Clinical trial NCT01565005: Microcephaly Genetic Deficiency in Neural Progenitors
Official title: Microcephaly Genetic Deficiency in Neural Progenitors: Genotyping, Phenotyping and Functional Neuro-anatomy and Neurobiology Comparative Primitive Microcephaly (MCPH) and the Fanconi Anemia (FA)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Microcephaly
Keywords: MCPH
FANCONI ANEMIA
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2012-03-28
Enrollment: 98
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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

Brief summary: 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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Compare neuroradiological phenotype and cognitive functioning with other MCPH-related patients
timeFrame: 3 years
Secondary outcomes:
measure: Establish a clear organizational chart for the diagnosis of primary microcephaly
timeFrame: 3 years
Other outcomes:
Locations:
city: Paris
country: France
facility: Robert Debre Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Parsi
name: Alain VERLOES, PU-PH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ruaud L, Drunat S, Elmaleh-Berges 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.
citation: 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.