1Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India
2Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India
Copyright © 2022 The Korean Movement Disorder Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Conflicts of Interest
The authors have no financial conflicts of interest.
Funding Statement
None
Author Contributions
Conceptualization: Vikram Venkappayya Holla, Koti Neeraja, Albert Stezin, Pramod Kumar Pal. Data curation: Koti Neeraja, Vikram Venkappayya Holla, Albert Stezin, Shweta Prasad. Formal analysis: Vikram Venkappayya Holla, Koti Neeraja, Shweta Prasad. Investigation: Vikram Venkappayya Holla, Koti Neeraja, Bharat Kumar Surisetti. Methodology: Vikram Venkappayya Holla, Koti Neeraja, Pramod Kumar Pal. Project administration: Manjunath Netravathi, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal. Resources: Vikram Venkappayya Holla, Manjunath Netravathi, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal. Supervision: Vikram Venkappayya Holla, Ravi Yadav, Pramod Kumar Pal. Visualization: Vikram Venkappayya Holla, Pramod Kumar Pal. Writing—original draft: Vikram Venkappayya Holla, Koti Neeraja. Writing—review & editing: Albert Stezin, Shweta Prasad, Bharat Kumar Surisetti, Manjunath Netravathi, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal.
Case | AAO | Phenotype | Gene | Variant | Inheritance | ACMG classification |
---|---|---|---|---|---|---|
1 | 15 | Focal, combined (DP) | PLA2G6 | ENST00000332509;c.835delA;p.Ile279SerfsTer26† | AR, CH | LP (PVS1PM2) |
ENST00000332509;c.991G>T;p.Asp331Tyr† | LP (PM2PP2-5) | |||||
2 | 10 | Generalised, combined (DP) | PLA2G6 | ENST00000332509;c.2222G>A;p.arg742Gln | AR, Hm | P (PP5PM2,5PP2) |
3* | 18 | Generalised, combined (DP) | PLA2G6 | ENST00000332509;c.2222G>A;p.arg742Gln | AR, Hm | P (PP5PM2,5PP1,2) |
4* | 19 | Generalised, combined (DP) | PLA2G6 | ENST00000332509;c.2222G>A;p.arg742Gln | AR, Hm | P (PP5PM2,5PP1,2) |
5 | 7 | Generalised, isolated | GLB1 | ENST00000307363;c.246-2A>G | AR, CH | P (PVS1PM2PP3) |
ENST00000307363;c.1325G>A;p.Arg442Gln | P (PP5PM2,3PP2,3) | |||||
6* | 4 | Generalised, combined (DP) | GLB1 | ENST00000307363;c.1325G>A;p.Arg442Gln | AR, CH | P (PP5PM2PP1-3) |
ENST00000307363;c.1022G>T;p.Gly341Val† | LP (PM2,3PP1-3) | |||||
7* | 3 | Generalised, combined (DP) | GLB1 | ENST00000307363;c.1325G>A;p.Arg442Gln | AR, CH | P (PP5PM2PP1-3) |
ENST00000307363;c.1022G>T;p.Gly341Val† | LP (PM2,3PP1-3) | |||||
8 | 1 | Multifocal, combined (DCh) | GCH1 | ENST00000491895;c.542T>C;p.Val181Ala† | AR, Hm | LP (PM1,2PP2,3) |
9 | 1 | Generalised, complex (DId) | GCH1 | ENST00000491895;c.614T>C;p.Val205Ala† | AR, CH | LP (PM1,2,5PP2,3) |
ENST00000491895;c.610G>A;p.Val204Ile | LP (PM1,2PP2,3) | |||||
10 | 11 | Generalised, isolated | TOR1A | ENST00000351698;c.907_909del;p.Glu303del | AD, Ht | P (PP5PS3PM1,2,4PP3) |
11 | 8 | Multifocal, isolated | TOR1A | ENST00000351698;c.907_909del;p.Glu303del | AD, Ht | P (PP5PS3PM1,2,4PP3) |
12 | 20 | Generalised, isolated | TH | ENST00000381178;c.525delG;p.Leu176SerfsTer61† | AR, CH | LP (PVS1PM2) |
ENST00000381178:c.1481C>T;p.Thr494Met† | LP (PM2PP2,3,5) | |||||
13 | 17 | Multifocal, combined (DCh) | TH | ENST00000381178;c.1117C>T;p.Arg373Cys† | AR, Hm | LP (PM1,2PP2,3) |
14 | 20 | Generalised, isolated | PRKN | ENST00000366898;c.124C>T;p.Arg42Cys† | AR, CH | LP (PM1,2,5PP2,3) |
ENST00000366898;c.1076G>A;p.Gly359Asp† | LP (PM1,2PP2,3) | |||||
15 | 17 | Segmental, combined (DP) | PRKN | ENST00000366898;c.(171+1_172-1)_(412+1_413-1)del† | AR, Hm | |
16 | 43 | Multifocal, isolated | THAP1 | ENST00000254250;c.71+1G>C† | AD, Ht | LPVS1PM2PP3) |
17 | 6 | Generalised, complex (DS) | NDUFA12 | ENST00000327772;c.60_61delCCinsT;p.Arg21GlufsTer18† | AR, Hm | LP (PVS1PM2) |
18 | 13 | Generalised, complex (DCo) | ATP7B | ENST00000242839;c.3485C>T;p.Ser1162Phe† | AR, Hm | P (PS3PM1,2PP2-4) |
19 | 10 | Generalised, complex (DC) | FA2H | ENST00000219368;c.130C>A;p.Pro44Thr† | AR, Hm | LP (PM1,2,5) |
20 | 2 | Generalised, complex (DCo) | NPC1 | ENST00000269228;c.2473T>C;p.Tyr825His† | AR, Hm | LP (PM2,5PP2,3) |
* belongs to same family and segregation analysis was performed by Sanger analysis;
† novel mutations.
