Identification of Novel GCK and HNF4α Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age

Background. Maturity-onset diabetes of the young (MODY) is commonly misdiagnosed as type 1 or type 2 diabetes. Common reasons for misdiagnosis are related to limitations in genetic testing. A precise molecular diagnosis is essential for the optimal treatment of patients and allows for early diagnosis of their asymptomatic family members. Objective. The aim of this study was to identify rare monogenic variants of common MODY genes in Japanese pediatric patients. Methods. We investigated 45 Japanese pediatric patients based on the following clinical criteria: development of diabetes before 17 years of age, a family history of diabetes, testing negative for glutamate decarboxylase-65 (GAD 65) antibodies and insulinoma-2-associated autoantibodies (IA-2A), no significant obesity, and evidence of endogenous insulin production. Genetic screening for MODY1 (HNF4α), MODY2 (GCK), MODY3 (HNF1α), and MODY5 (HNF1β) was performed by direct sequencing followed by multiplex ligation amplification assays. Results. We identified 22 missense variants (3 novel variants) in 27 patients (60.0%) in the GCK, HNF4α, and HNF1α genes. We also detected a whole exon deletion in the HNF1β gene and an exon 5–6 aberration in the GCK gene, each in one proband (4.4%). There were a total of 29 variations (64.4%), giving a relative frequency of 53.3% (24/45) for GCK, 2.2% (1/45) for HNF4α, 6.7% (3/45) for HNF1α, and 2.2% (1/45) for HNF1β genes. Conclusions. Clinicians should consider collecting and assessing detailed clinical information, especially regarding GCK gene variants, in young antibody-negative patients with diabetes. Correct molecular diagnosis of MODY better predicts the clinical course of diabetes and facilitates individualized management.

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Family History of Diabetes Is Associated with Increased Risk of Recurrent DKA in Pediatric Patients in Rhode Island

Diabetes ◽

10.2337/db18-1378-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1378-P

Author(s):

JANAKI D. VAKHARIA ◽

SUNGEETA AGRAWAL ◽

JANINE BACIC ◽

LISA S. TOPOR

Keyword(s):

Family History ◽

Rhode Island ◽

Pediatric Patients ◽

Family History Of Diabetes ◽

Increased Risk ◽

History Of

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Clinical characteristics and outcome of hospitalized children and adolescent patients with type 1 diabetes during the COVID-19 pandemic: data from a single center surveillance study in Egypt

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0099 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Eman Monir Sherif ◽

Yasmine Ibrahim Elhenawy ◽

Randa Mahmoud Matter ◽

Hanan Hassan Aly ◽

Rasha Adel Thabet ◽

...

Keyword(s):

Type 1 Diabetes ◽

Pediatric Patients ◽

Surveillance Study ◽

Single Center ◽

Children And Adolescent ◽

Mean Delay ◽

Patients With Diabetes ◽

Constant Feature ◽

Inflammatory Syndrome

Abstract Objectives COVID-19 pandemic significantly impacted the diagnosis of type 1 diabetes and its acute complications. Thus, the study aimed to evaluate the characteristics of pediatric patients with type 1 diabetes hospitalized during the first wave of the pandemic and the prevalence of new onset diabetes among patients with evidence of COVID-19 infection. Methods A single-center surveillance study included all patients with diabetes admitted to Children’s Hospital, Ain Shams University, in Egypt between May to August 2020. Data were collected to evaluate patients’ clinical and laboratory characteristics as well as their outcomes. Results Thirty-six patients were admitted during the study period. The mean age was 8.4 ± 3.8 years. Patients presented late to the emergency department with a mean delay of 3.05 ± 1.19 days from onset of symptoms. 34/36 patients presented in diabetic ketoacidosis (DKA), 50% presenting in severe DKA. Almost 81% of the patients were newly diagnosed. During the study period, SARS-CoV-2 PCR was found positive in four patients, COVID Ig M antibodies were positive in another two patients; all were symptomatic requiring ICU admission. Four patients showed a picture suggestive of the multi-inflammatory syndrome (MIS-C); cardiac affection was a constant feature. Conclusions The pandemic affected both the prevalence and severity of DKA among pediatric patients. The increased prevalence of severe DKA could be partly related to delayed hospital admission or the effect of COVID-19 in triggering DKA. Efforts should be done to continuously raise awareness about diabetes in children as well as the importance of seeking timely medical guidance.

