Abstract
Aims
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 subjects with KCNJ11 mutations and their sibling controls.
Methods
Through our Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/), we evaluated 23 subjects with KCNJ11 mutations with (n=9) and without (n=14) global developmental delay successfully treated with sulfonylurea and 20 healthy sibling controls, using a battery of targeted neuropsychological and behavioural assessments with scaled scores that are comparable across a wide range of ages.
Results
Subjects with KCNJ11-related diabetes without global developmental delay had significant differences compared to sibling controls on a range of assessments including IQ, measures of academic achievement and executive function. KCNJ11 subjects with global delay exhibited significant differences in behavioural symptoms with a tendency to avoid social contact and displayed a reduced ability to adapt to new circumstances. Parents reported more immature behaviour, gross mood swings, bizarre thoughts, other unusual and severe behaviours and there were also significant deficits in all subdomains of daily living skills.
Conclusions
This series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction of individuals with KCNJ11-diabetes and is the first to compare outcome with sibling controls. Our data demonstrates the variety of neurodevelopmental problems seen in those with KCNJ11 mutations, even in those without recognized global developmental delays. These data can be used to counsel families and guide structured neurodevelopmental assessments and treatments based on the initial genetic diagnosis in patients with neonatal diabetes.
Keywords: Neonatal Diabetes Mellitus, KCNJ11, Developmental delay, epilepsy and neonatal diabetes
Introduction
Neonatal diabetes mellitus (NDM) is a predominantly monogenic disorder and occurs in approximately 1 in 90,000–160,000 live births [1–5]. There are an expanding list of over 25 genes identified associated with NDM but many of these are syndromic, with clinical clues that can direct genetic testing [6]. Heterozygous activating mutations in the ATP-sensitive potassium (KATP) channel genes KCNJ11 and ABCC8 are the most common causes of permanent NDM and usually allow for treatment with oral sulfonylureas (SU) instead of insulin [7–8].
Many patients with KATP-related NDM also exhibit a spectrum of neurodevelopmental problems, from mild learning disorders to significant cognitive dysfunction as well as seizures [9]. These developmental impairments are likely due to mutated KATP channels that are widely expressed in the brain; however, the possibility that early diabetes and consequent glycaemic excursions could contribute to such dysfunction has not been addressed in a systematic fashion [10–11]. Further evidence for the role of KATP channel activity in pathogenesis of these neurological problems is that sulfonylurea treatment can produce measureable improvement in neurodevelopmental outcomes in some patients [12]. Those with the constellation of developmental delay, epilepsy and neonatal diabetes have been referred to as having developmental delay, epilepsy, neonatal diabetes (DEND) or intermediate DEND (iDEND) syndrome. While those without obvious neurodevelopmental impairment have been considered to have neonatal diabetes in isolation, it remains unclear whether these patients might also have milder dysfunction [13].
We used a variety of behavioural and neuropsychological assessments to compare children with KCNJ11-related NDM (with and without DEND/iDEND) with healthy sibling controls. We aimed to identify appropriate early behavioural and developmental measures to aid clinicians and families confronted by this common genetic form of neonatal diabetes. We further hypothesized that those without gross delay would also have differences in at least some measures in comparison to sibling controls.
Methods
Subjects with KCNJ11-related permanent NDM and their unaffected siblings were consented for participation through the University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry/). The Registry collects longitudinal information regarding diagnosis and treatment of diabetes, other medical problems or complications, family history of diabetes, and results of genetic testing through surveys and medical records. All subjects were consented for participation through protocols approved by the Institutional Review Board at the University of Chicago.
We carried out standardized neuropsychological and behavioural assessments that allowed for scaled scores comparable across a wide range of ages, thus allowing for a larger number of subjects to participate. These measures included Wechsler Abbreviated Scales of Intelligence (WASI-II), Delis-Kaplan Executive Function System (D–KEFS) Trail Making Test, Wechsler Adult Intelligence Scale (WAIS-IV) Digit Span subtest, Wechsler Intelligence Scale for Children (WISC-IV) Digit Span subtest and Wechsler Individual Achievement Test (WIAT-III) (Supplemental Table 1). Parental report forms of the Behavior Assessment System for Children (BASC-2), the Behavior Rating Inventory of Executive Function (BRIEF) and the Vineland Adaptive Behavior Scales were also used.
