Impact of Sulphonylureas on Neurodevelopmental Outcomes in KCNJ11-related Intermediate Developmental Delay, Epilepsy and Neonatal Diabetes (iDEND) Syndrome

The goal of this observational study is to learn about the impact of the diabetes drug glibenclamide (glyburide) on neurodevelopment in individuals with iDEND (developmental delay, epilepsy and neonatal diabetes) due to the V59M mutation in the KCNJ11 gene. The main question it aims to answer is whether initiating sulphonylurea (SU) therapy in the first year of life results in better neurodevelopmental outcomes in affected individuals, in comparison to starting therapy later than 12 months of age.

Participants will undergo a neurodevelopmental assessment comprising parental and teacher completion of standardised questionnaires, and where possible face to face neuropsychological testing.

Researchers will compare the outcomes of these standardised tests in the individuals who started SU therapy \<12 months of age in comparison to those who started \>12 months of age.

Background:

The role of the KATP channel in the pancreas The KATP channel is made up of 4 pore-forming Kir6.2 subunits (encoded by the KCNJ11 gene) and 4 regulatory SUR1 subunits (encoded by the ABCC8 gene). In the pancreas, the KATP channel plays a central role in glucose-stimulated insulin secretion.

KATP channel mutations cause neonatal diabetes that can be treated with oral sulphonylureas Neonatal diabetes is defined as diabetes occurring in the first 6 months of life; it has an incidence of approximately 1 in 200,000 live births. Neonatal diabetes is due to a monogenic defect, and mutations in the KCNJ11 and ABCC8 genes are the commonest cause. These are important to diagnose as over 90% of patients can switch from insulin treatment to an oral sulphonylurea with a resulting improvement in glycaemic control which is maintained long-term.

Central Nervous System features occur in patients with neonatal diabetes due to KATP mutations.

Around 20% of patients with mutations in the KCNJ11 gene have an overt severe neurological phenotype. This is consistent with the expression of the KATP channel in the brain. There is a phenotype/genotype relationship e.g. most patients with the V59M mutation have the intermediate DEND syndrome (iDEND - Developmental delay, Epilepsy and Neonatal Diabetes), with moderate developmental delay and substantial intellectual disability. DEND syndrome is characterised by severe developmental delay and epilepsy diagnosed within the first 12 months of life. People with iDEND syndrome also show hyperactivity, impulsivity, inattention and impaired visuomotor performance. Autism (comprising impaired language and social interaction and restricted/repetitive behaviours), ADHD and anxiety disorders have been reported in individuals with the V59M mutation. Mouse models with V59M mutations have replicated the hyperactive phenotype seen in humans. These finding suggests a possible role for the KATP channel in neurodevelopment.

Previous research suggests earlier initiation of treatment results in more favourable CNS outcomes After switching from insulin to oral sulphonylureas, some patients with a V59M mutation have a clear but incomplete improvement in neurological / cognitive function suggesting that the KATP channel in the CNS responds in part to sulphonylureas. Sulphonylurea therapy is also associated with changes in brain perfusion patterns, in particular improved cerebellar perfusion. The timing of initiation of sulphonylurea therapy appears to be important; one study showed an inverse correlation between age of initiation of treatment with sulphonylureas and performance in the visual-motor integration test (a neuromotor coordination task) in patients with V59M/A mutations. Another prospective study showed improved neurological and psychomotor function in a group of patients with a mixture of KATP channel mutations (only one of which was V59M); this improvement was greater in the younger patients.

The reason for greater neurological improvements in younger patients may relate to greater neuroplasticity in the brain in the first 12 months of life; if this is the case then it is crucial to make a genetic diagnosis of KATP channel neonatal diabetes early and transfer patients as soon as possible to sulphonylurea therapy.

Despite its clinical importance, to date there has been no formal study of whether age of first treatment with a sulphonylurea affects neurodevelopmental outcomes in patients with V59M mutations.

Aim:

To establish whether early treatment with sulphonylureas improves neurodevelopmental outcomes in patients with the V59M mutation in the KCNJ11 gene.

Objectives:

1. To identify and recruit the largest international cohort of individuals with V59M mutations reported to date.
2. To characterise the neurodevelopmental phenotype in these patients using standardised validated questionnaires and assessments.
3. To compare outcomes in those who started treatment with SU in the first 12 months of life vs those who started treatment later than 12 months.

Methods:

Data collection form will be completed by clinicians / researchers using parent/carer report and / or review of notes +/- clinical observation. The study procedure for each participant is as follows:

* Standard medical, perinatal and social history including major milestones
* Developmental Assessment (see below)

  * Development and Wellbeing Assessment (DAWBA) to establish ICD-10/DSM-IV / V psychiatric diagnoses and Strengths and Difficulties Questionnaire (SDQ) to provide a quantitative measure of psychiatric morbidity in five key areas (hyperactivity, emotional, conduct problems, peer relationships, prosocial behaviour) and overall impact. The DAWBA and SDQ are standardised, validated questionnaires given to informants (usually parents and teachers) and patients themselves if aged 11 years or over and able to complete them. These can be completed online, and normative data derived from large population surveys is available.
  * Leiter-3 International Performance Scale Cognitive battery where neither the examiner nor the child is required to speak, and the child is not required to read or write either. As the test is nonverbal, it is especially suitable for children and adolescents who are cognitively delayed, disadvantaged, nonverbal or non-English speaking, speech or hearing impaired, motor impaired, have a diagnosis of ADHD or autism. Provides IQ scores and scaled scores for its subtests.
  * CCC-2 (Children's Communication Checklist) - parental questionnaire used to identify communication problems in children aged 4-16.

Data analysis:

Patients will be divided into 2 groups based on starting SU treatment (1) \>12 months and (2) \<12 months. Where possible scores on the above tests will be converted to SD scores using normative population data. Results from the 2 groups will be compared using non-parametric statistical methods to establish whether, for the same mutation, the age at which treatment is initiated impacts on the degree of developmental delay, psychopathology and impact.

Eligibility Criteria:
Inclusion Criteria:

* Current age ≥2 years
* Heterozygous for a V59M mutation in the KCNJ11 gene
* Successfully transferred to oral sulphonylurea therapy
* Willing to participate

Exclusion Criteria:

* Never able to transfer to oral sulphonylurea therapy
* Unwilling to participate