Kabuki Syndrome
Conditions
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.
Interventions
DIETARY_SUPPLEMENTModified Atkins diet
12 weeks of modified Atkins diet
Sponsors
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
15 participants with Kabuki syndrome will receive a 12 week dietary intervention.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MAD Diet Group 10 adult participants with confirmed KMT2D pathogenic mutations. Baseline labs and education about Modified Atkins Diet. Then 12 weeks on a Modified Atkins Diet.
Modified Atkins diet: 12 weeks of modified Atkins diet | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | MAD Diet Group |
|---|---|
| Age, Continuous | 24.9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 7 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
Beery Developmental Test of Visual Motor Integration
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Measures | Beery Developmental Test of Visual Motor Integration | 16.3 raw score | Standard Deviation 4.76 |
| Measures After 12 Weeks of MAD | Beery Developmental Test of Visual Motor Integration | 17.2 raw score | Standard Deviation 4.16 |
Primary
Beery Developmental Test of Visual Perception
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Measures | Beery Developmental Test of Visual Perception | 20.7 raw score | Standard Deviation 3.02 |
| Measures After 12 Weeks of MAD | Beery Developmental Test of Visual Perception | 21.2 raw score | Standard Deviation 3.12 |
Primary
Benton Judgement of Line Orientation
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).
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Measures | Benton Judgement of Line Orientation | 8.6 score on a scale | Standard Deviation 7.65 |
| Measures After 12 Weeks of MAD | Benton Judgement of Line Orientation | 11.6 score on a scale | Standard Deviation 8.11 |
Primary
Brief Visuospatial Memory Test
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Measures | Brief Visuospatial Memory Test | 10.9 score on a scale | Standard Deviation 8.17 |
| Measures After 12 Weeks of MAD | Brief Visuospatial Memory Test | 11.7 score on a scale | Standard Deviation 8.29 |
| BVMT Immediate Score Post-MAD | Brief Visuospatial Memory Test | 4.1 score on a scale | Standard Deviation 3.7 |
| BVMT Delayed Score Post-MAD | Brief Visuospatial Memory Test | 5 score on a scale | Standard Deviation 3.83 |
Primary
Hopkins Verbal Learning Test
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Measures | Hopkins Verbal Learning Test | 22.9 score on a scale | Standard Deviation 6.98 |
| Measures After 12 Weeks of MAD | Hopkins Verbal Learning Test | 24.3 score on a scale | Standard Deviation 7.01 |
Primary
NIH Toolbox Picture Sequence Memory
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Measures | NIH Toolbox Picture Sequence Memory | 92.4 score on a scale | Standard Deviation 14.23 |
| Measures After 12 Weeks of MAD | NIH Toolbox Picture Sequence Memory | 93.2 score on a scale | Standard Deviation 17.34 |
Primary
Wechsler Intelligence Scale for Children -V Block Design
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Measures | Wechsler Intelligence Scale for Children -V Block Design | 19.3 raw score | Standard Deviation 8.37 |
| Measures After 12 Weeks of MAD | Wechsler Intelligence Scale for Children -V Block Design | 21.4 raw score | Standard Deviation 10.11 |
Secondary
Caregiver Behavior Rating Scales: GAS-ID
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Measures | Caregiver Behavior Rating Scales: GAS-ID | 12 score on a scale | Standard Deviation 6.91 |
| Measures After 12 Weeks of MAD | Caregiver Behavior Rating Scales: GAS-ID | 11.3 score on a scale | Standard Deviation 6.27 |
Secondary
DNA Methylation Analysis
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.
Time frame: Every 3 weeks for 12 weeks