Phelan McDermid Syndrome
Conditions
Keywords
Phelan McDermid Syndrome, 22q13 deletion Syndrome, Growth hormone, Autism, Insulin like growth factor 1
Brief summary
Phelan McDermid syndrome (PMS) is a rare genetic form of autism spectrum disorder (ASD) due to deletions or mutations in the SHANK3 gene. This is a pilot open labeled trial of growth hormone therapy in children with PMS targeting social withdrawal and repetitive behavior. This research study will include children with PMS between 2-12 years of age who will receive growth hormone daily for 12 weeks, if found to be eligible. The aim of this study is to evaluate the effect of growth hormone on behavioral outcomes such as the aberrant behavior checklist social withdrawal subscale (ABC-SW) and repetitive behavior scale- revised (RBS-R). The effects of growth hormone on visual evoked potentials will also be assessed. Growth hormone increases insulin like growth factor 1 (IGF-1) levels and a previous trial of IGF-1 therapy in PMS children showed improvement in these behavioral scales. Growth hormone has been studied for decades with an excellent safety profile and fewer adverse effects compared to IGF-1 therapy in other conditions. Hence, this may be a viable therapeutic option. There is no treatment currently available for PMS and this trial is therefore extremely important.
Detailed description
BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic form of autism spectrum disorder (ASD) associated with developmental delay and hypotonia. IGF-1 promotes brain vessel growth, neurogenesis, and synaptogenesis. The research team previous clinical trial of IGF-1 in patients with Phelan McDermid Syndrome has shown improvement in core ASD symptoms using the Aberrant Behavior Checklist (ABC) and the Repetitive Behavior Scale-Revised (RBS-R). Growth hormone (GH) binds to its receptor and initiates a cascade of events which directly increases synthesis and release of IGF-1 levels. HYPOTHESIS: The study team hypothesize that rise in IGF-1 stimulated by growth hormone (GH) administration should produce improvement in behavior in children and adolescents with PMS as previously demonstrated with use of IGF-1. RESEARCH PLAN: The study team seek to recruit 10 patients with PMS and administer growth hormone as once daily subcutaneous injections for 12 weeks at standard doses. The study team will monitor baseline anthropometric measures, laboratory parameters for growth, IGF-1 levels, and bone age prior to therapy and continue to monitor safety laboratory parameters during and after therapy. The goal of therapy would be to maintain IGF-1 levels between 1-2SD above the mean for age and puberty. Evaluations will include validated behavioral scales. Visual evoked potentials (VEPs) will be used as biomarkers of visual sensory reactivity.
Interventions
DRUGRecombinant human Growth hormone
Subcutaneous growth hormone injections given once daily at a dose between 0.15mg/kg/week to 0.47 mg/kg/week titrated based on IGF-1 levels in serum for a duration of 12 weeks.
Sponsors
Swathi Sethuram
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Known pathogenic deletions or mutations in SHANK3 gene diagnosed by array CGH and/or direct sequencing. * Children between 2 and 12 years of age. * Open epiphyses on bone age x ray
Exclusion criteria
* closed epiphyses; * active or suspected neoplasia; * intracranial hypertension; * hepatic insufficiency; * renal insufficiency; * cardiomegaly/valvulopathy; * history of allergy to growth hormone or any component of the formulation (mecasermin); * history of extreme prematurity (\<1000 grams) with associated early neo-natal complications, e.g. intra-cerebral * hemorrhage, prolonged hypoxia, prolonged hypoglycemia; * patients with comorbid conditions who are deemed too medically compromised to tolerate the risk of experimental treatment with growth hormone. * Patient with visual problems that preclude the use of VEP's
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ABC - Social Withdrawal Subscale | After 12 weeks of growth hormone therapy | A caregiver report symptom checklist. 58-item instrument into 5 subscales: Irritability (score 0-45); Lethargy/Social Withdrawal (score 0-48); Stereotypic Behavior (score 0-21); Hyperactivity (score 0-48); Inappropriate Speech (score 0-12). Total scale 0-174, with higher score indicating more aberrant behavior. |
| Repetitive Behavior Scale-Revised (RBS-R) | After 12 weeks of growth hormone therapy | A 43 item instrument with total score from 0-129, with higher score indicating more restricted, repetitive and stereotyped behaviors. Subscales Stereotyped Behavior (0-27) Self-injurious Behavior (0-24) Compulsive Behavior (0-18) Ritualistic Behavior (0-36) Sameness Behavior (0-33) Restricted Behavior (0-12) |
| The Sensory Profile | After 12 weeks of growth hormone therapy | The full Sensory Profile has 125 items and the short version contains 38 items. Parents use a Likert scale to rate how frequently their child demonstrates a particular behavior (ranging from 1 = always to 5 = never). Total scale for the Short Sensory Profile 38-190, with a lower score indicates greater deviation from typically developing children and indicates more sensory reactivity symptoms. Subscales Tactile (7-35) Taste / Smell (4-20) Movement (3-15) Sensation (7-35) Auditory (6-30) Low Energy / Weak (6-30) Visual / Auditory (5-25) |
| The Sensory Assessment for Neurodevelopmental Disorders (SAND) | After 12 weeks of growth hormone therapy | a clinician-administered assessment and corresponding caregiver interview that is not dependent on verbal or cognitive ability and is therefore appropriate for severely affected or nonverbal individuals with PMS. Responses are rated by a trained examiner on an algorithm. Scores are dichotomous, 0 (not present) or 1 (present) and are based on a summary of observed sensory behaviors throughout the duration of the observation. A total SAND score ranging from 0 to 90. Higher scores represent a higher level of sensory reactivity symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Evoked Potentials (VEP) | After 12 weeks of growth hormone therapy | A noninvasive technique to evaluate the functional integrity of visual pathways in the brain from the retina to the visual cortex via the optic nerve/optic radiations. The VEP is recorded from the head's surface, over the visual cortex, and is extracted from ongoing EEG through signal averaging. VEPs reflect the sum of excitatory and inhibitory postsynaptic potentials occurring on apical dendrites (Zemon et al., 1986) which modulate excitatory and inhibitory signals received by the pyramidal cells. |