Subjects were divided into three groups based on clinical phenotypes: KCNJ11-related NDM with global developmental delay (DEND or iDEND); KCNJ11-related NDM without global developmental delay; and healthy sibling controls. Subjects were considered to have global developmental delay if they were previously reported to have significant delays in two or more developmental domains: gross motor, fine motor, speech and language, cognition, personal and social development, or activities of daily living.
Results are expressed as mean ± standard deviation unless indicated. Data from pre-school Behavior Rating Inventory of Executive Function assessment (BRIEF-P) for children aged 2–5 years was combined with data from the BRIEF assessments completed by parents for those aged 5–18 years. Data was analyzed using Graphpad Prism 6 (GraphPad Software, CA, USA, http://www.graphpad.com). Nonparametric analyses were performed using the Kruskal-Wallis ANOVA test or Mann–Whitney U test for group comparisons. Group differences were considered significant if P<0.05.
Results
Twenty-three subjects with KCNJ11-related NDM, including nine with global developmental delay (7 V59M, 1 V59A and 1 Y330C) and fourteen without global delay (7 R201H, 3 R201C, 1 W68C, 1 E322K, 1 R50Q, and 1 A174G), and twenty sibling controls participated in the study (Table 1). The majority of individuals with KCNJ11-related NDM with global developmental delay were unable to complete the assessments of intellectual and executive functioning due to the severity of their delay.
Table 1.
Study participants
| KCNJ11-related NDM with global developmental delay | KCNJ11-related NDM without delay | Sibling controls | |
|---|---|---|---|
| n | 9 | 14 | 20 |
| Age at SU initiation | 1.13 (0.43–8.35) | 6.04 (1.24–13.73) | N/A |
| Age at Assessment | 7.21 (5.83–12.90) | 11.44 (6.52–17.93) | 9.23 (6.70–11.16) |
| Female (%) | 5 (55.6) | 8 (57.1) | 10 (50.0) |
| Mutations | 7 x V59M 1 x V59A 1 x Y330C |
7 x R201H 3 x R201C 1 x R50Q, W68C, A174G, E322K |
N/A |
SU, sulfonylurea
N/A, not applicable
Median and Interquartile ranges in parentheses. N/A- not applicable
Assessments of intellectual and executive function
We compared ten subjects with KCNJ11-related NDM without global developmental delay and ten sibling controls (Table 2). Only two subjects with KCNJ11-related NDM with global developmental delay were able to complete some assessments of intellectual and executive functioning, with scores consistently lowest of all those assessed (data not shown).
Table 2.
Assessments of intellectual and executive function
| KCNJ11-related NDM without delay | Sibling controls | P | |
|---|---|---|---|
| WASI-II (n) | 10 | 9 | |
| IQ | 91.1±11.3 | 111.0±8.3 | <0.005 |
| Matrix reasoning | 47.9±7.1 | 55.1±8.9 | NS (0.09) |
| Matrix Vocabulary | 48.1±4.5 | 58.8±6.4 | <0.01 |
| D-KEFS (n) (Scaled Score) | 9 | 7 | |
| Condition 1 Visual scanning | 8.0±2.2 | 11.7±2.7 | <0.01 |
| Condition 2 Number sequencing | 8.2±3.0 | 11.57±2.4 | <0.05 |
| Condition 3 Letter sequencing | 8.0±2.5 | 11.0±4.7 | <0.05 |
| Condition 4 number-letter switching | 7.6±2.8 | 9.86±3.3 | NS |
| Condition 5 Motor speed | 9.9±1.6 | 10.6±3.9 | NS |
| WISC-IV (n) (Standard Scores) | 9 | 9 | |
| Backward | 7.7±2.4 | 11.4±2.2 | <0.005 |
| Forward | 7.6±1.8 | 10.7±1.6 | <0.005 |
| Combined | 7.1±1.9 | 11.0±1.7 | <0.001 |
| WIAT-III (n) (Standard Scores) | 10 | 10 | |
| Numerical | 93.7±11.5 | 102.5±14.7 | NS |
| Spelling | 99.9±14.3 | 103.3±15.3 | NS |
| Reading | 95.9±9.5 | 110.4±11.0 | <0.01 |
NS, Not statistically significant
Individuals with KCNJ11-related NDM without global developmental delay had significant differences in executive functioning, especially when compared to sibling controls (Table 2). Those with mutations in KCNJ11 had reduced general intellectual ability based on both the matrix reasoning and vocabulary assessments of the WASI-II. The KCNJ11 group was also noted to perform worse in the areas of visual scanning speed, number sequencing and letter sequencing assessed through the D-KEFS Trail Making Test. The WISC-IV revealed gross deficits in auditory working memory in those with a KCNJ11 mutation, with the WISC-IV Digit Span test revealing difficulty with manipulation of verbal information. Word reading difficulties were also evident in those with mutations, as assessed by the WIAT-III.
