Maturity-onset Diabetes Of The Young Patients Research Articles

Comparison of the optical coherence tomography-angiography (OCT-A) vascular measurements between molecularly confirmed MODY and age-matched healthy controls.

Previous structural, vascular density, and perfusion studies have mostly comprised type 1 and type 2 diabetes, even in the absence of retinopathy. The current study aimed to compare macular vessel density (VD) measurements between maturity-onset diabetes of the young (MODY) patients and controls. The macular VD of superficial, deep retina, and choriocapillaris (CC), and central macular thickness (CMT), foveal avascular zone (FAZ), FAZ perimetry, VD of the total retina at 300µm around the FAZ (FD), and acirculatory index (AI) measurements were taken and analyzed via OCT-A (RTVue XR 100-2 Avanti, AngioVue) and were compared between molecularly confirmed MODY (glucokinase (GCK) variants) patients and healthy controls. Twenty-five MODY patients and 30 healthy controls were included in the study. The mean plasma hemoglobin A1c level in the MODY group was 6.39 ± 0.38. The mean age was 13.8 ± 2.1 in the MODY group and was 12.6 ± 2.5years among controls. There was no significant difference in terms of the age, superficial and deep retinal VD, FAZ, FAZ perimetry, CMT, FD, or AI between the groups. Compared to the healthy controls, a slight but significant increase in the CC-VD was detected in the MODY group, but only in the parafoveal and perifoveal regions (p = 0.034, p = 0.009). The significant CC-VD increase in the MODY group might be associated with hyperglycemia and/or relatively poor and vulnerable peripheral vascular CC perfusion compared to the central. Previous thickness and VD results of childhood or adolescent diabetes were distributed in a wider range, suggesting that various factors, including some not yet clearly defined, may affect the choroidal vasculature independently of glycemia or as a contributing factor.

A New Tool to Identify Pediatric Patients with Atypical Diabetes Associated with Gene Polymorphisms.

Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort. We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion. The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies. We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.

MODY Probability Calculator Is Suitable for MODY Screening in China: A Population-based Study.

Selecting appropriate individuals for genetic testing is essential due to the optimal treatment for maturity-onset diabetes of the young (MODY). However, how to effectively screen for MODY in China remains unclear. To validate the performance of current screening strategies in selecting patients with MODY based on a nationwide type 2 diabetes cohort. A panel of 14 MODY genes was analyzed from 1911 type 2 diabetes patients who were ages 15 to 35 years. Variants were evaluated according to the American College of Medical Genetics and Genomics guidelines. Based on this cohort, we simulated the 2 most frequently used screening strategies, including the traditional MODY criteria and the MODY probability calculator (MPC), to assess their ability to select patients with MODY. From a total of 1911 participants, 42 participants harbored pathogenic/likely pathogenic variants. The performance of the traditional criteria was sensitivity: 19.0%, specificity: 72.9%, positive predictive value (PPV): 1.6%, and missing rate: 81.0%. The optimal cut-off for MPC was 40.7%. Based on this cut-off value, the performance was sensitivity: 54.8%, specificity: 81.0%, PPV: 6.1%, and missing rate: 45.2%. Moreover, hemoglobin A1c, insulin treatment, and family history of diabetes have poor discrimination between MODY and young-onset type 2 diabetes. The MPC is better than traditional criteria in terms of both sensitivity and PPV. To ensure more MODY patients benefit from optimal treatment, we therefore suggest that routine genetic testing be performed on all type 2 diabetes patients who are between the ages of 15 and35 years and have MPC probability value over 40.7%.

SAT081 Maturity Onset Diabetes Of The Young (MODY) Due To A New BLK Gene Mutation