| Change in Auditory Event Related Potentials (AERP) | Baseline and 12 weeks of growth hormone therapy | AERP is useful for characterizing early processing of auditory tones and habituation to rapidly repeated stimuli as in speech processing. AERP amplitudes are measured at 12 weeks and compared to baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phelan-McDermid Syndrome Patients with Phelan-McDermid syndrome receive 12 weeks of growth hormone therapy
Recombinant human Growth hormone: Subcutaneous growth hormone injections given once daily at a dose between 0.15mg/kg/week to 0.47 mg/kg/week titrated based on IGF-1 levels in serum for a duration of 12 weeks. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Phelan-McDermid Syndrome |
|---|---|
| Age, Continuous | 7.5 years STANDARD_DEVIATION 3.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 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 | 4 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
ABC - Social Withdrawal Subscale
A caregiver report symptom checklist. 58-item instrument into 5 subscales: Irritability (score 0-45); Lethargy/Social Withdrawal (score 0-48); Stereotypic Behavior (score 0-21); Hyperactivity (score 0-48); Inappropriate Speech (score 0-12). Total scale 0-174, with higher score indicating more aberrant behavior.
Time frame: After 12 weeks of growth hormone therapy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Hyperactivity 12 weeks | 16.5 score on a scale | Standard Deviation 7.7 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Inappropriate Speech baseline | 3.3 score on a scale | Standard Deviation 4.3 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Inappropriate Speech 12 weeks | 2.3 score on a scale | Standard Deviation 3.8 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Irritability baseline | 10.31 score on a scale | Standard Deviation 7.6 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Irritability 12 weeks | 4.6 score on a scale | Standard Deviation 2.3 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Social Withdrawal baseline | 14.8 score on a scale | Standard Deviation 7.4 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Social Withdrawal 12 weeks | 6.2 score on a scale | Standard Deviation 3.4 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Stereotypy baseline | 8.8 score on a scale | Standard Deviation 6.9 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Stereotypy 12 weeks | 5.1 score on a scale | Standard Deviation 1.8 |
| Phelan-McDermid Syndrome | ABC - Social Withdrawal Subscale | Hyperactivity baseline | 33.3 score on a scale | Standard Deviation 6.2 |
Primary
Repetitive Behavior Scale-Revised (RBS-R)
A 43 item instrument with total score from 0-129, with higher score indicating more restricted, repetitive and stereotyped behaviors. Subscales Stereotyped Behavior (0-27) Self-injurious Behavior (0-24) Compulsive Behavior (0-18) Ritualistic Behavior (0-36) Sameness Behavior (0-33) Restricted Behavior (0-12)
Time frame: After 12 weeks of growth hormone therapy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Self-injurious Behavior at Week 12 | 1.3 score on a scale | Standard Deviation 1.8 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Compulsive Behavior at baseline | 2.8 score on a scale | Standard Deviation 3.2 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Compulsive Behavior at Week 12 | 1.3 score on a scale | Standard Deviation 1.6 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Ritualistic Behavior at baseline | 1.2 score on a scale | Standard Deviation 1.2 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Sameness Behavior at baseline | 2.3 score on a scale | Standard Deviation 2.4 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Sameness Behavior at Week 12 | 2.0 score on a scale | Standard Deviation 1.7 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Restricted Behavior at baseline | 2.0 score on a scale | Standard Deviation 2.2 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Restricted Behavior at Week 12 | 1.2 score on a scale | Standard Deviation 1.5 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Total at baseline | 13.3 score on a scale | Standard Deviation 6.1 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Total at Week 12 | 10.7 score on a scale | Standard Deviation 3.1 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Self-injurious Behavior at baseline | 0.7 score on a scale | Standard Deviation 0.8 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Stereotyped Behavior at baseline | 4.3 score on a scale | Standard Deviation 1.7 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Stereotyped Behavior at Week 12 | 4.0 score on a scale | Standard Deviation 2.4 |
| Phelan-McDermid Syndrome | Repetitive Behavior Scale-Revised (RBS-R) | Ritualistic Behavior at Week 12 | 0.8 score on a scale | Standard Deviation 1.2 |
Primary
The Sensory Assessment for Neurodevelopmental Disorders (SAND)
a clinician-administered assessment and corresponding caregiver interview that is not dependent on verbal or cognitive ability and is therefore appropriate for severely affected or nonverbal individuals with PMS. Responses are rated by a trained examiner on an algorithm. Scores are dichotomous, 0 (not present) or 1 (present) and are based on a summary of observed sensory behaviors throughout the duration of the observation. A total SAND score ranging from 0 to 90. Higher scores represent a higher level of sensory reactivity symptoms.
