The researchers came to the four-generation Belgian family via a man with FTLD. Among 29 family members in the study, nine were affected: two had FTLD; four had unspecified dementia; two had dementia with parkinsonism and one had ALS. (A further two family members had some symptoms associated with ALS, such as low muscle strength, but were never diagnosed with the disease.)

Cruts and colleagues scanned the DNA of these relatives for loci that co-segregated with any of these conditions. Their studies pointed to a region of chromosome 9 and, with near-statistical significance, one on chromosome 14. The researchers sequenced the coding portions of 73 candidate genes in the two regions but were unable to find specific variants that were present only in affected family members and not in controls within the family or in the general population.

“I think everyone will agree that there is some genetic variant at 9p that influences ALS and dementia,” wrote Michael van Es of University Medical Center Utrecht in The Netherlands, who was not involved with the latest study, in an e-mail to ARF. Multiple analyses have pointed to that part of the genome (see ARF related news story on van Es et al., 2009; Luty et al., 2008; Valdmanis et al., 2007; Vance et al., 2006). Between the current and past studies, researchers have sequenced all the amino acid-encoding DNA in the suspect region, Cruts said, so now they must start looking for non-coding variants. For example, he suggested, a variant in a regulatory region could cause disease.

Another possibility is that the variant is due to an inversion, insertion, or deletion. The genome sequencing technique Cruts and colleagues used—comparative genomic hybridization—is likely to miss these chromosomal abnormalities if they are less than 1 kilobase in length. The researchers are taking two approaches to find those kinds of variants. “We are using the very old-fashioned and the next-generation technologies,” he said. The old-fashioned is restriction fragment length analysis, which can identify, from fragments that are too short or too long, missing or excess DNA. The second approach is next-generation DNA sequencing—faster, but also more expensive—that will allow the scientists to sequence the region with higher resolution so they can discover small changes.

The chromosome 9 locus, having popped up in so many studies, appears to be a fairly solid lead. This paper is the first, however, to point to chromosome 14. Each affected person in the family carried both chromosome variants, according to the study. That suggests they might work in tandem somehow. For example, the body might be able to function properly with variation at just one locus, but not at both. Or perhaps, Cruts suggested, one variant affects a gene that modifies a gene at the other locus. In support of these hypotheses, one family member carried only the chromosome 9 variant—and was not sick. It is also possible, Cruts conceded, that the chromosome 14 link is simply a false-positive match that will not be confirmed in other studies.

These genetic variants, whatever they may be, cause a diverse set of symptoms in affected individuals. However, the diversity of conditions fits well with an idea, supported by many researchers, that ALS and FTLD lie at opposite ends of a spectrum of disorders (Geser et al., 2009). The two conditions are linked by TDP-43 proteinopathy, which was evident in the single member of the Belgian family whose autopsy tissue was available. Cruts suspects that the diseases in this family are the same pathology at different parts of the nervous system, and suggested that other variation in a person’s genes may determine whether the brain, spinal cord, or both are affected.—Amber Dance.

Reference:
Gijselinck I, Engelborghs S, Maes G, Cuijt I, Peeters K, Mattheijssens, Jorit Geert, Cras P, Martin JJ, De Deyn PP, Kumar-Singh S, Van Broeckhoven C, Cruts M. Identification of 2 loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol. 2010 May;67(5):606-16. Abstract