Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome

Joubert Syndrome Clinical Trial

— JSCORS  

Official title:

Assessment of the Prevalence and Mutational Spectrum of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome and Cerebello-oculo-renal Syndromes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00873678
• Other study ID #: P051079
• Status: Completed
• Phase: N/A
• First received: March 31, 2009
• Last updated: June 2, 2010
• Start date: March 2007
• Est. completion date: January 2010

Study information

• Verified date: March 2010
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Observational

Clinical Trial Summary

Primary objective:

• assessment of the prevalence of AHI1 mutations in Joubert syndrome and cerebello-oculo-renal syndromes (JS/CORS)

Secondary objective:

• assessment of the prevalence of CEP290 mutations and NPHP1 homozygous deletions in JS/CORS

• caracterization of mutational spectrum of AHI1, NPHP1, CEP290 genes in JS/CORS.

• evaluation of genotype-phenotype correlation in JS/CORS.

Description:

Design: multicentric Aims of this study: to describe clinical and genetic basis of Joubert syndrome and cerebello-oculo-renal syndromes.Joubert syndrome (JS) is characterized by hypotonia, abnormal ocular movements and neonatal breathing dysregulation evolving into developmental delay, ataxia, oculomotor apraxia with variable mental retardation. The neuroradiological hallmark of JS is a complex midbrain-hindbrain malformation consisting of vermis hypoplasia/dysplasia, a deepened interpeduncular fossa, and thickened, elongated and mal-orientated superior cerebellar peduncles (Molar Tooth Sign, MTS). Other organs could be involved in JS (kidneys :nephronophthisis or cystic dysplastic kidneys; eyes : Leber Congenital Amaurosis, retinopathy, colobomas); liver : hepatic fibrosis; others: polydactyly, tongue hamartomas, situs inversus). Several associated central nervous system malformations were described : polymicrogyria, hydrocephalus, corpus callosum anomalies and encephalocele. This pleiotropic involvement identifies a large spectrum of cerebello-oculo-renal syndromes or JS Related Disorders (JSRD).

Joubert syndrome and cerebello-oculo-renal syndromes (JS/CORS) are autosomal recessive conditions associated with a high risk of recurrence for further pregnancies (25%). In 2004 mutations in AHI1 gene (Abelson helper integration site gene) were identified in 7-11% JS but the disease is caracterized by a wide genetic heterogeneity. At least five others genes are involved in JS/CORS : NPHP1, which homozygous deletions are responsible for a small percentage of JS (2%) and more recently CEP290 gene which exact mutations prevalence remained to be evaluated.

Using molecular analysis of those three genes (sequencing of 29 coding exons of AHI1 and 54 exons of CEP290, searching for NPHP1 homozygous deletions by PCR analysis) we project to study respective prevalence of mutations of those three genes and described associated phenotypes in 65 JSCORS patients. This work will allowed to described genotype-phenotypes correlation in JSCORS and to progress in the characterization of the underlying pathogenetic mechanisms. It will be the first step before identification of novel disease genes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: January 2010
• Est. primary completion date: January 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Child or adult patients without age maximum

• Affected with JS/CORS défined by neurologic disease with at least one of the following symptoms :

• neonatal hypotonia or developmental delay (before age 3) or mental retardation (QD<70) (after age 3).

• Ataxia

• Oculomotor apraxia

• and on MRI :

• vermis hypoplasia/agenesia defined by insufficient development of cerebellar vermis.

• And molar tooth defined by thickened, elongated and mal-orientated superior cerebellar peduncles on axial sections.

Exclusion Criteria:

• Chromosomal anomalies identified by caryotype

• Absence of signature of informed consent.

• Absence of affiliation to social security

Study Design

Observational Model: Family-Based, Time Perspective: Cross-Sectional

Related Conditions & MeSH terms

• Abnormalities, Multiple
• Cerebellar Diseases
• Cerebello-oculo-renal Syndromes
• Eye Abnormalities
• Joubert Syndrome
• Syndrome

Intervention

Biological:
• Whole blood sample
Whole blood sample (10 ml)

Locations

Country	Name	City	State
France	Hopital Trousseau	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assessment of the prevalence of AHI1 mutations in Joubert syndrome and cerebello-oculo-renal syndromes (JS/CORS)		At the inclusion visit	No
Secondary	Assessment of the prevalence of CEP290 mutations and NPHP1 homozygous deletions in JS/CORS ; Caracterization of mutational spectrum of AHI1, NPHP1, CEP290 genes in JS/CORS ; Evaluation of genotype-phenotype correlation in JS/CORS.		At the inclusion visit	No