Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review

Aarthy, Ramasamy; Aston-Mourney, Kathryn; Mikocka‐Walus, Antonina; Radha, Venkatesan; Amutha, Anandakumar; Anjana, Ranjit Mohan; Unnikrishnan, Ranjit; Mohan, Viswanathan

doi:10.1016/j.jdiacomp.2020.107640

Cited by 51 publications

(41 citation statements)

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“…The clinical phenotype of our MODY2 subject (F1-IV.2) was similar to that described in previous reports ( 56 ). We recommended fasting blood glucose measurement, 2-h OGTT, and genetic testing of this mutation for each at-risk or affected family members.…”

Section: Resultssupporting

confidence: 86%

“…Indeed, the GCK small domain has been specifically considered a mutation hotspot of Southern Italy ( 57 ). Of note, it has been observed that some subjects suffering from GCK -MODY were treated with low daily doses of OHA and/or insulin ( 50 , 56 ). Therefore, the identification of this mutation among a large cohort of Tunisian patients with mild non-progressive early-onset hyperglycemia or gestational diabetes can facilitate early diagnosis of this disease and allow for a personalized treatment.…”

Section: Resultsmentioning

confidence: 99%

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Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

et al. 2021

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Introduction/AimsMaturity-Onset Diabetes of the Young (MODY) is a monogenic non-autoimmune diabetes with 14 different genetic forms. MODY-related mutations are rarely found in the Tunisian population. Here, we explored MODY related genes sequences among seventeen unrelated Tunisian probands qualifying the MODY clinical criteria.Materials and MethodsThe GCK and HNF1A genes were systematically analyzed by direct sequencing in all probands. Then, clinical exome sequencing of 4,813 genes was performed on three unrelated patients. Among them, 130 genes have been reported to be involved in the regulation of glucose metabolism, β-cell development, differentiation and function. All identified variants were analyzed according to their frequencies in the GnomAD database and validated by direct sequencing.ResultsWe identified the previously reported GCK mutation (rs1085307455) in one patient. The clinical features of the MODY2 proband were similar to previous reports. In this study, we revealed rare and novel alterations in GCK (rs780806456) and ABCC8 (rs201499958) genes with uncertain significance. We also found two likely benign alterations in HNF1A (rs1800574) and KLF11 (rs35927125) genes with minor allele frequencies similar to those depicted in public databases. No pathogenic variants have been identified through clinical exome analysis.ConclusionsThe most appropriate patients were selected, following a strict clinical screening approach, for genetic testing. However, the known MODY1-13 genes could not explain most of the Tunisian MODY cases, suggesting the involvement of unidentified genes in the majority of Tunisian affected families.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

et al. 2021

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“…With the increase in next-generation sequencing (NGS) capabilities, other rarer MODY cases have been reported [ 105 , 106 ]. The current knowledge for possible molecular pathophysiology in rarer forms of MODY were extensively summarised elsewhere [ 107 , 108 , 109 ].…”

Section: Molecular Pathophysiology Of the Most Common Mody Subtypesmentioning

confidence: 99%

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

Skoczek

Dulak

Kachamakova‐Trojanowska

2021

IJMS

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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.

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“…The notion that some forms of MODY traditionally classified as monogenic are actually oligogenic is not speculation [ 10 ]. Recent studies have shown that certain forms of MODY such as HNF1B -MODY and NEUROD1 -MODY are oligogenic, with different clinical phenotypes even in the same family with the same causative mutation [ 3 , 4 , 11 ]. We also revealed that the small heterodimer partner (SHP) pathogenic variant, which coexists with an HNF1A pathogenic variant, modifies the age of diagnosis, illustrating its oligogenic nature [ 10 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although MODY has been traditionally regarded as a monogenic form of diabetes, recent studies have found that some forms of MODY, including HNF1B -MODY and NEUROD1 -MODY, are in fact oligogenic, with low–moderate penetrance [ 3 , 4 ]. Their clinical presentation can differ even in the same family with the same mutation, suggesting that genetic and environmental background play an important role in determining the phenotype of certain MODYs.…”

mentioning

confidence: 99%

First Japanese Family With PDX1-MODY (MODY4): A Novel PDX1 Frameshift Mutation, Clinical Characteristics, and Implications

Yoshiji

Horikawa

Kubota

et al. 2021

Journal of the Endocrine Society

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Context The PDX1 gene encodes pancreatic and duodenal homeobox, a critical transcription factor for pancreatic β-cell differentiation and maintenance of mature β-cells. Heterozygous loss-of-function mutations cause PDX1-MODY (MODY4). Case Description Our patient is an 18-year-old lean man who developed diabetes at 16 years of age. Given his early-onset age and leanness, we performed genetic testing. Targeted next-generation sequencing and subsequent Sanger sequencing detected a novel heterozygous frameshift mutation (NM_00209.4:c.218delT. NP_000200.1: p.Leu73Profs*50) in the PDX1 transactivation domain that resulted in loss-of-function and was validated by an in vitro functional study. The proband and his 56-year-old father, who had the same mutation, both showed markedly reduced insulin and gastric inhibitory polypeptide (GIP) secretion compared with the dizygotic twin sister, who was negative for the mutation and had normal glucose tolerance. The proband responded well to sitagliptin, suggesting its utility as a treatment option. Notably, the proband and his father showed intriguing phenotypic differences: the proband had been lean for his entire life but developed early-onset diabetes requiring an antihyperglycemic agent. In contrast, his father was overweight, developed diabetes much later in life, and did not require medication, suggesting the oligogenic nature of PDX1-MODY. A review of all reported cases of PDX1-MODY also showed heterogeneous phenotypes regarding onset age, obesity, and treatment, even in the presence of the same mutation. Conclusions We identified the first Japanese family with PDX1-MODY. The similarities and differences found among the cases highlight the wide phenotypic spectrum of PDX1-MODY.

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Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review

Cited by 51 publications

References 85 publications

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

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

First Japanese Family With PDX1-MODY (MODY4): A Novel PDX1 Frameshift Mutation, Clinical Characteristics, and Implications

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