Behavioural assessments
We used dedicated behavioural assessments to compare six subjects with KCNJ11-related NDM with global developmental delay, nine subjects with KCNJ11-related NDM without global developmental delay, and fourteen sibling controls. Those with KCNJ11-related NDM, both with and without global developmental delay, had significant differences in behavioural symptoms (Tables 3 and 4). Individuals with mutations in KCNJ11 demonstrated global deficits across four metacognition scales of executive functioning and also exhibited an inability to control impulsive behaviour as assessed using the BRIEF.
Table 3.
Behavior Assessment System for Children (BASC-2)
| KCNJ11-related NDM with global developmental delay | KCNJ11-related NDM without delay | Sibling controls | ANOVA P value | KCNJ11-related NDM without delay vs. Controls | |
|---|---|---|---|---|---|
| BASC-2 (n) (T scores) | 6 | 9 | 14 | ||
| Externalization Problems | 59.3±8.2 | 51.4±8.0 | 46.5±11.1 | <0.05 | NS |
| Internalization Problems | 46.3±9.0 | 52.0±9.5 | 46.3±11.4 | NS | NS |
| Behavioural Symptoms Index | 61.2±10.3 | 50.7±7.6 | 45.1±9.2 | <0.05 | NS |
| Adaptive Skill | 33.7±15.4 | 50.3±10.5 | 52.4±9.5 | NS (0.08) | NS |
| Mean score of BSI | 58.2±7.9 | 49.0±4.5 | 46.4±7.0 | <0.05 | NS |
| Mean score of adaptive skills | 36.5±13.4 | 52.1±7.9 | 52.2±7.9 | NS (0.07) | NS |
| Hyperactivity | 65.3±12.7 | 51.2±8.5 | 50.4±15.2 | <0.05 | NS |
| Aggression | 52.0±6.4 | 51.6±7.7 | 45.6±9.9 | NS (0.06) | NS (0.09) |
| Conduct Problems | 54.3±8.2 | 50.0±17.5 | 43.5±10.0 | NS | NS |
| Anxiety | 42.5±11.1 | 55.9±12.3 | 50.1±8.8 | NS | NS |
| Depression | 53.8±13.8 | 51.6±7.7 | 47.3±9.4 | NS | NS |
| Somatization | 52.3±7.0 | 47.1±6.5 | 43.6±11.6 | <0.05 | NS |
| Atypicality | 63.8±13.3 | 49.6±8.4 | 43.7±4.6 | <0.005 | NS (0.09) |
| Withdrawal | 56.0±8.2 | 48.1±9.2 | 42.9±4.5 | <0.05 | NS |
| Attention Problems | 64.8+14.0 | 50.1+11.1 | 48.1+11.2 | NS (0.05) | NS |
| Adaptability | 37.7±5.4 | 48.9±10.5 | 52.3±8.9 | <0.05 | NS |
| Social Skills | 43.8±15.4 | 51.8±9.1 | 54.6±9.8 | NS | NS |
| Leadership Skills | 36.7±13.8 | 52.3±13.1 | 56.5±7.8 | NS (0.08) | NS |
| ADL | 30.2±14.7 | 48.4±9.5 | 50.7±10.4 | <0.05 | NS |
| Functional Communication | 33.5±14.8 | 51.4±12.5 | 49.6±8.1 | NS | NS |
NS, Not statistically significant
Table 4.
