Top

Published in:

Open Access 25-06-2022 | Frontotemporal Dementia | Original Article

Genetic landscape of early-onset dementia in Hungary

Authors: Dora Csaban, Anett Illes, Toth-Bencsik Renata, Peter Balicza, Klara Pentelenyi, Viktor Molnar, Andras Gezsi, Zoltan Grosz, Aniko Gal, Tibor Kovacs, Peter Klivenyi, Maria Judit Molnar

Published in: Neurological Sciences | Issue 9/2022

Abstract

Introduction

Early-onset dementias (EOD) are predominantly genetically determined, but the underlying disease-causing alterations are often unknown. The most frequent forms of EODs are early-onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD).

Patients

This study included 120 Hungarian patients with EOD (48 familial and 72 sporadic) which had a diagnosis of EOAD (n = 49), FTD (n = 49), or atypical dementia (n = 22).

Results

Monogenic dementia was detected in 15.8% of the patients. A pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was present in 6.7% of cases and disease-causing variants were detected in other known AD or FTD genes in 6.7% of cases (APP, PSEN1, PSEN2, GRN). A compound heterozygous alteration of the TREM2 gene was identified in one patient and heterozygous damaging variants in the CSF1R and PRNP genes were detected in two other cases. In two patients, the coexistence of several heterozygous damaging rare variants associated with neurodegeneration was detected (1.7%). The APOE genotype had a high odds ratio for both the APOE ɛ4/3 and the ɛ4/4 genotype (OR = 2.7 (95%CI = 1.3–5.9) and OR = 6.5 (95%CI = 1.4–29.2), respectively). In TREM2, SORL1, and ABCA7 genes, 5 different rare damaging variants were detected as genetic risk factors. These alterations were not present in the control group.

Conclusion

Based on our observations, a comprehensive, targeted panel of next-generation sequencing (NGS) testing investigating several neurodegeneration-associated genes may accelerate the path to achieve the proper genetic diagnosis since phenotypes are present on a spectrum. This can also reveal hidden correlations and overlaps in neurodegenerative diseases that would remain concealed in separated genetic testing.

Available only for authorised users

Ramos-Campoy O, Antonell A, Falgàs N et al (2020) Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants. Neurobiol Aging 72:1–9. https://doi.org/10.1016/j.neurobiolaging.2020.02.008CrossRef

Cacace R, Sleegers K, Van Broeckhoven C (2016) Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s Dement 12:733–748. https://doi.org/10.1016/j.jalz.2016.01.012CrossRef

Lok HC, Kwok JB (2021) The role of white matter dysfunction and leukoencephalopathy/leukodystrophy genes in the aetiology of frontotemporal dementias: Implications for novel approaches to therapeutics. Int J Mol Sci 22:1–21. https://doi.org/10.3390/ijms22052541CrossRef

Sirkis DW, Geier EG, Bonham LW et al (2019) Recent advances in the genetics of frontotemporal dementia. Curr Genet Med Rep 7:41–52. https://doi.org/10.1007/s40142-019-0160-6CrossRefPubMedPubMedCentral

Giau V, Senanarong V, Bagyinszky E et al (2019) Analysis of 50 neurodegenerative genes in clinically diagnosed early-onset Alzheimer’s disease. Int J Mol Sci 20:1514. https://doi.org/10.3390/ijms20061514CrossRefPubMedCentral

Molnar MJ, Bencsik P (2006) Establishing a neurological-psychiatric biobank: banking, informatics, ethics. Cell Immunol 244:101–104. https://doi.org/10.1016/j.cellimm.2007.02.013CrossRefPubMed

Vera V, Viktor M, András G et al (2021) Hungarian genomic data warehouse supporting the healthy ageing research. Orv Hetil 62:1079–1088. https://doi.org/10.1556/650.2021.32131CrossRef

Illés A, Csabán D, Grosz Z et al (2019) The role of genetic testing in the clinical practice and research of early-onset parkinsonian disorders in a hungarian cohort: Increasing challenge in genetic counselling, improving chances in stratification for clinical trials. Front Genet 10https://doi.org/10.3389/fgene.2019.01061

Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760. https://doi.org/10.1093/bioinformatics/btp324CrossRefPubMedPubMedCentral

10.

Cingolani P, Platts A, Wang LL et al (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6:80–92. https://doi.org/10.4161/fly.19695CrossRef

11.

Landrum MJ, Lee JM, Benson M et al (2016) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44:D862–D868. https://doi.org/10.1093/nar/gkv1222CrossRefPubMed

12.

Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–423. https://doi.org/10.1038/gim.2015.30CrossRefPubMedPubMedCentral

13.

