Background: Infancy-onset diabetes is largely monogenic before 6 months of age, whereas autoimmune type 1 diabetes is more likely from 6-12 months of age. As the most common neonatal diabetes, ...patients with KATP channel mutations exhibit a spectrum of neurodevelopmental disability that is largely related to brain expression of mutated channels. It is not known how glycemic dysregulation of any type of early-onset diabetes may affect brain development.
Methods: Subjects included from UChicago Monogenic Diabetes Registry with diabetes diagnosed under a year of age currently aged 4-20 years and unaffected sibling controls. Known KATP channel mutations or other rare causes affecting brain development were excluded. Measures of intellectual function (IF), executive function (EF), visual motor integration (VMI) and academic achievement (AA) were utilized (Table 1). A two-sample t-test was conducted comparing each group assuming unequal variance.
Results: Comprehensive testing was completed for those with infancy-onset diabetes and siblings (Table 1). There were no significant differences on any measure, though mean scores trended lower in the affected group.
Conclusion: Our findings show no difference in IF, EF, VMI, AA in children diagnosed with diabetes in infancy compared to their unaffected siblings. Our conclusions are limited due to a small sample size; differences may be subtle and require a larger sample size to be identified.
Disclosure
M. McCauley: None. A.M. Denson: None. L.R. Letourneau-Freiberg: None. M.N. Scott: None. S.W. Greeley: None.
Funding
American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)
The University of Chicago National Monogenic Diabetes Registry houses a novel dataset of people presenting with possible or known monogenic diabetes and has over a decade of data points, despite the ...rarity of the disease relative to T1DM and especially T2DM. Currently, determination of genetic testing, including which specific panel or genes is most appropriate to sequence, is a manual process introducing variability and subjectivity.
Aim: To test and compare performance of several models against the manual process and each other in identifying maturity-onset diabetes of the young (MODY) from available clinical information.
Methods: Statistical models for prediction of monogenic diabetes were applied to clinical data for cases suspected of having MODY. The models tested in the study with this dataset ranged from the traditional methods of regression to more modern approaches of neural nets, classification trees, clustering, and other machine learning algorithms for classification of MODY against type 1 and type 2 and a possible subset of monogenic diabetes subtypes.
Results: Using a sample size of N=330, with 70 testing positive for either GCK, HNF1A, or HNF4A, exploratory data models were able to achieve 75-80% validation accuracy (random validation data set at 10-20% of N) while internal human classification accuracy was roughly 42% over the same samples. The traditional logistic regression and neural net had equivalent performance.
Conclusions: The 3750 participants within the Registry and more than a decade of follow-up presents a unique opportunity to assess which clinical features are most predictive in identifying those with monogenic diabetes. The results of this work will direct future testing efforts within the Registry to assist in efficient diagnosis of these uncommon yet clinically important forms of diabetes.
Disclosure
R. P. Mulligan: None. L. R. Letourneau-freiberg: None. T. L. Bowden: None. P. Tian: None. B. Kandasamy: None. L. H. Philipson: Advisory Panel; Self; Nevro Corp., Research Support; Self; Provention Bio, Inc. S. W. Greeley: None. R. N. Naylor: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK020595)
Monogenic forms of diabetes have received increased attention and genetic testing is more widely available; however, many patients are still misdiagnosed as having type 1 (T1D) or type 2 diabetes. ...This review will address updates to monogenic diabetes prevalence, identification, treatment, and genetic testing.
The creation of a T1D genetic risk score and the use of noninvasive urinary C-peptide creatinine ratios have provided new tools to aid in the discrimination of possible monogenic diabetes from likely T1D. Early, high-dose sulfonylurea treatment in infants with a KCNJ11 or ABCC8 mutation continues to be well tolerated and effective. As the field moves towards more comprehensive genetic testing methods, there is an increased opportunity to identify novel genetic causes. Genetic testing results continue to allow for personalized treatment but should provide patient information at an appropriate health literacy level.
Although there have been clinical and genetic advances in monogenic diabetes, patients are still misdiagnosed. Improved insurance coverage of genetic testing is needed. The majority of data on monogenic diabetes has been collected from Caucasian populations, therefore, research studies should endeavor to include broader ethnic and racial diversity to provide comprehensive information for all populations.
Purpose of Review
The goal of this review is to provide updates on congenital (neonatal) diabetes from 2011 to present, with an emphasis on publications from 2015 to present.
Recent Findings
There ...has been continued worldwide progress in uncovering the genetic causes of diabetes presenting within the first year of life, including the recognition of nine new causes since 2011. Management has continued to be refined based on underlying molecular cause, and longer-term experience has provided better understanding of the effectiveness, safety, and sustainability of treatment. Associated conditions have been further clarified, such as neurodevelopmental delays and pancreatic insufficiency, including a better appreciation for how these “secondary” conditions impact quality of life for patients and their families.
Summary
While continued research is essential to understand all forms of congenital diabetes, these cases remain a compelling example of personalized genetic medicine.
Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into β-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four ...times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.