Behavior Rating Inventory of Executive Function (BRIEF) and Vineland Adaptive Behavior Scales
| KCNJ11-related NDM with global developmental delay | KCNJ11-related NDM without delay | Sibling controls | ANOVA P value | KCNJ11-related NDM without delay vs Controls P value | |
|---|---|---|---|---|---|
| BRIEF (n) (T scores) | 5 | 10 | 14 | ||
| Inhibit | 71.6±10.6 | 59.2±13.7 | 50.0±11.9 | <0.05 | NS (0.09) |
| Shift | 61.4±9.4 | 54.3±10.4 | 46.9±8.8 | <0.05 | NS |
| Emotional Control | 61.8±13.2 | 50.4±12.2 | 49.6±10.3 | NS | NS |
| Working Memory | 72.3±7.1 | 61.3±13.1 | 48.2±11.7 | <0.01 | <0.05 |
| Plan/Organize | 64.4±10.7 | 59.7±14.7 | 48.1±12.7 | <0.05 | <0.05 |
| Megacognition Index | 71.5±6.8 | 59.9±11.4 | 47.5±12.8 | <0.01 | <0.05 |
| Global Executive Composite | 72.8±6.8 | 59.3±12.3 | 47.6±12.1 | <0.005 | <0.05 |
| Vineland (n) (V-scale/ Standard Scores) | 7 | 11 | 7 | ||
| Receptive | 12.0±6.2 | 14.5±4.7 | 16.0±2.1 | NS | NS |
| Expressive | 9.4±4.2 | 12.5±3.9 | 17.3±3.3 | <0.01 | <0.05 |
| Written | 11.3±8.2 | 12.1±3.1 | 15.7±3.7 | <0.05 | NS (0.07) |
| Communication | 75.3±33.9 | 89.8±20.2 | 109.4±19.2 | <0.05 | <0.05 |
| Personal | 9.1±4.4 | 16.0±4.6 | 16.4±3.5 | <0.05 | NS |
| Domestic | 11.0±3.2 | 12.7±3.5 | 15.9±1.9 | <0.05 | <0.05 |
| Community | 8.3±4.2 | 13.7±3.2 | 17.9±1.6 | <0.001 | <0.05 |
| Daily Living Skills | 69.7±16.8 | 94.7±15.7 | 110.0±14.1 | <0.005 | NS |
| Interpersonal | 10.3±2.4 | 12.0±4.0 | 16.9±1.9 | <0.01 | <0.05 |
| Play and Leisure | 8.6±2.9 | 13.0±3.7 | 15.1±2.4 | <0.01 | NS |
| Coping | 10.7±3.2 | 16.7±3.0 | 16.7±1.8 | <0.05 | NS |
| Socialization | 66.0±7.8 | 95.2±16.0 | 107.7±10.9 | <0.005 | NS |
| Adaptive Behaviour Composite | 69.7±19.8 | 94.8±18.0 | 107.7±16.5 | <0.05 | NS |
NS, Not statistically significant
Those with mutations in KCNJ11 have a tendency to avoid social contact and display a reduced ability to adapt in new circumstances. Behavioural characteristics reported on the BASC-2 more frequently in those with KCNJ11 mutations are: immature behaviour, gross mood swings, bizarre thoughts, other unusual and severe behaviours, and being considered “odd”. Vineland-II results suggested significant deficits in all subdomains of daily living skills (personal, domestic and community) in those with KCNJ11-related NDM.
