Microcephaly Genetic Deficiency in Neural Progenitors (MICROFANC)

Microcephaly Genetic Deficiency in Neural Progenitors: Genotyping, Phenotyping and Functional Neuro-anatomy and Neurobiology Comparative Primitive Microcephaly (MCPH) and the Fanconi Anemia (FA)

The purpose of this study is to:

I. Compare neuroradiological phenotype and cognitive functioning of MCPH patients caused by ASPM mutations already characterized and published (Passemard et al. 2009a) with other MCPH-related patients (patients with MCPH1, WDR62, CDK5RAP2, CEP 152, CENPJ, STIL, or PCNT mutations)

II. Describe the neuro-radiological and cognitive phenotype of microcephalic patients suffering from Fanconi anemia, and compared them to subjects with:

• Fanconi anemia but normal OFC (head circumference)
• MCPH patients
• Healthy control subjects Our hypothesis is that mutations in genes responsible of microcephaly impact differentially cortical brain development and functioning

Study Overview

• Status: Completed
• Conditions: Microcephaly

Detailed Description

Phenotyping study on 2 different cohorts of rare disease affected patients:

• Group1: MCPH (including different MCPH subtypes)
• Group2: Fanconi Anemia (with or without microcephaly)

Inclusion criteria:

Common to each group:

• Age > 3 years
• Access to french "Social Security"
• No contraindication for MRI

Group1:

• Primary microcephaly without gross malformation within or extra nervous central system
• OFC < -2SD at birth and < -3 SD after age 6months
• Mutation in one MCPH gene

Group2:

Proven Fanconi Anemia with:

• Positive chromosome breakage blood test
• One of the 3 following elements:

FANCD2 positive test Fibroblast sensitivity to mitomycin Mutation in one FANC gene

Control subjects:

• No antecedent
• Normal education

Aims:

1. Description of neurological, neuropsychological and radiological phenotype for each group

2. Phenotype comparison:

   • groups 1&2
   • group1 or 2 with control subjects
   • different MCPH subtypes within group1
   • with or without microcephaly within group2
3. Epidemiological data on these rare diseases in our population

Protocol:

Patients from both groups and control subjects will be evaluated in CIC for 1 day ½. They will be examined by a child neurologist and a geneticist. All of them will have cranial MRI (1.5Tesla). Neuropsychological assessment will be performed (Wechsler scales) for patients and control subjects.

• Study Type: Observational
• Enrollment (Actual): 98

Contacts and Locations

Study Locations

• France
  • Paris, France, 75019
    • Robert Debré Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Group1:

• Primary microcephaly without gross malformation within or extra nervous central system
• OFC < -2SD at birth and < -3 SD after age 6months
• Mutation in one MCPH gene

Group2:

Proven Fanconi Anemia with:

• Positive chromosome breakage blood test
• One of the 3 following elements:

FANCD2 positive test Fibroblast sensitivity to mitomycine Mutation in one FANC gene

Description

Inclusion Criteria:

Patients aged ≥ 3 years:

• Microcephalic phenotype consistent with MCPH (recruitment already done as part of a network GIS-Rare Diseases Institute). MCPH patients have already been selected in the cohort "Robert Debré."
• Holders of a Fanconi anemia characterized in terms of cytogenetics, enzyme and/or molecular (patients in the cohort "Saint Louis" followed by the KRC rare aplastic anemia)
• Healthy controls aged ≥ 5 years siblings of patients with Fanconi Anemia

Exclusion Criteria:

Patients with Fanconi anemia:

• bone marrow < 3 years
• Post-transplantation neurological complications
• developmental, genetic or environmental additional pathology

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Microcephaly; Microcephaly Intellectual abilities Cranial MRI
FANCONI ANEMIA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare neuroradiological phenotype and cognitive functioning with other MCPH-related patients	The purpose of this study is to: Compare neuroradiological phenotype and cognitive functioning of MCPH patients caused by ASPM mutations already characterized and published (Passemard et al. 2009a) with other MCPH-related patients (patients with MCPH1, WDR62, CDK5RAP2, CEP 152, CENPJ, STIL, or PCNT mutations)	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Establish a clear organizational chart for the diagnosis of primary microcephaly	I. Establish a clear organizational chart for the diagnosis of primary microcephaly from the detailed description of the patient's phenotype II. Establish epidemiological data on the molecular genetic causes involved in human primary microcephaly	3 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Alain VERLOES, PU-PH, Assistance Publique - Hôpitaux de Parsi

Publications and helpful links

General Publications

• Ruaud L, Drunat S, Elmaleh-Bergès M, Ernault A, Guilmin Crepon S; MCPH Consortium, El Ghouzzi V, Auvin S, Verloes A, Passemard S. Neurological outcome in WDR62 primary microcephaly. Dev Med Child Neurol. 2022 Apr;64(4):509-517. doi: 10.1111/dmcn.15060. Epub 2021 Sep 25.
• Nasser H, Vera L, Elmaleh-Berges M, Steindl K, Letard P, Teissier N, Ernault A, Guimiot F, Afenjar A, Moutard ML, Heron D, Alembik Y, Momtchilova M, Milani P, Kubis N, Pouvreau N, Zollino M, Guilmin Crepon S, Kaguelidou F, Gressens P, Verloes A, Rauch A, El Ghouzzi V, Drunat S, Passemard S. CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects. J Med Genet. 2020 Jun;57(6):389-399. doi: 10.1136/jmedgenet-2019-106474. Epub 2020 Feb 3.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2013
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: February 29, 2012
• First Submitted That Met QC Criteria: March 26, 2012
• First Posted (Estimate): March 28, 2012

Study Record Updates

• Last Update Posted (Actual): March 2, 2018
• Last Update Submitted That Met QC Criteria: March 1, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: MCPH; FANCONI ANEMIA
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Congenital Abnormalities; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Anemia; DNA Repair-Deficiency Disorders; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Microcephaly; Fanconi Anemia
• Other Study ID Numbers: P 100128