Clinical and genetic characteristics of late-onset Huntington's disease in a large European cohort.
41 CAG triplets
Enroll-HD
age of onset
allele expansion
late-onset Huntington's disease
Journal
European journal of neurology
ISSN: 1468-1331
Titre abrégé: Eur J Neurol
Pays: England
ID NLM: 9506311
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
15
03
2022
received:
13
01
2022
accepted:
24
03
2022
pubmed:
1
4
2022
medline:
15
6
2022
entrez:
31
3
2022
Statut:
ppublish
Résumé
Huntington's disease (HD) is an autosomal dominant condition caused by CAG-triplet repeat expansions. CAG-triplet repeat expansion is inversely correlated with age of onset in HD and largely determines the clinical features. The aim of this study was to examine the phenotypic and genotypic correlates of late-onset HD (LoHD) and to determine whether LoHD is a more benign expression of HD. This was a retrospective observational study of 5053 White European HD patients from the ENROLL-HD database. Sociodemographic, genetic and phenotypic variables at baseline evaluation of subjects with LoHD, common-onset HD (CoHD) and young-onset HD (YoHD) were compared. LoHD subjects were compared with healthy subjects (HS) aged ≥60 years. Differences between the CoHD and LoHD groups were also explored in subjects with 41 CAG triplets, a repeat number in the lower pathological expansion range associated with wide variability in age at onset. Late-onset HD presented predominantly as motor-onset disease, with a lower prevalence of both psychiatric history and current symptomatology. Absent/unknown HD family history was significantly more common in the LoHD group (31.2%) than in the other groups. The LoHD group had more severe motor and cognitive deficits than the HS group. Subjects with LoHD and CoHD with 41 triplets in the larger allele were comparable with regard to cognitive impairment, but those with LoHD had more severe motor disorders, less problematic behaviors and more often an unknown HD family history. It is likely that cognitive disorders and motor symptoms of LoHD are at least partly age-related and not a direct expression of the disease. In addition to CAG-triplet repeat expansion, future studies should investigate the role of other genetic and environmental factors in determining age of onset.
Sections du résumé
BACKGROUND AND PURPOSE
Huntington's disease (HD) is an autosomal dominant condition caused by CAG-triplet repeat expansions. CAG-triplet repeat expansion is inversely correlated with age of onset in HD and largely determines the clinical features. The aim of this study was to examine the phenotypic and genotypic correlates of late-onset HD (LoHD) and to determine whether LoHD is a more benign expression of HD.
METHODS
This was a retrospective observational study of 5053 White European HD patients from the ENROLL-HD database. Sociodemographic, genetic and phenotypic variables at baseline evaluation of subjects with LoHD, common-onset HD (CoHD) and young-onset HD (YoHD) were compared. LoHD subjects were compared with healthy subjects (HS) aged ≥60 years. Differences between the CoHD and LoHD groups were also explored in subjects with 41 CAG triplets, a repeat number in the lower pathological expansion range associated with wide variability in age at onset.
RESULTS
Late-onset HD presented predominantly as motor-onset disease, with a lower prevalence of both psychiatric history and current symptomatology. Absent/unknown HD family history was significantly more common in the LoHD group (31.2%) than in the other groups. The LoHD group had more severe motor and cognitive deficits than the HS group. Subjects with LoHD and CoHD with 41 triplets in the larger allele were comparable with regard to cognitive impairment, but those with LoHD had more severe motor disorders, less problematic behaviors and more often an unknown HD family history.
CONCLUSIONS
It is likely that cognitive disorders and motor symptoms of LoHD are at least partly age-related and not a direct expression of the disease. In addition to CAG-triplet repeat expansion, future studies should investigate the role of other genetic and environmental factors in determining age of onset.
