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

NCT00136630 | Completed

• 1 other identifier: RBM01-59 _ AOM03059
• Study Type: observational
• Target: 175
• Locations: 1 country
• Sites: 8

Brief Summary

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.

Conditions

Spinocerebellar Ataxias; Spastic Paraplegias

Keywords

dominant spinocerebellar degenerations; new rate scales; natural history; molecular biology; candidate genes

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

French population

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France: lead
• Assistance Publique - Hôpitaux de Paris: collaborator

Study Sites (8)

Hôpital Pellegrin

Bordeaux, 33000, France

Location

CHU de Grenoble

Grenoble, 38000, France

Location

Hôpital Neurologique Pierre Wertheimer

Lyon, 69003, France

Location

Hôpital La Timone

Marseille, 13005, France

Location

Hôpital Carémeau

Nîmes, 30000, France

Location

Hôpital Pitié-Salpêtrière

Paris, 75013, France

Location

Hôpital Charles Nicolle

Rouen, 76000, France

Location

Hôpital Purpan

Toulouse, 31000, France

Location

Related Publications (13)

• 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.

  PMID: 16193476 RESULT

• 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.

  PMID: 15313841 RESULT

• 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.

  PMID: 15365159 RESULT

• 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.

  PMID: 16501573 RESULT

• 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.

  PMID: 16055926 RESULT

• 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.

  PMID: 17098887 RESULT

• 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.

  PMID: 17597328 RESULT

• 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.

  PMID: 17605047 RESULT

• 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.

  PMID: 17957230 RESULT

• 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.

  PMID: 18378516 RESULT

• 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.

  PMID: 18853458 RESULT

• 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.

  PMID: 24780882 DERIVED

• 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.

  PMID: 22491195 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Spinocerebellar Ataxias; Paraplegia

Condition Hierarchy (Ancestors)

Cerebellar Ataxia; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Spinocerebellar Degenerations; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Ataxia; Dyskinesias; Neurologic Manifestations; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Paralysis; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Alexandra Dürr, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

• Broussolle Emmanuel, MD, PhD

  Hôpitaux Civils de Lyon

  PRINCIPAL INVESTIGATOR

• Pierre Labauge, MD, PhD

  Hôpitaux de Nîmes

  PRINCIPAL INVESTIGATOR

• Cyril Goizet, MD

  Hôpitaux de Bordeaux

  PRINCIPAL INVESTIGATOR

• Patrick Calvas, MD, PhD

  Hôpitaux de Toulouse

  PRINCIPAL INVESTIGATOR

• Jean-Philippe Azulay, MD, PhD

  Assistance Publique - Hôpitaux de Marseille

  PRINCIPAL INVESTIGATOR

• Didier Hannequin, MD, PhD

  Hôpitaux de Rouen

  PRINCIPAL INVESTIGATOR

• Pierre Pollak, MD, PhD

  Hôpitaux de Grenoble

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: FAMILY BASED
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2005
• First Posted: August 29, 2005
• Study Start: May 1, 2005
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2020
• Last Updated: August 25, 2021

Record last verified: 2021-08

Locations

FR (8)