Table 1 Clinical, pathological, and genetical characteristics of patients with TK2 mutations
Patient | Gender | Ethnicity | Age at diagnose | Age of death/alive | Clinical findings | Histochemical findings | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
Ptosis | Limb-girdle muscle weakness | Respiratory failure | Facial muscle weakness | RRF | COX- | Lipid accumulation | |||||
1 | M | Latino | 3.5 yr | Alive | + | + | − | + | + | − | + |
2 | F | Indian | 46 yr | Alive | − | + | − | + | + | + | − |
3 | M | Hispanic | 2.8 yr | 4.75 yr | − | − | + | − | + | − | − |
4 | M | Hispanic | 1.5 yr | Alive | − | − | + | − | − | − | − |
5 | F | Hispanic | 14 yr | Alive | − | − | + | − | − | − | + |
6 | F | NA | 13mo | 22mo | − | − | − | − | − | + | − |
7 | M | Swedish | 18mo | 3.5 years | − | + | + | − | + | + | + |
8 | F | Japanese | Birth | 10 months | − | + | + | − | NA | + | + |
9 | M | NA | 22 yr | Alive | − | + | + | + | NA | + | − |
10 | M | NA | 2mo | 10mo | − | − | − | − | + | + | − |
11 | F | Spanish | 6mo | Alive | − | + | − | + | + | + | − |
12 | F | NA | 74 yr | Alive | + | + | + | + | NA | + | + |
13 | M | Sephardic-Jewish | 3.5 yr | Alive | − | + | − | − | + | NA | − |
14 | M | Ashkenazi Jewish | 24mo | 16 yr | + | − | + | − | + | + | − |
15 | F | African American | 24mo | 6 yr | − | − | + | − | + | + | − |
16 | M | Brazilian | 7mo | 19 yr | − | + | + | − | + | + | − |
17 | F | Chilean | 24mo | Alive | − | + | − | − | + | + | − |
18 | F | NA | Birth | NA | + | + | − | − | + | + | − |
19 | F | NA | 12 yr | NA | + | − | − | + | + | + | − |
20 | M | NA | 50 yr | NA | + | − | − | + | + | + | − |
21 | F | NA | 23 yr | NA | − | − | − | + | + | + | − |
22 | M | NA | 15 yr | NA | + | − | − | + | + | + | − |
23 | F | NA | 12 yr | NA | + | − | − | + | NA | NA | − |
24 | F | NA | 30 yr | NA | + | − | − | + | + | + | − |
25 | M | Chinese | 10mo | 2 yr | − | + | + | − | + | + | − |
26 | M | Chinese | 12mo | 2 yr | − | + | + | − | + | + | − |
27 | F | Chinese | 1 yr | 2 yr | − | + | + | − | + | + | − |
28 | M | NA | 14mo | Alive | − | − | − | − | + | + | − |
29 | M | NA | 16 yr | Alive | − | − | − | + | + | + | − |
30 | F | NA | 23 yr | 43 yr | − | − | + | + | + | + | + |
31 | F | Italian | 8 yr | NA | + | + | − | + | + | + | − |
32 | M | Latin American | 9mo | NA | − | − | + | − | + | + | − |
33 | F | Latin American | 9 yr | NA | − | − | + | − | + | − | − |
34 | M | Caucasian | 2 yr | NA | + | − | + | − | + | + | − |
35 | M | Latin American | Birth | NA | + | − | + | − | + | + | − |
36 | M | Caucasian | 4 yr | NA | − | − | + | − | + | + | − |
37 | M | Caucasian | 5mo | 3 yr | − | − | − | − | + | − | − |
38 | M | Chinese | 2 yr | 3.5 yr | − | − | + | − | + | + | − |
39 | F | NA | 0.08 yr | 2 yr | − | − | − | − | NA | NA | NA |
