Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations

NCT ID: NCT00136630

Last Updated: 2021-08-25

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

175 participants

Study Classification

OBSERVATIONAL

Study Start Date

2005-05-31

Study Completion Date

2020-05-31

Brief Summary

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The autosomal dominant spinocerebellar degenerations are a highly heterogeneous, clinically and genetically, group of rare diseases and of severe evolution. So far, the responsible genes for less than 50% of the cases are known and because of their rarity, there are no phenotype-genotype correlations and well-defined disease history.

The aims of the project are to develop and validate quantitative tools of the cerebellar syndrome and of the spasticity, to establish links between the phenotype and the result of the molecular analysis, to identify new loci/genes responsible for these disorders, and to establish the natural history of the disease according to the genotype.

To this end, a prospective and multicentric study is proposed for recruiting and evaluating, clinically, a cohort of 225 patients; 150 of them are already followed-up in the centers involved. A DNA collection will be set up in order to search for the implication of new loci and genes. A clinico-genetic database will be set up combining data from successive clinical evaluations and those of genotyping.

This strategy will allow access to genetic counselling and molecular diagnosis (positive, presymptomatic or prenatal diagnoses), based on a rational strategy from phenotype-genotype correlations and the information concerning the relative frequency of the genes. The detailed description, with the help of new evaluation tools and of the follow-up of the natural history of the disease according to the genotype, constitutes a crucial step in the design of therapeutical trials in these orphan disorders. Furthermore, the regular follow-up by specialized centers will allow better care of the patients.

Detailed Description

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Conditions

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Spinocerebellar Ataxias Spastic Paraplegias

Study Design

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Observational Model Type

FAMILY_BASED

Study Time Perspective

PROSPECTIVE

Eligibility Criteria

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Inclusion Criteria

* Progressive ataxia or paraplegia,
* Familial history of the disease (patients),
* Over 18 years of age
* No presentation of neurological or osteoarticular disorders

Exclusion Criteria

* Refusal to participate in the protocol,
* An unknown familial history,
* Presenting with an interrecurrent disorder making the evaluation of the disease (stroke, dementia) impossible
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role collaborator

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Alexandra Dürr, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Broussolle Emmanuel, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpitaux Civils de Lyon

Pierre Labauge, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpitaux de Nîmes

Cyril Goizet, MD

Role: PRINCIPAL_INVESTIGATOR

Hôpitaux de Bordeaux

Patrick Calvas, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpitaux de Toulouse

Jean-Philippe Azulay, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Marseille

Didier Hannequin, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpitaux de Rouen

Pierre Pollak, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpitaux de Grenoble

Locations

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Hôpital Pellegrin

Bordeaux, , France

Site Status

CHU de Grenoble

Grenoble, , France

Site Status

Hôpital Neurologique Pierre Wertheimer

Lyon, , France

Site Status

Hôpital La Timone

Marseille, , France

Site Status

Hôpital Carémeau

Nîmes, , France

Site Status

Hôpital Pitié-Salpêtrière

Paris, , France

Site Status

Hôpital Charles Nicolle

Rouen, , France

Site Status

Hôpital Purpan

Toulouse, , France

Site Status

Countries

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France

References

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Klebe S, Durr A, Rentschler A, Hahn-Barma V, Abele M, Bouslam N, Schols L, Jedynak P, Forlani S, Denis E, Dussert C, Agid Y, Bauer P, Globas C, Wullner U, Brice A, Riess O, Stevanin G. New mutations in protein kinase Cgamma associated with spinocerebellar ataxia type 14. Ann Neurol. 2005 Nov;58(5):720-9. doi: 10.1002/ana.20628.

Reference Type RESULT
PMID: 16193476 (View on PubMed)

Stevanin G, Hahn V, Lohmann E, Bouslam N, Gouttard M, Soumphonphakdy C, Welter ML, Ollagnon-Roman E, Lemainque A, Ruberg M, Brice A, Durr A. Mutation in the catalytic domain of protein kinase C gamma and extension of the phenotype associated with spinocerebellar ataxia type 14. Arch Neurol. 2004 Aug;61(8):1242-8. doi: 10.1001/archneur.61.8.1242.

Reference Type RESULT
PMID: 15313841 (View on PubMed)

Stevanin G, Durr A, Dussert C, Penet C, Brice A. Mutations in the FGF14 gene are not a major cause of spinocerebellar ataxia in Caucasians. Neurology. 2004 Sep 14;63(5):936. doi: 10.1212/01.wnl.0000137020.30604.1e. No abstract available.

Reference Type RESULT
PMID: 15365159 (View on PubMed)

Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JP, Nolte D, Mock AF, Evidente VG, Fee DB, Muller U, Durr A, Brice A, Papazian DM, Pulst SM. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet. 2006 Apr;38(4):447-51. doi: 10.1038/ng1758. Epub 2006 Feb 26.

