Approach to the Patient with MODY-Monogenic Diabetes

Abstract

Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These diagnoses are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multi-generation family history, lab evaluation (HbA1c, glutamic acid decarboxylase antibodies (GADA), islet antigen 2 antibodies (IA-2A), and Zinc Transporter 8 antibodies (ZnT8)). The presence of clinical features with 3 (or more) negative antibodies is indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (> 25% PPV suggestive of MODY) and 2-hour post-prandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a > 0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from Type 1 Diabetes) 1,2. Treatment, as well monitoring for microvascular and macrovascular complications is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first line therapy (historically sulfonylurea treatment in many variants).

Discoveries from the study of longstanding type 1 diabetes

“…It is necessary to acknowledge that these study populations may include individuals with a classification of diabetes other than type 1. For example, monogenic diabetes variants (especially the more common HNF1α and HNF4α [also known as HNF1A and HNF4A, respectively] may be confused with a diagnosis of type 1 diabetes [22,23]. This was systematically studied in the Joslin Medalist cohort in which 7.9% of participants were found to have likely pathogenic variants in genetic studies [15].…”

“…For example, in a study of 77 individuals with fairly long-duration HNF1α diabetes, the lowest C-peptide level was 0.36 nmol/l, which far exceeded the highest level observed in the Joslin Medalist cohort. Moreover, 0.2 nmol/l has recently been proposed as a threshold above which to prompt monogenic diabetes screening, again exceeding the highest levels in the Joslin Medalist cohort [22]. However, future work should focus on the determination of genetic factors, including the polygenic risk score for type 1 diabetes and targeted genetic screening.…”

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

“…The patients should be followed to determine the efficacy of the treatment and to monitor the possible vascular complications in HNF1A-and HNF4A-MODY subtypes. The most recent therapeutic approaches for MODY patients were summarised recently by Broome et al [ 145 ].…”

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

“…Childhood type 2 DM can be confused with MODY owing to a family history and presenting features, as well as obesity or overweight as a possible confounding factor [11]. Clinically, MODY should be considered in patients with atypical features for type 2 DM, including diabetes onset before the age of 45 years, a normal or low BMI, lack of acanthosis nigricans, and normal serum triglyceride levels and/or normal or elevated high-density lipoprotein cholesterol concentrations [43]. In addition, high-sensitivity C-reactive protein levels are low in HNF1A-MODY and can be used to distinguish between HNF1A-MODY and type 2 DM [44].…”

“…However, MODY can be differentiated from type 1 DM by atypical features of type 1 DM. including the absence of pancreatic autoantibodies, low insulin requirements, evidence of endogenous insulin production with detectable serum C-peptide (> 0.6 ng/mL), and the absence of DKA [43]. An additional, non-invasive 2-h postprandial urinary C-peptide to creatinine ratio (UCPCR) test can be used to distinguish between long-standing type 1 DM and HNF1A-MODY and HNF4A-MODY.…”