40 | M | NA | 0.5 yr | 6 yr | + | − | − | − | NA | NA | NA |
41 | M | NA | 0.92 yr | NA | − | − | − | − | NA | NA | NA |
42 | M | NA | 0.83 yr | 1.5 yr | − | − | − | − | NA | NA | NA |
43 | M | NA | 1.25 yr | NA | − | − | − | − | NA | NA | NA |
44 | F | NA | 2 yr | NA | − | − | − | + | NA | NA | NA |
45 | M | NA | 3 yr | NA | + | − | − | − | NA | NA | NA |
46 | M | NA | 1.08 yr | 1.5 yr | − | − | − | − | NA | NA | NA |
47 | M | NA | 1.17 yr | NA | − | − | − | − | NA | NA | NA |
48 | M | NA | 4.42 yr | NA | − | − | − | − | NA | NA | NA |
49 | F | NA | 4 yr | NA | + | − | − | + | NA | NA | NA |
50 | F | Chinese | 8mo | 13mo | − | + | + | − | + | + | + |
Patient | Laboratory examination | TK2 mutation1(Exon) | Mutation type | TK2 mutation 2 (Exon) | Mutation type | MtDNA content | References | ||
|---|---|---|---|---|---|---|---|---|---|
Elevated serum CK | EMG | Respiratory chain enzyme activity | |||||||
1 | + | Myopathic | NA | c.361C > A, p.His121Asn(5) | Missense | c.361C > A, p.His121Asn (5) | Missense | NA | Wang et al., (2018) [23] |
2 | + | NA | NA | c.469-470insTGGG(7) | Frameshift | c.156 + 6 T > G(intron) | Splicing substitutions | Low level | Wang et al., (2018) [23] |
3 | + | Myopathic | NA | c.173A > G, p.Asn58Ser(3) | Missense | c.173A > G, p.Asn58Ser (3) | Missense | NA | Wang et al., (2018) [23] |
4 | + | NA | NA | c.361C > A, p.His121Asn (5) | Missense | c.361C > A, p.His121Asn (5) | Missense | NA | Wang et al., (2018) [23] |
5 | + | NA | NA | c.604_606delAAG p.Lys202del(8) | Frameshift | c.575G > A p.Arg192Lys(8) | Missense | NA | Wang et al., (2018) [23] |
6 | + | NA | Complex I (63%), Complex IV (66%) | C.416C > T p.Ala139Val(6) | Missense | C.209 T > C p.Phe70Ser(3) | Missense | NA | Mazurova et al., (2017) [37] |
7 | + | Normal | NA | c.156 + 5G > C(intron) | Splicing substitutions | c.332C > T p.Thr111Ile(5) | Missense | 29% | Roos et al., (2014) [38] |
8 | + | NA | Complex I, III, IV and V markedly decreased | c.125-1G > C(1) | Splicing substitutions | c.574A > G, p.Arg192Gly(8) | Missense | 8.0% | Termglinchan et al., (2016) [7] |
9 | + | NA | NA | c.323C > T p.Thr108Met(5) | Missense | c.323C > T p.Thr108Met (5) | Missense | 55.0% | Paradas et al., (2013) [39] |
10 | NA | NA | Complex IV decreased | C.547C > G p.Arg183Gly(8) | Missense | C.760C > T p.Arg254*(10) | Nonsense | 60.0% | Carrozzo et al., (2003) [40] |
11 | + | Myopathic | Complex III decreased | c.323C > T p.Thr108Met (5) | Missense | c.323C > T p.Thr108Met (5) | Missense | 18.0% | Martín-Hernández et al., (2017) [41] |
12 | NA | NA | NA | c.103C > T, p.Gln35*(1) | Nonsense | c.582 G > T p.Lys194Asn(8) | Missense | 185% | Alston et al., (2013) [42] |
13 | − | NA | Complex I and I + III reduction | C.268C > T p.His90Asn(4) | Missense | C.268C > T p.His90Asn (4) | Missense | NA | Leshinsky-Silver et al., (2008) [43] |