Reference Type RESULT
PMID: 16501573 (View on PubMed)

Depienne C, Tallaksen C, Lephay JY, Bricka B, Poea-Guyon S, Fontaine B, Labauge P, Brice A, Durr A. Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases. J Med Genet. 2006 Mar;43(3):259-65. doi: 10.1136/jmg.2005.035311. Epub 2005 Jul 31.

Reference Type RESULT
PMID: 16055926 (View on PubMed)

Depienne C, Fedirko E, Forlani S, Cazeneuve C, Ribai P, Feki I, Tallaksen C, Nguyen K, Stankoff B, Ruberg M, Stevanin G, Durr A, Brice A. Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. J Med Genet. 2007 Apr;44(4):281-4. doi: 10.1136/jmg.2006.046425. Epub 2006 Nov 10.

Reference Type RESULT
PMID: 17098887 (View on PubMed)

Depienne C, Fedirko E, Faucheux JM, Forlani S, Bricka B, Goizet C, Lesourd S, Stevanin G, Ruberg M, Durr A, Brice A. A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP. Neurogenetics. 2007 Aug;8(3):231-3. doi: 10.1007/s10048-007-0090-4. Epub 2007 Jun 28.

Reference Type RESULT
PMID: 17597328 (View on PubMed)

Hanein S, Durr A, Ribai P, Forlani S, Leutenegger AL, Nelson I, Babron MC, Elleuch N, Depienne C, Charon C, Brice A, Stevanin G. A novel locus for autosomal dominant "uncomplicated" hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3. Hum Genet. 2007 Nov;122(3-4):261-73. doi: 10.1007/s00439-007-0396-1. Epub 2007 Jun 28.

Reference Type RESULT
PMID: 17605047 (View on PubMed)

Ribai P, Depienne C, Fedirko E, Jothy AC, Viveweger C, Hahn-Barma V, Brice A, Durr A. Mental deficiency in three families with SPG4 spastic paraplegia. Eur J Hum Genet. 2008 Jan;16(1):97-104. doi: 10.1038/sj.ejhg.5201922. Epub 2007 Oct 24.

Reference Type RESULT
PMID: 17957230 (View on PubMed)

du Montcel ST, Charles P, Ribai P, Goizet C, Le Bayon A, Labauge P, Guyant-Marechal L, Forlani S, Jauffret C, Vandenberghe N, N'guyen K, Le Ber I, Devos D, Vincitorio CM, Manto MU, Tison F, Hannequin D, Ruberg M, Brice A, Durr A. Composite cerebellar functional severity score: validation of a quantitative score of cerebellar impairment. Brain. 2008 May;131(Pt 5):1352-61. doi: 10.1093/brain/awn059. Epub 2008 Mar 31.

Reference Type RESULT
PMID: 18378516 (View on PubMed)

Goizet C, Boukhris A, Mundwiller E, Tallaksen C, Forlani S, Toutain A, Carriere N, Paquis V, Depienne C, Durr A, Stevanin G, Brice A. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Hum Mutat. 2009 Feb;30(2):E376-85. doi: 10.1002/humu.20920.

Reference Type RESULT
PMID: 18853458 (View on PubMed)

Tezenas du Montcel S, Durr A, Rakowicz M, Nanetti L, Charles P, Sulek A, Mariotti C, Rola R, Schols L, Bauer P, Dufaure-Gare I, Jacobi H, Forlani S, Schmitz-Hubsch T, Filla A, Timmann D, van de Warrenburg BP, Marelli C, Kang JS, Giunti P, Cook A, Baliko L, Melegh B, Boesch S, Szymanski S, Berciano J, Infante J, Buerk K, Masciullo M, Di Fabio R, Depondt C, Ratka S, Stevanin G, Klockgether T, Brice A, Golmard JL. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet. 2014 Jul;51(7):479-86. doi: 10.1136/jmedgenet-2013-102200. Epub 2014 Apr 29.

Reference Type DERIVED
PMID: 24780882 (View on PubMed)

Tezenas du Montcel S, Charles P, Goizet C, Marelli C, Ribai P, Vincitorio C, Anheim M, Guyant-Marechal L, Le Bayon A, Vandenberghe N, Tchikviladze M, Devos D, Le Ber I, N'Guyen K, Cazeneuve C, Tallaksen C, Brice A, Durr A. Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. Arch Neurol. 2012 Apr;69(4):500-8. doi: 10.1001/archneurol.2011.2713.

Reference Type DERIVED
PMID: 22491195 (View on PubMed)

Related Links

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Other Identifiers

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RBM01-59 _ AOM03059

Identifier Type: -

Identifier Source: org_study_id

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