Table 2.
The clinical characteristic of patients harboring TBK1 mutations
| Function | Population | Mutation | Diagnosis | Age at onset (y) | Disease duration | Family history | Initial symptoms | Cognitive impairment | MNp | Bulbar sign | Reference |
|---|---|---|---|---|---|---|---|---|---|---|---|
| LoF | Japanese | c.1644‐1G>A | ALS | 58 | >7 | Y | Bulbar, lower limbs | N | UMN+LMN | Y | Naruse et al. (2018) |
| LoF | Italian | c.358+5G>A | ALS | 62 | >1.4 | N | Spinal | N | LMN | NA | Pozzi et al. (2017) |
| NA | Italian | c.1644–5_1644‐2delAATA | ALS | 43 | >2.2 | N | Spinal | N | UMN+LMN | NA | Pozzi et al. (2017) |
| LoF | French | IVS18‐2A>G | FTD‐ALS | NA | NA | NA | NA | Y | NA | NA | Le Ber et al. (2015) |
| LoF | Spanish | p.Gln*2 | FTD | 56 | >4.41 | NA | NA | Y | NA | NA | van der Zee et al. (2017) |
| NA | French | p.Thr4Ala | FTD | NA | NA | NA | NA | Y | NA | NA | Le Ber et al. (2015) |
| NA | French | p.Gly26Glu | ALS | NA | NA | NA | NA | NA | NA | NA | Le Ber et al. (2015) |
| LoF | German | p.Lys29Argfs*15 | FTD | 73 | 4 | NA | NA | Y | NA | NA | van der Zee et al. (2017) |
| LoF | NA | p.Lys30 Glu76del | ALS | NA | NA | NA | NA | NA | NA | NA | van der Zee et al. (2017) |
| FMV | German | p.Arg47Hisa | ALS | NA | NA | NA | NA | NA | NA | NA | Freischmidt et al. (2015) |
| ALS | NA | NA | NA | NA | NA | NA | NA | ||||
| ALS | NA | NA | NA | Spinal | NA | NA | NA | ||||
| LoF | Italian | p.Leu59Phefs*16 | ALS | 36 | 4.3 | N | Spinal | N | NA | NA | Pozzi et al. (2017) |
| NA | Chinese | p.Leu62Pro | ALS | 47 | 2.2 | N | Limb | N | NA | NA | Shu et al. (2016) |
| LoF | German | p.Thr77Trpfs*4a | ALS | 35 | >5 | Y | Spinal | NA | NA | NA | Freischmidt et al. (2015) |
| ALS | 58 | 3 | Y | NA | NA | NA | NA | ||||
| LoF | Spanish | p.Thr79del | ALS‐FTD | 56 | 1.5 | NA | NA | Y | NA | Y | van der Zee et al. (2017) |
| FMV | Bulgarian | p.Leu94Ser | ALS | 44 | >10 | Y | Spinal | NA | NA | NA | van der Zee et al. (2017) |
| NA | Chinese | p.Leu94Ser | ALS | NA | 3.2 | NA | NA | NA | NA | NA | Pang et al. (2017) |
| LoF | Swedish | p.Val97Phefs*2 | ALS | 62 | <1 | Y | NA | NA | NA | NA | van der Zee et al. (2017) |
| FMV | Swedish | p.Tyr105Cys | ALS | NA | NA | N | NA | NA | NA | NA | Freischmidt et al. (2015) |
| LoF | Italian | p.Arg117* | FTD | 67 | 7.1 | Y | NA | Y | NA | NA | van der Zee et al. (2017) |
| American | p.Arg117*b | FTD | 68 | 4 | N | NA | Y | NA | Y | Pottier et al. (2015) | |
| FMV | Spanish | p.Gly121Asp | ALS | 34 | >5 | NA | Spinal | NA | NA | NA | van der Zee et al. (2017) |
| LoF | German | p.Arg127* | ALS | 70 | NA | NA | NA | NA | NA | Y | van der Zee et al. (2017) |