Franklin by Genoox. https://franklin.genoox.com. Accessed 17 Jan 2022

14.

Zádori D, Füvesi J, Timár E et al (2017) The report of p.Val717Phe mutation in the APP gene in a Hungarian family with Alzheimer disease: a phenomenological study. Alzheimer Dis Assoc Disord Publish Ah 1–3. https://doi.org/10.1097/wad.0000000000000206

15.

Chiang HH, Forsell C, Lilius L et al (2013) Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration. Eur J Hum Genet 21:1260–1265. https://doi.org/10.1038/ejhg.2013.37CrossRefPubMedPubMedCentral

16.

Chen-Plotkin AS, Martinez-Lage M, Sleiman PMA et al (2011) Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. Arch Neurol 68:488. https://doi.org/10.1001/archneurol.2011.53CrossRefPubMedPubMedCentral

17.

Liu CY, Ohki Y, Tomita T et al (2017) Two novel mutations in the first transmembrane domain of presenilin1 cause young-onset Alzheimer’s disease. J Alzheimer’s Dis 58:1035–1041. https://doi.org/10.3233/JAD-161203CrossRef

18.

Ochalek A, Mihalik B, Avci HX et al (2017) Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimer’s Res Ther 9:1–19. https://doi.org/10.1186/s13195-017-0317-zCrossRef

19.

Karch CM, Hernández D, Wang JC et al (2018) Human fibroblast and stem cell resource from the dominantly inherited Alzheimer network. Alzheimer’s Res Ther 10:1–11. https://doi.org/10.1186/s13195-018-0400-0CrossRef

20.

Klunemann HH, Ridha BH, Magy L et al (2005) The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64:1502–1507. https://doi.org/10.1212/01.WNL.0000160304.00003.CACrossRefPubMed

21.

Ng ASL, Jayne Y, Yi Z et al (2018) Neurobiology of aging targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement. Neurobiol Aging 68:160.e15-160.e19. https://doi.org/10.1016/j.neurobiolaging.2018.04.003CrossRef

22.

Kim M-O, Takada LT, Wong K et al (2018) Genetic PrP Prion diseases. Cold Spring Harb Perspect Biol 10:a033134. https://doi.org/10.1101/cshperspect.a033134CrossRefPubMedPubMedCentral

23.

Campion D, Charbonnier C, Nicolas G (2019) SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol 138:173–186. https://doi.org/10.1007/s00401-019-01991-4CrossRefPubMed

24.

Del Bo R, Di Fonzo A, Ghezzi S et al (2007) SPG11: a consistent clinical phenotype in a family with homozygous spatacsin truncating mutation. Neurogenetics 8:301–305. https://doi.org/10.1007/s10048-007-0095-zCrossRefPubMed

25.

Foroud T, Uniacke SK, Liu L et al (2003) Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 60:796–801. https://doi.org/10.1212/01.WNL.0000049470.00180.07CrossRefPubMed

26.

Queralt R, Ezquerra M, Lleó A et al (2002) A novel mutation (V89L) in the presenilin 1 gene in a family with early onset Alzheimer’s disease and marked behavioural disturbances. J Neurol Neurosurg Psychiatry 72:266–269. https://doi.org/10.1136/jnnp.72.2.266CrossRefPubMedPubMedCentral

27.

Ezquerra M, Carnero C, Blesa R, Oliva R (2000) A novel presenilin 1 mutation (Leu166Arg) associated with early-onset Alzheimer disease. Arch Neurol 57:485–488. https://doi.org/10.1001/archneur.57.4.485CrossRefPubMed

28.

Ryan NS, Nicholas JM, Weston PSJ et al (2016) Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol 15:1326–1335. https://doi.org/10.1016/S1474-4422(16)30193-4CrossRefPubMed

29.

ALZFORUM | NETWORKING FOR A CURE. https://www.alzforum.org/papers/csf-and-blood-biomarkers-diagnosis-alzheimers-disease-systematic-review-and-meta-analysis. Accessed 10 Apr 2022

30.

Lacour M, Quenez O, Rovelet-Lecrux A et al (2019) Causative mutations and genetic risk factors in sporadic early onset Alzheimer’s disease before 51 years. J Alzheimer’s Dis 71:227–243. https://doi.org/10.3233/JAD-190193CrossRef

31.

Hoogmartens J, Cacace R, Van Broeckhoven C (2021) Insight into the genetic etiology of alzheimer’s disease: a comprehensive review of the role of rare variants. Alzheimer’s Dement Diagnosis, Assess Dis Monit 13:1–14. https://doi.org/10.1002/dad2.12155CrossRef

32.

