemic hypoglycemia (29,30); the mechanism is not well understood but might be related to HNF4A-dependent temporal gene expression or to early hypersecretion of insulin, resulting in later beta-cell exhaustion (28). (Table 1)

Making the Diagnosis A diagnosis of MODY should be suspected when there are clinical features that are not typical of type 1 diabetes:

• • • •

A family history of diabetes affecting 2 generations (i.e. 1 parent and a first-degree relative of the affected parent) Absence of pancreatic autoimmunity Low insulin requirements or significant c-peptide levels 5 years postdiagnosis (31) Stable, nonprogressive fasting hyperglycemia.

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Table 2 Canadian children <18 years of age clinically diagnosed with type 2 diabetes vs. maturity-onset diabetes of the young

Mean age (years)±SD % female % Caucasian % positive family history of diabetes % obese % acanthosis nigricans % comorbidity PCOS Dyslipidemia Hypertension ALT >90 U/L Mean BMI z-score (95% CI]

Type 2 diabetes (n=227)

MODY (n=31)

p value

13.7±2.5 57.8 24.4 84.8

9.8±6.5 58.1 71.0 86.2

0.003 1 <0.0001 0.5

95.1 73.5

15.8 6.7

<0.0001 <0.0001

8.4 44.2 28.6 21.7 2.08 (2.04, 2.12)

0 10 3.5 0 0.12 (−0.14, 0.64)

0.1 0.0002 0.002 0.003 <0.0001

ALT, alanine aminotransferase; BMI, body mass index; MODY, maturity-onset diabetes of the young; PCOS, polycystic ovary syndrome. Note: Amed et al, unpublished data.

Patients with MODY are often misclassified as having type 1 or type 2 diabetes and, as a result, are given inappropriate therapy. In the U.S. SEARCH for Diabetes in Youth study, only 6% of children and youth with confirmed MODY were correctly classified by their healthcare providers, and most were inappropriately treated with insulin or metformin (6). Studies from single diabetes centres report similar rates of misclassification of MODY, ranging from 5% to 7% (7,8). In 1 study, patients with clinical diagnoses of type 1 diabetes were offered genetic testing for MODY if there was at least 1 clinical characteristic that was unusual for type 1 diabetes (i.e. negative pancreatic antibodies, evidence of endogenous insulin production, a multigenerational family history of diabetes). No cases of MODY were identified among patients with only 1 atypical clinical characteristic; however, among those with 2 or more atypical characteristics, 50% had a genetic mutation associated with MODY (8). Therefore, these clinical criteria indicative of “non-type 1 diabetes” can be used to identify which patients are appropriate candidates for molecular genetic testing. Clinical features of MODY can overlap with type 1 or type 2 diabetes, making the diagnoses challenging. Young patients with type 1 or type 2 diabetes and MODY can similarly present with symptoms of weight loss, polyuria, polydipsia and nocturia. A positive family history and parental history of diabetes are reported at the same frequency in patients with MODY and type 2 diabetes (6,9). Positive pancreatic autoantibodies have been reported in 1% of patients with MODY (32). Identification of differentiating features of the various subtypes of diabetes can help to ensure initiation of the most appropriate treatments. In a study of Canadian children and youth with clinically diagnosed MODY and type 2 diabetes, those with MODY, rather than type 2 diabetes, were diagnosed at younger ages, were more likely to be Caucasian and were less likely to be obese or have acanthosis nigricans (Table 2). The U.S. SEARCH for Diabetes study did a similar comparison of youth with MODY (confirmed on genetic testing) vs. youth with measurable c-peptide and no pancreatic autoimmunity who tested negative for MODY and found that those with MODY had fewer type 2 diabetes-like features, including lower BMI z-scores, smaller waist circumferences (84.9±19.2 vs. 103.0±25.1; p=0.01) and higher insulin sensitivity indexes (6.5±0.3 vs. 5.6±0.1; p<0.01) (6). Unique to the Canadian Oji-Cree population is the HNF1A G319S variant, which confers earlier onset diabetes, less obesity and lower insulin levels in carriers of diabetes vs. noncarriers with a defect in insulin secretion resulting from reduced HNF1A activity (33). Differentiating this variant from HNF1A-MODY is a gene dosedependent gradient in the homozygote, heterozygote and wild-type

