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Genetische Architektur der amyotrophen Lateralsklerose und frontotemporalen Demenz

Überlappung und Unterschiede

Genetic architecture of amyotrophic lateral sclerosis and frontotemporal dementia

Overlap and differences

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Zusammenfassung

Amyotrophe Lateralsklerose (ALS) und frontotemporale Demenz (FTD) überlappen nicht nur klinisch, sondern auch neuropathologisch und genetisch. Gerade in den letzten Jahren ist eine große Zahl neuer Gene identifiziert worden, die beiden Erkrankungen zugrunde liegen können, z. B. C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10 oder SQSTM1. Andere Gene wiederum finden sich nahezu ausschließlich bei einer der beiden Erkrankungen, z. B. SOD1 bei ALS oder MAPT bei FTD. Dieses verweist auf eine große Anzahl gemeinsamer Mechanismen, jedoch auch eine gewisse zellspezifische Vulnerabilität. Die jüngst identifizierten Gene sind nicht nur entscheidende Grundsteine für die Erforschung der Pathophysiologie von ALS und FTD, sondern auch der erste Schritt für die Entwicklung kausaler gen- oder Pathway-spezifischer molekularer Therapien. Mutationen in diesen Genen finden sich auch bei einer zunehmenden Anzahl scheinbar „sporadischer“ ALS- bzw. FTD-Patienten. Angesichts der zunehmenden genetischen Heterogenität mit nunmehr >25 bekannten Genen für ALS und FTD sollte die genetische Diagnostik bei familiären und sporadischen Patienten nach Ausschluss einer C9orf72-Repeat-Expansion möglichst nicht mehr als Einzelgendiagnostik erfolgen, sondern gleich als Next-generation-sequencing-Diagnostik mittels Panel oder „whole exome sequencing“.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) overlap not only clinically, but also with respect to shared neuropathology and genes. A large number of novel genes has recently been identified which underlie both diseases, e. g., C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10, or SQSTM1. In contrast, other genes are still largely associated with only one of the two diseases, e. g., SOD1 with ALS or MAPT with FTD. These genetic findings indicate a large number of shared mechanisms, yet along with still a certain cell-specific vulnerability. The recently identified genes are not only key to investigate the pathophysiology underlying ALS and FTD, but also the first step in the development of causal gene- or pathway-specific therapies. Mutations in these genes are also found in a substantial share of seemingly “sporadic” ALS and FTD patients. Given the large genetic heterogeneity with more than >25 genes having been identified for ALS and FTD, genetic diagnostics should – after exclusion of C9orf72 repeat expansions – no longer resort to single gene-diagnostics, but rather use next generation sequencing panels or whole exome sequencing.

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Literatur

  1. Andersen PM, Nilsson P, Ala-Hurula V et al (1995) Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase. Nat Genet 10:61–66

    Article  CAS  PubMed  Google Scholar 

  2. Blauwendraat C, Wilke C, Jansen IE et al (2016) Pilot whole-exome sequencing of a German early-onset Alzheimer’s disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging 37(208):e211–e207

    Google Scholar 

  3. Blauwendraat C, Wilke C, Simon-Sanchez J, Jansen IE, Reifschneider A, Capell A, Haass C, Castillo-Lizardo M, Biskup S, Maetzler W, Rizzu P, Heutink P, Synofzik M (2017) The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects. Genetics in Medicine: in press

  4. Cirulli ET, Lasseigne BN, Petrovski S et al (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:1436–1441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cruts M, Gijselinck I, Van Langenhove T et al (2013) Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci 36:450–459

    Article  CAS  PubMed  Google Scholar 

  6. Freischmidt A, Wieland T, Richter B et al (2015) Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 18:631–636

    Article  CAS  PubMed  Google Scholar 

  7. Gijselinck I, Van Langenhove T, van der Zee J et al (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11:54–65

    Article  CAS  PubMed  Google Scholar 

  8. Gijselinck I, Van Mossevelde S, van der Zee J et al (2015) Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. Neurology 85:2116–2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hubers A, Just W, Rosenbohm A et al (2015) De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients. Neurobiol Aging 36(3117):e3111–e3116

    Google Scholar 

  10. Hubers A, Marroquin N, Schmoll B et al (2014) Polymerase chain reaction and Southern blot-based analysis of the C9orf72 hexanucleotide repeat in different motor neuron diseases. Neurobiol Aging 35(1214):e1211–e1216

    Google Scholar 

  11. Hubers A, Weishaupt JH, Ludolph AC (2013) Genetics of amyotrophic lateral sclerosis. Nervenarzt 84:1213–1219

    Article  CAS  PubMed  Google Scholar 

  12. Ingre C, Landers JE, Rizik N et al (2013) A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. Neurobiol Aging 34(1708):e1701–e1706

    Google Scholar 

  13. Kleinberger G, Capell A, Brouwers N et al (2016) Reduced secretion and altered proteolytic processing caused by missense mutations in progranulin. Neurobiol Aging 39(220):e217–e226

    Google Scholar 

  14. Kuhnlein P, Sperfeld AD, Vanmassenhove B et al (2008) Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. Arch Neurol 65:1185–1189

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lehmer C, Oeckl P, Weishaupt JC et al (2017) Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD. EMBO J. doi:10.15252/emmm.201607486

