Genetic Analysis of Novel and Known Genes Implicated in Frontotemporal Dementia andand Amyotrophic Lateral Sclerosis

  • A family pedigree

    Pedigree of a family with autosomal dominant inheritance of FTD and ALS studied in our laboratory. Note that some patients have ALS (right side of symbol in black), some patients have FTD (left side of symbol in black) and some patients have a combined diagnosis of FTD and ALS (complete symbol in black).

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are closely related conditions with overlapping clinical, genetic and neuropathological features. ALS and FTD often co-occur in the same family and the prevalence of FTD in ALS populations may approach 40 percent. The recent identification of TDP-43 as the major pathological protein in both ALS and the most common pathological subtype of FTD (FTLD-TDP) provides additional evidence to suggest that these conditions are part of a clinicopathological spectrum of disease.

In the last few years, increasing evidence suggests the presence of a causal gene responsible for the combined phenotype of FTD and ALS on chromosome 9p. This locus was first described in two independent reports in 2006 and since then at least six groups have reported families with autosomal dominant FTD and ALS with significant or suggestive linkage to chromosome 9p. It has been suggested that mutations in the gene at chromosome 9p may be implicated in 60 percent of families with FTD-ALS.

We recently identified a large autosomal dominant family with FTD and ALS with conclusive linkage to chromosome 9p. The minimum candidate region in this family overlaps with previously reported regions linked to FTD-ALS on chromosome 9p and significantly reduces the candidate region to a 3.7 Mb interval between D9S169 and D9S251, containing only 10 genes. Current work in our laboratory includes a thorough analysis of the candidate region in this family, including next generation sequencing, with the ultimate goal to identify the FTD-ALS disease gene on chromosome 9p. Identification of this novel disease gene is expected to provide better insight into the pathogenic mechanisms underlying ALS and TDP-43 proteinopathy, which could lead to improved diagnosis, more effective genetic counseling and the development of more rational therapeutic strategies.