Abstract
To report the phenomenology of movement disorder (MD) in neurological Wilson disease (NWD), and correlate these with MRI, and biomarkers of oxidative stress, excitotoxicity, and inflammation. Eighty-two patients were included, and their phenomenology of MD was categorized. The severity of dystonia was assessed using the Burke-Fahn-Marsden score, and chorea, athetosis, myoclonus, and tremor on a 0–4 scale. The MRI changes were noted. Serum glutamate, cytokines, and oxidative stress markers were measured. Movement disorders were noted in 78/82 (95.1%) patients and included dystonia in 69 (84.1%), chorea in 31 (37.8%), tremor in 24 (29.3%), parkinsonism in 19 (23.2%), athetosis in 13 (15.9%), and myoclonus in 9 (11.0%) patients. Dystonia was more frequently observed in the patients with thalamic (76.8 vs 23.2%), globus pallidus (72.0 vs 28.0%), putamen (69.5 vs 30.5%), caudate (68.3 vs 31.7%) and brainstem (61.0 vs 39.0%) involvement, and tremor with cerebellar involvement (37.5 vs 5.2%). The median age of onset of neurological symptoms was 12 (5–50) years. WD patients had higher levels of malondialdehyde (MDA), glutamate, and cytokines (IL-6, IL-8, IL-10, and TNFα) and lower levels of glutathione and total antioxidant capacity (TAC) compared with the controls. Serum glutamate, IL-6, IL-8, and plasma MDA levels were increased with increasing neurological severity, while glutathione and TAC levels decreased. The severity of dystonia related to the number of MRI lesions. MD is the commonest neurological symptoms in WD. Oxidative stress, glutamate, and cytokine levels are increased in WD and correlate with neurological severity.
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The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Abbreviations
- WD:
-
Wilson disease
- NWD:
-
neurological Wilson disease
- Cu:
-
copper
- MD:
-
movement disorder
- BFM score:
-
Burke-Fahn-Marsden score
- MDA:
-
malondialdehyde
- TAC:
-
total antioxidant capacity
- XIAP:
-
X-link inhibitory apoptotic protein
- KF:
-
Keiser- Fleisher
References
Albanese A et al. (2013) Dystonia rating scales: critique and recommendations Movement disorders : official journal of the Movement Disorder Society 28:874-883 doi:https://doi.org/10.1002/mds.25579
Alvarez-Cordoba M et al (2019) Precision medicine in pantothenate kinase-associated neurodegeneration. Neural Regen Res 14:1177–1185. https://doi.org/10.4103/1673-5374.251203
Argyelan M et al (2009) Cerebellothalamocortical connectivity regulates penetrance in dystonia. J Neurosci 29:9740–9747. https://doi.org/10.1523/JNEUROSCI.2300-09.2009
Asanuma K et al (2005) Decreased striatal D2 receptor binding in non-manifesting carriers of the DYT1 dystonia mutation. Neurology 64:347–349. https://doi.org/10.1212/01.WNL.0000149764.34953.BF
Balint B, Mencacci NE, Valente EM, Pisani A, Rothwell J, Jankovic J, Vidailhet M, Bhatia KP (2018) Dystonia Nature reviews. Disease primers 4:25. https://doi.org/10.1038/s41572-018-0023-6
Bandmann O, Weiss KH, Kaler SG (2015) Wilson’s disease and other neurological copper disorders. The Lancet Neurology 14:103–113. https://doi.org/10.1016/S1474-4422(14)70190-5
Bhatia KP, Marsden CD (1994) The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain J Neurol 117(Pt 4):859–876. https://doi.org/10.1093/brain/117.4.859
Brewer GJ (2001) Wilson’s disease: a clinical guide to recognition, diagnosis, and management. Kluwer Academic Publishers, Boston; Dordrecht
Brooks DJ (1993) PET studies on the early and differential diagnosis of Parkinson’s disease Neurology 43:S6–16
Carbon M, Su S, Dhawan V, Raymond D, Bressman S, Eidelberg D (2004) Regional metabolism in primary torsion dystonia: effects of penetrance and genotype. Neurology 62:1384–1390. https://doi.org/10.1212/01.wnl.0000120541.97467.fe
Ciarmiello A, Giovacchini G, Orobello S, Bruselli L, Elifani F, Squitieri F (2012) 18F-FDG PET uptake in the pre-Huntington disease caudate affects the time-to-onset independently of CAG expansion size. Eur J Nucl Med Mol Imaging 39:1030–1036. https://doi.org/10.1007/s00259-012-2114-z
Comella CL, Leurgans S, Wuu J, Stebbins GT, Chmura T, Dystonia Study G (2003) Rating scales for dystonia: a multicenter assessment Movement disorders : official journal of the Movement Disorder Society 18:303–312 doi:https://doi.org/10.1002/mds.10377
Czlonkowska A et al (2018) Wilson disease Nature reviews. Disease primers 4:21. https://doi.org/10.1038/s41572-018-0018-3
Czlonkowska A, Tarnacka B, Moller JC, Leinweber B, Bandmann O, Woimant F, Oertel WH (2007) Unified Wilson’s Disease Rating Scale - a proposal for the neurological scoring of Wilson’s disease patients. Neurol Neurochir Pol 41:1–12
Daroff RB (2016) Bradley’s neurology in clinical practice. Vol. 2 Vol. 2. Elsevier, London
European Association for Study of L (2012) EASL clinical practice guidelines: Wilson’s disease. J Hepatol 56:671–685. https://doi.org/10.1016/j.jhep.2011.11.007
Ferenci P (2006) Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Hum Genet 120:151–159. https://doi.org/10.1007/s00439-006-0202-5
Ferenci P (2017) Diagnosis of Wilson disease. Handb Clin Neurol 142:171–180. https://doi.org/10.1016/B978-0-444-63625-6.00014-8
Goyal MK, Sinha S, Patil SA, Jayalekshmy V, Taly AB (2008) Do cytokines have any role in Wilson’s disease? Clin Exp Immunol 154:74–79. https://doi.org/10.1111/j.1365-2249.2008.03755.x
Grimm G et al (1991) Comparison of functional and structural brain disturbances in Wilson’s disease. Neurology 41:272–276. https://doi.org/10.1212/wnl.41.2_part_1.272
Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9:515–540. https://doi.org/10.1016/0891-5849(90)90131-2
Kalita J, Kumar V, Chandra S, Kumar B, Misra UK (2014a) Worsening of Wilson disease following penicillamine therapy. Eur Neurol 71:126–131. https://doi.org/10.1159/000355276
Kalita J, Kumar V, Misra UK (2016) A study on apoptosis and anti-apoptotic status in Wilson disease. Mol Neurobiol 53:6659–6667. https://doi.org/10.1007/s12035-015-9570-y
Kalita J, Kumar V, Misra UK, Bora HK (2018) Memory and learning dysfunction following copper toxicity: biochemical and immunohistochemical basis. Mol Neurobiol 55:3800–3811. https://doi.org/10.1007/s12035-017-0619-y
Kalita J, Kumar V, Misra UK, Bora HK (2020a) Movement disorder in copper toxicity rat model: role of inflammation and apoptosis in the corpus striatum. Neurotox Res 37:904–912. https://doi.org/10.1007/s12640-019-00140-9
Kalita J, Kumar V, Misra UK, Parashar V, Ranjan A (2020b) Adjunctive antioxidant therapy in neurologic Wilson’s disease improves the outcomes. Journal of molecular neuroscience : MN 70:378–385. https://doi.org/10.1007/s12031-019-01423-8
Kalita J, Kumar V, Misra UK, Ranjan A, Khan H, Konwar R (2014b) A study of oxidative stress, cytokines and glutamate in Wilson disease and their asymptomatic siblings. J Neuroimmunol 274:141–148. https://doi.org/10.1016/j.jneuroim.2014.06.013
Kalita J, Kumar V, Ranjan A, Misra UK (2015a) Role of oxidative stress in the worsening of neurologic Wilson disease following chelating therapy. NeuroMolecular Med 17:364–372. https://doi.org/10.1007/s12017-015-8364-8
Kalita J, Misra UK, Kumar V, Parashar V (2019) Predictors of seizure in Wilson disease: a clinico-radiological and biomarkers study. Neurotoxicology 71:87–92. https://doi.org/10.1016/j.neuro.2018.12.005
Kalita J, Misra UK, Pradhan PK (2011) Oromandibular dystonia in encephalitis. J Neurol Sci 304:107–110. https://doi.org/10.1016/j.jns.2011.02.001
Kalita J, Ranjan A, Misra UK (2015b) Oromandibular dystonia in Wilson’s disease movement disorders clinical practice 2:253–259 doi:https://doi.org/10.1002/mdc3.12171
Kim B, Chung SJ, Shin HW (2013) Trientine-induced neurological deterioration in a patient with Wilson’s disease. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 20:606–608. https://doi.org/10.1016/j.jocn.2012.02.041
Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW, Seo JK, Yeon KM (2006) MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation. AJNR Am J Neuroradiol 27:1373–1378
King AD et al (1996) Cranial MR imaging in Wilson’s disease. AJR Am J Roentgenol 167:1579–1584. https://doi.org/10.2214/ajr.167.6.8956601
Kinghorn KJ et al. (2015) Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction Brain : a journal of neurology 138:1801-1816 doi:https://doi.org/10.1093/brain/awv132
Kluska A et al. (2019) Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson’s disease phenotype Liver international : official journal of the International Association for the Study of the Liver 39:177-186 doi:https://doi.org/10.1111/liv.13967
Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V (2001) Method for the measurement of antioxidant activity in human fluids. J Clin Pathol 54:356–361. https://doi.org/10.1136/jcp.54.5.356
Krystkowiak P et al (2007) Reliability of the Burke-Fahn-Marsden scale in a multicenter trial for dystonia. Movement disorders : official journal of the Movement Disorder Society 22:685–689. https://doi.org/10.1002/mds.21392
Litwin T, Dziezyc K, Karlinski M, Chabik G, Czepiel W, Czlonkowska A (2015) Early neurological worsening in patients with Wilson’s disease. J Neurol Sci 355:162–167. https://doi.org/10.1016/j.jns.2015.06.010
Litwin T, Gromadzka G, Czlonkowska A, Golebiowski M, Poniatowska R (2013) The effect of gender on brain MRI pathology in Wilson’s disease. Metab Brain Dis 28:69–75. https://doi.org/10.1007/s11011-013-9378-2
Lizarraga KJ, Gorgulho A, Chen W, De Salles AA (2016) Molecular imaging of movement disorders. World Journal of Radiology 8:226–239. https://doi.org/10.4329/wjr.v8.i3.226
Llanos RM, Mercer JF (2002) The molecular basis of copper homeostasis copper-related disorders. DNA Cell Biol 21:259–270. https://doi.org/10.1089/104454902753759681
Lorincz MT (2010) Neurologic Wilson’s disease Annals of the New York. Acad Sci 1184:173–187. https://doi.org/10.1111/j.1749-6632.2009.05109.x
Machado A, Chien HF, Deguti MM, Cancado E, Azevedo RS, Scaff M, Barbosa ER (2006) Neurological manifestations in Wilson’s disease: report of 119 cases. Movement disorders : official journal of the Movement Disorder Society 21:2192–2196. https://doi.org/10.1002/mds.21170
Medici V, Huster D (2017) Animal models of Wilson disease. Handb Clin Neurol 142:57–70. https://doi.org/10.1016/B978-0-444-63625-6.00006-9
Misra UK, Kalita J (2010) Spectrum of movement disorders in encephalitis. J Neurol 257:2052–2058. https://doi.org/10.1007/s00415-010-5659-4
Musacco-Sebio R et al. (2014) Oxidative damage to rat brain in iron and copper overloads Metallomics : integrated biometal science 6:1410-1416 doi:https://doi.org/10.1039/c3mt00378g
Nahmias C, Garnett ES, Firnau G, Lang A (1985) Striatal dopamine distribution in parkinsonian patients during life. J Neurol Sci 69:223–230. https://doi.org/10.1016/0022-510x(85)90135-2