14 | + | Myopathic | NA | c.635 T > A, p.Thr212Asn(9) | Missense | AT ins 337(5) | Frameshift | NA | Oskoui et al., (2006) [26] |
15 | + | Myopathic | NA | c.360G > A p.Arg120Arg (5) | Synonymous | c.361C > A, p.His121Asn (5) | Missense | NA | Oskoui et al., (2006) [26] |
16 | + | NA | NA | c.323C > T p.Thr108Met (5) | Missense | c.372_373delTCinsCT, p.Gln125X(5) | Nonsense | NA | Oskoui et al., (2006) [26] |
17 | + | Neurogenic | NA | c.278A > G p.Asn93Ser(4) | Missense | AT ins 337(5) | Frameshift | NA | Oskoui et al., (2006) [26] |
18 | + | Myopathic | Complex I, III, IV decreased | c.323C > T p.Thr108Met (5) | Missense | c.323C > T p.Thr108Met (5) | Missense | NA | Béhin et al., (2012) [44] |
19 | + | NA | Complex I, III and IV deficit | c.323C > T p.Thr108Met (5) | Missense | c.323C > T p.Thr108Met (5) | Missense | 17.0% | Domínguez-González et al., (2019) [45] |
20 | + | NA | Normal | c.604–606 AAGdel p.Lys202del(8) | Frameshift | c.604–606 AAGdel p.Lys202del(8) | Frameshift | 66.0% | Domínguez-González et al., (2019) [45] |
21 | − | NA | Complex I, III and IV deficit | c.323C > T p.Thr108Met (5) | Missense | c.323C > T p.Thr108Met(5) | Missense | 35.0% | Domínguez-González et al., (2019) [45] |
22 | + | NA | Complex I, III and IV deficit | c.623A > G p.Tyr208Cys(9) | Missense | c.623A > G p.Tyr208Cys(9) | Missense | NA | Domínguez-González et al., (2019) [45] |
23 | + | NA | NA | c.623A > G p.Tyr208Cys(9) | Missense | c.623A > G p.Tyr208Cys(9) | Missense | NA | Domínguez-González et al., (2019) [45] |
24 | + | NA | Normal | c.323C > T p.Thr108Met 5) | Missense | c.323C > T p.Thr108Met(5) | Missense | 53.0% | Domínguez-González et al., (2019) [45] |
25 | + | Myopathic | NA | c.144_145del p.Glu48fs(2) | Frameshift | c.547C > T p.Arg183Trp(8) | Missense | NA | Hu et al., (2020) [46] |
26 | + | Normal | NA | c.659 T > C p.Leu220Pro(9) | Missense | c.497A > T p.Asp166Val(7) | Missense | NA | Hu et al., (2020) [46] |
27 | + | NA | NA | c.497A > T p.Asp166Val(7) | Missense | c.328C > T p.Gln110*(5) | Nonsense | NA | Hu et al., (2020) [46] |
28 | + | NA | Complex I, III and IV deficit | c.416C > T, p.Ala139Val (6) | Missense | c.416C > T, p.Ala139Val(6) | Missense | NA | Papadimas et al., (2020) [47] |
29 | + | NA | Normal | c.323C > T p.Thr108Met (5) | Missense | c.323C > T p.Thr108Met(5) | Missense | < 30.0% | de Fuenmayor-Fernández de la Hoz et al., (2021) [48] |
30 | NA | NA | Complex I, III and IV deficit | c.323C > T, p.Thr108Met (5) | Missense | c.323C > T, p.Thr108Met (5) | Missense | NA | Laine-Menéndez et al., (2021) [49] |
31 | + | NA | NA | c.278A > G, p.Asn93Ser (4) | Missense | c.543del, p.Leu182Phefs ∗ 11(8) | Frameshift | 30.0% | Manini et al., (2022) [50] |