genotypes for severity of hyperglycemia at diagnosis, BMI, acanthosis nigricans, fasting insulin and insulin resistance (34). Biomarkers that effectively discriminate MODY from other forms of diabetes can be useful in identifying patients who would benefit from genetic testing for MODY. Pancreatic autoantibodies and serum or urine c-peptide levels can help to distinguish MODY from type 1 diabetes. Islet autoantibodies in patients with MODY (i.e. GAD and IA-2) are reported to occur at the same frequency as in the general population (<1%) (32). Therefore, their presence makes the diagnosis of MODY very unlikely; however, if clinical characteristics are strongly suggestive of MODY, genetic testing should be pursued. Islet autoantibodies reduce in prevalence with duration of diabetes, so they are most useful and most discriminative of type 1 diabetes soon after diagnosis (35). Unlike type 1 diabetes, endogenous insulin production in MODY persists after the honeymoon period, so it can be used to differentiate type 1 diabetes from MODY. A 120-minute postmeal, urine C-peptide creatinine ratio (UCPCR) can assess endogenous insulin accurately (36), and a UCPCR ≥0.2 nmol/mmol (collected after the largest meal) in patients >5 years postdiagnosis has 97% sensitivity and 96% specificity for differentiating HNF1A/ HNF4A MODY from type 1 diabetes (37). In children and youth with type 1 diabetes, UCPCR is significantly lower (0.05 nmol/mmol) compared to those with MODY (3.51 nmol/mmol) and type 2 diabetes (4.01 nmol/mmol) and is similarly sensitive and specific (31). A random blood C-peptide level of ≥0.2 nmol/L in those diagnosed younger than 30 years of age and of more than than 3 years’ duration has also been suggested to select patients for MODY testing (38). Therefore, an assessment of endogenous insulin, either in blood or urine, using appropriate cutoffs (39) is useful to identify those with persistent C-peptide levels >3 to 5 years after diagnosis who may benefit from genetic testing. The most discriminative biomarker of type 1 diabetes at diagnosis is autoantibody testing; <1% of patients with MODY are expected to be autoantibody positive. HDL-cholesterol levels are higher in HNF1A-MODY than in type 2 diabetes, so they can be used as biomarkers to help discriminate MODY from type 2 diabetes (26) in combination with other features, such as the absence of obesity, increased waist circumference and insulin resistance, which are commonly present in type 2 diabetes. High-sensitivity C-reactive protein (hs-CRP) has shown some promise in differentiating HNF1A-MODY from type 1 diabetes, type 2 diabetes and GCK-MODY. Levels of hs-CRP are significantly lower in patients with HNF1A-MODY (mean 0.20 mg/L) compared to those of patients with type 1 diabetes, type 2 diabetes or GCK-MODY (mean 0.81 mg/L) as well as to nondiabetic individuals (mean 0.48 mg/L). Combining hs-CRP with other clinical criteria achieves sensitivities and specificities that approach 80% in differentiating HNF1AMODY from other subtypes of diabetes (40). Molecular genetic testing using Sanger DNA sequencing is the gold standard for diagnosing MODY and is offered by specialist centres globally, including in the United Kingdom (see www.diabetesgenes.org) (4); however, universal genetic testing is not feasible so, therefore, clinical characteristics and the natural history of the disease must guide clinical decision making. Best-practice guidelines for molecular genetic testing have been published (13), and clinical tools exist to help clinicians identify which patients are best suited for molecular genetic testing. The MODY probability calculator is a clinical prediction model that is available online (http://www.diabetesgenes.org/content/mody-probability-calculator); it calculates the probability that an individual has MODY. In validation studies of this prediction model, Shields et al suggest that in patients not receiving insulin within 6 months of diagnoses, molecular genetic testing be initiated if the post-test probability of having monogenic diabetes is >25%. In individuals treated with insulin within 6 months of diagnosis, the implications of a positive genetic test are highly significant (i.e. subcutaneous insulin injections discontinued and therapy with an oral sulfonylurea initiated) and, therefore,

