PREDICTING DIABETES USING GENETIC RISK SCORES Diabetes Care Volume 42, February 2019 215 Pamela Bowman,1,2 Jacob Day,1,2 Cognitive, Neurological, and Lorna Torrens,3 Maggie H. Shepherd,1,2 Bridget A. Knight,1,2 Tamsin J. Ford,1 Behavioral Features in Adults Sarah E. Flanagan,1 Ali Chakera,1,2 With KCNJ11 Neonatal Diabetes Andrew T. Hattersley,1,2 and Adam Zeman1 Diabetes Care 2019;42:215–224 | https://doi.org/10.2337/dc18-1060 OBJECTIVE Central nervous system (CNS) features in children with permanent neonatal diabetes (PNDM) due to KCNJ11 mutations have a major impact on affected families. Sulfonylurea therapy achieves outstanding metabolic control but only partial improvement in CNS features. The effects of KCNJ11 mutations on the adult brain and their functional impact are not well understood. We aimed to characterize the CNS features in adults with KCNJ11 PNDM compared with adults with INS PNDM. RESEARCH DESIGN AND METHODS Adults with PNDM due to KCNJ11 mutations (n =8)orINS mutations (n =4) underwent a neurological examination and completed standardized neuropsycho- logical tests/questionnaires about development/behavior. Four individuals in each group underwent a brain MRI scan. Test scores were converted to Z scores using normative data, and outcomes were compared between groups. RESULTS In individuals with KCNJ11 mutations, neurological examination was abnormal in seven of eight; predominant features were subtle deficits in coordination/motor sequencing. All had delayed developmental milestones and/or required learning support/special schooling. Half had features and/or a clinical diagnosis of autism spectrum disorder. 1University of Exeter Medical School, Exeter, U.K. KCNJ11 mutations were also associated with impaired attention, working memory, 2Exeter National Institute for Health Research and perceptual reasoning and reduced intelligence quotient (IQ) (median IQ KCNJ11 Clinical Research Facility, Exeter, U.K. 3 vs. INS mutations 76 vs. 111, respectively; P = 0.02). However, no structural brain Kent Neuropsychology Service, Kent and Med- way NHS and Social Care Partnership Trust, abnormalities were noted on MRI. The severity of these features was related to Gillingham, U.K. the specific mutation, and they were absent in individuals with INS mutations. Corresponding author: Pamela Bowman, [email protected] CONCLUSIONS KCNJ11 fi Received 15 May 2018 and accepted 22 Septem- PNDM is associated with speci c CNS features that are not due to long- ber 2018 standing diabetes, persist into adulthood despite sulfonylurea therapy, and rep- This article contains Supplementary Data online resent the major burden from KCNJ11 mutations. at http://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc18-1060/-/DC1. KCNJ11 gene mutations are the commonest cause of permanent neonatal diabetes P.B. and J.D. contributed equally to this study. (PNDM), which presents in the first 6 months of life and affects 1 in 100,000 live births © 2018 by the American Diabetes Association. Readers may use this article as long as the work is (1). KCNJ11 is expressed in the pancreas and brain as well as other tissues and encodes properly cited, the use is educational and not for the Kir6.2 subunit of the KATP channel. In the pancreas, the KATP channel links in- profit, and the work is not altered. More infor- creasing blood glucose to insulin secretion, but activating KCNJ11 mutations prevent mation is available at http://www.diabetesjournals channel closure in response to metabolically generated ATP and result in diabetes (2). .org/content/license. Clinically, patients present in an insulin-deficient state, and prior to discovery of See accompanying articles, pp. 189, disease-causing variants in the KCNJ11 gene, they required insulin therapy. It was later 192, 200, 208, and e16. 216 CNS Features in KCNJ11 Neonatal Diabetes Diabetes Care Volume 42, February 2019 shown that KCNJ11 PNDM could be (23–26) and resolution of functional cer- ketoacidosis at diagnosis, as seen in treated with sulfonylurea tablets, which ebellar and temporal lobe abnormali- type 1 diabetes (34,35). However, cere- bind and close the channel, allowing in- ties on single-photon emission computed bral edema in KCNJ11 PNDM gives rise sulin secretion, excellent metabolic con- tomography (SPECT) scanning (24,27). to a pattern of neurological impairment trol, and reduced glycemic variability (3). The improvement in CNS features may distinct from that seen as a direct result For many patients and their families, be limited as a result of poor penetration of brain KATP channel dysfunction (36). transferring from insulin to oral sulfo- of the sulfonylurea across the blood- More subtle neurocognitive problems nylureas vastly improved quality of life brain barrier or active transport