Background
Neonatal diabetes mellitus (NDM) caused by mutations in KCNJ11 can be successfully treated with high dose oral sulfonylureas; however, little data is available on the risk of hypoglycemia.
...Objective
To determine the frequency, severity, and clinical significance of hypoglycemia in KCNJ11‐related NDM.
Methods
Utilizing the University of Chicago Monogenic Diabetes Registry, parents completed an online questionnaire addressing hypoglycemia. Continuous glucose monitoring (CGM) data was available for 7 subjects.
Results
Thirty subjects with KCNJ11‐related permanent NDM (166 patient‐years on sulfonylurea) had median sulfonylurea dose of 0.39 mg/kg/day (0.24‐0.88 IQR, interquartile range) with median HbA1c 5.7% (39 mmol/mol) (5.5‐6.1 IQR, 37‐43 mmol/mol). Hypoglycemia (<70 mg/dL) was reported monthly once or less frequently in 89.3% of individuals, but 3 (10.7%) reported once weekly or more. Of all hypoglycemic episodes reported, none involved seizures or unconsciousness and thus did not meet the current ISPAD definition of severe hypoglycemia. Seven individuals wore a CGM for a total of 912 hours with blood sugars falling below 70 mg/dL for 5.8% of the time recorded, similar to ranges reported for people without diabetes.
Conclusions
In our cohort of KCNJ11‐related permanent NDM, hypoglycemia is infrequent and mild despite the high doses of sulfonylurea used and near‐normal level of glycemic control. Long‐term follow‐up on larger numbers will be required to clarify the incidence and determinants of hypoglycemia in this unique population.
The majority of patients with diabetes are diagnosed as having either type 1 or type 2 diabetes. However, when encountered in clinical practice, some patients may not match the classic diagnostic ...criteria or expected clinical presentation for either type of the disease. Latent autoimmune, ketosis-prone, and monogenic diabetes are nonclassical forms of diabetes that are often misdiagnosed as either type 1 or type 2 diabetes. Recognizing the distinguishing clinical characteristics and understanding the diagnostic criteria for each will lead to appropriate treatment, facilitate personalized medicine, and improve patient outcomes.
Mutations in GATA6, GATA4 and PDX1 cause congenital diabetes and pancreatic hypoplasia (PH) or agenesis. We investigated clinical features and treatment of 10 PH patients through the University of ...Chicago National Monogenic Diabetes Registry. Data was self-reported or extracted from medical records. Similar to previous cohorts, congenital heart defects, gallbladder agenesis, and exocrine pancreatic insufficiency were often present, whereas features such as recurrent infections and epilepsy have not been reported previously (Figure 1). Weight gain and glycemic control were often poor, yet there were no episodes of DKA over 110 patient-years (Figure 2). Close multi-subspecialty follow-up of these complex patients may improve frequent difficulties with weight gain and highly labile blood sugars.
Disclosure
A.M. Denson: None. M. Freemark: Research Support; Self; Rhythm Pharmaceuticals, Inc. I.H. Thomas: None. H. Abdullatif: None. J.B. Nogueira: None. R. Benjamin: None. L.R. Letourneau: None. R.N. Naylor: None. S.W. Greeley: None.
Funding
American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institutes of Health (R01DK104942, P30DK020595, UL1TR002389)
Introduction & Objective: RADIANT is a multicenter, US-based study of the causes of atypical diabetes and how it informs overall understanding of diabetes etiology and heterogeneity. A key goal is ...equitable inclusion so that knowledge gained will be broadly applicable. Populations at risk for underrepresentation in research include those with low socioeconomic status. We assessed area deprivation index (ADI), a census-based socioeconomic index, of RADIANT participants. We evaluated the relationship of ADI with participant characteristics. Methods: Participants with valid U.S. addresses and available ADI ranking were included in the study. Participant characteristics were summarized; 2021 ADI values were constructed based on participant address. ADI values were compared to the expected value of 50th percentile via the Wilcoxon test and compared among groups via the Kruskal-Wallis test. Results: There were 892 RADIANT participants included in the analysis. The median U.S. ADI of participants was 28, lower than the expected value of 50 (p<0.001). Only 24.5% of participants had ADI >50th percentile. Median ADI differed by race, but not ethnicity, with Asian participants having the lowest median ADI (13), compared to Blacks (29) and Whites (29) (p<0.01). Median ADI did not differ by referral source (e.g., provider vs. self-referral). ADI compared across ~3 consecutive years was statistically different (Median ADI 24, 30, 29; p<0.05), driven by an increase from year 1 to year 2. Conclusion: This study found that a low number of RADIANT participants live in areas of high deprivation, suggesting ascertainment bias in enrollment and highlighting the need for continued development of recruitment practices that will engage individuals likely to face barriers to research participation and who simultaneously carry a higher disease burden from diabetes. Disclosure L.R. Letourneau-Freiberg: None. T.I. Pollin: None. R.N. Naylor: None. Funding National Institute of Health (DK118638); National Institute of Health (U54 DK118612)
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