The Cognitive Variability in NF1 and TSC Monozygotic Twins (COVANTT)

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

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.

Study Overview

• Status: Unknown
• Conditions: Tuberous Sclerosis Complex; Neurofibromatosis Type I

• Study Type: Observational
• Enrollment (Anticipated): 116

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands, 3000 CA
    • Recruiting
    • Erasmus MC
    • Contact: Ype Elgersma, Prof.; Phone Number: +31 10 7037739; Email: y.elgersma@erasmusmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Monozygotic twin pairs with genetically confirmed Neurofibromatosis type I or Tuberous Sclerosis Complex

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Neurofibromatosis type I (NF1); Monozygotic twin pairs with genetically confirmed Neurofibromatosis type I
Tuberous Sclerosis Complex (TSC); Monozygotic twin pairs with genetically confirmed Tuberous Sclerosis Complex

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Investigators: Principal Investigator: Ype Elgersma, Prof., Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Anticipated): April 1, 2017
• Study Completion (Anticipated): April 1, 2017

Study Registration Dates

• First Submitted: April 29, 2015
• First Submitted That Met QC Criteria: May 4, 2015
• First Posted (Estimate): May 7, 2015

Study Record Updates

• Last Update Posted (Estimate): May 7, 2015
• Last Update Submitted That Met QC Criteria: May 4, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Loss of heterozygosity; Von Recklinghausen's disease; Bourneville's disease; Cognitive variability
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Nerve Sheath Neoplasms; Neurocutaneous Syndromes; Peripheral Nervous System Neoplasms; Hamartoma; Neoplasms, Multiple Primary; Sclerosis; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Tuberous Sclerosis
• Other Study ID Numbers: MEC-2014-483