Amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) is a rare clinical entity, in which both disorders are variably associated in the same patient or within the family. This adult-onset disorder, which is rapidly fatal, occurs in some families with autosomal dominant (AD) transmission and age-dependant penetrance. Two studies have provided evidence for linkage of this condition to chromosome 15 (in a single family) and to chromosome 9 (in five families). However, none of these loci have been yet confirmed. Through a national network of 10 centres with specialists for FTD and/or ALS, we have identified 35 probands with ALS-FTD, including 13 with a family history consistent with AD inheritance. At an initial step, mutations in the SOD1 and tau genes, respectively responsible for autosomal dominant forms of ALS and FTD, will be excluded by direct sequencing. We will then extend the pedigree of the 13 autosomal dominant families to all consenting first, second and eventually third degree relatives, using well defined criteria for FTD and ALS. The same strategy will be applied to newly identified families during the course of the project (at least, seven families with AD inheritance expected). Linkage studies will be performed in the 20 families using markers from the two candidate regions on chromosome 9 and 15. In a second step, refinement of the candidate region will be obtained by analyzing the linked families with a high density of microsatellite markers. This should lead to the refinement of the candidate regions, allowing to search for mutations in candidate genes. Genes located within the critical regions will be prioritized for their analysis by sequencing, according to their expression in the nervous system and to their function. Once the responsible gene(s) will be identified, it will then possible to define its spectrum of mutations and to establish genotype/phenotype correlations. Alternatively, if none of the candidate regions is confirmed, a genome wide search will be performed, allowing to identify one or more loci for ALS-FTD. The same strategy would then be applied to identify the corresponding gene(s). This project, which benefits from the expertise of a nationwide clinical network, from INSERM U289 for molecular analyses, and from INSERM U535 for genetic epidemiology analysis should contribute for identifying the molecular basis of this devastating disorder with practical consequences for genetic counselling in ALS-FTD families, and with the perspective of elucidating the pathophysiology of this disorder.

Condition	Phase
Frontotemporal dementia and/or Lateral amyotrophic sclerosis	Phase I

Further Study Details: 

Expected Total Enrollment:  350

The objectives of this study are:

1. to clinically evaluate and characterise families with the phenotype of Amyotrophic Lateral Sclerosis with Fronto-Temporal Dementia (ALS-FTD),
2. to exclude the responsibility of the tau and SOD1 genes,
3. to test the corresponding families for linkage to the previously identified regions of chromosome 9 and 15,
4. to reduce the candidate interval in order to facilitate gene identification,
5. to characterise the responsible mutations and to establish phenotype-genotype correlations,
6. to perform a genome wide scan, in a further step, if sufficient informative families are identified, with the families for which linkage to chromosomes 9 and 15 is excluded in order to identify a new candidate locus.

Ages Eligible for Study:  18 Years   -   80 Years,  Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

Inclusion Criteria:

- ALS with FTD, "pure" FTD but with knowledge of relatives with ALS-FTD or "pure" ALS, "pure" ALS but with knowledge of relatives with ALS-FTD or "pure" FTD, not carriers of a mutation in the tau and SOD1 genes

Exclusion Criteria:

- Lack of signed informed consent, lack of genealogical information

Please refer to this study by ClinicalTrials.gov identifier  NCT00140777

Alexis Brice, MD      0033142162182    brice@ccr.jussieu.fr

France
      Pitié-Salpêtrière Hospital, Paris,  75013,  France; Recruiting
      Pitié-Salpêtrière Hospital - Centre du Langage et de Neuropsychologie, Paris,  75013,  France; Recruiting
      Hôpital de la Timone Adultes, Marseille,  13005,  France; Recruiting
      Hôpital Sainte-Marguerite, Marseille,  13009,  France; Recruiting
      Hôpital Charles Nicolle, Rouen,  76000,  France; Recruiting
      Hôpital Bellevue, Saint-Etienne,  42000,  France; Recruiting
      Pitié-Salpêtrière Hospital - Fédération de Neurologie, Paris,  75013,  France; Recruiting
      Hôpital Guillaume et René Laennec, Nantes,  44000,  France; Recruiting
      Hôpital Civil, Strasbourg,  67000,  France; Recruiting

Study chairs or principal investigators

Alexis Brice, MD,  Principal Investigator,  Assistance Publique - Hôpitaux de Paris, University Paris 6   

Study ID Numbers:  A03081DS
Last Updated:  August 31, 2005
Record first received:  August 30, 2005
ClinicalTrials.gov Identifier:  NCT00140777
Health Authority: France: Ministry of Health
ClinicalTrials.gov processed this record on 2005-09-06