Neurodevelopmental and behavioral features represent the main challenge for many patients with permanent neonatal diabetes (PNDM) due to activating variants in the KCNJ11 gene, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel. Individuals with the p.(Val59Met) KCNJ11 variant have developmental delay, childhood-onset generalized epilepsy, and neonatal diabetes (intermediate developmental delay, epilepsy, and neonatal diabetes [iDEND] syndrome [1]). There are also high rates of autism spectrum disorder, attention deficits, hyperactivity, and impaired visuomotor performance (2,3). KCNJ11 PNDM can be treated with sulfonylureas, which bind to mutant KATP channels in the pancreas and restore functioning, allowing affected individuals to discontinue insulin. There is often a mild but incomplete improvement in neurological function after sulfonylureas are started, suggesting that brain KATP channels respond in part to sulfonylureas (4).
Earlier sulfonylurea transfer may lead to better neurodevelopmental outcomes (3,4), likely due to increased neuronal plasticity in infancy. KATP channel dysfunction begins in utero, evidenced by low birth weights in KCNJ11 PNDM due to impaired fetal insulin secretion. Glyburide crosses the placenta and enters the fetal circulation (5); therefore, it may be possible to target brain KATP channels at the earliest possible opportunity, via maternal glyburide treatment. Here, we describe the neurodevelopmental outcome in a patient with the p.(Val59Met) variant who, in addition to being treated early postnatally, was exposed to glyburide in utero due to treatment of maternal gestational diabetes mellitus.
The case patient, a 17-year-old female, was born at term weighing 2,400 g (z score −2.59). Her mother was diagnosed with gestational diabetes mellitus and serendipitously treated with glyburide 0.75 mg/day from 10 weeks’ gestation throughout pregnancy. At 6 weeks the patient presented with fever and raised cerebrospinal fluid glucose. She was diagnosed with neonatal diabetes and started insulin therapy. This was switched to glyburide (titrated up to 1 mg/kg/day) after 2 weeks, when genetic analysis identified a de novo heterozygous p.(Val59Met) pathogenic variant in the KCNJ11 gene.
The parents of our case patient reported she had excellent speech development and was communicating in sentences at the expected age for this milestone. Her walking was delayed (27 months), and she had physiotherapy and occupational therapy from 13 months to 3 years. She developed complex partial seizures at 18 months and was diagnosed with attention deficit/hyperactivity disorder at 9 years. Her medications at that time comprised glyburide (8.75 mg three times daily), oxcarbazepine (675 mg daily), levetiracetam (500 mg daily), and atomoxetine. Antiepileptic medication was stopped at 16 years, and she has remained seizure free.
Our case has attended age-appropriate mainstream schooling since the age of 5 years and will graduate with a diploma in general education this year. She has required some additional learning support, particularly in Mathematics and English, and her parents reported some challenges with visuospatial awareness, e.g., following directions. She played for the school soccer team and is a competent cyclist.
The developmental trajectory described for this case contrasts with that of other p.(Val59Met) patients who have significant impairment requiring high levels of support and are unable to continue in mainstream schooling (1,2). This was demonstrated by the striking differences in the “draw a man” task performed by our case patient aged 9 years, in comparison with adolescents or adults with the same p.(Val59Met) variant who started sulfonylurea treatment later (Fig. 1). It is unusual for a patient with this variant to have normal speech development and to graduate from mainstream education with a view to independent living (1,2), as observed in this case. Her comparatively better developmental outcomes support the rationale for early sulfonylurea treatment, to target mutant KATP channels in the brain at a time of greater neuroplasticity. In support of this concept, a human-induced pluripotent stem cell organoid model expressing p.(Val59Met) showed aberrant cortical neural network formation and reduced synchronization in comparison with wild type; abnormalities could be partly reversed with sulfonylurea (tolbutamide) treatment (6).
A–C: “Draw a man” task performed by case patient described and two other patients with the p.(Val59Met) KCNJ11 variant, both of whom were older and transferred to sulfonylureas (SU) at a later age.
A–C: “Draw a man” task performed by case patient described and two other patients with the p.(Val59Met) KCNJ11 variant, both of whom were older and transferred to sulfonylureas (SU) at a later age.
To date, this case patient is the only reported individual with the p.(Val59Met) variant known to have had exposure to glyburide in utero. Although the dose was relatively small, it is likely to have impacted brain KATP channels antenatally, in addition to the likely beneficial effect of early postnatal treatment. This is supported by research suggesting that full-scale intelligence quotient scores in patients with the p.(Val59Met) variant are usually in the moderate intellectual disability range even when glyburide is started 0–2 years postnatally (7). The potential to further improve outcomes with treatment in pregnancy will become increasingly important as we offer noninvasive prenatal testing (NIPT) for pregnant mothers with KATP channel–related PNDM. Noninvasive prenatal testing affords an opportunity to identify affected fetuses early and, if the variant is maternally inherited or if the mother has gestational diabetes mellitus for another reason, provide targeted glyburide therapy via the affected mother to improve neurodevelopment (5). However, at present this prospect remains speculative, and formal research studies are needed to assess whether antenatal sulfonylurea therapy provides additional benefits to early postnatal treatment and, if so, what dose of glyburide is most effective for this purpose while maintaining safety and avoiding adverse events during pregnancy and in the neonatal period.
Importantly, our case patient had additional support in early childhood through physiotherapy, occupational therapy, and specific educational interventions. She also received adjunctive pharmacological treatment with drugs that act in the brain. Future research is needed to dissect the relative contributions of genetic and nongenetic determinants of neurodevelopment in affected individuals, the factors affecting its variability, and how the timing of medical interventions can modify outcomes. This will enable further precision in our approach to treatment of neonatal diabetes.
Article Information
Acknowledgments. The authors thank the case patient and family for their contributions to the information included in this report.
Funding. This study was supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre and Clinical Research Facility. This study was also supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942).
The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. All authors contributed to data collection. P.B. drafted the manuscript and all other authors reviewed and approved it prior to submission. P.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Handling Editors. The journal editors responsible for overseeing the review of the manuscript were John B. Buse and Thomas P.A. Danne.