| FMV | German | p.Arg143Cys | FTD | 45 | NA | Y | NA | Y | NA | NA | van der Zee et al. (2017) |
| NA | French | p.Arg143Cys | ALS | NA | NA | NA | NA | NA | NA | NA | Le Ber et al. (2015) |
| LoF | French | p.Thr156Argfs*6 | FTD‐ALS | NA | NA | NA | NA | Y | NA | NA | Le Ber et al. (2015) |
| LoF | Belgian | p.Asp167del | ALS | 60 | <1 | NA | NA | NA | NA | NA | van der Zee et al. (2017) |
| LoF | German | p.Tyr185*a | ALS | 47 | >6 | Y | Spinal | N | UMN+LMN | N | Freischmidt et al. (2015) |
| ALS | 37 | 3 | Y | NA | NA | NA | NA | ||||
| ALS | 41 | 6 | Y | NA | NA | NA | NA | ||||
| ALS | 40 | 3 | Y | NA | NA | NA | NA | ||||
| LoF | Italian | p.Asp118Asn | ALS | 81 | >2.9 | N | Spinal | Y | LMN | NA | Pozzi et al. (2017) |
| FMV | German | p.Arg229Ser | ALS | 47 | NA | NA | NA | NA | NA | NA | van der Zee et al. (2017) |
| FMV | Portuguese | p.Gly244Valc | FTD‐ALS | 41 | <2 | Y | Bulbar | Y | NA | Y | van der Zee et al. (2017) |
| FMV | German | p.Ile246Thr | ALS | 57 | <2 | NA | Bulbar | NA | NA | Y | van der Zee et al. (2017) |
| NA | Belgian | p.Arg271Leu | FTD | 80 | 7 | Y | NA | Y | NA | NA | Gijselinck et al. (2015) |
| LoF | Belgian | p.Gly272_Thr331del | FTD | 48 | 2.4 | Y | NA | Y | NA | NA | van der Zee et al. (2017) |
| NA | Scottish | p.Leu277Val | MND | 26 | 11.8 | N | limb | NA | NA | NA | Black et al. (2017) |
| FMV | Italian | p.Lys291Glu | ALS | 74 | >2.75 | N | Spinal | Y | LMN | NA | Pozzi et al. (2017) |
| FMV | Belgian | p.Lys291Glu | FTD | 52 | <9 | Y | NA | Y | NA | NA | van der Zee et al. (2017) |
| Belgian | p.Lys291Glu | FTD | 60 | 4 | Y | NA | Y | NA | NA | Gijselinck et al. (2015) | |
| FMV | Swedish | p.Ile305Thr | ALS | NA | NA | N | NA | NA | NA | NA | Freischmidt et al. (2015) |
| FMV | American | p.Leu306Ile | FTD‐ALS | 70 | 2 | N | Y | Y | NA | NA | Pottier et al. (2015) |
| FMV | Swedish | p.Arg308Gln | ALS | 37.9 | 3.5 | N | Spinal | N | UMN+LMN | Y | Freischmidt et al. (2015) |
| NA | French | p.Thr320Ile | ALS | NA | NA | NA | NA | NA | NA | NA | Le Ber et al. (2015) |
| LoF | Swedish | p.Thr320Glnfs*40a | ALS | 60.1 | 1.9 | Y | Spinal | NA | UMN+LMN | Y | Freischmidt et al. (2015) |
| ALS | NA | NA | Y | NA | NA | NA | NA | ||||
| NA | Belgian | p.His322Tyr | ALS | 64 | 2 | N | NA | NA | NA | NA | Gijselinck et al. (2015) |
| NA | Chinese | p.Ile334Thr | ALS | 51 | 4 | N | Limb | N | NA | NA | Shu et al. (2016) |
| NA | Chinese | p.His336Arg | ALS | NA | 3.5 | NA | NA | NA | NA | NA | Pang et al. (2017) |
| FMV | Italian | p.Arg357Gln | ALS | 36 | >1.7 | N | Spinal | N | NA | NA | Pozzi et al. (2017) |