back also occur in the presence of diabetes in relation to diabetes (4). out of the brain, leading to subtherapeu- per se, particularly if metabolic control is Central nervous system (CNS) features tic concentrations in the cerebrospinal poor and diabetes is diagnosed before occur in children with KCNJ11 PNDM in fluid (CSF) (28). This, and anecdotal clin- age 7 years (37). Further, individuals with addition to diabetes. These are thought ical experience of greater CNS response type 2 diabetes are at increased risk of to result from expression of aberrant KATP with higher doses of sulfonylurea, has developing Alzheimer disease in later life, channels in the brain. The precise role(s) prompted clinical recommendations of and this may in part be due to chronic of KATP channels in the human CNS has glyburide doses of ;1 mg/kg/day in metabolic disturbance and changes in not been fully elucidated, but rodent people with severe neurological features insulin signaling (38). Indeed, there is studies suggest that they play a role in secondary to KCNJ11 mutations (29). evidence from both animal and human glucose sensing and homeostasis as well However, the neurobehavioral features studies that insulin plays a key role in as seizure propagation (5,6). KCNJ11 is continue to have a huge impact on central processes including memory and expressed in many brain areas, but there families despite sulfonylurea treatment learning (38). The nonspecific diabetes- are particularly high levels of expression (16). This contrasts markedly with the related cognitive features could con- in the cerebellum (7,8). The cerebellum outstanding metabolic response that found assessment of CNS phenotype is well-known for its role in motor learn- changed lives by alleviating the anxiety in people with KCNJ11 mutations; how- ing and coordination (9), but it also has associated with poor metabolic control ever, people with INS mutations are well functions relating to language, executive (4). A key question is whether the CNS placed to control for them. There has function, and mood; furthermore, cere- features continue to represent the major been no previous detailed comparison of bellar abnormalities have been linked burden from KCNJ11 mutations in adult the CNS phenotype in people with INS with autism (10,11). Documented CNS life. To date, all studies characterizing and KCNJ11 mutations. features in children with KCNJ11 muta- CNS features in KCNJ11 PNDM have been The aim of this study was to charac- tions range from subtle neuropsycholog- conducted in predominantly pediatric terize the neurological and neuropsycho- ical impairments that specifically affect cohorts (12–14,16,23). However, brain logical features in adults with KCNJ11 attention, praxis, and executive function development continues beyond child- PNDM compared with these features in to the severe and overt Developmental hood and adolescence (30,31). No study adults with INS PNDM. Delay, Epilepsy and Neonatal Diabe- has comprehensively assessed the tes [DEND]/intermediate DEND [iDEND] CNSoutcomesinadultswithKCNJ11 RESEARCH DESIGN AND METHODS syndrome (12–15). Other associated fea- mutations. Ethics Approval tures may include psychiatric morbidity, Mutations in the INS gene are a less Ethics approval was obtained from the specifically, neurodevelopmental disor- common cause of neonatal diabetes, National Research Ethics Service Com- ders and anxiety disorders, visuomotor accounting for ;10% of cases (1). Het- mittee South West–Exeter. impairments, and sleep disturbance (16– erozygous dominant negative INS muta- 18). The severity of the CNS phenotype is tions often affect protein synthesis, Sample Size and Patient Recruitment related to the genotype. For example, the resulting in production of structurally We identified 34 patients .16 years old V59M mutation is frequently associated abnormal preproinsulin and proinsulin with KCNJ11 mutations and 9 patients with iDEND syndrome and neurodevelop- within the b-cell, endoplasmic reticulum .16 years old with INS mutations who mental features, whereas the R201H stress, and cell death. Individuals with had received a molecular genetic diagno- mutation, previously associated with these mutations also typically present sis in Exeter and who had been diagnosed diabetes alone, has been more recently with insulin deficiency but, unlike those with permanent neonatal diabetes before linked with subtle neuropsychological with KCNJ11 PNDM, require lifelong 6 months of age. We approached poten- features (12). Historically, the severity treatment with replacement doses of in- tial participants either directly at a neo- of CNS features was thought to be re- sulin (32). The INS gene is not expressed natal diabetes family event in Exeter or latedtothefunctionalseverityofthe