Rochelle N. Naylor

Neonatal Diabetes: An Expanding List of Genes Allows for Improved Diagnosis and Treatment

There has been major progress in recent years uncovering the genetic causes of diabetes presenting in the first year of life. Twenty genes have been identified to date. The most common causes accounting for the majority of cases are mutations in the genes encoding the two subunits of the ATP-sensitive potassium channel (KATP), KCNJ11 and ABCC8, and the insulin gene (INS), as well as abnormalities in chromosome 6q24. Patients with activating mutations in KCNJ11 and ABCC8 can be treated with oral sulfonylureas in lieu of insulin injections. This compelling example of personalized genetic medicine leading to improved glucose regulation and quality of life may—with continued research—be repeated for other forms of neonatal diabetes in the future.

Neonatal diabetes mellitus: a model for personalized medicine.

Neonatal diabetes mellitus occurs in approximately 1 out of every 100,000 live births. It can be either permanent or transient, and recent studies indicate that is likely to have an underlying genetic cause, particularly when diagnosed before 6 months of age. Permanent neonatal diabetes is most commonly due to activating mutations in either of the genes encoding the two subunits of the ATP-sensitive potassium channel. In most of these patients, switching from insulin to oral sulfonylurea therapy leads to improved metabolic control, as well as possible amelioration of occasional associated neurodevelopmental disabilities. It remains to be determined what is the most appropriate treatment of other causes. The diagnosis and treatment of neonatal diabetes, therefore, represents a model for personalized medicine.

Cost-Effectiveness of MODY Genetic Testing: Translating Genomic Advances Into Practical Health Applications

OBJECTIVE To evaluate the cost-effectiveness of a genetic testing policy for HNF1A-, HNF4A-, and GCK-MODY in a hypothetical cohort of type 2 diabetic patients 25–40 years old with a MODY prevalence of 2%. RESEARCH DESIGN AND METHODS We used a simulation model of type 2 diabetes complications based on UK Prospective Diabetes Study data, modified to account for the natural history of disease by genetic subtype to compare a policy of genetic testing at diabetes diagnosis versus a policy of no testing. Under the screening policy, successful sulfonylurea treatment of HNF1A-MODY and HNF4A-MODY was modeled to produce a glycosylated hemoglobin reduction of −1.5% compared with usual care. GCK-MODY received no therapy. Main outcome measures were costs and quality-adjusted life years (QALYs) based on lifetime risk of complications and treatments, expressed as the incremental cost-effectiveness ratio (ICER) (USD/QALY). RESULTS The testing policy yielded an average gain of 0.012 QALYs and resulted in an ICER of 205,000 USD. Sensitivity analysis showed that if the MODY prevalence was 6%, the ICER would be ∼50,000 USD. If MODY prevalence was >30%, the testing policy was cost saving. Reducing genetic testing costs to 700 USD also resulted in an ICER of ∼50,000 USD. CONCLUSIONS Our simulated model suggests that a policy of testing for MODY in selected populations is cost-effective for the U.S. based on contemporary ICER thresholds. Higher prevalence of MODY in the tested population or decreased testing costs would enhance cost-effectiveness. Our results make a compelling argument for routine coverage of genetic testing in patients with high clinical suspicion of MODY.

Who should have genetic testing for maturity‐onset diabetes of the young?