| Swedish | p.Arg357Gln | ALS | 61.1 | 3 | Y | Bulbar | N | UMN+LMN | Y | Freischmidt et al. (2015) | |
| NA | Sardinian | p.Arg384Thr | ALS | NA | 1.6 | Y | Limb | N | UMN+LMN | Y | Borghero et al. (2016) |
| NA | Italian | p.Ile397Thr | ALS | 65 | >5 | N | Spinal | Y | UMN+LMN | NA | Pozzi et al. (2017) |
| LoF | Belgian | p.Ser398Profs*11 | ALS | 59 | >6.25 | Y | NA | NA | NA | Y | van der Zee et al. (2017) |
| NA | Chinese | p.Leu399fsa | ALS | 60 | 5.7 | Y | Right arm | Y | LMN | N | Williams et al. (2015) |
| ALS | 73 | 8 | Y | Right leg | NA | UMN | NA | ||||
| NA | American | p.Lys401Glu | AD | 80 | 10 | NA | Y | Y | NA | NA | Pottier et al. (2015) |
| LoF | Swedish | p.Ala417* | FTD | 68 | 2.25 | Y | NA | Y | NA | NA | van der Zee et al. (2017) |
| Swedish | p.Ala417*a | ALS | 65 | >7.3 | Y | Spinal | Y | UMN+LMN | Y | Freischmidt et al. (2015) | |
| FTD | NA | NA | Y | Spinal | Y | NA | Y | ||||
| ALS | 56 | 2 | Y | Spinal | N | UMN+LMN | Y | ||||
| Swedish | p.Ala417* | ALS | 62.2 | 1.7 | N | Bulbar | N | UMN+LMN | Y | Freischmidt et al. (2015) | |
| Swedish | p.Ala417* | FTD‐ALS | 61.9 | 6.3 | N | Spinal | Y | UMN+LMN | Y | Freischmidt et al. (2015) | |
| Swedish | p.Ala417* | ALS | 64.7 | 2.7 | N | Bulbar | N | UMN+LMN | Y | Freischmidt et al. (2015) | |
| FMV | Portuguese | p.Ile418Val | FTD | 53 | <1 | Y | NA | Y | NA | NA | van der Zee et al. (2017) |
| NA | Italian | p.Tyr424Asp | ALS | 68 | >0.75 | NA | Spinal | Y | UMN+LMN | Y | Piaceri et al. (2018) |
| LoF | French | p.Arg440X | ALS | NA | NA | Y | NA | NA | NA | NA | Le Ber et al. (2015) |
| French | p.Arg440Xa | ALS | 47 | 13.0 | Y | Spinal | N | UMN+LMN | Y | Freischmidt et al. (2015) | |
| FTD‐ALS | 58 | 3.0 | Y | Spinal | Y | UMN | NA | ||||
| ALS | 73 | 4.0 | Y | Spinal | NA | UMN | Y | ||||
| ALS | Y | NA | NA | NA | NA | ||||||
| FTD | 60 | 16.0 | Y | NA | Y | NA | NA | ||||
| NA | Sardinian | p.Arg444Gln | FTD‐ALS | 72 | >0.8 | N | Cognition impairment | Y | UMN+LMN | Y | Borghero et al. (2016) |
| LoF | Chinese | p.Arg444X | FTD‐ALS | 55 | 4 | N | Cognition impairment+Limb | Y | NA | Y | Tsai et al. (2016) |
| LoF | Spanish | p.Trp445* | FTD+CBS | 78 | >6 | NA | NA | Y | NA | NA | van der Zee et al. (2017) |
| LoF | Danish | p.Ile450Lysfs*15a | ALS | 56.9 | 1.9 | Y | Spinal | N | UMN+LMN | Y | Freischmidt et al. (2015) |
| ALS+D | 71 | 3 | Y | Spina | Y | NA | Y | ||||
| ALS | 77 | >0.7 | Y | Bulbar | N | UMN+LMN | Y | ||||
| ALS | 71 | 2 | Y | Spinal | N | NA | Y | ||||
| ALS | 51 | 2.2 | Y | Spinal | N | UMN+LMN | N | ||||
| Swedish | p.Ile450Lysfs*15a | ALS | 54.9 | >3.2 | Y | Spinal | N | UMN+LMN | Y | Freischmidt et al. (2015) | |
| ALS | 54 | 3 | Y | Spinal | N | UMN+LMN | Y | ||||
