Synaptic Plasticity and Cognitive Function in RASopathies

Study Overview
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Brief Summary
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The project is targeting cognitive impairment, one of the main health problems of patients with RAS pathway disorders. The aim of this study is to translate findings of animal studies to humans. This has been done by the applicants successfully for Lovastatin in Nf1. This result will be transferred to patients with Noonan Syndrome. lamotrigine is most likely a more effective and promising substance improving synaptic plasticity and consecutive cognitive function. It is expected that both substances are improving synaptic plasticity as well as alertness and changes in alertness may be a precondition for improvement of cognition.

Official Title
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Improvement of Synaptic Plasticity and Cognitive Function in RAS Pathway Disorders

Conditions
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Impaired Cognition, Impaired Synaptic Plasticity

Intervention / Treatment
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* Drug: Lovastatin
* Drug: Lamotrigine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group 1: NS, Group 2: NF1 (both genetically assured) Age ≥16 years The adolescent (≥16) and legal guardian who are capable to give their consent and understand the aim and rationale of the study. In case of doubts, an independent medical practitioner will evaluate the capacity to consent. Signed informed consent if ≥ 16 years and legal guardian. Persons who are ≥ 18 years old and capable to give their consent and understand the aim and rationale of the study. In case of doubts, an independent medical practitioner will evaluate the capacity to consent. Signed informed consent if ≥ 18 years. Male participants and female participants who are not capable of bearing children or who use a method of contraception that is medically approved by the health authority of the respective country. Exclusion Criteria: Epilepsy Medication with known CNS effects Severe mental retardation Side effects during previous medication with and contraindications for LTG and/or LOV and/or TMS Psychiatric diseases Previous history of allergic reactions with LTG and LOV medications Potentially unreliable patients Patients who are not suitable for the study in the opinion of the investigator Pregnancy (incl. positive urine pregnancy test) Persons who are incapable of giving consent or do not understand the aim or rationale of the study.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Monocenter, randomized, double-blind, parallel-group, placebo controlled, cross-over design with a series of three experiments (Noonan Syndrome: 2 experiments; Neurofibromatosis type 1 1 experiment) and n=14 participants per experiments
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exp. I: Noonan Syndrome - Lovastatin<br>200 mg Lovastatin daily for four days / Lovastatin-placebo (cross-over) prior to transcranial magnetic stimulation and test of attentional performance | Drug: Lovastatin<br>* oral application prior to transcranial magnetic stimulation intervention<br>|
| Experimental: Exp. II: Noonan Syndrome - Lamotrigine<br>300 mg Lamotrigine single dose / Lamotrigine-placebo prior to transcranial magnetic stimulation and test of attentional performance | Drug: Lamotrigine<br>* oral application prior to transcranial magnetic stimulation intervention<br>|
| Experimental: Exp. III: Neurofibromatosis Type 1 - Lamotrigine<br>300 mg Lamotrigine single dose / Lamotrigine-placebo prior to transcranial magnetic stimulation and test of attentional performance | Drug: Lamotrigine<br>* oral application prior to transcranial magnetic stimulation intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term potentiation (LTP)-like plasticity measured with transcranial magnetic stimulation (TMS) | Changes in peak-to-peak amplitudes of motor evoked potentials (MEP) | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference between the neuropsychological testing of attention (Test of attentional performance) after placebo and after medication (LTG and LOV) | Response time (seconds) for alertness, visual scanning, Go/no Go, Incompatibility | 12 months | 
| Differences in short interval cortical inhibition (SICI) after placebo and after medication (LTG and LOV) | Changes in SICI | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RASopathies, neurofibromatosis type 1, noonan syndrome, synaptic plasticity, transcranial magnetic stimulation