32 | + | NA | NA | c.547C > T p.Arg183Trp(8) | Missense | c.547C > T p.Arg183Trp(8) | Missense | 25.0% | Manini et al., (2022) [50] |
33 | NA | NA | NA | c.173A > G p.Asn58Ser(3) | Missense | c.173A > G p.Asn58Ser(3) | Missense | 86.0% | Manini et al., (2022) [50] |
34 | + | NA | NA | c.389G > A p.Arg130Gln(6) | Missense | c.129_132delAGAA(2) | Frameshift | 24.0% | Manini et al., (2022) [50] |
35 | + | NA | NA | c.361C > A p.His121Asn (5) | Missense | c.361C > A p.His121Asn (5) | Missense | 72.0% | Manini et al., (2022) [50] |
36 | + | NA | NA | C.157-2A > G, 157minus2AtoG(intron) | Splicing substitutions | c.588A > T p.Arg196Ser(8) | Missense | 73.0% | Manini et al., (2022) [50] |
37 | + | NA | NA | c.323C > T; p.Thr108Met (5) | Missense | C.698 T > C p. Leu233Pro(10) | Missense | 5.0% | Manini et al., (2022) [50] |
38 | + | NA | NA | c.659 T > C p.Leu220Pro(8) | Missense | c.161G > A p. Cys54Tyr(3) | Missense | NA | Wu et al., (2018) [51] |
39 | NA | NA | Complex I, II + III, I + III, IV decreased | c.159C > G p.Ile53Met(3) | Missense | c.159C > G p.Ile53Met(3) | Missense | 14.0% | Garone et al., (2018) [24] |
40 | NA | Myopathic | NA | c.198C > G p.Cys66Trp;(3) | Missense | c.644 T > C p.Leu215Pro(9) | Missense | 8.4% | Garone et al., (2018) [24] |
41 | NA | NA | Complex II + III, IV decreased | C.311C > A p.Arg104His(5) | Missense | c.388C > T p.Arg130Trp6) | Missense | 31.0% | Garone et al., (2018) [24] |
42 | + | NA | NA | c.372_373delTCinsCT p.Gly125X(5) | Nonsense | C.395 T > C p.Met132Thr(6) | Missense | 10.0% | Garone et al., (2018) [24] |
43 | + | NA | Complex I, IV decreased | c.159C > G p.Ile53Met(3) | Missense | c.159C > G p.Ile53Met(3) | Missense | 14.0% | Garone et al., (2018) [24] |
44 | + | Neurogenic | Complex II + III, IV,decreased | C.335_336dup p.Val113Metfs20*;(5) | Frameshift | c.278A > G p.Asn93Ser(4) | Missense | 21.0% | Garone et al., (2018) [24] |
45 | + | Myopathic | NA | c.198C > G p.Cys66Trp;(3) | Missense | c.644 T > C p.Leu215Pro(9) | Missense | 9.2% | Garone et al., (2018) [24] |
46 | + | NA | Complex I, IV decreased | c.133C > T p.Gln45* (2) | Nonsense | c.173A > G p.Asn58Ser(3) | Missense | 5.0% | Garone et al., (2018) [24] |
47 | + | Myopathic | Complex I, III, IV decreased | c.360_361delinsAA p.His121Trp;(5) | Frameshift | c.575G > A p.Arg192Lys (8) | Missense | 17.0% | Garone et al., (2018) [24] |
48 | + | NA | NA | c.150dup p.Ser51fs;(2) | Frameshift | c.375G > C p.Gln125His(5) | Missense | 24.0% | Garone et al., (2018) [24] |
49 | + | Myopathic | Complex I, III, IV decreased | c.347C > T p.Thr116Ile;(5) | Missense | c.347C > T p.Thr116Ile(5) | Missense | 31.0% | Garone et al., (2018) [24] |
50 | + | Myopathic | Complex I, II, IV decreased | E5-E10 del | Deletion | c.311C > A p.Arg104His(5) | Missense | 23.4% | This study |