Six generations of CHMP2B-mediated Frontotemporal Dementia: Clinical features, predictive testing, progression, and survival
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Six generations of CHMP2B-mediated Frontotemporal Dementia : Clinical features, predictive testing, progression, and survival. / Roos, Peter; Johannsen, Peter; Lindquist, Suzanne G.; Brown, Jeremy M.; Waldemar, Gunhild; Duno, Morten; Nielsen, Troels T.; Budtz-Jorgensen, Esben; Gydesen, Susanne; Holm, Ida E.; Collinge, John; Isaacs, Adrian M.; Nielsen, Jørgen E.
In: Acta Neurologica Scandinavica, Vol. 145, No. 5, 2022, p. 529-540.Research output: Contribution to journal › Review › Research › peer-review
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TY - JOUR
T1 - Six generations of CHMP2B-mediated Frontotemporal Dementia
T2 - Clinical features, predictive testing, progression, and survival
AU - Roos, Peter
AU - Johannsen, Peter
AU - Lindquist, Suzanne G.
AU - Brown, Jeremy M.
AU - Waldemar, Gunhild
AU - Duno, Morten
AU - Nielsen, Troels T.
AU - Budtz-Jorgensen, Esben
AU - Gydesen, Susanne
AU - Holm, Ida E.
AU - Collinge, John
AU - Isaacs, Adrian M.
AU - Nielsen, Jørgen E.
PY - 2022
Y1 - 2022
N2 - ObjectivesChromosome 3-linked frontotemporal dementia (FTD-3) is caused by a c.532-1G > C mutation in the CHMP2B gene. It is extensively studied in a Danish family comprising one of the largest families with an autosomal dominantly inherited frontotemporal dementia (FTD).This retrospective cohort study utilizes demographics to identify risk factors for onset, progression, life expectancy, and death in CHMP2B-mediated FTD. The pedigree of 528 individuals in six generations is provided, and clinical descriptions are presented. Choices of genetic testing are evaluated.Materials and MethodsDemographic and lifestyle factors were assessed in survival analysis in all identified CHMP2B mutation carriers (44 clinically affected FTD-3 patients and 16 presymptomatic CHMP2B mutation carriers). Predictors of onset and progression included sex, parental disease course, education, and vascular risk factors. Life expectancy was established by matching CHMP2B mutation carriers with average life expectancies in Denmark.ResultsDisease course was not correlated to parental disease course and seemed unmodified by lifestyle factors. Diagnosis was recognized at an earlier age in members with higher levels of education, probably reflecting an early dysexecutive syndrome, unmasked earlier in people with higher work-related requirements.Carriers of the CHMP2B mutation had a significant reduction in life expectancy of 13 years. Predictive genetic testing was chosen by 20% of at-risk family members.ConclusionsCHMP2B-mediated FTD is substantiated as an autosomal dominantly inherited disease of complete penetrance. The clinical phenotype is a behavioral variant FTD. The disease course is unpredictable, and life expectancy is reduced. The findings may be applicable to other genetic FTD subtypes.
AB - ObjectivesChromosome 3-linked frontotemporal dementia (FTD-3) is caused by a c.532-1G > C mutation in the CHMP2B gene. It is extensively studied in a Danish family comprising one of the largest families with an autosomal dominantly inherited frontotemporal dementia (FTD).This retrospective cohort study utilizes demographics to identify risk factors for onset, progression, life expectancy, and death in CHMP2B-mediated FTD. The pedigree of 528 individuals in six generations is provided, and clinical descriptions are presented. Choices of genetic testing are evaluated.Materials and MethodsDemographic and lifestyle factors were assessed in survival analysis in all identified CHMP2B mutation carriers (44 clinically affected FTD-3 patients and 16 presymptomatic CHMP2B mutation carriers). Predictors of onset and progression included sex, parental disease course, education, and vascular risk factors. Life expectancy was established by matching CHMP2B mutation carriers with average life expectancies in Denmark.ResultsDisease course was not correlated to parental disease course and seemed unmodified by lifestyle factors. Diagnosis was recognized at an earlier age in members with higher levels of education, probably reflecting an early dysexecutive syndrome, unmasked earlier in people with higher work-related requirements.Carriers of the CHMP2B mutation had a significant reduction in life expectancy of 13 years. Predictive genetic testing was chosen by 20% of at-risk family members.ConclusionsCHMP2B-mediated FTD is substantiated as an autosomal dominantly inherited disease of complete penetrance. The clinical phenotype is a behavioral variant FTD. The disease course is unpredictable, and life expectancy is reduced. The findings may be applicable to other genetic FTD subtypes.
KW - CHMP2B
KW - Frontotemporal Dementia
KW - Hereditary degenerative disorders
U2 - 10.1111/ane.13578
DO - 10.1111/ane.13578
M3 - Review
C2 - 34997757
VL - 145
SP - 529
EP - 540
JO - Acta Neurologica Scandinavica, Supplement
JF - Acta Neurologica Scandinavica, Supplement
SN - 0065-1427
IS - 5
ER -
ID: 290517359