The Cognitive Variability in NF1 and TSC Monozygotic Twins

Study Overview
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Brief Summary
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Both Neurofibromatosis type 1 (NF1) and Tuberous Sclerosis Complex (TSC) are highly heterogeneous diseases. Cognitive features seem to vary widely even between family members carrying the same mutation. This phenotypic variability is not well understood, but is generally assumed to be caused by modifier genes which regulate the affected pathways. However, recent studies brought forward an alternative explanation for the phenotypic variability. Post-mortem studies showed that second hit mutations causing loss of the second ('healthy') allele are more widespread than previously believed. These loss of heterozygosity (LOH) mutations cause bi-allelic loss of the disease-linked gene and are known to cause the gross of somatic features in both diseases (like neurofibromas and hamartomas). Hence, it could be the stochastic occurrence of second-hit mutations in the brain are the cause of the variable cognitive phenotypes. To investigate to what extent these LOH mutations in the brain contribute to the phenotype and to what extent this variation is due to genetic modifiers factors is unknown. The investigators therefore propose to elucidate this variability by comparing the correlation of cognitive features of monozygotic twins with NF1 or TSC to healthy twins in the population. If modifier genes are the cause of the variability of cognitive features in NF1 and TSC the investigators expect that the variability in cognitive tests in monozygotic twins is the same as monozygotic twins in the healthy population. However, if the variability is caused by the occurrence of LOH mutations, the investigators expect to have a lower correlation in our monozygotic patients compared to the healthy twins.

Official Title
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The Cognitive Variability in Neurofibromatosis Type I and Tuberous Sclerosis Complex Monozygotic Twins

Conditions
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Neurofibromatosis Type I, Tuberous Sclerosis Complex

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant is part of a monozygotic twin pair (which is genetically confirmed); NF1 or TSC patients with a genetically confirmed diagnosis; Oral and written informed consent by participant in case ≥ 18 years of age. Oral and written informed consent by both caregivers and assent by participant in case of minor participants. Exclusion Criteria: A potential subject of whom the twin sibling is not willing or able to participate in this study, will be excluded from participation in this study. Symptomatic brain pathology.
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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Neurofibromatosis type I (NF1)<br>Monozygotic twin pairs with genetically confirmed Neurofibromatosis type I | |
| Tuberous Sclerosis Complex (TSC)<br>Monozygotic twin pairs with genetically confirmed Tuberous Sclerosis Complex | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of full intelligence quotient | Depending on age and cognitive development: Bayley Scales of Infant Development (BSID-III) or Wechsler Scale of Intelligence (Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) or Wechsler Intelligence Scale for Children (WISC-III) or Wechsler Adult Intelligence Scale (WAIS-III) ) | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of word reading ability | One-minute word-reading test | 1 day | 
| Correlation of attention problems | Conners ADHD rating scale | 1 day | 
| Correlation of behavioural problems | Child Behaviour Checklist or Adult Behaviour Checklist (CBCL/ABCL) | 1 day | 
| Correlation of autistic features | Social Responsiveness Scale (SRS) | 1 day | 
| Correlation of visuospatial judgement (NF1 twins only) | Judgement of Line Orientation (JLO) | 1 day | 
| Correlation of executive control (TSC twins only) | Trail-Making Test parts A & B (TMT) | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Von Recklinghausen's disease, Bourneville's disease, Cognitive variability, Loss of heterozygosity