From Medscape Medical News > Neurology
Yael Waknine
September 26, 2011 — Researchers have identified a single genetic mutation that has been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD): 2 neurodegenerative disorders that have distinct, but sometimes overlapping, symptoms.
New research published online September 21 in Neuron links the neurodegenerative diseases with the presence of a hexanucleotide (GGGGCC) repeat expansion within the noncoding area of a gene on chromosome 9p21 called C9ORF72.
Whereas healthy individuals had no more than about 20 repeats of the string, patients with ALS or FTD were found to have from hundreds to thousands of copies. The region has no known function, and its role in the disease remains unclear.
"We believe that when the defective gene is transcribed into a messenger RNA molecule, the expanded repeat section causes the RNA to bind tightly to certain proteins, forming clumps within the brain cells," Rosa Rademakers, PhD, senior investigator, said in a news release.
"By binding these proteins, the abnormal RNA may prevent these proteins from carrying out their normal functions in the cell."
In a second study, also published online September 21, a team of researchers examined people in Finland, where ALS is nearly twice as common as in other white populations, according to lead study author Bryan Traynor, MD, from the National Institute on Aging in Bethesda, Maryland.
Using next-generation sequencing, the researchers found that the C9ORF72 mutations occurred in 46% of familial ALS cases and 21.1% of "sporadic" cases with no family history of the disorder. The repeat expansion was also found in 33% of familial cases in other European populations.
These findings were independently corroborated in a US/Canadian study led by researchers at the Mayo Clinic in Jacksonville, Florida, who identified the genetic lesion in 23.5% of familial cases of ALS, 11.7% of familial cases of FDD, and 3% to 4% of sporadic cases for both disorders.
According to the authors, identification of the defect and availability of a rapid and reliable screening method may aid in the early diagnosis of patients with ALS who are at risk for cognitive impairment and patients with FTD who are at risk for progressive paralysis.
Future screening of population-based cohorts may also unravel the overlap between the conditions and identify additional genetic and environmental factors that push symptoms toward one end of the ALS/FTD spectrum.
"This is tremendously exciting," commented ALS Association Chief Scientist Lucie Bruijn, PhD, in the news release. "These findings will significantly impact the field as we begin to understand more about the consequence of these changes to the disease process, aid our understanding of FTD and ALS, potentially provide a diagnostic tool, and enable the development of new therapeutic approaches."
Dr. Traynor's team was supported by the ALS Association's Abendroth ALS Genetic Discovery Fund, with additional support from the Robert Packard Institute of ALS Research at Johns Hopkins. Dr. Rademakers' team was supported by the ALS Association's Florida Chapter and Richard Essey. Both studies were also supported by the National Institute on Aging and the National Institute on Neurological Diseases and Stroke.
Neuron. Published online September 21, 2011. Rademakers abstract, Traynor abstract
Yael Waknine
September 26, 2011 — Researchers have identified a single genetic mutation that has been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD): 2 neurodegenerative disorders that have distinct, but sometimes overlapping, symptoms.
New research published online September 21 in Neuron links the neurodegenerative diseases with the presence of a hexanucleotide (GGGGCC) repeat expansion within the noncoding area of a gene on chromosome 9p21 called C9ORF72.
Whereas healthy individuals had no more than about 20 repeats of the string, patients with ALS or FTD were found to have from hundreds to thousands of copies. The region has no known function, and its role in the disease remains unclear.
"We believe that when the defective gene is transcribed into a messenger RNA molecule, the expanded repeat section causes the RNA to bind tightly to certain proteins, forming clumps within the brain cells," Rosa Rademakers, PhD, senior investigator, said in a news release.
"By binding these proteins, the abnormal RNA may prevent these proteins from carrying out their normal functions in the cell."
In a second study, also published online September 21, a team of researchers examined people in Finland, where ALS is nearly twice as common as in other white populations, according to lead study author Bryan Traynor, MD, from the National Institute on Aging in Bethesda, Maryland.
Using next-generation sequencing, the researchers found that the C9ORF72 mutations occurred in 46% of familial ALS cases and 21.1% of "sporadic" cases with no family history of the disorder. The repeat expansion was also found in 33% of familial cases in other European populations.
These findings were independently corroborated in a US/Canadian study led by researchers at the Mayo Clinic in Jacksonville, Florida, who identified the genetic lesion in 23.5% of familial cases of ALS, 11.7% of familial cases of FDD, and 3% to 4% of sporadic cases for both disorders.
According to the authors, identification of the defect and availability of a rapid and reliable screening method may aid in the early diagnosis of patients with ALS who are at risk for cognitive impairment and patients with FTD who are at risk for progressive paralysis.
Future screening of population-based cohorts may also unravel the overlap between the conditions and identify additional genetic and environmental factors that push symptoms toward one end of the ALS/FTD spectrum.
"This is tremendously exciting," commented ALS Association Chief Scientist Lucie Bruijn, PhD, in the news release. "These findings will significantly impact the field as we begin to understand more about the consequence of these changes to the disease process, aid our understanding of FTD and ALS, potentially provide a diagnostic tool, and enable the development of new therapeutic approaches."
Dr. Traynor's team was supported by the ALS Association's Abendroth ALS Genetic Discovery Fund, with additional support from the Robert Packard Institute of ALS Research at Johns Hopkins. Dr. Rademakers' team was supported by the ALS Association's Florida Chapter and Richard Essey. Both studies were also supported by the National Institute on Aging and the National Institute on Neurological Diseases and Stroke.
Neuron. Published online September 21, 2011. Rademakers abstract, Traynor abstract