AAO, age at onset; ACMG, American College of Medical Genetics and Genomics; AD, autosomal dominant; AR, autosomal recessive; CH, compound heterozygous; DC, dystonia cerebellar; DCh, dystonia chorea; DCo, dystonia with cognitive decline; DId, dystonia with intellectual disability; DP, dystonia parkinsonism; DS, dystonia spasticity; Hm, homozygous; Ht, heterozygous; LP, likely pathogenic; P, pathogenic; PVS, very strong evidence of pathogenicity; PS, strong evidence of pathogenicity; PM, moderate evidence of pathogenicity; PP, supportive evidence of pathogenicity.
Comments on this article
Features | Overall (n = 48) | Genetic diagnosis |
p value | |
---|---|---|---|---|
Yes (n = 20) | No (n = 28) | |||
Sex (male/female) | 35/13 | 15/5 | 20/8 | 0.78 |
Age at testing (years) | 25.2 ± 14.0 | 22.5 ± 11.2 | 27.0 ± 16.1 | 0.28 |
Age at onset (years) | 16.0 ± 14.1 | 11.9 ± 9.6 | 19.1 ± 16.3 | 0.08 |
Infantile onset | 3 (6.2) | 2 (10) | 1 (3.5) | 0.56 |
Childhood onset | 25 (52) | 11 (55) | 14 (50) | 0.77 |
Adolescence | 8 (16.6) | 6 (30) | 2 (7.1) | 0.05 |
Early adulthood | 5 (10.4) | 0 | 5 (17.8) | - |
Late adulthood | 7 (14.6) | 1 (5) | 6 (21.4) | 0.21 |
Body distribution | - | |||
Focal dystonia | 7 (14.6) | 1 (5) | 6 (21.4) | 0.21 |
Multifocal dystonia | 4 (8.3) | 4 (20) | 0 | - |
Segmental dystonia | 4 (8.3) | 1 (5) | 3 (10.7) | 0.63 |
Generalized dystonia | 33 (68.7) | 14 (70) | 19 (67.8) | > 0.99 |
Associated features | - | |||
Isolated dystonia | 18 (37.5) | 6 (30) | 12 (42.8) | 0.54 |
Combined dystonia | 18 (37.5) | 9 (45) | 9 (32.1) | 0.4 |
Dystonia-parkinsonism | 13 (72.2) | 7 (77.8) | 6 (66.7) | > 0.99 |
Dystonia-chorea | 4 (22.2) | 2 (22.2) | 2 (22.2) | > 0.99 |
Dystonia-myoclonus | 1 (5.6) | 0 (0) | 1 (11.1) | - |
Complex dystonia | 12 (25.0) | 5 (25) | 7 (25) | > 0.99 |
Dystonia-cerebellar ataxia | 4 (33.3) | 1 (20) | 3 (42.8) | 0.60 |
Dystonia-spasticity | 5 (41.7) | 1 (20) | 4 (57.1) | 0.30 |
Dystonia with cognitive decline | 2 (16.7) | 2 (40) | 0 | - |
Dystonia with intellectual disability | 1 (8.3) | 1 (20) | 0 | - |
Family history (families) | 5/46 (10.9) | 3 (16.6) | 2 (7.1) | 0.40 |
Case | AAO | Phenotype | Gene | Variant | Inheritance | ACMG classification |
---|---|---|---|---|---|---|
1 | 15 | Focal, combined (DP) | PLA2G6 | ENST00000332509;c.835delA;p.Ile279SerfsTer26 |
AR, CH | LP (PVS1PM2) |
ENST00000332509;c.991G>T;p.Asp331Tyr |
LP (PM2PP2-5) | |||||
2 | 10 | Generalised, combined (DP) | PLA2G6 | ENST00000332509;c.2222G>A;p.arg742Gln | AR, Hm | P (PP5PM2,5PP2) |
3 |
18 | Generalised, combined (DP) | PLA2G6 | ENST00000332509;c.2222G>A;p.arg742Gln | AR, Hm | P (PP5PM2,5PP1,2) |
4 |
19 | Generalised, combined (DP) | PLA2G6 | ENST00000332509;c.2222G>A;p.arg742Gln | AR, Hm | P (PP5PM2,5PP1,2) |
5 | 7 | Generalised, isolated | GLB1 | ENST00000307363;c.246-2A>G | AR, CH | P (PVS1PM2PP3) |