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Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution

Scientific Reports ◽

10.1038/srep29732 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 14

Author(s):

Wei-Xia Lin ◽

Han-Shi Zeng ◽

Zhan-Hui Zhang ◽

Man Mao ◽

Qi-Qi Zheng ◽

...

Keyword(s):

Molecular Diagnosis ◽

Geographic Distribution ◽

Pediatric Patients ◽

Mutation Spectrum ◽

Citrin Deficiency

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Causation Research on Diabetic Foot Complications—What I Learned From Roger Pecoraro: The 2021 Roger E. Pecoraro Award Lecture

10.2337/figshare.15048282 ◽

2021 ◽

Author(s):

Edward J. Boyko

Keyword(s):

Risk Factors ◽

Diabetic Foot ◽

Past History ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Clinical Information ◽

Arterial Perfusion ◽

Primary Care Population ◽

Foot Complications ◽

Patients With Diabetes

Roger Pecoraro made important contribution to diabetic foot research and is primarily responsible for instilling in me an interest in these complications. Our collaboration in the final years of his life led to the development of the Seattle Diabetic Foot Study. At the time it began, the Seattle Diabetic Foot Study was perhaps unique in being a prospective study of diabetic foot ulcer conducted in a non-specialty primary care population of patients with diabetes and without foot ulcer. Important findings from this research include the demonstration that neurovascular measurements, diabetes characteristics, past history of ulcer or amputation, body weight, and poor vision all significantly and independently predict foot ulcer risk. A prediction model from this research that included only readily available clinical information showed excellent ability to discriminate between patients who did and did not develop ulcer during follow-up (area under ROC curve=0.81 at one year). Identification of limb-specific amputation risk factors showed considerable overlap with those risk factors identified for foot ulcer, but suggested arterial perfusion as playing a more important role. Risk of foot ulcer in relation to peak plantar pressure estimated at the site of the pressure measurement showed a significant association over the metatarsal heads, but not other foot locations, suggesting that the association between pressure and this outcome may differ by foot location. The Seattle Diabetic Foot Study has helped to expand our knowledge base on risk factors and potential causes of foot complications. Translating this information into preventive interventions remains a continuing challenge.

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Improved Accuracy of Continuous Glucose Monitoring Systems in Pediatric Patients with Diabetes Mellitus: Results from Two Studies

Diabetes Technology & Therapeutics ◽

10.1089/dia.2015.0380 ◽

2016 ◽

Vol 18 (S2) ◽

pp. S2-23-S2-33 ◽

Cited By ~ 48

Author(s):

Lori Laffel

Keyword(s):

Diabetes Mellitus ◽

Continuous Glucose Monitoring ◽

Pediatric Patients ◽

Glucose Monitoring ◽

Monitoring Systems ◽

Patients With Diabetes ◽

Improved Accuracy

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Prevalence and phenotypic features of diabetes due to recessive, non-syndromic WFS1 mutations

Acta Endocrinologica ◽

10.1530/eje-21-0097 ◽

2021 ◽

Author(s):

Mingqiang Zhu ◽

Yangxi Li ◽

Guanping Dong ◽

Xuefeng Chen ◽

Ke Huang ◽

...