Abstract Disclosure: D. Taha: None. R. Thirunagari: None. A. Adhikari: None. Background: The BLK gene is a tyrosine protein kinase involved in cell proliferation and differentiation. It has been identified as a modulator of beta cell function and plays a role in the regulation of insulin synthesis and secretion. We describe the case of a patient presenting with prediabetes associated with a heterozygous c.1366 C>T of the BLK gene. Case Report: We report a 10 year old Asian female who presented with a hemoglobin A1c (HbA1c) level of 6.1% (4.0-5.7), within prediabetes range. Her weight was 44 kg (Z score 1.34), height 148.2 cm (Z score 1.52) and BMI was 20 kg/m2 (85th percentile; Z score 1.06). She had no acanthosis nigricans by exam and she was at early Tanner stage 2 of puberty. Initial evaluation revealed normal C-Peptide level of 2.1 ng/mL (0.9-6.9), normal insulin level of 21.1 mcUnits/mL (3 - 25). She had normal complete blood count and comprehensive metabolic profile, and normal thyroid function tests. Glutamic acid decarboxylase (GAD65) antibodies and islet cell antibodies were negative. She had an oral glucose tolerance test which revealed a fasting glucose level of 101 mg/dL and a 2-hour glucose level of 158 mg/dL. Lipid profile was normal. She was advised regarding healthy lifestyle changes and her HbA1c level was stable. She was lost to follow-up until 16 years of age when she presented with irregular menstrual cycles and was diagnosed with polycystic ovary syndrome. Her HbA1c was elevated at 6.3% with a normal insulin level. Cortisol and thyroid function tests were normal. Pancreatic antibodies including GAD65, IA-2, insulin antibodies, islet cell antibodies, and zinc transporter 8 antibodies, were negative. C-peptide level was normal at 4.3 ng/mL (1.1-4.4). Family history was significant for patient’s father and paternal grandmother having diabetes and taking Metformin. Patient’s father was diagnosed with diabetes at 13 years of age. Maturity onset diabetes of the young (MODY) panel/ sequencing and deletion/duplication analysis was performed at GeneDx and revealed that she is heterozygous for a c.1366 C>T; p.Arg456Cys (R456C) variant in exon 13 of the BLK gene. This variant has not been previously published as a pathogenic or benign variant to our knowledge. No additional variants were identified in any of the MODY genes on this panel (ABCC 8, APPL1, CEL, GCK, GLUD1, HADH, HNF1A, HNF 1B, HNF4A, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1). Conclusion: Variants of the BLK gene have been reported in association with autosomal dominant MODY, type 11. We report a pediatric patient presenting with MODY prediabetes associated with a heterozygous c.1366 C>T; p.R456C variant in the BLK gene. To our knowledge, this variant has not been previously reported in MODY patients. We propose that this is a pathogenic variant and review this rare MODY form. Presentation: Saturday, June 17, 2023

SAT088 Poor Sleep Quality And Insufficient Sleep Duration Are Common In Maturity Onset Diabetes Of The Young

Abstract Disclosure: M.A. Arosemena: None. K. Wroblewski: None. E. Tasali: None. L. Philipson: Research Investigator; Self; Novo Nordisk, Novartis Pharmaceuticals. Background: Poor sleep quality and insufficient sleep duration are highly common in type 1 and type 2 diabetes. Maturity Onset Diabetes of the Young (MODY) is a unique form of diabetes that is usually characterized by patients being lean, not using insulin, or using diabetes-related technology. This subpopulation has not been studied in regards to their sleep patterns. Objective: To evaluate objective and subjective sleep patterns and their association with glycemic variability in adults with MODY. Methods: Adults with MODY were recruited from the Monogenic Diabetes Registry at the University of Chicago. Subjective sleep quality was measured by a validated survey, the Pittsburgh Sleep Quality Index (PSQI), and sleep patterns were objectively assessed at home by wrist-worn accelerometry (Fitbit Inspire 2) for two consecutive weeks. Glycemic variability was assessed by 2 weeks of continuous glucose monitoring (CGM). Results: To date, a total of 51 patients completed the study. Participants (age:46 ± 12.4 years; BMI:24.6 ± 3.5 kg/m2, diabetes duration: 22.6 ± 13.5, HbA1c: 6.3 ±0.6%) were mostly white (84%), premenopausal (68%), and female (74%). Pathogenic variants included 51% GCK-MODY, 25% HNF1A-MODY, 16% HNF4A-MODY, and 8% HNF1B-MODY. Most participants (71%) reported engaging in regular exercise ( i.e., exercising more than twice and accumulating at least 90 min of moderate or 40 min of vigorous activity in an average week), 45% were only on diet and exercise as their diabetes therapy and 20% were on insulin. Only 27% were on diabetes-related technology (insulin pump and/or CGM) and 88% had no diabetes-related complications. Based on accelerometry (630 nights of analyzed Fitbit data; n=45) 39% of patients had a sleep duration of <7 hours, below the healthy adult recommendations, 90% had a wake after sleep onset (WASO) >40 minutes (normative criteria ≤40 minutes) and, 14% had a sleep efficiency <85% (normative criteria ≥85%)Most patients (69%) reported poor sleep quality with a PSQI mean score of 7.2±3.3 (a score of >5 reflecting poor sleep quality). The data analyses on the association between sleep and glycemic patterns (from CGM) are ongoing. Conclusion: Poor subjective and objective sleep quality and insufficient objective sleep duration are common among MODY patients despite most of them being lean, not on insulin or using diabetes-related technology. Further research should investigate sleep-glycemia relationship in this unique diabetes population. Presentation: Saturday, June 17, 2023

