Study of Modified Atkins Diet in Kabuki Syndrome

Early Phase 1

Completed

Conditions: Kabuki Syndrome

Interventions: Dietary Supplement: Modified Atkins diet

Registration Number: NCT04722315

Lead Sponsor: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Brief Summary: Animal models of Kabuki syndrome have showed a reversal of the cognitive phenotype with ketogenic diet. Modified Atkins diet is safer and easier tolerated than full ketogenic diet and still has the histone deacetylase inhibition believed to be responsible for the cognitive improvement. This study aims to examine a small number of adults with Kabuki syndrome before and after 12 weeks on a modified Atkins diet to determine if there is any cognitive improvement and if the diet can be tolerated.

Detailed Description: Consented participants will participate in an initial 2 day study visit. These participants will undergo cognitive and neurobehavioral testing and also will have baseline labs drawn and will meet with a Johns Hopkins nutritionist trained in modified Atkins diet for education. The labs are standard of care for diet initiation to rule out contraindications to the diet. Participants and/or their caregivers will keep a daily diet log and will be asked to download the free Carb Manager application onto their smartphone. They will send the logs and data back weekly. Participants will be given urine ketone strips and asked to use and record in their diet log twice weekly. Participants will have blood and urine samples collected locally every 3 weeks and sent back to study team to measure Beta-hydroxybutyrate, metabolic studies and methylation. Participants will return to Baltimore at the end of 12 weeks for a one day visit to repeat the cognitive assessment protocol, neurobehavioral measures, and repeat the initial and follow up lab tests.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

Inclusion Criteria

We will recruit 15 total participants with clinically-definite and genetically-confirmed Kabuki syndrome type 1 age 18 years and older. . will also be required.

Clinical diagnosis of KS will be made based on recently published consensus diagnosis criteria
Genetic confirmation of a pathogenic mutation in KMT2D

Exclusion Criteria

presence of another known genetic syndrome
a health problem that would make a modified Atkins diet harmful
inability to travel to Baltimore for 2 visits separated by 12 weeks

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
MAD diet group	Modified Atkins diet	15 adult participants with confirmed KMT2D pathogenic mutations. Baseline labs and education about Modified Atkins Diet. Then 12 weeks on a Modified Atkins Diet. Weekly urine dips for ketones and diet logs. Blood draw every 3 weeks.

Primary Outcome Measures

Name	Time	Method
Hopkins Verbal Learning Test	12 weeks	Established measure to determine verbal memory. Scores range from 0 to 36 and a higher score indicates more correct responses. Will assess change in score from baseline to post-diet.
Benton Judgement of Line Orientation	12 weeks	Established measure to determine visuospatial perception. There are 30 items and each item is worth 1 point. Will assess change in score from baseline to post-diet. A higher score indicates a better performance (range 0-30).
Brief Visuospatial Memory Test	12 weeks	Established measure to determine visuospatial memory. Immediate scores range from 0 to 36 and a higher score indicates more correct responses. Delayed scores range from 0 to 12 and a higher score indicates more correct responses. Will assess change in score from baseline to post-diet.
NIH Toolbox Picture Sequence Memory	12 weeks	Established measure to determine visuospatial memory. Scaled scores based on age have a mean of 100 and a standard deviation of 15 and higher scores indicate more correct responses. Will assess change in this score from baseline to post-diet.
Beery Developmental Test of Visual Motor Integration	12 weeks	Established measure to determine visuomotor integration. Since these were all adults, raw scores were used. Range is 1-27. Higher scores indicate more correct responses. Will assess change in this score from baseline to post-diet.
Beery Developmental Test of Visual Perception	12 weeks	Established measure to determine visual perception. Since these were all adults, raw scores were used. Range is 1-27. Higher scores indicate more correct responses. Will assess change in this score from baseline to post-diet.
Wechsler Intelligence Scale for Children -V Block Design	12 weeks	Established measure to determine visuospatial processing. Since these were all adults, raw scores were used. Range is 0-66. Higher scores indicate more correct responses. Will assess change in this score from baseline to post-diet. Will assess change in this score from baseline to post-diet.

Secondary Outcome Measures

Name	Time	Method
DNA Methylation Analysis	Every 3 weeks for 12 weeks	Measure genome-wide methylation signature in blood of participants. To obtain genome-scale methylation measurements, bisulfite treated DNA from patient blood samples will be processed on the Infinium HumanMethylation450 BeadChip at the Johns Hopkins SNP Center in accordance with the manufacturer's recommendation. The Infinium HumanMethylation450 BeadChip measures DNA methylation levels at 485,512 loci across the genome. The array data will then be analyzed to get the proportion of methylation at a given CpG site from 0 to 1. These will be logit transformed to create M-values. Kabuki syndrome is known to have a unique signature methylation profile (determined by M-values across loci) that can be detected in blood. This genome wide DNA methylation will be done every 3 weeks to determine whether this signature changes with dietary therapy.
Caregiver Behavior Rating Scales: GAS-ID	12 weeks	Rating scale for anxiety consists of 27 items with scores ranging from 0-70 with higher scores indicating more anxiety. Performed at baseline and post-diet.