Discussion
To our knowledge, this series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction of individuals with KCNJ11-diabetes, and is the first to provide detailed information on sibling controls. Our data support previous reports of those with KATP mutations noting a variety of neurodevelopmental problems that are likely due to direct effects of mutated KATP channels that are widely expressed in the brain [11].
As expected, those patients with a history of readily apparent global developmental delay (consistent with iDEND/DEND phenotype) had gross neurodevelopmental deficits that precluded their ability to complete many of the instruments utilized in our study. The more novel finding of our study is that the individuals who have mutations not associated with global developmental delay also had a milder degree of neurodevelopmental dysfunction. Intellectual and academic domains were significantly different between those with KCNJ11-related NDM without global developmental delay and sibling controls: specifically IQ, vocabulary development (both on WASI-II), and reading achievement (WIAT-III). Individuals with KCNJ11-related NDM without delay had lower performance than sibling controls in all measures of academic achievement, although a statistically significant difference was found only for reading scores. Compared to sibling controls, subjects with KCNJ11-related NDM without global delay showed difficulties in many areas of executive functioning on several different measures that we utilized: planning, organizing, strategizing, paying attention to and remembering details, and managing time and space. Thus patients with KCNJ11-related NDM who are not phenotypically categorized as having developmental delays may still have significant deficits in several critical neurodevelopmental areas. Although these patients appear in most cases able to have reasonably normal overall function, a better understanding of their underlying struggles would allow for more effective individual supports and/or accommodations. For example, the sibling controls had a higher-than-average level of achievement for IQ on the WASI-II (111.0+/−8.3), while the KCNJ11 patients without global delay were lower than average (91.1+/−11.3). Larger sample sizes may better define such group differences and identify subtle differences within mutation subtypes.
When analyzing behaviour, communication, socialization, and motor skills, several significant differences were noted between patients with KCNJ11-related NDM with and without global delay and sibling controls. Subjects with KCNJ11-related NDM showed more problematic behavioural traits including: externalizing behaviour problems, hyperactivity, somatization, atypicality, withdrawal, adaptability, and difficulty with activities of daily living. Executive functioning weaknesses seen in individuals with mutations in KCN11 likely contribute to the behavioural and academic problems reported by their parents on other standardized rating scales. While specific impairments in hand-eye tracking have been noted, our study and others would suggest more global deficits are associated with KATP mutations [9, 14].
Although prior evidence strongly suggests that specific KATP channel mutations impart different degrees of neurodevelopmental impairment, because previous reports have been inconsistent in the degree of impairment exhibited by individuals with specific mutations, we chose to categorize subjects according to overall developmental phenotype: those with or without global developmental delay. The fact that all patients with certain KCNJ11 mutations previously associated with significant impairment (e.g., V59M) were in the global delay category further supports the notion that impairment is mutation-dependent; however, our study also shows substantial inter-individual variation among those with the same mutation and thus emphasizes the need to study larger numbers of subjects over time to delineate the factors influencing neurodevelopmental outcome, such as the age of initiation of sulfonylurea therapy.
Careful characterization of the mutation specific neurodevelopmental problems may allow us to determine the potential beneficial cognitive effects of SU treatment over time. KATP channels are widely expressed in the brain [10] and just as SU therapy usually leads to dramatic improvements in glycaemic control, several reports have documented improvements in various aspects of neurologic function following SU treatment, though not in all cases [7, 9, 13, 15–21]. Although many factors such as severity of illness at diabetes diagnosis, frequency of hypoglycemic episodes and long-term degree of glycaemic control may influence the severity of neurodevelopmental impairment as well as the response to SU, one important limiting factor may be the degree to which SU drugs are able to penetrate the blood brain barrier and remain in cerebrospinal fluid [22]. In this regard, one recent imaging study suggests that SU can do so at least to some degree in that cerebral perfusion is improved with administration of SU in patients with KATP channel mutations [23]. Another key consideration is that earlier initiation of SU treatment during a potential window of plasticity during early brain development may be critical for optimal neurodevelopmental benefit, as suggested by our previous data showing better outcome on one specific measure in those treated at a very young age [24].