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molecular genetic testing should be initiated if the post-test probability is >10% (41). A Diabetes Diagnostics application that combines the MODY clinical prediction calculator with information from national and international diabetes guidelines as well as expert opinions from world leaders in monogenic diabetes is now available through the App Store for Apple devices. Management Diagnosing MODY accurately allows for initiation of the most suitable therapy and, more important, prevents inappropriate therapies. Patients with confirmed GCK-MODY do not need treatment except in the context of pregnancy and GDM. HNF1A and HNF4A MODY can be treated initially with diet and lifestyle modifications, but they may still experience high postprandial blood sugar levels. As beta cell function deteriorates over time, pharmacologic therapy becomes necessary to prevent diabetes-related complications. Patients with HNF1A and HNF4A are particularly sensitive to sulfonylureas (42), which are the most effective therapy and have been shown to result in better glycemic control than insulin therapy. Raile et al, in a comparison of youth with HNF1A-MODY treated with insulin alone vs. sulfonylureas or meglitinides (nonsulfonylurea insulin secretagogues), reported higher mean A1C levels in those taking insulin (7.5%) vs. oral agents (6.7%). Further, patients with HNF1A-MODY who are taking oral secretagogues alone rather than in combination with insulin had better glycemic control. There was no difference in the rates of severe hypoglycemia in those treated with insulin rather than oral secretagogues (43). The International Society for Pediatric and Adolescent Diabetes (ISPAD) clinical practice guidelines suggest an initial dose of sulfonylurea that is one-quarter of the normal adult starting dose in order to avoid hypoglycemia. Patients can often be maintained on low-dose sulfonylureas (i.e. 20 to 40 mg gliclazide daily) for decades (2). In patients who receive initial diagnoses of type 1 diabetes and are reclassified as having MODY on the basis of molecular diagnosis, the recommendation is to change drug treatment from insulin to sulfonylureas (2). Guidance for transferring patients confirmed to have MODY from insulin to sulphonylureas is also available at www.diabetesgenes.org. A recent study demonstrated that 40% of pediatric patients with HNF1A-MODY were still receiving insulin alone for management of their diabetes, indicating suboptimal uptake of the ISPAD guidelines (43). The fact that oral insulin secretagogues are not licensed for use in patients <18 years of age may contribute to this situation; however, increasing awareness of the ideal treatment of MODY in young people, particularly children and youth, is needed.

Conclusions MODY is a rare but increasingly well recognized cause of diabetes in young people, and it represents about 2% of all youth-onset diabetes. Misdiagnosis of MODY results in unnecessary treatment (i.e. insulin) and can significantly impact patients’ disease course and quality of life. Unfortunately, studies demonstrate that MODY is almost always misdiagnosed as type 1 or type 2 diabetes, emphasizing the need for both a more practiced approach to diagnosing diabetes subtypes in young people as well as improved access to genetic testing. Sophisticated clinical tools such as the MODY probability calculator are now available to help identify young patients with diabetes who might have MODY and would, therefore, benefit from genetic testing. Biomarkers (i.e. UCPCR≥0.2 nmol/mmol for differentiating HNF1A/4A MODY from type 1 diabetes and negative pancreatic autoimmunity), in combination with clinical characteristics, such as absence of insulin resistance and a multigenerational family history of diabetes, can help in identifying patients who should receive molecular

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genetic testing. Our understanding of MODY has advanced tremendously in the past 20 years, and it will continue to progress in the future. Our current knowledge, however, necessitates that MODY routinely become part of the differential diagnoses of diabetes subtypes in young people, that diabetologists recognize patients with potential diagnoses of MODY so as to prevent inappropriate management, and that access to molecular genetic testing become more widely available so that the right patients can be tested at the right times so they receive the right treatment.

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