Keyword(s):

Pediatric Patients ◽

Wolfram Syndrome ◽

Diabetic Patients ◽

Insulin Deficiency ◽

Patients With Diabetes ◽

Mild Diabetes ◽

Similar Phenotype ◽

Systemic Disorder ◽

Phenotypic Features

Objective: Recessive WFS1 mutations are known to cause Wolfram syndrome, a very rare systemic disorder. However, they were also found in non-syndromic diabetes in Han Chinese misdiagnosed with type 1 diabetes, a molecular cause that appears to be considerably more common than the fully expressed syndrome. We aimed to better define the incidence and clinical features of non-syndromic diabetes due to recessive WFS1 mutation. Design: We analyzed the genotype and phenotype of 320 consecutive incident Chinese pediatric diabetic patients diagnosed from 2016 to 2019 to search for non-syndromic diabetic cases due to recessive WFS1 mutation. Methods: A cohort of 105 pancreatic autoantibody-negative patients were recruited for exome sequencing. All patients tested positive for pathogenic diallelic WFS1 mutations were examined for phenotypic features (fundoscopy, audiogram, urine density). Results: We found three cases of non-syndromic diabetes due to recessive WFS1 mutations (incidence = 0.94% (95CI 0.25%-2.7%)). All three cases only had mild diabetes when diagnosed. All patients had well conserved fasting C-peptide when diagnosed but one of them progressed to T1D-like insulin deficiency. In addition, we found a fourth case with previously undetected features of Wolfram syndrome. Conclusions: Non-syndromic diabetes due to WFS1 mutation may be common among Chinese pediatric patients with diabetes. It is important to differentiate it from other MODY subtypes with similar phenotype by molecular diagnosis because of different prognosis and, potentially, therapy.

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Role of the KCNJ Gene Variants in the Clinical Outcome of Type 1 Diabetes

Hormone and Metabolic Research ◽

10.1055/a-1204-5443 ◽

2020 ◽

Vol 52 (12) ◽

pp. 856-860

Author(s):

Annalisa Blasetti ◽

Valeria Castorani ◽

Laura Comegna ◽

Simone Franchini ◽

Giovanni Prezioso ◽

...

Keyword(s):

Pediatric Patients ◽

Therapeutic Potential ◽

Insulin Requirement ◽

Gene Variants ◽

Nucleotide Polymorphisms ◽

Binding Function ◽

Inwardly Rectifying

AbstractDiabetes is considered as a disease with a wide and continuous clinical spectrum, ranging from Type 1 (T1D) and Type 2 Diabetes (T2D) with complex multifactorial causes. In the last years, particular attention has been focused on the predictive value and therapeutic potential of single nucleotide polymorphisms (SNPs). SNPs can alter the seed-sequence in miRNA’s loci and miRNA target sites causing changes in the structure and influencing the binding function. Only few studies have investigated the clinical influence of SNPs, in particular potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ) gene variants in T1D population. The aim of the study is to investigate the occurrence and the possible metabolic significance of KCNJ polymorphism in a group of pediatric patients with T1D. The study was performed in a cohort of 90 Caucasian children and adolescents with T1D and 93 healthy subjects. Rs5210 polymorphism has been analyzed with a prevalence of the GG genotype in the patient group suggesting its association with T1D. Therefore, a relationship was found between GG genotype and body mass index (BMI) at diagnosis and insulin requirement (IR) after 6 months. The study suggested an action for rs5210 in determining the metabolic features of T1D pediatric patients, by showing some clues of insulin resistance in patients carrying that polymorphism.

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FAMILY HISTORY OF DIABETES IS ASSOCIATED WITH INCREASED RISK OF RECURRENT DIABETIC KETOACIDOSIS IN PEDIATRIC PATIENTS

Endocrine Practice ◽

10.4158/ep-2019-0351 ◽

2020 ◽

Vol 26 (3) ◽

pp. 305-311

Author(s):

Janaki D. Vakharia ◽

Sungeeta Agrawal ◽

Janine Molino ◽

Lisa Swartz Topor

Keyword(s):

