Ein Geschwisterpaar mit frontotemporaler Lobärdegeneration und amyotropher Lateralsklerose und einer neuen Mutation im TBK1-Gen (Thr462Lysfs)

Zusammenfassung

Wir berichten über ein Geschwisterpaar mit den Krankheitsbildern einer frontotemporalen Lobärdegeneration (FTLD) und einer amyotrophen Lateralsklerose und einer neuen Mutation im TANK-bindende-Kinase-1(TBK1)-Gen (c.1385_1388CAGA, Thr462Lysfs), die durch ein Screening des „European Early-Onset Dementia Consortium“ identifiziert wurde. Die Patienten stellten sich mit 77 bzw. 75 Jahren mit einem demenziellen Syndrom sowie begleitenden bulbären Symptomen und progredienten Paresen vor. Beide verstarben bei progredienter Symptomatik wenige Monate nach Diagnosestellung. Kürzlich wurde eine Assoziation von Mutationen im TBK1-Gen mit dem Auftreten familiärer Formen von FTLD und ALS beschrieben. Ursächlich ist ein Funktionsverlust eines Allels, der zu einer verminderten Produktion des TBK1-Proteins führt. Für künftige Therapiestudien ist die Charakterisierung von TBK1-Mutationsträgern in präsymptomatischen Kohorten, wie z. B. in der „genetic frontotemporal dementia initiative“ (GENFI), von großer Bedeutung.

Abstract

We report on a pair of siblings with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) and a novel Thr462Lysfs mutation in the TANK-binding kinase 1 (TBK1) gene identified through the European Early-Onset Dementia Consortium. The patients presented at the age of 77 and 75 years and displayed dementia and bulbar symptoms as well as progressive paresis. After a progressive course, both of them died only a few months after diagnosis. Most recently, TBK1 mutations were identified in patients with FTD and ALS. A loss of expression of the mutant allele, leading to 50 % reduced TBK1 protein levels, seems to be causative. The occurrence of TBK1 mutations in FTD and ALS underlines the fact that FTD and ALS are part of the same disease spectrum. For future therapeutic trials, characterization of TBK1 mutation carriers in presymptomatic cohorts, such as the genetic frontotemporal dementia initiative (GENFI), is of great importance.

Schlüsselwörter

TBK1-Mutation - C9orf72 - GRN - FTLD - ALS - genetische Testung

Key words

TBK1-mutation - C9orf72 - GRN - FTD - ALS - genetic testing

• Literatur

• 1 Rascovsky K, Hodges JR, Knopman D et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011; 134: 2456-2477
• 2 Gorno-Tempini ML, Hillis AE, Weintraub S et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006-1014
• 3 Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 2002; 59: 1077-1079
• 4 Van Langenhove T, van der Zee J, Van Broeckhoven C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Annals of medicine 2012; 44: 817-828
• 5 Cruts M, Gijselinck I, Van Langenhove T et al. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends in neurosciences 2013; 36: 450-459
• 6 Callister JB, Pickering-Brown SM. Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. Experimental neurology 2014; 262: 84-90
• 7 Freischmidt A, Wieland T, Richter B et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nature neuroscience 2015; 18: 631-636
• 8 Weidberg H, Elazar Z. TBK1 mediates crosstalk between the innate immune response and autophagy. Science signaling 2011; 4: 1-3
• 9 Brooks BR, Miller RG, Swash M et al. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis and other motor neuron 2000; 1: 293-299
• 10 Gijselinck I, Van Mossevelde S, van der Zee J et al. Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. Neurology 2015; 85: 2116-2125
• 11 Le Ber I, De Septenville A, Millecamps S et al. TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts. Neurobiology of Aging 2015; 36: 3116.e5-3116.e8
• 12 Barbie DA, Tamayo P, Boehm JS et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2009; 462: 108-112
• 13 Fecto F, Siddique T. UBQLN2 / P62 cellular recycling pathways in amyotrophic lateral sclerosis and frontotemporal dementia. Muscle & nerve 2012; 45: 157-162
• 14 Maruyama H, Morino H, Ito H et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010; 465: 223-226
• 15 Al-Sarraj S, King A, Troakes C et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 2011; 122: 691-702
• 16 Da Q, Yang X, Xu Y et al. TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I. Journal of immunology 2011; 186: 3023-3030
• 17 Lee JA, Liu L, Gao FB. Autophagy defects contribute to neurodegeneration induced by dysfunctional ESCRT-III. Autophagy 2009; 5: 1070-1072
• 18 Van Mossevelde S, van der Zee J, Gijselinck I et al. Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort. Brain 2015; 139: 452-476
• 19 Lagier-Tourenne C, Baughn M, Rigo F et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proceedings of the National Academy of Sciences of the United States of America 2013; 110: E4530-E4539
• 20 Capell A, Liebscher S, Fellerer K et al. Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. Journal of Neuroscience 2011; 31: 1885-1894
• 21 Rohrer JD, Nicholas JM, Cash DM et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurology 2015; 14: 253-262
• 22 Turner M, Filippini N, Govind V et al. Pre-Symptomatic Loss Of Cerebral White Matter Integrity In Those At Genetic Risk Of Amyotrophic Lateral Sclerosis (S26.004). Neurology 2014; 82: S26.004