Prevalence of maturity-onset diabetes of the young in phenotypic type 2 diabetes in young adults: a nationwide, multi-center, cross-sectional survey in China.

Maturity-onset diabetes of the young (MODY) is the most common monogenic diabetes. The aim of this study was to assess the prevalence of MODY in phenotypic type 2 diabetes (T2DM) among Chinese young adults. From April 2015 to October 2017, this cross-sectional study involved 2429 consecutive patients from 46 hospitals in China, newly diagnosed between 15 years and 45 years, with T2DM phenotype and negative for standardized glutamic acid decarboxylase antibody at the core laboratory. Sequencing using a custom monogenic diabetes gene panel was performed, and variants of 14 MODY genes were interpreted as per current guidelines. The survey determined 18 patients having genetic variants causing MODY (6 HNF1A , 5 GCK , 3 HNF4A , 2 INS , 1 PDX1 , and 1 PAX4 ). The prevalence of MODY was 0.74% (95% confidence interval [CI]: 0.40-1.08%). The clinical characteristics of MODY patients were not specific, 72.2% (13/18) of them were diagnosed after 35 years, 47.1% (8/17) had metabolic syndrome, and only 38.9% (7/18) had a family history of diabetes. No significant difference in manifestations except for hemoglobin A1c levels was found between MODY and non-MODY patients. The prevalence of MODY in young adults with phenotypic T2DM was 0.74%, among which HNF1A -, GCK -, and HNF4A -MODY were the most common subtypes. Clinical features played a limited role in the recognition of MODY.

Targeted gene panel analysis of Japanese patients with maturity-onset diabetes of the young-like diabetes mellitus: Roles of inactivating variants in the ABCC8 and insulin resistance genes.

To investigate the genetic background of Japanese patients with suspected maturity-onset diabetes of the young (MODY). On 340 proband patients referred from across Japan, genomic variants were analyzed using a targeted multigene panel analysis combined with the multiplex ligation probe amplification (MLPA) analysis, mitochondrial m.3243A > G analysis and methylation-specific polymerase chain reaction of the imprinted 6q24 locus. Pathogenic/likely pathogenic variants were listed according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Additionally, variants with a population frequency <0.001 and Combined Annotation Dependent Depletion score >20 (CS >20) were listed as rare variants of uncertain significance-CS >20. A total of 157 pathogenic/likely pathogenic variants and 44 rare variants of uncertain significance-CS >20 were identified. In the pathogenic/likely pathogenic variants, alterations in the GCK gene were the most common (82, 52.2%) followed by HNF1A (29,18.5%), HNF4A (13, 8.3%) and HNF1B (13, 8.3%). One patient was a 29.5% mosaic with a truncating INSR variant. In the rare variants of uncertain significance-CS >20, 20 (45.5%) were in the genes coding for the adenosine triphosphate-sensitive potassium channel, KCNJ11 or ABCC8, and four were in the genes of the insulin-signaling pathway, INSR and PIK3R1. Four variants in ABCC8 were previously reported in patients with congenital hyperinsulinism, suggesting the inactivating nature of these variants, and at least two of our patients had a history of congenital hyperinsulinism evolving into diabetes. In two patients with INSR or PIK3R1 variants, insulin resistance was evident at diagnosis. Causative genomic variants could be identified in at least 46.2% of clinically suspected MODY patients. ABCC8-MODY with inactivating variants could represent a distinct category of MODY. Genes of insulin resistance should be included in the sequencing panel for MODY.

Maturity-Onset Diabetes of the Young: Mutations, Physiological Consequences, and Treatment Options.