Diabetes Mellitus ◽

Family History ◽

Diabetic Ketoacidosis ◽

Pediatric Patients ◽

Incidence Rate Ratio ◽

Family History Of Diabetes ◽

Increased Risk ◽

History Of

Objective: To determine the relationship between family history of diabetes mellitus (DM) and diabetic ketoacidosis (DKA) recurrence in youth with established type 1 diabetes mellitus (T1DM). Methods: We performed a retrospective chart review of patients with DKA admitted to a pediatric hospital between January, 2009, and December, 2014. We compared patients with recurrent (≥2 admissions) and nonrecurrent DKA (1 admission) and investigated patient level factors, including family history, that may be associated with DKA recurrence in pediatric patients with established T1DM. Results: Of the 131 subjects in the study, 51 (39%) subjects were in the recurrence group. Age ≥15 years old, public health insurance, and family history of T1DM or type 2 diabetes mellitus were associated with recurrent DKA admissions in both univariable and multivariable analyses. Family history was associated with DKA recurrence, with an incidence rate ratio of 1.5 (95% confidence interval = 1.0 to 2.3; P = .03). The association was not explained by type of familial diabetes, first degree relative status, or whether the family member lived in the household. Conclusion: Recognition that a positive family history of DM may be associated with a higher risk for DKA recurrence in patients with established T1DM may allow for targeted education and focus on a previously unidentified population at increased risk for DKA. Understanding the mechanism underlying the effect of family history of diabetes on the rates of DKA in patients with established T1DM may allow for improved identification and education of patients who may be at risk for DKA recurrence. Abbreviations: CI = confidence interval; DKA = diabetic ketoacidosis; EHR = electronic health record; IBD = inflammatory bowel disease; IRR = incidence rate ratio; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus

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MEFV Gene Variant Alleles in Normal Population of Northwest of Iran, Which Is Near to Mediterranean Sea

Genetics Research International ◽

10.1155/2019/6418759 ◽

2019 ◽

Vol 2019 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Farhad Salehzadeh ◽

Afshan Sharghi ◽

Atena Motayayagheni ◽

Saied Hosseini Asl ◽

Mahsa Mottaghi ◽

...

Keyword(s):

Normal Population ◽

Mefv Gene ◽

Mediterranean Area ◽

Compound Heterozygote ◽

Common Mutation ◽

Gene Variants ◽

Clinical Criteria ◽

Rheumatologic Diseases ◽

Healthy Control ◽

Northwest Of Iran

Background and Objective. MEFV gene codes the pyrine protein that has major role in FMF as an autoinflammatory disorder. FMF is more often seen in the people of the Mediterranean area. Considering the significant role of MEFV gene in many rheumatologic diseases and even nonrheumatologic disorders, it is necessary to identify different variations of these mutations in the healthy and normal population of this area. Methods. 224 healthy (unaffected or control) people based on the Cochran formula entered this study. The blood samples were screened for the 12 common MEFV gene variants polymorphisms according to manufacturer’s instructions (FMF Strip Assay, Vienna lab, Vienna, Austria). They filled a questionnaire containing required information. All healthy control cases initially were evaluated for FMF symptoms and signs in themselves and their first-degree relatives based on clinical criteria. All data were analyzed by simple statistical method. Results. Among 224 healthy control cases, 113 (50.4%) were male and 111 (49.6%) female. There were MEFV variants alleles in 57 patients (25%): 28 were male (49.1%) and 29 female (50.9%). The most frequent variants were E148Q (18.3%), followed by P369S (3.1%), V726A (2.2%), A744S (1.3%), and F479L, M694V, and R761H (0.8%), and eventually K695R (0.4%), respectively. Some variants such as M694I, M680I (G/C), M680I (G/A), and I692del were not seen in these samples. There were compound heterozygote variations of E148Q/P369S, E148Q/V726A, E148Q/P369S, and P369S/F479L in normal population without any findings in favor of FMF. Conclusion. Twenty-five percent of the normal populations of the northwest of Iran are carrying MEFV gene variants, and the most common mutation is E148Q (18.3%). The presence of M694I, M680I (G/C), M680I (G/A), I692del mutations in the normal population can be interpreted cautiously, while particular compound heterozygote mutations can be considered as normal variants.

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