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Genetic studies reveal complex interplay between inherited genes and neurological disorders.
Posted On: March 03, 2017
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Frontotemporal dementia affects men and women equally and is the second most common early onset dementia after Alzheimer disease.
Neurological diseases can be a major challenge to treat. Part of this challenge is that the same neurological disease can cause different symptoms and respond differently to therapies depending on the patient. Identifying defective genes associated with disease can aid in creating better, more customized therapeutics; however, as more genes are considered, another level of complexity can arise.
This is the case for a gene known as C9orf72, which is commonly mutated in individuals with amyotrophic lateral sclerosis (ALS) and/or a type of dementia known as frontotemporal dementia (FTD).
These diseases represent two different types of disorders: ALS affects nerve function, while FTD affects brain function. Thus, to help differentiate whether the C9orf72 mutation causes ALS or FTD, researchers have identified additional mutated genes that act as ‘modifiers’ to shift outcomes.
One such ‘modifier’ gene is ATXN2. This gene is present as one of three sizes based on the number of ‘CAG-repeats’ present within it: a normal form (22-23 repeats), an intermediate form (27-33 repeats) and a long form (>35 repeats).
In individuals with C9orf72 mutations, the intermediate form of ATXN2 predisposes individuals to ALS, but not FTD. On the other hand, it remains unclear whether the long form plays a role in disease onset in either of these patient groups.
To shed light on this, Krembil Clinician Investigator Carmela Tartaglia identified, for the first time, two patients with C9orf72 mutations who also had the long form of ATXN2 mutation. In contrast to people who have the intermediate length mutation of ATXN2, these two patients had FTD, but not ALS.
Dr. Carmela Tartaglia explains, “We were lucky to identify these two mutations as they are not often screened for at the same time. We first screened for the ATXN2 mutation because the patients had coordination problems, at which point we found the long form of the mutation. Then, because the patients had atypical symptoms, including significant behavioral and cognitive changes in addition to coordination problems, we screened for and found mutations in the C9orf72 gene.”
“Because the patients do not show signs of ALS, this study suggests that the long form of ATXN2 may modulate the pathologic mechanism of C9orf72 mutations differently than the intermediate length mutation.”
Taken together, these findings show that much more remains to be discovered about the interplay between genetics and symptoms in this disorder—findings that will inform improved diagnostics and the creation of better, more customized therapies.”
This work was supported by the Canadian Consortium on Neurodegeneration in Aging, the Weston Brain Institute and the Toronto General & Western Hospital Foundation.
Zhang M, Xi Z, Misquitta K, Sato C, Moreno D, Liang Y, Slow E, Rogaeva E, Tartaglia MC. C9orf72 and ATXN2 repeat expansions coexist in a family with ataxia, dementia, and parkinsonism. Mov Disord. 2017 Jan. doi: 10.1002/mds.26841.
This is the case for a gene known as C9orf72, which is commonly mutated in individuals with amyotrophic lateral sclerosis (ALS) and/or a type of dementia known as frontotemporal dementia (FTD).
These diseases represent two different types of disorders: ALS affects nerve function, while FTD affects brain function. Thus, to help differentiate whether the C9orf72 mutation causes ALS or FTD, researchers have identified additional mutated genes that act as ‘modifiers’ to shift outcomes.
One such ‘modifier’ gene is ATXN2. This gene is present as one of three sizes based on the number of ‘CAG-repeats’ present within it: a normal form (22-23 repeats), an intermediate form (27-33 repeats) and a long form (>35 repeats).
In individuals with C9orf72 mutations, the intermediate form of ATXN2 predisposes individuals to ALS, but not FTD. On the other hand, it remains unclear whether the long form plays a role in disease onset in either of these patient groups.
To shed light on this, Krembil Clinician Investigator Carmela Tartaglia identified, for the first time, two patients with C9orf72 mutations who also had the long form of ATXN2 mutation. In contrast to people who have the intermediate length mutation of ATXN2, these two patients had FTD, but not ALS.
Dr. Carmela Tartaglia explains, “We were lucky to identify these two mutations as they are not often screened for at the same time. We first screened for the ATXN2 mutation because the patients had coordination problems, at which point we found the long form of the mutation. Then, because the patients had atypical symptoms, including significant behavioral and cognitive changes in addition to coordination problems, we screened for and found mutations in the C9orf72 gene.”
“Because the patients do not show signs of ALS, this study suggests that the long form of ATXN2 may modulate the pathologic mechanism of C9orf72 mutations differently than the intermediate length mutation.”
Taken together, these findings show that much more remains to be discovered about the interplay between genetics and symptoms in this disorder—findings that will inform improved diagnostics and the creation of better, more customized therapies.”
This work was supported by the Canadian Consortium on Neurodegeneration in Aging, the Weston Brain Institute and the Toronto General & Western Hospital Foundation.
Zhang M, Xi Z, Misquitta K, Sato C, Moreno D, Liang Y, Slow E, Rogaeva E, Tartaglia MC. C9orf72 and ATXN2 repeat expansions coexist in a family with ataxia, dementia, and parkinsonism. Mov Disord. 2017 Jan. doi: 10.1002/mds.26841.