Abstract
Huntington’s disease is an incurable, adult-onset, autosomal dominant inherited disorder caused by an expanded trinucleotide repeat (CAG). In this study, we describe a Huntington’s disease patient displaying clinical symptoms of the behavioural variant of frontotemporal dementia in the absence of tremor and ataxia. The clinical onset was at the age of 36 years and the disease progressed slowly (18 years). Genetic testing revealed expanded trinucleotide CAG repeats in the Huntingtin gene, together with a Glu318Gly polymorphism in presenilin 1. Neuropathological assessment revealed extensive amyloid β (Aβ) aggregates in all cortical regions. No inclusions displaying hyperphosphorylated tau or phosphorylated transactive response DNA-binding protein 43 (TDP43) were found. A high number of p62 (sequestosome 1) immunopositive intranuclear inclusions were seen mainly in the cortex, while subcortical areas were affected to a lesser extent. Confocal microscopy revealed that the majority of p62 intranuclear lesions co-localised with the fused-in-sarcoma protein (FUS) immunostaining. The morphology of the inclusions resembled intranuclear aggregates in Huntington’s disease. The presented proband suffered from Huntington’s disease showed atypical distribution of FUS positive intranuclear aggregates in the cortical areas with concomitant Alzheimer’s disease pathology.
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References
Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18(4):484–496. doi:10.1111/j.1750-3639.2008.00147
Albani D, Roiter I, Artuso V, Batelli S, Prato F, Pesaresi M, Galimberti D et al (2007) Presenilin-1 mutation E318G and familial Alzheimer’s disease in the Italian population. Neurobiol Aging 28:1682–1688. doi:10.1016/j.neurobiolaging.2006.07.003
Aldudo J, Bullido MJ, Frank A, Valdivieso F (1998) Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol 44(6):985–986. doi:10.1002/ana.410440624
Chare L, Hodges JR, Leyton CE, McGinley C, Tan RH, Kril JJ, Halliday GM (2014) New criteria for frontotemporal dementia syndromes: clinical and pathological diagnostic implications. J Neurol Neurosurg Psychiatry 85(8):865–870. doi:10.1136/jnnp-2013-306948
Cruts M, Van Broeckhoven C (1998) Presenilin mutations in Alzheimer’s disease. Hum Mutat 11:183–190. doi:10.1002/(SICI)1098-1004(1998)11:3<183:AID-HUMU1>3.0.CO;2-J
Dermaut B, Cruts M, Slooter AJ, Van Gestel S, De Jonghe C, Vanderstichele H (1999) The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease. Am J Hum Genet 64:290–292. doi:10.1086/302200
Doi H, Okamura K, Bauer PO, Furukawa Y, Shimizu H, Kurosawa M, Machida Y, Miyazaki H, Mitsui K, Kuroiwa Y, Nukina N (2008) RNA-binding protein TLS is a major nuclear aggregate-interacting protein in Huntingtin exon 1 with expanded polyglutamine-expressing cells. J Biol Chem 283:6489–6500. doi:10.1074/jbc.M705306200
Doi H, Koyano S, Suzuki Y, Nukina N, Kuroiwa Y (2010) The RNA-binding protein FUS/TLS is a common aggregate-interacting protein in polyglutamine diseases. Neurosci Res 66:131–133. doi:10.1016/j.neures.2009.10.004
Ghosh R, Tabrizi SJ (2015) Clinical aspects of Huntington’s disease. Curr Top Behav Neurosci 22:3–31. doi:10.1007/7854_2013_238
Goldman JS, Johnson JK, McElligott K, Suchowersky O, Miller BL, Van Deerlin VM (2005) Presenilin 1 Glu318Gly polymorphism: interpret with caution. Arch Neurol 62(10):1624–1627. doi:10.1001/archneur.62.10.1624
Helisalmi S, Hiltunen M, Mannermaa A, Koivisto AM, Lehtovirta M, Alafuzoff I et al (2000) Presenilin mutations in Alzheimer’s disease. Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer’s disease? Neurosci Lett 278:65–68
Josephs KA, Petersen RC, Knopman DS et al (2006) Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66:41–48. doi:10.1212/01.wnl.0000191307.69661.c3
Nagaoka U, Kim K, Jana NR, Doi H, Maruyama M, Mitsui K, Oyama F, Nukina N (2004) Increased expression of p62 in expanded polyglutamine-expressing cells and its association with polyglutamine inclusions. J Neurochem 91:57–68
Nielsen TR, Bruhn P, Nielsen JE, Hjermind LE (2010) Behavioral variant of frontotemporal dementia mimicking Huntington’s disease. Int Psychogeriatr 22:674–677. doi:10.1017/S1041610210000098
Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC et al (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456–2477. doi:10.1093/brain/awr179
Roeber S, Mackenzie IR, Kretzschmar HA, Neumann M (2008) TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. Acta Neuropathol 116:147–157. doi:10.1007/s00401-008-0395-x
Rohrer JD, Rosen HJ (2013) Neuroimaging in frontotemporal dementia. Int Rev Psychiatry 25:221–229. doi:10.3109/09540261.2013.778822
Seelaar H, Klijnsma KY, de Koning I, van der Lugt A, Chiu WZ, Azmani A, Rozemuller AJ, van Swieten JC (2010) Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol 257:747–753. doi:10.1007/s00415-009-5404-z
Snowden J, Neary D, Mann D (2007) Frontotemporal lobar degeneration: clinical and pathological relationships. Acta Neuropathol 114:31–38
Taddei K, Fisher C, Laws SM, Martins G, Paton A, Clarnette RM et al (2002) Association between presenilin-1 Glu318Gly mutation and familial Alzheimer’s disease in the Australian population. Mol Psychiatry 7:776–781. doi:10.1038/sj.mp.4001072
Urwin H, Josephs KA, Rohrer JD et al (2010) FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol 120:33–41. doi:10.1007/s00401-010-0698-6
Whitwell JL, Jack CR Jr, Parisi JE, Knopman DS, Boeve BF, Petersen RC, Dickson DW, Josephs KA (2011) Imaging signatures of molecular pathology in behavioral variant frontotemporal dementia. J Mol Neurosci 45:372–378. doi:10.1007/s12031-011-9533-3
Zekanowski C, Pepłońska B, Styczyńska M, Religa D, Pfeffer A, Czyzewski K et al (2004) The E318G substitution in PSEN1 gene is not connected with Alzheimer’s disease in a large Polish cohort. Neurosci Lett 357:167–170. doi:10.1016/j.neulet.2003.12.052
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The work was supported by research Grants APVV 14-0872 and EU structural fund 26240220046.
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Sutovsky, S., Smolek, T., Alafuzoff, I. et al. Atypical Huntington’s disease with the clinical presentation of behavioural variant of frontotemporal dementia. J Neural Transm 123, 1423–1433 (2016). https://doi.org/10.1007/s00702-016-1579-5
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DOI: https://doi.org/10.1007/s00702-016-1579-5