Update on clinical screening of maturity-onset diabetes of the young (MODY)

Abstract

Background: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes, being characterized by beta-cell disfunction, early onset, and autosomal dominant inheritance. Despite the rapid evolution of molecular diagnosis methods, many MODY cases are misdiagnosed as type 1 or type 2 diabetes. High costs of genetic testing and limited knowledge of MODY as a relevant clinical entity are some of the obstacles that hinder correct MODY diagnosis and treatment. We present a broad review of clinical syndromes related to most common MODY subtypes, emphasizing the role of biomarkers that can help improving the accuracy of clinical selection of candidates for molecular diagnosis. Main body: To date, MODY-related mutations have been reported in at least 14 different genes. Mutations in glucokinase (GCK), hepatocyte nuclear factor-1 homeobox A (HNF1A), and hepatocyte nuclear factor-4 homeobox A (HNF4A) are the most common causes of MODY. Accurate etiological diagnosis can be challenging. Many biomarkers such as apolipoprotein-M (ApoM), aminoaciduria, complement components, and glycosuria have been tested, but have not translated into helpful diagnostic tools. High-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY and have been tested in some studies to discriminate HNF1A-MODY from other types of diabetes, although more data are needed. Overall, presence of pancreatic residual function and absence of islet autoimmunity seem the most promising clinical instruments to select patients for further investigation. Conclusions: The selection of diabetic patients for genetic testing is an ongoing challenge. Metabolic profiling, diabetes onset age, pancreatic antibodies, and C-peptide seem to be useful tools to better select patients for genetic testing. Further studies are needed to define cutoff values in different populations.

The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY)

“…Early-onset diabetes, insulin independence, and autosomal dominant inheritance are traditionally associated with MODY [ 15 ]. Age of onset is particularly useful for distinguishing MODY from other types of diabetes.…”

“…Age of onset is particularly useful for distinguishing MODY from other types of diabetes. However, MODY subtypes with variable age of onset, low penetrance, or atypical presentation may not fulfill classical diagnostic criteria [ 15 – 18 ]. Furthermore, in a study involving 922 families referred for MODY testing, spontaneous de novo mutations affecting GCK, HNF1A, or HNF4A genes were reported in 11 of the 150 individuals who did not have autosomal dominant inheritance of diabetes mellitus or a multigenerational family history of hyperglycemia [ 19 ].…”

“…Furthermore, in a study involving 922 families referred for MODY testing, spontaneous de novo mutations affecting GCK, HNF1A, or HNF4A genes were reported in 11 of the 150 individuals who did not have autosomal dominant inheritance of diabetes mellitus or a multigenerational family history of hyperglycemia [ 19 ]. Refinement of the classical diagnostic triad may significantly increase clinical suspicion for MODY and facilitate the process of selecting and referring suspected patients for genetic testing [ 15 , 17 , 20 ]. The refined diagnostic criteria for MODY include: persistent hyperglycemia in early adulthood (typically before 30 years); clinical features incompatible with type 1 or type 2 diabetes mellitus (T1DM, T2DM); diabetes in at least one first-degree relative; evidence of residual pancreatic function; and absence of beta cell autoimmunity.…”

“…1 . Overall, a diagnosis of MODY requires a high index of suspicion, clinical assessment, diabetes-specific tests, and comprehensive genetic testing [ 15 , 21 ].

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ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): A Report of a Chinese Family

“…MODY is an autosomal dominant hereditary disease leading to dysfunction of the pancreatic β-cells. Since its discovery, mutations have been identified for at least these 14 genes ( HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8 [ATP Binding Cassette Subfamily C Member 8], KCNJ11, and APPL1 ) for MODY ( 1 – 3 ). A very high prevalence of family members carry the mutated gene, and patients in the same family have similar clinical manifestations.…”