Maturity‐onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic disorders characterized by autosomal dominant inheritance of young‐onset, non‐insulin‐dependent diabetes. The genes involved are important in beta cell development, function and regulation and lead to disorders in glucose sensing and insulin secretion. Heterozygous GCK mutations cause impaired glucokinase activity resulting in stable, mild hyperglycaemia that rarely requires treatment. HNF1A mutations cause a progressive insulin secretory defect that is sensitive to sulphonylureas, most often resulting in improved glycaemic control compared with other diabetes treatment. MODY owing to mutations in the HNF4A gene results in a similar phenotype, including sensitivity to sulphonylurea treatment. HNF1B mutations most frequently cause developmental renal disease (particularly renal cysts) but may also cause MODY in isolation or may cause the renal cysts and diabetes syndrome (RCAD syndrome). Mutations in NEUROD1, PDX1 (IPF1), CEL and INS are rare causes of MODY. MODY is often misdiagnosed as type 1 or type 2 diabetes. However, a correct genetic diagnosis impacts treatment and identifies at‐risk family members. Thus, it is important to consider a diagnosis of MODY in appropriate individuals and to pursue genetic testing to establish a molecular diagnosis.

Genetics and pathophysiology of neonatal diabetes mellitus

Neonatal diabetes mellitus (NDM) is the term commonly used to describe diabetes with onset before 6 months‐of‐age. It occurs in approximately one out of every 100,000–300,000 live births. Although this term encompasses diabetes of any etiology, it is recognized that NDM diagnosed before 6 months‐of‐age is most often monogenic in nature. Clinically, NDM subgroups include transient (TNDM) and permanent NDM (PNDM), as well as syndromic cases of NDM. TNDM often develops within the first few weeks of life and remits by a few months of age. However, relapse occurs in 50% of cases, typically in adolescence or adulthood. TNDM is most frequently caused by abnormalities in the imprinted region of chromosome 6q24, leading to overexpression of paternally derived genes. Mutations in KCNJ11 and ABCC8, encoding the two subunits of the adenosine triphosphate‐sensitive potassium channel on the β‐cell membrane, can cause TNDM, but more often result in PNDM. NDM as a result of mutations in KCNJ11 and ABCC8 often responds to sulfonylureas, allowing transition from insulin therapy. Mutations in other genes important to β‐cell function and regulation, and in the insulin gene itself, also cause NDM. In 40% of NDM cases, the genetic cause remains unknown. Correctly identifying monogenic NDM has important implications for appropriate treatment, expected disease course and associated conditions, and genetic testing for at‐risk family members. Early recognition of monogenic NDM allows for the implementation of appropriate therapy, leading to improved outcomes and potential societal cost savings. (J Diabetes Invest, doi:10.1111/j.2040‐1124.2011.00106.x, 2011)

Sulfonylurea Treatment Before Genetic Testing in Neonatal Diabetes: Pros and Cons

CONTEXT Diabetes in neonates nearly always has a monogenic etiology. Earlier sulfonylurea therapy can improve glycemic control and potential neurodevelopmental outcomes in children with KCNJ11 or ABCC8 mutations, the most common gene causes. OBJECTIVE Assess the risks and benefits of initiating sulfonylurea therapy before genetic testing results become available. DESIGN, SETTING, AND PATIENTS Observational retrospective study of subjects with neonatal diabetes within the University of Chicago Monogenic Diabetes Registry. MAIN OUTCOME MEASURES Response to sulfonylurea (determined by whether insulin could be discontinued) and treatment side effects in those treated empirically. RESULTS A total of 154 subjects were diagnosed with diabetes before 6 months of age. A genetic diagnosis had been determined in 118 (77%), with 73 (47%) having a mutation in KCNJ11 or ABCC8. The median time from clinical diagnosis to genetic diagnosis was 10.4 weeks (range, 1.6 to 58.2 wk). In nine probands, an empiric sulfonylurea trial was initiated within 28 days of diabetes diagnosis. A genetic cause was subsequently found in eight cases, and insulin was discontinued within 14 days of sulfonylurea initiation in all of these cases. CONCLUSIONS Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available; however, larger numbers of cases must be studied. Given the potential beneficial effect on neurodevelopmental outcome, glycemic control, and the current barriers to expeditious acquisition of genetic testing, an empiric inpatient trial of sulfonylurea can be considered. However, obtaining a genetic diagnosis remains imperative to inform long-term management and prognosis.