ENST00000307363;c.1325G>A;p.Arg442Gln | P (PP5PM2,3PP2,3) | |||||
6 |
4 | Generalised, combined (DP) | GLB1 | ENST00000307363;c.1325G>A;p.Arg442Gln | AR, CH | P (PP5PM2PP1-3) |
ENST00000307363;c.1022G>T;p.Gly341Val |
LP (PM2,3PP1-3) | |||||
7 |
3 | Generalised, combined (DP) | GLB1 | ENST00000307363;c.1325G>A;p.Arg442Gln | AR, CH | P (PP5PM2PP1-3) |
ENST00000307363;c.1022G>T;p.Gly341Val |
LP (PM2,3PP1-3) | |||||
8 | 1 | Multifocal, combined (DCh) | GCH1 | ENST00000491895;c.542T>C;p.Val181Ala |
AR, Hm | LP (PM1,2PP2,3) |
9 | 1 | Generalised, complex (DId) | GCH1 | ENST00000491895;c.614T>C;p.Val205Ala |
AR, CH | LP (PM1,2,5PP2,3) |
ENST00000491895;c.610G>A;p.Val204Ile | LP (PM1,2PP2,3) | |||||
10 | 11 | Generalised, isolated | TOR1A | ENST00000351698;c.907_909del;p.Glu303del | AD, Ht | P (PP5PS3PM1,2,4PP3) |
11 | 8 | Multifocal, isolated | TOR1A | ENST00000351698;c.907_909del;p.Glu303del | AD, Ht | P (PP5PS3PM1,2,4PP3) |
12 | 20 | Generalised, isolated | TH | ENST00000381178;c.525delG;p.Leu176SerfsTer61 |
AR, CH | LP (PVS1PM2) |
ENST00000381178:c.1481C>T;p.Thr494Met |
LP (PM2PP2,3,5) | |||||
13 | 17 | Multifocal, combined (DCh) | TH | ENST00000381178;c.1117C>T;p.Arg373Cys |
AR, Hm | LP (PM1,2PP2,3) |
14 | 20 | Generalised, isolated | PRKN | ENST00000366898;c.124C>T;p.Arg42Cys |
AR, CH | LP (PM1,2,5PP2,3) |
ENST00000366898;c.1076G>A;p.Gly359Asp |
LP (PM1,2PP2,3) | |||||
15 | 17 | Segmental, combined (DP) | PRKN | ENST00000366898;c.(171+1_172-1)_(412+1_413-1)del |
AR, Hm | |
16 | 43 | Multifocal, isolated | THAP1 | ENST00000254250;c.71+1G>C |
AD, Ht | LPVS1PM2PP3) |
17 | 6 | Generalised, complex (DS) | NDUFA12 | ENST00000327772;c.60_61delCCinsT;p.Arg21GlufsTer18 |
AR, Hm | LP (PVS1PM2) |
18 | 13 | Generalised, complex (DCo) | ATP7B | ENST00000242839;c.3485C>T;p.Ser1162Phe |
AR, Hm | P (PS3PM1,2PP2-4) |
19 | 10 | Generalised, complex (DC) | FA2H | ENST00000219368;c.130C>A;p.Pro44Thr |
AR, Hm | LP (PM1,2,5) |
20 | 2 | Generalised, complex (DCo) | NPC1 | ENST00000269228;c.2473T>C;p.Tyr825His |
AR, Hm | LP (PM2,5PP2,3) |
Data are presented as mean ± standard deviation or number (%).
belongs to same family and segregation analysis was performed by Sanger analysis; novel mutations. AAO, age at onset; ACMG, American College of Medical Genetics and Genomics; AD, autosomal dominant; AR, autosomal recessive; CH, compound heterozygous; DC, dystonia cerebellar; DCh, dystonia chorea; DCo, dystonia with cognitive decline; DId, dystonia with intellectual disability; DP, dystonia parkinsonism; DS, dystonia spasticity; Hm, homozygous; Ht, heterozygous; LP, likely pathogenic; P, pathogenic; PVS, very strong evidence of pathogenicity; PS, strong evidence of pathogenicity; PM, moderate evidence of pathogenicity; PP, supportive evidence of pathogenicity.