| LoF | German | p.Thr462Lysfs*3 | ALS+D | 74 | 0.9 | Y | NA | Y | LMN | NA | van der Zee et al. (2017) |
| NA | German | p.Thr462Lysfs† | FTD‐ALS | 75 | <1 | Y | NA | Y | NA | Y | Schonecker et al. (2016) |
| FTD‐ALS | 77 | <1 | Y | NA | Y | NA | Y | ||||
| LoF | Korean | p.Ile472Serfs*8 | ALS | 53 | >3.8 | N | Bulbar | N | UMN | Y | Kim et al. (2017) |
| LoF | Scottish | p.Glu476fsc | MND | 44 | 2.83 | Y | Limb | NA | NA | NA | Black et al. (2017) |
| LoF | Swedish | p.Val479Glufs*4a | FTD‐ALS | 64.7 | 1.2 | Y | Spinal | Y | UMN+LMN | Y | Freischmidt et al. (2015) |
| FTD‐ALS | 58 | 3.0 | Y | Spinal | Y | NA | NA | ||||
| LoF | French | p.Tyr482X | FTD‐ALS | NA | NA | NA | NA | Y | NA | NA | Le Ber et al. (2015) |
| NA | Belgian | p.Ile515Thr | ALS | 59 | >10 | NA | NA | NA | NA | NA | Gijselinck et al. (2015) |
| LoF | Belgian | p.Ser518Leufs*32 | ALS | 64 | 0.5 | Y | NA | NA | NA | Y | van der Zee et al. (2017) |
| NA | Belgian | p.Ala535Thr | FTD | 52 | 10 | Y | NA | Y | NA | NA | Gijselinck et al. (2015) |
| FMV | Portuguese | p.Met559Arg | ALS | 60 | 6 | Y | Spinal | N | UMN+LMN | NA | Freischmidt et al. (2015) |
| FMV | Swedish | p.Ala571Val | ALS | 66.6 | 1.9 | N | Bulbar | N | UMN+LMN | Y | Freischmidt et al. (2015) |
| NA | Spanish | p.Arg573Glya | FTD | 65 | 13 | NA | NA | NA | NA | NA | Gomez‐Tortosa et al. (2017) |
| FTD | 61 | 6 | Y | NA | NA | NA | NA | ||||
| Dysarthria | 60 | 17 | Y | Memory deficit | Y | N | Y | ||||
| D | 65 | 4 | Y | Memory deficit | Y | N | Y | ||||
| PLS | 66 | 9 | Y | Bulbar | NA | UMN | Y | ||||
| PLS | 61 | 6 | Y | Bulbar | NA | N | Y | ||||
| FMV | Swedish | p.Met598Val | ALS | 61.8 | >2.5 | N | Bulbar | N | UMN+LMN | Y | Freischmidt et al. (2015) |
| LoF | Belgian | p.Glu643dela | FTD‐ALS | 62 | 11.3 | Y | NA | Y | NA | NA | Gijselinck et al. (2015) and van der Zee et al. (2017) |
| D | 71 | 10 | Y | NA | Y | NA | NA | ||||
| D | 86 | 4 | Y | Spinal | Y | NA | NA | ||||
| ALS | 69 | 3 | Y | NA | NA | NA | NA | ||||
| FTD | 69 | 6 | Y | NA | Y | NA | NA | ||||
| D | 70 | 3 | Y | NA | Y | NA | NA | ||||
| FTD | 63 | >3 | Y | NA | Y | NA | NA | ||||
| FTD | 66 | 6 | Y | NA | Y | NA | NA | ||||
| FTD | 61 | 13 | Y | NA | Y | NA | NA | ||||
| D | 63 | 6 | Y | NA | Y | NA | NA | ||||
| D | 73 | 11 | NA | NA | Y | NA | NA | ||||
| D | 82 | 4 | NA | NA | Y | NA | NA | ||||
| ALS | 63 | 1 | NA | NA | NA | NA | NA | ||||
| German | p.Glu643del | ALS | NA | NA | N | NA | NA | NA | NA | Freischmidt et al. (2015) | |
| German | p.Glu643del | ALS | NA | NA | N | Spinal | NA | UMN | Y | Freischmidt et al. (2015) | |