Schulte EC, Fukumori A, Mollenhauer B et al (2015) Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease. Eur J Hum Genet 23:1328–1333. https://doi.org/10.1038/ejhg.2014.300CrossRefPubMedPubMedCentral

33.

De Roeck A, Van Broeckhoven C, Sleegers K (2019) The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics. Acta Neuropathol 138:201–220. https://doi.org/10.1007/s00401-019-01994-1CrossRefPubMedPubMedCentral

34.

Zhou S-LL, Tan C-CC, Hou X-HH et al (2019) TREM2 variants and neurodegenerative diseases: a systematic review and meta-analysis. J Alzheimer’s Dis 68:1171–1184. https://doi.org/10.3233/JAD-181038CrossRef

35.

Maderna E, Visonà S, Bolcato V et al (2021) Neuropathological Alzheimer’s disease lesions in Nasu-Hakola disease with TREM2 mutation: atypical distribution of neurofibrillary changes. J Alzheimer’s Dis 79:25–30. https://doi.org/10.3233/JAD-201085CrossRef

36.

Kim EJ, Kim YE, Jang JHW et al (2018) Analysis of frontotemporal dementia, amyotrophic lateral sclerosis, and other dementia-related genes in 107 Korean patients with frontotemporal dementia. Neurobiol Aging 72:186.e1-186.e7. https://doi.org/10.1016/j.neurobiolaging.2018.06.031CrossRef

37.

Zhao Y, Ho P, Yih Y et al (2011) LRRK2 variant associated with Alzheimer’s disease. Neurobiol Aging 32:1990–1993. https://doi.org/10.1016/j.neurobiolaging.2009.11.019CrossRefPubMed

38.

Monfrini E, Melzi V, Buongarzone G et al (2018) A de novo C19orf12 heterozygous mutation in a patient with MPAN. Park Relat Disord 48:109–111. https://doi.org/10.1016/j.parkreldis.2017.12.025CrossRef

39.

Balicza P, Bencsik R, Lengyel A et al (2020) Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability. Neurol Genet 6:e515. https://doi.org/10.1212/nxg.0000000000000515CrossRefPubMedPubMedCentral

40.

Taipa R, Pereira C, Reis I et al (2016) DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology. Brain 139:1680–1687. https://doi.org/10.1093/brain/aww080CrossRefPubMed

41.

Faber I, Martinez ARM, de Rezende TJR et al (2018) SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage. NeuroImage Clin 19:848–857. https://doi.org/10.1016/j.nicl.2018.05.031CrossRefPubMedPubMedCentral

42.

Cesani M, Lorioli L, Grossi S et al (2016) Mutation update of ARSA and PSAP genes causing metachromatic leukodystrophy. Hum Mutat 37:16–27. https://doi.org/10.1002/humu.22919CrossRefPubMed

43.

Zhou X, Sun L, Bracko O et al (2017) Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nat Commun 8:1–14. https://doi.org/10.1038/ncomms15277CrossRef

44.

Liu J, Wang Q, Jing D et al (2019) Diagnostic approach of early-onset dementia with negative family history: implications from two cases of early-onset Alzheimer’s disease with de Novo PSEN1 Mutation. J Alzheimer’s Dis 68:551–558. https://doi.org/10.3233/JAD-181108CrossRef

Title: Genetic landscape of early-onset dementia in Hungary
Authors: Dora Csaban
Anett Illes
Toth-Bencsik Renata
Peter Balicza
Klara Pentelenyi
Viktor Molnar
Andras Gezsi
Zoltan Grosz
Aniko Gal
Tibor Kovacs
Peter Klivenyi
Maria Judit Molnar
Publication date: 25-06-2022
Publisher: Springer International Publishing
Keywords: Frontotemporal Dementia
Frontotemporal Dementia
Alzheimer's Disease
Dementia
Alzheimer's Disease
Dementia
Published in: Neurological Sciences / Issue 9/2022
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-022-06168-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genetic landscape of early-onset dementia in Hungary

Abstract

Introduction

Patients

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Patients

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 9/2022

Reporting of “usual care” as the control group in randomized clinical trials of physiotherapy interventions for multiple sclerosis is poor: a systematic review

Parkinsonism in idiopathic normal pressure hydrocephalus: is it time for defining a clinical tetrad?

COVID-19 infection and Down syndrome—challenges and future directions for care in children

Challenges of practicing neuro-endovascular interventions in a resource-limited country; Ghana in focus

Sex influences clinical phenotype in frontotemporal dementia

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort