1Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
2Department of Neurology, National Taiwan University Hospital Hsinchu branch, Hsinchu, Taiwan
3Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
4Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
6Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
7Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
8Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Copyright © 2023 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.
Data Availability Statemen
The datasets generated and/or analyzed during the present study are available from the corresponding author upon reasonable request.
Conflicts of Interest
The authors have no financial conflicts of interest.
Funding Statement
This work was supported by grants from the National Taiwan University Hospital (110-A154).
Author contributions
Conceptualization: Sung-Pin Fan, Chin-Hsien Lin, Yen-Hsuan Ni. Data curation: all authors. Formal analysis: Sung-Pin Fan. Funding acquisition: Chin-Hsien Lin, Yen-Hsuan Ni. Investigation: Sung-Pin Fan, Chin-Hsien Lin, Yen-Hsuan Ni. Methodology: all authors. Project administration: Chin-Hsien Lin, Yen-Hsuan Ni. Resources: Chin-Hsien Lin, Yen-Hsuan Ni. Software: Sung-Pin Fan. Supervision: Chin-Hsien Lin, Yen-Hsuan Ni. Validation: Sung-Pin Fan, Chin-Hsien Lin, Yen-Hsuan Ni. Visualization: Sung-Pin Fan, Chin-Hsien Lin, Yen-Hsuan Ni. Writing—original draft: Sung-Pin Fan. Writing—review & editing: Chin-Hsien Lin, Yen-Hsuan Ni.
Hepatic form (n = 74) | Neuropsychiatric form (n = 49) | p-value | ||
---|---|---|---|---|
Current age (yr) (range) | 28.1 ± 12.4 (5–62) | 39.2 ± 14.1 (10–70) | < 0.01† | |
Onset age (yr) (range) | 15.3 ± 11.4 (3–45) | 24.2 ± 11.3 (12–50) | < 0.01† | |
Gender, male | 38 (51.4) | 30 (61.2) | 0.28 | |
K-F ring | 31 (41.9) | 38 (77.6) | < 0.01† | |
Liver cirrhosis | 29 (39.2) | 29 (59.2) | < 0.01† | |
Liver failure | 3 (4.1) | 2 (4.1) | 0.99 | |
Lab data | ||||
Ceruloplasmin (mg/dL) | 6.3 ± 3.9 | 4.9 ± 3.9 | 0.03* | |
Cu level at diagnosis (ppb) | 568.1 ± 112.9 | 334.4 ± 137.9 | 0.16 | |
24-hour urine Cu level (μg) | 372.4 ± 148.2 | 148.0 ± 132.4 | 0.17 | |
MMSE | 27.0 ± 3.8 | 25.9 ± 3.7 | 0.09 | |
Movement disorders at diagnosis | 8 (10.8) | 43 (87.8) | < 0.01† | |
Kinetic tremor | 8 (10.8) | 15 (30.6) | < 0.01† | |
Parkinsonism | 0 (0) | 8 (16.3) | < 0.01† | |
Dystonia | 0 (0) | 12 (24.5) | < 0.01† | |
Ataxia | 0 (0) | 8 (16.3) | < 0.01† | |
Psychiatric symptoms at diagnosis | 9 (12.2) | 22 (45.8) | < 0.01† | |
Depression | 4 (5.4) | 11 (22.9) | < 0.01† | |
Anxiety | 6 (8.1) | 6 (12.5) | 0.53 | |
Psychosis | 0 (0) | 11 (22.9) | < 0.01† | |
Seizure | 1 (1.3) | 4 (8.2) | 0.08 | |
Medications | ||||
Zinc | 57 (77.0) | 37 (75.5) | 0.64 | |
D-penicillamine | 52 (70.3) | 41 (83.7) | 0.16 | |
Trientine | 13 (17.6) | 10 (20.4) | 0.81 | |
Outcomes | ||||
Liver transplantation | 6 (8.1) | 3 (6.1) | 0.48 | |
ICU admission | 6 (8.1) | 8 (16.3) | 0.24 | |
mRS ≥ 3 | 5 (6.8) | 19 (38.8) | < 0.01† | |
Death | 2 (2.7) | 2 (4.2) | 0.99 | |
Genetic variants (n = 59, including 30 hepatic form and 29 neuropsychiatric form) | ||||
p.R778L, allelic number (allelic %) | 19/60 (31.7) | 7/58 (12.1) | 0.02* | |
p.P992L, allelic number (allelic %) | 10/60 (16.7) | 4/58 (6.9) | 0.11 | |
p.T935M, allelic number (allelic %) | 7/60 (11.7) | 4/58 (6.9) | 0.37 |
Hepatic form (n = 34) | Neuropsychiatric form (n = 26) | p-value | |
---|---|---|---|
Current age (yr) (range) | 25.8 ± 13.2 (15–55) | 35.3 ± 12.6 (20–63) | < 0.01* |
Onset age (yr) (range) | 17.5 ± 12.1 (10–32) | 26.7 ± 13.4 (15–50) | < 0.01* |
Gender, male | 18 (51.4) | 30 (61.2) | 0.28 |
Total brain volume (%) | 76.23 ± 8.31 | 69.35 ± 7.62 | < 0.01* |
Supratentorial volume (%) | 67.52 ± 7.43 | 60.23 ± 7.13 | < 0.01* |
Cortical gray matter volume (%) | 32.23 ± 3.72 | 30.28 ± 5.45 | 0.05 |
Subcortical gray matter volume (%) | 4.25 ± 0.63 | 3.22 ± 0.43 | < 0.01* |
Caudate nucleus | 0.46 ± 0.09 | 0.31 ± 0.08 | < 0.01* |
Putamen | 0.63 ± 0.16 | 0.44 ± 0.11 | < 0.01* |
Globus pallidum | 0.27 ± 0.07 | 0.20 ± 0.04 | < 0.01* |
Thalamus | 1.09 ± 0.18 | 0.94 ± 0.16 | < 0.01* |
White matter volume (%) | 31.23 ± 7.81 | 27.45 ± 6.62 | 0.08 |
Cerebellum (%) | 9.52 ± 1.21 | 8.9 ± 1.03 | 0.05 |
Carriers with homozygous or compound heterozygous p.R778L variant (n = 22) |
Carriers without p.R778L variant (n = 37) | p-value‡ | Pairwise comparisons§ | |||
---|---|---|---|---|---|---|
Homozygous (n = 4) | Compound heterozygous (n = 18) | |||||
Clinical presentations | ||||||
Hepatic form | 4 (100) | 12 (66.7) | 25 (67.6) | 0.02* | Homozygous p.R778L < non-p.R778L | |
Neuropsychiatric form | 0 (0) | 6 (33.3) | 12 (32.4) | 0.04* | Homozygous p.R778L < non-p.R778L | |
Age of diagnosis (yr) | 5.0 ± 1.2 | 15.1 ± 2.9 | 17.6 ± 2.2 | 0.04* | Homozygous p.R778L < non-p.R778L | |
K-F ring | 1 (25) | 5 (27.8) | 19 (51.4) | 0.21 | Homozygous and compound heterozygous p.R778L < non-p.R778L | |
Abnormal liver function | 4 (100) | 14 (77.8) | 29 (78.4) | 0.57 | ||
Cirrhosis | 0 (0) | 4 (22.2) | 14 (37.8) | 0.16 | ||
Lab data | ||||||
Ceruloplasmin (mg/dL) | 3.6 ± 0.78 | 4.89 ± 1.18 | 7.04 ± 0.66 | 0.003† | Homozygous p.R778L < non-p.R778L | |
Compound heterozygous p.R778L < non-p.R778L | ||||||
Cu level at diagnosis (ppb) | 111.5 ± 54.5 | 240.9 ± 42.5 | 628.4 ± 191.7 | 0.03* | Homozygous p.R778L < non-p.R778L | |
24-hour urine Cu level (μg) | 82.73 ± 7 | 168.0 ± 54.9 | 430.7 ± 233.3 | 0.74 | ||
Follow-up outcome | ||||||
Liver transplantation | 0 (0) | 1 (5.6) | 3 (8.1) | 0.78 | ||
mRS ≥ 3 | 0 (0) | 4 (18.2) | 18 (48.6) | 0.002† | Homozygous p.R778L < non-p.R778L | |
ICU admission | 0 (0) | 1 (5.6) | 3 (8.1) | 0.78 |
Values are presented as mean ± standard deviation or n (%) unless otherwise indicated.
* p < 0.05;
† p < 0.01;
‡ the p value is obtained based on ANOVA or or the Kruskal-Wallis test for comparisons between three groups;
§ pairwise comparisons between two of the tree groups were considered statistically significant when p < 0.05.
K-F ring, Kayser–Fleischer ring; Cu, copper; mRS, modified rankin scale; ICU, intensive care unit.
Covariates | Coefficient | Standard error | Hazard ratio | 95% confidence interval | p-value |
---|---|---|---|---|---|
Onset age | 0.058 | 0.023 | 1.059 | 1.014–1.108 | 0.01* |
Gender | 0.157 | 0.513 | 1.169 | 0.428–3.197 | 0.76 |
Allelic number of ATP7B p.R778L variant | -1.006 | 0.439 | 0.366 | 0.154–0.865 | 0.02* |
Serum ceruloplasmin level | -0.214 | 0.091 | 0.808 | 0.676–0.965 | 0.02* |
K-F ring | 0.002 | 0.613 | 1.002 | 0.301–3.333 | 0.81 |
Follow-up < 10 years (n = 58) | Follow-up ≥ 10 years (n = 65) | p-value | |
---|---|---|---|
Clinical presentations | |||
Current age (yr) | 30.6 ± 14.6 | 39.7 ± 13.5 | < 0.01† |
Onset age (yr) | 21.3 ± 12.5 | 16.2 ± 9.7 | 0.04* |
Gender, male | 35 (60.3) | 42 (64.6) | 0.94 |
Neuropsychiatric form | 32 (55.2) | 29 (44.6) | 0.02* |
K-F ring | 40 (68.9) | 38 (58.5) | 0.23 |
Lab data | |||
Ceruloplasmin (mg/dL) | 5.4 ± 3.9 | 6.2 ± 4.5 | 0.28 |
Cu level at diagnosis (ppb) | 341.9 ± 276.3 | 515.5 ± 187.2 | 0.12 |
24-hour urine Cu level (μg) | 305.3 ± 129.1 | 224.9 ± 114.3 | 0.53 |
Initial brain MRI features (%) | |||
Caudate nucleus | 0.45 ± 0.12 | 0.49 ± 0.11 | 0.69 |
Putamen | 0.69 ± 0.19 | 0.73 ± 0.15 | 0.04* |
Globus pallidum | 0.22 ± 0.11 | 0.30 ± 0.09 | 0.02* |
Thalamus | 1.10 ± 0.17 | 1.12 ± 0.19 | 0.45 |
Medications | |||
Zinc | 45 (77.5) | 50 (76.9) | 0.82 |
D-penicillamine | 46 (79.3) | 48 (73.8) | 0.16 |
Trientine | 10 (17.2) | 10 (15.4) | 0.21 |
Genetic variants (n = 59, including 34 with F/U < 10 years and 25 with F/U ≥ 10 years) | |||
Homozygous p.R778L | 0 (0) | 4 (16.0) | 0.03* |
Compound heterozygous p.R778L | 7 (20.6) | 11 (44.0) | |
Non-p.R778L variants | 27 (79.4) | 10 (40.0) |
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