We have shown recently that the age at which the SU is started also has a considerable effect on the success of the treatment on glycaemic control, with older patients needing a higher dose of medication to achieve a comparable level of glycaemic control [25]. This suggests some greater difficulty in overcoming long-term changes that may have occurred in beta cell function during the many years during which channel closure was not possible and insulin secretion did not occur. In the same way, it would be expected that significant changes in neurodevelopmental pathways occur over time as a result of the lack of channel closure in the brain and it is likely that not all of these chronic changes will be reversible. It has been suggested that early initiation with higher doses of SU may be needed to ensure a high enough concentration to allow effective closure of KATP channels widely present within the brain [26]. Mutated KATP channels causing diabetes might also lower the excitability of key neurons, thereby inhibiting their function or that of entire pathways in the brain. While further study is required to determine the best pharmacological intervention, our data can be used to counsel families and guide structured neurodevelopmental assessments and treatments based on the initial genetic diagnosis in patients with neonatal diabetes. Further study of these defects and how they respond to SUs may reveal details of neuronal control of the behaviors and functions we studied.
Conclusions
The results of this large series suggest that a multidisciplinary approach to neurodevelopmental testing and support should be provided for all children with KCNJ11-related diabetes, even those without obvious difficulties. In order to ensure such appropriate surveillance and treatment measures are taken, families should be made aware of the potential for neurodevelopmental and behavioural sequalae, Future longitudinal studies aimed at assessing the neurodevelopmental trajectories for each patient will give us further insight into this interesting genetic form of diabetes. In addition, larger collaborative studies may identify mutation-specific and treatment-related outcomes. We encourage clinicians to refer children for standardized assessments of behaviour and development, including evaluation of motor, cognitive, communicative, adaptive, and executive functioning, starting from an early age.
Supplementary Material
Novelty Statement.
The current series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction in individuals with KCNJ11-related diabetes, in whom such impairment is likely due to brain expression of mutated channels.
The study is the first to provide detailed information on sibling controls, which was essential for demonstrating significant differences on a range of assessments including IQ, measures of academic achievement and executive function, even in subjects without any history of global developmental delay.
KCNJ11 subjects with global delay exhibited significant differences in behavioural symptoms, as well as significant deficits in all subdomains of daily living skills.
Acknowledgments
Statement of Funding Sources:
This work was supported by National Institutes of Health grants P30DK020595, K23DK094866 and R03DK103096 as well as by a grant from the American Diabetes Association (1-11-CT-41), and a gift from the Kovler Family Foundation. M.E. Msall’s efforts are supported in part by grant T73MC11047-01-00 from the Department of Health and Human Services Leadership Education in Neurodevelopmental and Related Disorders Training Program. The funders had no involvement in study design, data collection, data analysis, manuscript preparation and/or publication decisions.
We gratefully acknowledge funding support provided by the National Institutes of Health through grants P30DK020595, K23DK094866 and R03DK103096, as well as by a grant from the American Diabetes Association (1-11-CT-41), and a gift from the Kovler Family Foundation. M.E. Msall’s efforts are supported in part by grant T73MC11047-01-00 from the Department of Health and Human Services Leadership Education in Neurodevelopmental and Related Disorders Training Program. We thank all the clinicians providing care for patients within the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu). We are most grateful to all of the wonderful patients and families who participated in these studies.
Abbreviations
- BASC
Behavior Assessment System for Children
- BRIEF
Behavior Rating Inventory of Executive Function
- DEND
Developmental delay, epilepsy and neonatal diabetes
- D–KEFS
Delis-Kaplan Executive Function System
- iDEND
Intermediate DEND
- KATP
ATP-sensitive potassium
- NDM
Neonatal diabetes mellitus
- SU
sulfonylureas
- WAIS-IV
Wechsler Adult Intelligence Scale
- WASI-II
Wechsler Abbreviated Scales of Intelligence
- WIAT-III
Wechsler Individual Achievement Test
- WISC-IV
Wechsler Intelligence Scale for Children
Footnotes
Conflict of Interest Disclosure:
The authors have no conflicts to declare.
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