Brain volume is related to neurological impairment and to copper overload in Wilson’s disease

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Abstract

Introduction

To determine whether brain volume was associated with functional and neurological impairments and with copper overload markers in patients with Wilson’s disease.

Methods

In 48 treatment-naïve patients, we assessed functional and neurological impairments with the Unified Wilson’s Disease Rating Scale, measured normalized brain volumes based on magnetic resonance images, and assessed concentration of non-ceruloplasmin-bound copper. We correlated brain volume measures with functional and neurological impairment scores and copper overload indices.

Results

Functional and neurological impairments correlated with all brain volume measures, including the total brain volume and the volumes of white matter and gray matter (both peripheral gray matter and deep brain nuclei). Higher non-ceruloplasmin-bound copper concentrations were associated with greater functional and neurological impairments and lower brain volumes.

Conclusions

Our findings provided the first in vivo evidence that the severity of brain atrophy is a correlate of functional and neurological impairments in patients with Wilson’s disease and that brain volume could serve as a marker of neurodegeneration induced by copper.

Electronic supplementary material

The online version of this article (10.1007/s10072-019-03942-z) contains supplementary material, which is available to authorized users.

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Most cited references 23

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Diagnosis and phenotypic classification of Wilson disease.

Peter Ferenci, Karel Caca, Georgios Loudianos … (2003)

Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non-neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) (1, 2). The Wilson disease gene ATP7B encodes a P-type ATPase. More than 200 disease causing mutations of this gene have been described so far (3). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian (4-6) or R778L in Japanese (7), Chinese and Korean patients). Studies of phenotype-genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16-18, 2001). After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.

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Wilson's disease: cranial MRI observations and clinical correlation.

S Sinha, Arun Taly, Nayana K Venugopal … (2006)

Study of MRI changes may be useful in diagnosis, prognosis and better understanding of the pathophysiology of Wilson's disease (WD). We aimed to describe and correlate the MRI abnormalities of the brain with clinical features in WD. MRI evaluation was carried out in 100 patients (57 males, 43 females; mean age 19.3+/-8.9 years) using standard protocols. All but 18 patients were on de-coppering agents. Their history, clinical manifestations and scores for severity of disease were noted. The mean duration of illness and treatment were 8.3+/-10.8 years and 7.5+/-7.1 years respectively. MRI of the brain was abnormal in all the 93 symptomatic patients. The most conspicuous observations were atrophy of the cerebrum (70%), brainstem (66%) and cerebellum (52%). Signal abnormalities were also noted: putamen (72%), caudate (61%), thalami (58%), midbrain (49%), pons (20%), cerebral white matter (25%), cortex (9%), medulla (12%) and cerebellum (10%). The characteristic T2-W globus pallidal hypointensity (34%), "Face of giant panda" sign (12%), T1-W striatal hyperintensity (6%), central pontine myelinosis (7%), and bright claustral sign (4%) were also detected. MRI changes correlated with disease severity scores (P<0.001) but did not correlate with the duration of illness. MRI changes were universal but diverse and involved almost all the structures of the brain in symptomatic patients. A fair correlation between MRI observations and various clinical features provides an explanation for the protean manifestations of the disease.

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Gender differences in Wilson's disease.

T. Litwin, G. Gromadzka, A Członkowska (2012)

Wilson's disease (WD) is an inherited disorder of copper metabolism. Although well documented in many disorders, gender hasn't been directly addressed in WD; therefore, our aim was to evaluate gender differences in WD. We analyzed data on 627 consecutive WD patients entered into our registry (1958-2010). We observed a male predominance in our population of WD patients (327 males vs. 290 females; p<0.05). At disease diagnosis, 510/627 patients were symptomatic, most patients had the neuropsychiatric WD form (345/510; p<0.01). The neuropsychiatric form occurred predominantly in men versus women (209/278 vs. 136/232; p<0.01), especially the rigidity-tremor (71/111 vs. 40/111; p<0.05), rigidity (23/33 vs. 10/33; p=0.07) and psychiatric forms (46/71 vs. 25/71; p=0.06). The hepatic form occurred more frequently in women (96/165 vs. 69/165; p<0.01) and women developed the neuropsychiatric form 2 years later than men (29.4 vs. 27.1; p<0.05). According to our findings, the neuropsychiatric form of WD is predominant at diagnosis in both genders. The hepatic form of WD occurs more frequently in women, and women develop the neuropsychiatric form of disease almost 2 years later than men. We speculate these differences may be due to the protective effect of estrogens and iron metabolism differences. Copyright © 2011 Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Lukasz Smolinski:

ORCID: http://orcid.org/0000-0002-2389-4145

(+48 22) 45 82 537 , lsmolinski@ipin.edu.pl

Journal

Journal ID (nlm-ta): Neurol Sci

Journal ID (iso-abbrev): Neurol. Sci

Title: Neurological Sciences

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1590-1874

ISSN (Electronic): 1590-3478

Publication date (Electronic): 30 May 2019

Publication date PMC-release: 30 May 2019

Publication date (Print): 2019

Volume: 40

Issue: 10

Pages: 2089-2095

Affiliations

[1 ]ISNI 0000 0001 2237 2890, GRID grid.418955.4, Second Department of Neurology, , Institute of Psychiatry and Neurology, ; Sobieskiego 9, 02-957 Warsaw, Poland

[2 ]ISNI 0000 0001 2237 2890, GRID grid.418955.4, Department of Radiology, , Institute of Psychiatry and Neurology, ; Warsaw, Poland

Author information

Lukasz Smolinski http://orcid.org/0000-0002-2389-4145

Article

Publisher ID: 3942

DOI: 10.1007/s10072-019-03942-z

PMC ID: 6745045

PubMed ID: 31147855

SO-VID: 2f5dfbd8-51a4-4a19-bab1-5cae5d741ee7

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 9 November 2018

Date accepted : 16 May 2019

Funding

Funded by: Institute of Psychiatry and Neurology

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ScienceOpen disciplines: Neurosciences

Keywords: wilson’s disease,unified wilson’s disease rating scale,volumetric mri

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: wilson’s disease, unified wilson’s disease rating scale, volumetric mri

Brain volume is related to neurological impairment and to copper overload in Wilson’s disease

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Most cited references 23

Diagnosis and phenotypic classification of Wilson disease.

Wilson's disease: cranial MRI observations and clinical correlation.

Gender differences in Wilson's disease.

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