Ozcelik D, Uzun H (2009) Copper intoxication; antioxidant defenses and oxidative damage in rat brain. Biol Trace Elem Res 127:45–52. https://doi.org/10.1007/s12011-008-8219-3
Ranjan A, Kalita J, Kumar S, Bhoi SK, Misra UK (2015) A study of MRI changes in Wilson disease and its correlation with clinical features and outcome. Clin Neurol Neurosurg 138:31–36. https://doi.org/10.1016/j.clineuro.2015.07.013
Reed E, Lutsenko S, Bandmann O (2018) Animal models of Wilson disease. J Neurochem 146:356–373. https://doi.org/10.1111/jnc.14323
Roberts EA, Schilsky ML, American Association for Study of Liver D (2008) Diagnosis and treatment of Wilson disease: an update Hepatology 47:2089–2111 doi:https://doi.org/10.1002/hep.22261
Scheiber IF, Mercer JF, Dringen R (2014) Metabolism and functions of copper in brain. Prog Neurobiol 116:33–57. https://doi.org/10.1016/j.pneurobio.2014.01.002
Sinha S, Taly AB, Prashanth LK, Ravishankar S, Arunodaya GR, Vasudev MK (2007) Sequential MRI changes in Wilson’s disease with de-coppering therapy: a study of 50 patients. Br J Radiol 80:744–749. https://doi.org/10.1259/bjr/48911350
Sinha S, Taly AB, Ravishankar S, Prashanth LK, Vasudev MK (2010) Wilson’s disease: (31)P and (1)H MR spectroscopy and clinical correlation. Neuroradiology 52:977–985. https://doi.org/10.1007/s00234-010-0661-1
Svetel M, Kozic D, Stefanova E, Semnic R, Dragasevic N, Kostic VS (2001) Dystonia in Wilson’s disease Movement disorders : official journal of the Movement Disorder Society 16:719–723 doi:https://doi.org/10.1002/mds.1118
Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR (2007) Wilson disease: description of 282 patients evaluated over 3 decades. Medicine 86:112–121. https://doi.org/10.1097/MD.0b013e318045a00e
Tambasco N, Romoli M, Calabresi P (2018) Selective basal ganglia vulnerability to energy deprivation: experimental and clinical evidences. Prog Neurobiol 169:55–75. https://doi.org/10.1016/j.pneurobio.2018.07.003
Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW (1995) The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet 9:210–217. https://doi.org/10.1038/ng0295-210
Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27:502–522. https://doi.org/10.1016/0003-2697(69)90064-5
Yu XE, Gao S, Yang RM, Han YZ (2019) MR imaging of the brain in neurologic Wilson disease. AJNR Am J Neuroradiol 40:178–183. https://doi.org/10.3174/ajnr.A5936
Zhang F, Dryhurst G (1994) Effects of L-cysteine on the oxidation chemistry of dopamine: new reaction pathways of potential relevance to idiopathic Parkinson’s disease. J Med Chem 37:1084–1098. https://doi.org/10.1021/jm00034a006
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This work was funded by the intramural grant from the Sanjay Gandhi Post Graduate Medical Sciences, Lucknow, India (39:287).
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Supplementary video 1
A child with neurological Wilson disease admitted with severe dystonia. He had mouth open oromandibular dystonia leading to dysarthria and dysphagia needing nasogastric feeding. His truncal and limb dystonia was so severe that he was screaming with pain. He was prescribed intravenous lorazepam to control his painful dystonic spells. (AVI 9632 kb)
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Kalita, J., Kumar, V., Misra, U.K. et al. Movement Disorder in Wilson Disease: Correlation with MRI and Biomarkers of Cell Injury. J Mol Neurosci 71, 338–346 (2021). https://doi.org/10.1007/s12031-020-01654-0
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DOI: https://doi.org/10.1007/s12031-020-01654-0