Monogenic diabetes is a group of disorders caused by mutations in any one of a number of genes essential for the appropriate function of the insulin producing beta-cells in the pancreas. Some patients have mutations in genes that encode proteins that are also expressed in extra-pancreatic tissues and thus have other features in addition to the diabetes, such as intellectual impairment. Estimates suggest that monogenic forms of diabetes could represent as much as 2% of all diabetes cases. Diabetes diagnosed before one year of age is a rare occurrence but such patients are especially likely to have an underlying monogenic cause. The University of Chicago Neonatal Diabetes Registry now includes clinical and genetic information on over 300 subjects with diabetes diagnosed prior to one year of age. The largest subgroup of these cases have mutations in the most common genetic cause of neonatal diabetes: activating mutations in the gene KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, which plays a critical role in insulin secretion. Patients with KCNJ11-related neonatal diabetes who were previously treated with insulin exhibit clinically excellent glucose control with minimal hypoglycemia when treated with sulfonylureas (usually glyburide) that promote closure of overly activated mutant channels. Because of the expression of mutated KATP channels in the brain, these patients also exhibit a spectrum of neurodevelopmental disability. Subjects with activating KCNJ11 mutations display a variety of neurological defects, from those with mild problems such as hyperactivity, to cases with moderate speech and motor delay with subsequent moderate cognitive impairment and visuomotor dis-coordination, as well as rare mutations causing severe global developmental disability progressing to mental retardation and seizures. The fact that KATP channels are found widely expressed throughout the brain suggests that they are likely to have roles in several different capacities;however, the neuronal function of these channels remains poorly understood. Importantly, limited study by our group and others has suggested that although sulfonylurea treatment improves the neurological functioning in these patients, they remain impaired. Subjects with KCNJ11-related diabetes represent an unparalleled opportunity to investigate a human model of specific disruption the KATP channels that are expressed widely within the brain. In this application, we thus propose the following Aims: 1) To characterize the neurodevelopmental and eye tracking impairments in KCNJ11 diabetes;2) To characterize neuroanatomical abnormalities in KCNJ11 diabetes;3) To characterize abnormal sleep patterns in KCNJ11 diabetes. Subjects 18 years of age or older will undergo detailed brain imaging, polysomnography, videonystagmography, neuropsychological and neurocognitive assessments. Establishing the clinical, neurodevelopmental and anatomical sequelae of dysfunctional KATP channels within the brain may offer a unique insight into human physiology and pathology. In addition, our studies have clear implications for children with KCNJ11 mutations. By gaining a more detailed and comprehensive understanding of the struggles they face, clinicians will be better equipped to provide the many supports they require, including multi-specialty therapies as well as medical intervention. Since high dose monotherapy with sulfonylureas appears to result in limited neurological improvement, the data gained through the proposed studies will form the basis for future trials of alternative or additional medical treatments that may be more effective in regards to correcting channel functioning within the brain. The proposed studies will not only reveal much detail about the role of the channels in the brain but will also allow for validation o the several proposed measures that could be utilized to track improvement (or lack thereof) in future interventional studies. These patients have many clinical characteristics in common with other neurodevelopmental and behavioral disorders including motor coordination and cognitive deficits, hyperactivity and inattention, among others. We anticipate that these studies will elucidate the role of KATP channels within the brain and will also lay the groundwork for future studies into the role of KATP channels in many other neurodevelopmental disorders.
The proposed studies of patients with human neonatal diabetes due to mutations in the KCNJ11 gene will result in a deeper understanding of the various manifestations of their disease, including a spectrum of neurodevelopmental problems. Reliable outcome measures of the neurodevelopmental disabilities have been lacking but will be essential in determining the most appropriate long-term treatment for these patients and possibly those with other forms of monogenic diabetes. The proposed studies should lead to novel insight into how KCNJ11 potassium channels expressed in the brain are essential for normal brain functioning. This could have ramifications in regards to mechanisms of disease and best treatment for the many patients in the US with various neurodevelopmental disorders - including autism spectrum - who share several features in common with KCNJ11 diabetes patients.