| Belgian | p.Glu643del | FTD | 64 | >9.1 | Y | NA | Y | NA | NA | van der Zee et al. (2017) | |
| Belgian | p.Glu643del | ALS | 51 | 1.7 | Y | NA | NA | NA | Y | van der Zee et al. (2017) | |
| Belgian | p.Glu643del | ALS | 63 | 3 | NA | NA | NA | NA | NA | van der Zee et al. (2017) | |
| Belgian | p.Glu643del | FTD | 70 | 3.5 | Y | NA | Y | NA | NA | van der Zee et al. (2017) | |
| Belgian | p.Glu643del | FTD | 69 | >8.3 | NA | NA | Y | NA | NA | van der Zee et al. (2017) | |
| Belgian | p.Glu643del | FTD | 70 | > 6 | N | NA | Y | NA | NA | Gijselinck et al. (2015) | |
| Belgian | p.Glu643del | FTD | 69 | > 7 | N | NA | Y | NA | NA | Gijselinck et al. (2015) | |
| Belgian | p.Glu643del | ALS | 41 | <1 | N | Bulbar | NA | NA | Y | Gijselinck et al. (2015) | |
| LoF | French | p.Gln655X | FTD‐ALS | NA | NA | NA | NA | Y | NA | NA | Le Ber et al. (2015) |
| NA | French | p.Met662Thr | FTD‐ALS | NA | NA | NA | NA | Y | NA | NA | Le Ber et al. (2015) |
| NA | Sardinian | p.Met690fsd | ALS | 66 | >8.6 | N | Limb | N | LMN | Y | Borghero et al. (2016) |
| LoF | Danish | p.690‐713dela | ALS | 62.7 | 3.8 | Y | Spinal | N | UMN+LMN | Y | Freischmidt et al. (2015) |
| ALS | 52 | 2.0 | Y | Spinal | Y | NA | Y | ||||
| ALS‐FTD | 74 | 1.2 | Y | Spinal | Y | UMN+LMN | Y | ||||
| mono paresis | 52 | >0.5 | Y | Spinal | N | LMN | N | ||||
| possible FTD | NA | NA | Y | Spinal | Y | NA | NA | ||||
| Swedish | p.690‐713dela | ALS | 64 | 2.2 | Y | Bulbar | N | UMN+LMN | Y | Freischmidt et al. (2015) | |
| FTD‐ALS | 65 | 5.0 | Y | Spinal | Y | UMN+LMN | Y | ||||
| possible FTD | 78 | 3.0 | Y | NA | Y | NA | NA | ||||
| D | 65 | 2.0 | Y | NA | Y | NA | NA | ||||
| FMV | American | p.Glu696Lys | AD | 78 | 6.0 | NA | NA | Y | NA | Y | Pottier et al. (2015) |
| Swedish | p.Glu696Lys | ALS‐FTD | 61 | 1.3 | N | Bulbar | Y | UMN+LMN | Y | Freischmidt et al. (2015) | |
| Swedish | p.Glu696Lysa | ALS | 65.5 | 1.7 | Y | Bulbar | N | UMN+LMN | Y | Freischmidt et al. (2015) | |
| ALS | NA | Y | Bulbar | NA | NA | Y | |||||
| LoF | Scottish | p.Ala705fse | MND | 46 | 1.91 | N | Bulbar | NA | NA | Y | Black et al. (2017) |
NCBI Reference Sequence of TBK1 protein: NP_037386.1.
AD: Alzheimer's disease; ALS: amyotrophic lateral sclerosis; CBS: corticobasal syndrome; D:dementia; FMV: functional missense variant; FTD: frontotemporal dementia; LoF: loss of function; MND: motor neuron disease; N: no; NA: not assessed; PLS: primary lateral sclerosis; Y: yes.
aMembers of a family carrying the same TBK1 variant. bCo‐exist with OPTN mutation p.Gly538Glufs*27. cCo‐exist with C9orf72 repeat expansion. dCo‐exist with SQSTM1 mutation p.Arg33Val. eCo‐exist with OPTN mutation p.Gln314Leu.