Dutch Study Reveals New Genes and Disease Mechanisms Associated with ALS

Dutch researchers have identified new genes and biological mechanisms possibly involved in frontotemporal dementia (FTD) with and without amyotrophic lateral sclerosis (ALS).

The study, “Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS,” appeared in the journal Scientific Reports. Dr. Y. Pijnenburg of Amsterdam’s VU University Medical Center led the research.

Although ALS patients typically don’t have dementia, researchers have observed that when patients do, their symptoms resemble those of FTD. In fact, prior studies found evidence of ALS in FTD patients with no previously known diagnosis or family history of ALS. An estimated 15 percent of FTD patients also have ALS.

In an FTD study aiming to find risk variants — or gene alterations that increase the risk of developing a particular disease — scientists identified genes associated with immune responses and mechanisms that regulate the degradation of cellular material. However, researchers believe other genetic factors may be involved.

Adding certain chemical groups to the DNA is one example of mechanisms that regulate gene expression, collectively called epigenetics. Researchers observed that augmented levels of methyl groups linked to the DNA are linked to less severe clinical outcomes in FTD. However, comprehensive studies of the association of these DNA changes with FTD with or without concomitant ALS are still needed.

The authors conducted a genome-wide search in 128 FTD patients, seven of which also had ALS, and 193 controls. They assessed the possibility of identifying clinical subtypes of FTD by determining DNA methylation levels. Their analysis showed that FTD-ALS cases could clearly be distinguished.

The research specified genes with increased susceptibility for abnormal transcription. This is the first step in gene expression, which converts DNA into messenger RNA. The study also detected genes at risk for simple alterations to the DNA and higher or lower levels of DNA methylation.

This detailed approach led to nine out of an initial pool of 224 candidate genes potentially involved in FTD-ALS and only one out an initial pool of 14 candidate genes in FTD without ALS. These findings were independently validated in several genes, including DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35 and ELP2/SLC39A6

Furthermore, the authors found that specific modifications in histones — or proteins that function as spools around which the DNA wraps — could be detected in FTD-ALS. Histone modifications had previously been associated with neurological function and could be a therapeutic target.

Overall, said researchers, their findings could “demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.”