    Google Scholar 

  16. Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995–1007

    Article  CAS  PubMed  Google Scholar 

  17. Mahoney CJ, Beck J, Rohrer JD et al (2012) Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135:736–750

    Article  PubMed  PubMed Central  Google Scholar 

  18. Muller K, Andersen PM, Hubers A et al (2014) Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain 137:e309

    Article  PubMed  Google Scholar 

  19. Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  CAS  PubMed  Google Scholar 

  20. Parton MJ, Broom W, Andersen PM et al (2002) D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a Cis-acting disease modifier in the recessive haplotype. Hum Mutat 20:473

    Article  PubMed  Google Scholar 

  21. Pottier C, Ravenscroft TA, Sanchez-Contreras M et al (2016) Genetics of FTLD: overview and what else we can expect from genetic studies. J Neurochem 138(Suppl 1):32–53

    Article  CAS  PubMed  Google Scholar 

  22. Rayaprolu S, Fujioka S, Traynor S et al (2013) TARDBP mutations in Parkinson’s disease. Parkinsonism Relat Disord 19:312–315

    Article  PubMed  Google Scholar 

  23. Renton AE, Chio A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23

    Article  CAS  PubMed  Google Scholar 

  24. Rosen DR, Siddique T, Patterson D et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    Article  CAS  PubMed  Google Scholar 

  25. Snowden JS, Rollinson S, Thompson JC et al (2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135:693–708

    Article  PubMed  PubMed Central  Google Scholar 

  26. Synofzik M, Born C, Rominger A et al (2014) Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease. Neurobiol Aging 35(1212):e1211–e1215

    Google Scholar 

  27. Synofzik M, Maetzler W, Grehl T et al (2012) Screening in ALS and FTD patients reveals 3 novel UBQLN2 mutations outside the PXX domain and a pure FTD phenotype. Neurobiol Aging 33(2949):e2913–e2947

    Google Scholar 

  28. Synofzik M, Ronchi D, Keskin I, Basak AN, Wilhelm C, Gobbi C, Birve A, Biskup S, Zecca C, Fernandez-Santiago R, Kaugesaar T, Schols L, Marklund SL, Andersen PM (2012) Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS. Human molecular genetics 21:3568–3574

  29. Van Mossevelde S, van der Zee J, Gijselinck I et al (2016) Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort. Brain 139:452–467

    Article  PubMed  Google Scholar 

  30. Vatsavayai SC, Yoon SJ, Gardner RC et al (2016) Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain 139:3202–3216

    Article  PubMed  Google Scholar 

  31. Wallon D, Rovelet-Lecrux A, Deramecourt V et al (2012) Definite behavioral variant of frontotemporal dementia with C9ORF72 expansions despite positive Alzheimer’s disease cerebrospinal fluid biomarkers. J Alzheimers Dis 32:19–22

    CAS  PubMed  Google Scholar 

  32. Weishaupt JH, Hyman T, Dikic I (2016) Common molecular pathways in amyotrophic lateral sclerosis and frontotemporal dementia. Trends Mol Med 22:769–783

    Article  CAS  PubMed  Google Scholar 

  33. Weishaupt JH, Waibel S, Birve A et al (2013) A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany. Neurobiol Aging 34(1516):e1519–e1515

    Google Scholar 

  34. Wilke C, Pomper JK, Biskup S et al (2016) Atypical parkinsonism in C9orf72 expansions: a case report and systematic review of 45 cases from the literature. J Neurol 263:558–574

    Article  PubMed  Google Scholar 

  35. Woollacott IO, Rohrer JD (2016) The clinical spectrum of sporadic and familial forms of frontotemporal dementia. J Neurochem 138(Suppl 1):6–31

    Article  CAS  PubMed  Google Scholar 

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Förderung

M. Synofzik wird durch ein Clinician Scientist Stipendium der Else Kröner Fresenius Stiftung unterstützt. J. Weishaupt wird durch die Charcot Stiftung für ALS unterstützt. M. Otto wird unterstützt durch das BMBF: JPND networks SOPHIA, BiomarkAPD, PreFrontAls, KNDD-FTLDc, die Stiftung BW und die EU (Fair-Park II).

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Authors and Affiliations

  1. Abteilung für Neurodegeneration, Zentrum für Neurologie & Hertie-Institut für Klinische Hirnforschung, Universität Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Deutschland

    M. Synofzik

  2. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Tübingen, Deutschland

    M. Synofzik

  3. Neurologische Universitätsklinik Ulm, Universität Ulm, Ulm, Deutschland

    M. Otto, A. Ludolph & J. H. Weishaupt

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  1. M. Synofzik
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  4. J. H. Weishaupt
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Correspondence to M. Synofzik.

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Interessenkonflikt

M. Synofzik hat Honoraria von Actelion Pharmaceuticals Ltd. erhalten, M. Otto war beratend für die Firma Axon Neuroscience und Biogen tätig und hat Vortragshonorare von der Firma Lilly und Teva erhalten; A. Ludolph und J. H. Weishaupt geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Synofzik, M., Otto, M., Ludolph, A. et al. Genetische Architektur der amyotrophen Lateralsklerose und frontotemporalen Demenz. Nervenarzt 88, 728–735 (2017). https://doi.org/10.1007/s00115-017-0349-4

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