Maturity-Onset Diabetes of the Young (MODY) is a rare form of diabetes which affects between 1% and 5% of diagnosed diabetes cases. Clinical characterizations of MODY include onset of diabetes at an early age (before the age of 30), autosomal dominant inheritance pattern, impaired glucose-induced secretion of insulin, and hyperglycemia. Presently, 14 MODY subtypes have been identified. Within these subtypes are several mutations which contribute to the different MODY phenotypes. Despite the identification of these 14 subtypes, MODY is often misdiagnosed as type 1 or type 2 diabetes mellitus due to an overlap in clinical features, high cost and limited availability of genetic testing, and unfamiliarity with MODY outside of the medical profession. The primary aim of this review is to investigate the genetic characterization of the MODY subtypes. Additionally, this review will elucidate the link between the genetics, function, and clinical manifestations of MODY in each of the 14 subtypes. In providing this knowledge, we hope to assist in the accurate diagnosis of MODY patients and, subsequently, in ensuring they receive appropriate treatment.

Study of the frequency and clinical features of maturity-onset diabetes in the young in the pediatric and adolescent diabetes population in Iran.

Maturity-onset diabetes of the young (MODY), an autosomal dominant disease, is frequently misdiagnosed as type 1 or 2 diabetes. Molecular diagnosis is essential to distinguish them. This study was done to investigate theprevalence of MODY subtypes and patients' clinical characteristics. A total of 43 out of 230 individuals with diabetes were selected based on the age of diagnosis >6months, family history of diabetes, absence of marked obesity, and measurable C-peptide. Next-generation and direct SANGER sequencing was performed to screen MODY-related mutations. The variants were interpreted using the Genome Aggregation Database (genomAD), Clinical Variation (ClinVar), and pathogenicity prediction tools. There were 23 males (53.5%), and the mean age at diabetes diagnosis was 6.7±3.6years. Sixteen heterozygote single nucleotide variations (SNVs) from 14 patients (14/230, 6%) were detected, frequently GCK (37.5%) and BLK (18.7%). Two novel variants were identified in HNF4A and ABCC8. Half of the detected variants were categorized as likely pathogenic. Most prediction tools predicted Ser28Cys in HNF4A as benign and Tyr123Phe in ABCC8 as a pathogenic SNV. Six cases (42.8%) with positive MODY SNVs had islet autoantibodies. At diagnosis, age, HbA1c, and C-peptide level were similar between SNV-positive and negative patients. This is the first study investigating 14 variants of MODY in Iran. The results recommend genetic screening for MODY in individuals with unusual type 1 or 2 diabetes even without family history. Treatment modifies depending on the type of patients' MODY and is associated with the quality of life.

Assessment of Knowledge and practice of Maturity Onset Diabetes of the Young (MODY) among Primary care physicians in Najran, Saudi Arabia

Background: Maturity-onset diabetes of the young (MODY) is a type of monogenic diabetes first described as a mild and asymptomatic form of diabetes mellitus that was observed in non-obese children, and young adults. With the development of genetic technology, many genes linked to MODY have been sequenced and described. MODY is a kind of diabetes inherited and a mutation in one of eleven genes causes it. MODY could be the cause of up to 5% of all diabetes cases. MODY patients, like other diabetics, have difficulty controlling their blood sugar levels. Methods: This study is a cross-sectional study among primary care physicians (PCPs) in the Najran region. The questionnaire was created following a series of conversations between a panel of experts, which included subject specialists, researchers, and language experts. Pilot study with 15 respondents was also conducted to observe the clarity of the content of the questionnaire and its validity. The questionnaire’s Cronbach alpha was computed. It was created in English and disseminated through Google forms link and in a printed form as well. The questionnaire has two main sections, one for knowledge and the other for practice with MODY. Results: 12% completely responded to questions regarding definition of MODY, 55.5% have knowledge regarding mode of inheritance of MODY, 9% were aware about the type of the MODY, 60% were aware about typical symptoms of MODY, Diagnostic tools of MODY (45%), Possible presentations of MODY (6%), Therapeutic modalities of MODY (39%), Complications of MODY (20%), Differences between MODY and T1DM and T2DM (6.8%), while overall knowledge score was 53.8%. Conclusion: This study emphasized the importance of PCPs among individuals participating in intensive teaching programs in order to promote early detection of MODY and beginning of the proper treatment for the disease. Keywords: Knowledge, practice, primary care physicians, Maturity Onset Diabetes of the Young (MODY).

1125-P: Obstructive Sleep Apnea and Insomnia Are Highly Prevalent in Monogenic Diabetes

Background: Sleep disorders are highly common in type 1 and type 2 diabetes with important cardiometabolic implications. Maturity Onset Diabetes of the Young (MODY) has unique features compared to type 1 or type 2 diabetes, such that patients are generally lean and not using insulin. Objective: To evaluate primary sleep disorders in patients with MODY. Methods: Participants were recruited from the Monogenic Diabetes Registry at the University of Chicago. The presence and severity of obstructive sleep apnea (OSA) was objectively assessed by a validated home OSA screening device (WatchPAT) . Insomnia was assessed by a validated survey, the Insomnia Severity Index. Results: Demographic characteristics are shown in Table 1. The majority of the patients were white lean women, not using insulin with no diabetic complications. Among all patients (n=24) , OSA was found in 58% (64% had mild OSA, 22% had moderate OSA, 14% had severe OSA) . Among lean patients (n=15) , 53% had mild-to-moderate OSA and 47% had no OSA. Based on the Insomnia Severity Index score, 71% of patients had some degree of insomnia (17% clinical insomnia, 54% subthreshold insomnia) and 29% no insomnia. Conclusion: OSA and insomnia were highly prevalent in MODY patients despite their lack of most traditional risk factors for sleep disorders. Given their unique characteristics, further research should investigate the pathophysiology of sleep disorders in this population. Disclosure M.A.Arosemena: None. K.Wroblewski: None. E.Tasali: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Dompé, Novo Nordisk, provention BIo.

Clinical profiling and screening for HNF4α and GCK gene mutations in Kashmiri patients with maturity-onset diabetes of the young (MODY)

AimMaturity-onset Diabetes of Young (MODY) is a monogenic form of diabetes affecting 1–5% of young (often ≤25 years) diabetic patients exhibiting an autosomal dominant mode of inheritance. Considering the significance of genetic polymorphisms in a variety of diseases, this study aimed to determine the association between HNF4α and GCK gene polymorphisms and the risk of MODY in the Kashmir community, as well as their clinical differences. MethodThe study was conducted on clinically confirmed MODY patients (n = 50), and age and gender-matched controls (25 T1DM and 25 non-diabetic) recruited from the endocrinology department of the hospital, for evaluating the HNF4α and GCK mutation. Under standard conditions, PCR-mediated amplification was done to evaluate the respective exons. Preliminary mutations were detected using restriction enzymes (BfaI and HhaI), which were then followed by sequencing of representative samples. The diabetic history, clinical and biochemical data were obtained after proper consent. ResultsOur data revealed no association of HNF4α (exon7) and GCK (exon8) gene mutation with MODY disease susceptibility in the Kashmiri population. On diagnosis, no MODY patient was given immediate insulin; instead, metformin (68%) or sulphonyl-urea (28%) and dietary changes (4%) were recommended. Later in life, 54% of MODY patients develop insulin dependency. The MODY probability was calculated to be 73.88% (±4.56). HbA1c levels were lower [7.48% (±1.64)] than in T1DM [9.17(±2.29%)]. ConclusionsYoung early-onset diabetic patients were able to keep their HbA1c and blood glucose levels stable with a modified diet and metformin/sulphonyl-urea, but they may become insulin-dependent in the future, as seen in our study. As a result, prompt diagnosis and management are essential for avoiding complications. Furthermore, no HNF4α (exon7) or GCK (exon 8) mutations were found in MODY patients or T1DM/healthy non-diabetic controls.

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY).

High-sensitivity C-reactive protein (hs-CRP) is used in the differential diagnosis of maturity-onset diabetes of the young (MODY)-3, but other inflammatory markers have not been investigated in MODY patients. We aimed to compare the serum levels of anti-inflammatory and proinflammatory cytokines between MODY patients and healthy subjects and show the inflammatory features in MODY subtypes. Thirty patients with clinically suspected MODY and 34 healthy controls were included in this study. Next-generation sequencing (NGS) was used for the molecular diagnosis of MODY subtypes. Serum levels of cytokines were measured using a multiplexed cytokine assay and hs-CRP concentration was determined by the immunoturbidimetric assay. The hs-CRP levels were higher in both NGS-confirmed (MODY, n=17) (p=0.009) and NGS-unconfirmed (non-MODY, n=13) patients (p<0.001) than those in controls. However, IL-1β (p=0.001), IL-6 (p=0.018), IL-31 (p=0.003), TNF-α (p<0.001), and sCD40L (p=0.007) levels of MODY patients and IL-1β (p=0.002), IL-31 (p<0.001), IL-22 (p=0.018), and sCD40L (p=0.039) levels of non-MODY patients were lower than those of controls. While hs-CRP levels were lower in MODY3 patients than non-MODY3 patients (p=0.009), IL-17A (p=0.006) and IL-23 (p=0.016) levels for the first time in this study were found to be higher in patients with MODY3 than in patients with other MODY subtypes (p<0.05). MODY patients had lower serum levels of the proinflammatory cytokines IL-1β, IL-6, TNF-α, IL-31, and sCD40L compared to healthy controls. High IL-17A and IL-23 levels along with low hs-CRP levels may be potential markers to distinguish MODY3 from other MODY subtypes.

Knowledge and practice among primary care physicians in Najran (south west region), Saudi Arabia regarding Maturity Onset Diabetes of the Young (MOD

Background: Maturity Onset Diabetes of the Young (MODY) is a disease that is caused by a single gene. This indicates that it is the result of a single gene mutation. MODY can be caused by a variety of gene mutations. When a family member who has MODY, relatives are at a higher risk of developing the disease. Maturity Onset Diabetes of the Young is a kind of diabetes mellitus that is inherited. A mutation in one of eleven genes causes it. MODY could be the cause of up to 5% of all diabetes cases. MODY patients, like other diabetics, have difficulty controlling their blood sugar levels. Methods: This was a crosssectional study among primary care physicians (PCPs) in the Najran region (13). The questionnaire was created following a series of conversations between a panel of experts, which included subject specialists, researchers, and language experts. Pilot study with 15 respondents was also conducted to observe the clarity of the content of the questionnaire and its validity. The questionnaire’s Cronbach alpha was computed. It was created in English and disseminated through Google as well as on printed forms. The forms had two main sections, one for knowledge and the other for practice regarding MODY. Results: 12% responding completely regarding definition of MODY, 55.5% have knowledge regarding mode of inheritance of Mody, 9% were aware about the type of the MODY,60% were about typical symptoms of MODY, Diagnostic tools of MODY (45%), Possible presentations of MODY (6%), Therapeutic modalities of MODY (39%), Complications of MODY (20%)Differences between Mody and T1DM and T2DM 6.80 while overall knowledge score was 53.8% Conclusion: Clinicians should maximize alternative therapy in the era of CF modulators and correctors to improve outcomes and prevent long-term morbidity and mortality. Key words: knowledge, practice, primary care physicians, Maturity Onset Diabetes of the Young (MODY)

Clinical and genetic features of maturity-onset diabetes of the young in pediatric patients: a 12-year monocentric experience

BackgroundA retrospective observational study was conducted to assess the prevalence of maturity onset diabetes of the young (MODY) in a large paediatric population of Southern Italy newly diagnosed with diabetes. Clinical and genetic features of the identified MODY patients were also described.MethodsGenetic testing was performed in children and adolescents newly diagnosed with diabetes who presented autoantibody negativity and fasting C-peptide levels ≥ 0.8 ng/mL. Patients with a low insulin daily dose and optimal glycaemic control after two years from diabetes onset were also investigated for monogenic diabetes, regardless of their autoimmunity status and/or C-peptide levels.ResultsA prevalence of 6.5% of MODY was found. In particular, glucokinase-MODY was the most common type of MODY. The mean age at diagnosis was 9.1 years. Clinical presentation and biochemical data were heterogeneous also among patients belonging to the same MODY group.ConclusionsWe found a relatively high prevalence of MODY among paediatric patients with a new diagnosis of diabetes in comparison to literature data. Our findings highlight that a more detailed clinical evaluation along with easier and less expensive approachability to genetic testing may allow diagnosing an increasing number of MODY cases. A correct, prompt diagnosis is crucial to choose the most appropriate treatment and offer adequate genetic counselling.

A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes.

Maturity-onset diabetes of the young (MODY) has about a dozen known causal genes to date, the most common ones being HNF1A, HNF4A, HNF1B and GCK. The phenotype of this clinically and genetically heterogeneous form of diabetes depends on the gene in which the patient has the mutation. We have tested 450 Hungarian index patients with suspected MODY diagnosis with Sanger sequencing and next-generation sequencing and found a roughly 30% positivity rate. More than 70% of disease-causing mutations were found in the GCK gene, about 20% in the HNF1A gene and less than 10% in other MODY-causing genes. We found 8 pathogenic and 9 likely pathogenic mutations in the HNF1A gene in a total of 48 patients and family members. In the case of HNF1A-MODY, the recommended first-line treatment is low dose sulfonylurea but according to our data, the majority of our patients had been on unnecessary insulin therapy at the time of requesting their genetic testing. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of the MODY subtype in order to choose the most appropriate treatment.

Maturity Onset Diabetes of the Young-New Approaches for Disease Modelling.

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.

Molecular and clinical assessment of maturity-onset diabetes of the young revealed low mutational rate in Moroccan families

BackgroundMaturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance. To offer an adequate patient management and therapeutic treatment for MODY patients, in addition to an early efficient diagnosis of their asymptomatic relatives, it is crucial to set an accurate molecular diagnosis. Hence, our aim was to determine the frequency of HNF1A and GCK genes among Moroccan-suspected MODY patients.MethodsTwenty suspected MODY patients were screened for HNF1A and GCK mutations using Sanger sequencing and MLPA methods. Segregation analysis of identified mutations was performed among family members. The pathogenic nature of missense variants was predicted using bioinformatic tools.ResultsA total of two mutations were revealed among all patients raising the diagnostic rate to 10%. We identified a large novel GCK deletion (c.209-?_1398+?del) by MLPA in one patient and a previously reported missense substitution (c.92G > A) in HNF1A gene.ConclusionThis is the first investigation to perform the molecular diagnosis of MODY suspected patients. Our findings constitute a primary contribution towards unraveling the genetic landscape involved in the pathogenesis of MODY disease in Morocco.

Genetic characterization of suspected MODY patients in Pakistan by next generation sequencing—a pilot study

Maturity onset diabetes of the young (MODY) is the genetic form of diabetes inherited in autosomal dominant pattern. The diagnosis of MODY is challenging and confirmed by genetic testing. The objective of this study was to investigate MODY in Pakistani patients using next-generation sequencing. The next-generation sequencing was performed to know the cause of disease in 07 patients phenotypically suspected for MODY from Pakistan. These patients were selected based on the high probability score through MODY probability calculator. Only those genetic variants were retained which were having low frequency as per available data bases and their potential effects on protein as assessed by bioinformatics prediction tools. Four heterozygous variants were found among patients. This includes mutation in HNF1a gene (c.526+1G>A) that is already reported for causative for MODY type 3 which is most prevalent among all MODY sub-types. Other variants were identified in GCK (c.-45G>A), KLF11 (c.*96dupA), and CEL (c.1235C>T). This study was the first in Pakistan to investigate the MODY using next-generation sequencing for clinical applications. There is huge public health burden of diabetes in the country. The study identified mutation in one known MODY gene. More extensive studies involving large sample size are required in future.

Identification of Maturity-Onset Diabetes of the Young Caused by Mutation in FOXM1 via Whole-Exome Sequencing in Northern China.

Diabetes mellitus is a highly heterogeneous disorder encompassing different types with particular clinical manifestations, while maturity-onset diabetes of the young (MODY) is an early-onset monogenenic diabetes. Most genetic predisposition of MODY has been identified in European and American populations. A large number of Chinese individuals are misdiagnosed due to defects of unknown genes. In this study, we analyzed the genetic and clinical characteristics of the Northern China. A total of 200 diabetic patients, including 10 suspected MODY subjects, were enrolled, and the mutational analysis of monogenic genes was performed by whole-exome sequencing and confirmed by familial information and Sanger sequencing. We found that clinical features and genetic characteristics have varied widely between MODY and other diabetic subjects in Northern China. FOXM1, a key molecule in the proliferation of pancreatic β-cells, has a rare mutation rs535471991, which leads to instability within the phosphorylated domain that impairs its function. Our findings indicate that FOXM1 may play a critical role in MODY, which could reduce the misdiagnose rate and provide promising therapy for MODY patients.