Abstract
Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.
Highlights
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The two major classes of diabetes were included as insulin dependent diabetes mellitus (IDDM) or type 1 diabetes mellitus (T1DM), and non-insulin dependent diabetes mellitus (NIDDM) or type 2 diabetes mellitus (T2DM)
In 1999, World Health Organization (WHO) recommended that the classification of diabetes should encompass different aetiological types of diabetes, and the clinical stages of the disease and reintroduced the terms T1DM and T2DM, as they were omitted in the report from 1985 [2]
Summary
MODY is a rare condition, accounting for 1–5% of all diabetes cases [9,10] and 1–6% of paediatric cases of diabetes [11], which means that 1:10,000 adults can be affected [12]. The most common forms of MODY are caused by mutations in the glucokinase gene (GCK-MODY) and hepatocyte nuclear factor genes (HNF1A-, HNF1B- and HNF4A-MODY) which together are responsible for around 99% of all MODY cases [13]. Mutations in MODY-associated genes were shown to be a significant risk factor for T2DM [22–25]. These big population studies highlight the high rate of misdiagnosed individuals, which subsequently leads to inappropriate treatment strategies [23,25]. Phosphotyrosine interacting with PH domain and leucine zipper 1 regulating insulin release regulating insulin release insulin signaling pathway permanent or transient neonatal diabetes neonatal diabetes in homozygote insulin secretion defect; child or adult-onset diabetes unknown unknown unknown
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