Creation of the Web-Based University of Chicago Monogenic Diabetes Registry: Using Technology to Facilitate Longitudinal Study of Rare Subtypes of Diabetes

Background: Monogenic diabetes is a group of disorders caused by mutations in any one of a number of genes. Although a monogenic diagnosis—estimated to represent as much as 2% of all diabetes patients—can have a transformational impact on treatment, the majority of monogenic cases remain unidentified and little is known about their natural history. We thus created the first United States Monogenic Diabetes Registry (http://www.kovlerdiabetescenter.org/registry/) for individuals with either neonatal diabetes diagnosed before 1 year of age or with a phenotype suggestive of maturity-onset diabetes of the young. Methods: Inclusion criteria and consent documents are viewable on our Web site, which allows secure collection of contact information to facilitate telephone consent and enrollment. Relevant medical, family, and historical data are collected longitudinally from a variety of sources and stored in our Web-accessible secure database. Results: We have enrolled well over 700 subjects in the registry so far, with steady recruitment of those diagnosed under 1 year of age and increasing enrollment of those diagnosed later in life. Initially, participants were mostly self-referred but are increasingly being referred by their physicians. Comprehensive survey and medical records data are collected at enrollment, with ongoing collection of longitudinal data. Associated private Facebook and email discussion groups that we established have already fostered active participation. Conclusions: Our early success with the Monogenic Diabetes Registry demonstrates the effectiveness of low-cost Web-based tools, including surveys, the Research Electronic Data Capture database program, and discussion groups, for efficient enrollment and support of rare patients, and collection and maintenance of their data.

Diabetes Presentation in Infancy: High Risk of Diabetic Ketoacidosis

Diabetes in childhood has been associated with increased morbidity and mortality, but the risks for diabetes in infancy remain unclear. Cases with onset of hyperglycemia in the first 6 months of life consist predominantly of monogenic diabetes, whereas type 1 autoimmune diabetes accounts for the majority of cases beyond this threshold. Regardless of etiology, diabetes symptoms tend to be difficult to recognize in an infant, putting patients at increased risk for delays in diagnosis, which may lead to higher blood glucose levels and diabetic ketoacidosis (DKA) at presentation. Here, we report a high degree of morbidity among a cohort of subjects with infancy-onset diabetes. We examined diagnosis records from 88 cases with diabetes onset ≤13 months of age collected through the University of Chicago Monogenic Diabetes Registry (1). We assessed laboratory values and sign/symptoms, and if a causal mutation for diabetes was detected, participants were subdivided by similar mutation subtypes. Data were managed using REDCap electronic data capture tools and analyzed using Stata version 14 (StataCorp, 2015). The majority of participants were male ( n = 46, …

Role of Noninsulin Therapies Alone or in Combination in Chromosome 6q24-Related Transient Neonatal Diabetes: Sulfonylurea Improves but Does Not Always Normalize Insulin Secretion

Chromosome 6q24-related transient neonatal diabetes (6q24-TND) is a rare form of diabetes caused by an overexpression of PLAGL1 and HYMAI (1). After remitting in infancy, diabetes recurs in most patients later in life. While the best treatment remains unknown, many patients are managed with insulin (1). We sought to characterize β-cell function and glucose homeostasis in patients with 6q24-TND and assess their response to sulfonylurea (SU) therapy. Adults with 6q24-TND and recurrence of hyperglycemia requiring insulin therapy later in life were identified through The University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry) and invited to participate in a trial of SU therapy. Four patients with insulin doses of 0.41–0.76 units/kg/day attempted the trial. Three were available for a mixed-meal test (MMT) and arginine stimulation test (AST) on day one and day five of SU treatment. All insulin products were withheld on the morning of day one. Subjects ingested 7 mL/kg (maximal 360 mL) of BOOST High Protein (http://www.boost.com) within 5 …

Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls.

KCNJ11‐related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in patients with KCNJ11 mutations and their sibling controls.