Identifiants
pubmed: 35357736
doi: 10.1111/ene.15340
pmc: PMC9324106
doi:
Types de publication
Journal Article
Observational Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
1940-1951Informations de copyright
© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
Références
Clin Genet. 2021 Jan;99(1):133-142
pubmed: 33020896
Lancet Neurol. 2017 Sep;16(9):701-711
pubmed: 28642124
Genome Med. 2009 Aug 21;1(8):80
pubmed: 19725930
Mov Disord. 2012 Feb;27(2):272-6
pubmed: 22173986
Eur J Neurol. 2022 Jul;29(7):1940-1951
pubmed: 35357736
Hum Mol Genet. 2021 Oct 1;30(R2):R254-R263
pubmed: 34169318
PLoS Curr. 2010 Sep 28;2:
pubmed: 20890398
Cell. 1993 Mar 26;72(6):971-83
pubmed: 8458085
Am J Hum Genet. 2020 Jul 2;107(1):96-110
pubmed: 32589923
Cell. 2015 Jul 30;162(3):516-26
pubmed: 26232222
Nature. 1983 Nov 17-23;306(5940):234-8
pubmed: 6316146
Mov Disord. 2009 Oct 15;24(13):2012-5
pubmed: 19672992
Cortex. 2017 Oct;95:51-62
pubmed: 28843844
Parkinsonism Relat Disord. 2019 Apr;61:101-105
pubmed: 30528461
J Neurol Sci. 2009 Jan 15;276(1-2):159-62
pubmed: 18977004
Ann Neurol. 1997 May;41(5):689-92
pubmed: 9153534
J Med Genet. 1993 Dec;30(12):991-5
pubmed: 8133510
Tremor Other Hyperkinet Mov (N Y). 2020 Jul 09;10:21
pubmed: 32775035
Age Ageing. 1994 Nov;23(6):445-8
pubmed: 9231935
Aging (Albany NY). 2016 Jul;8(7):1485-512
pubmed: 27479945
Am J Hum Genet. 1985 Mar;37(2):350-7
pubmed: 3157315
Nat Genet. 1993 Aug;4(4):398-403
pubmed: 8401589
Neurology. 1995 Mar;45(3 Pt 1):443-7
pubmed: 7898693
Front Neurosci. 2020 Jun 12;14:605
pubmed: 32655354
Arch Neurol. 1998 Jun;55(6):835-43
pubmed: 9626775
J Huntingtons Dis. 2015;4(1):99-105
pubmed: 26333261
Neuropsychiatry Neuropsychol Behav Neurol. 2001 Oct-Dec;14(4):219-26
pubmed: 11725215
J Huntingtons Dis. 2017;6(2):95-103
pubmed: 28671137
Gen Hosp Psychiatry. 2008 Mar-Apr;30(2):155-61
pubmed: 18291297
Front Cell Dev Biol. 2021 Aug 13;9:683459
pubmed: 34485280
Am J Hum Genet. 1988 Nov;43(5):695-704
pubmed: 2973230
J Neurol Neurosurg Psychiatry. 1985 Jun;48(6):530-4
pubmed: 3159849
Mov Disord Clin Pract. 2016 Jun 22;4(2):212-224
pubmed: 30363395
South Med J. 1983 Oct;76(10):1266-70
pubmed: 6226105
J Huntingtons Dis. 2020;9(2):115-128
pubmed: 32417788
Neurology. 1979 Jan;29(1):1-3
pubmed: 154626
Neurology. 2018 Jun 12;90(24):1087-1088
pubmed: 29743206
Cell. 2019 Aug 8;178(4):887-900.e14
pubmed: 31398342
Front Neural Circuits. 2013 Feb 18;7:19
pubmed: 23423362
Hum Mol Genet. 2017 Oct 1;26(19):3859-3867
pubmed: 28934397
Parkinsonism Relat Disord. 2014 Jul;20(7):726-30
pubmed: 24721491
Neurosci Biobehav Rev. 2015 May;52:178-92
pubmed: 25770041
J Neurol Neurosurg Psychiatry. 1999 Jan;66(1):52-6
pubmed: 9886451
Lancet. 1984 May 19;1(8386):1100-2
pubmed: 6144830
Neurol Sci. 2020 Apr;41(4):869-876
pubmed: 31820322
PLoS One. 2013 Jul 22;8(7):e68951
pubmed: 23894380
Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):397-408
pubmed: 19548255
NeuroRx. 2004 Apr;1(2):255-62
pubmed: 15717026
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3498-503
pubmed: 14993615