Time frame: After 12 weeks of growth hormone therapy
Population: Data not collected due to pandemic.
Primary
The Sensory Profile
The full Sensory Profile has 125 items and the short version contains 38 items. Parents use a Likert scale to rate how frequently their child demonstrates a particular behavior (ranging from 1 = always to 5 = never). Total scale for the Short Sensory Profile 38-190, with a lower score indicates greater deviation from typically developing children and indicates more sensory reactivity symptoms. Subscales Tactile (7-35) Taste / Smell (4-20) Movement (3-15) Sensation (7-35) Auditory (6-30) Low Energy / Weak (6-30) Visual / Auditory (5-25)
Time frame: After 12 weeks of growth hormone therapy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phelan-McDermid Syndrome | The Sensory Profile | Tactile at Week 12 | 31.7 score on a scale | Standard Deviation 2 |
| Phelan-McDermid Syndrome | The Sensory Profile | Sensation at Week 12 | 20.0 score on a scale | Standard Deviation 3.8 |
| Phelan-McDermid Syndrome | The Sensory Profile | Visual / Auditory at Week 12 | 22.7 score on a scale | Standard Deviation 1.5 |
| Phelan-McDermid Syndrome | The Sensory Profile | Tactile at Baseline | 31.5 score on a scale | Standard Deviation 2.1 |
| Phelan-McDermid Syndrome | The Sensory Profile | Taste / Smell at Baseline | 18.2 score on a scale | Standard Deviation 3.6 |
| Phelan-McDermid Syndrome | The Sensory Profile | Taste / Smell at Week 12 | 19.4 score on a scale | Standard Deviation 1.3 |
| Phelan-McDermid Syndrome | The Sensory Profile | Movement at Baseline | 13.3 score on a scale | Standard Deviation 1.6 |
| Phelan-McDermid Syndrome | The Sensory Profile | Movement at Week 12 | 13.7 score on a scale | Standard Deviation 1.8 |
| Phelan-McDermid Syndrome | The Sensory Profile | Sensation at Baseline | 17.5 score on a scale | Standard Deviation 4.8 |
| Phelan-McDermid Syndrome | The Sensory Profile | Auditory at Baseline | 20.0 score on a scale | Standard Deviation 1.9 |
| Phelan-McDermid Syndrome | The Sensory Profile | Auditory at Week 12 | 22.0 score on a scale | Standard Deviation 2.4 |
| Phelan-McDermid Syndrome | The Sensory Profile | Low Energy / Weak at Baseline | 16.5 score on a scale | Standard Deviation 6.9 |
| Phelan-McDermid Syndrome | The Sensory Profile | Low Energy / Weak at Week 12 | 20.5 score on a scale | Standard Deviation 5.2 |
| Phelan-McDermid Syndrome | The Sensory Profile | Visual / Auditory at Baseline | 22.3 score on a scale | Standard Deviation 2.3 |
| Phelan-McDermid Syndrome | The Sensory Profile | Total at Baseline | 139.3 score on a scale | Standard Deviation 12.7 |
| Phelan-McDermid Syndrome | The Sensory Profile | Total at Week 12 | 148.8 score on a scale | Standard Deviation 12.8 |
Secondary
Change in Auditory Event Related Potentials (AERP)
AERP is useful for characterizing early processing of auditory tones and habituation to rapidly repeated stimuli as in speech processing. AERP amplitudes are measured at 12 weeks and compared to baseline.
Time frame: Baseline and 12 weeks of growth hormone therapy
Population: Data not collected due to pandemic.
Secondary
Visual Evoked Potentials (VEP)
A noninvasive technique to evaluate the functional integrity of visual pathways in the brain from the retina to the visual cortex via the optic nerve/optic radiations. The VEP is recorded from the head's surface, over the visual cortex, and is extracted from ongoing EEG through signal averaging. VEPs reflect the sum of excitatory and inhibitory postsynaptic potentials occurring on apical dendrites (Zemon et al., 1986) which modulate excitatory and inhibitory signals received by the pyramidal cells.
Time frame: After 12 weeks of growth hormone therapy
Population: Data not collected due to pandemic.