A case report of Wilson’s disease presenting with predominant neurological symptoms

Introduction

Wilson’s disease (WD) is a rare genetic disorder characterized by impaired hepatic copper transport, resulting in copper accumulation in multiple organs. It is caused by a mutation in the ATP7B copper transporter gene (1). Neurological manifestations, particularly movement disorders, pose diagnostic challenges (2). WD may present without hepatic symptoms (3), it is essential to consider the WD phenotype classifications (H1, H2, N1, N2, and Nx) as mentioned by Ferenci et al. in Liver International (4). Additionally, the Leipzig score should be utilized as a diagnostic tool for WD. The presented case highlights the diagnostic journey of a patient with unusual progression and postural involvement. This report addresses the diagnostic dilemma, underscores the significance of early detection, and emphasizes the relevance of considering WD in the differential diagnosis of movement disorders. We present this case in accordance with the CARE reporting checklist (available at https://jxym.amegroups.com/article/view/10.21037/jxym-24-35/rc).

Case presentation

The patient is a 24-year-old female with a history of abnormal body movements and episodic fits exhibited a gradual decline marked by continuous, involuntary abnormal movements affecting the lower limbs. The symptoms began approximately two years prior to diagnosis, with a gradual progression of movement abnormalities. Assessment revealed no significant cognitive impairment or psychiatric symptoms. There is no family history of neurological disease. The patient’s parents are not consanguineously married.

She uniquely developed sustained dystonia of the right arm, along with action tremors in the left arm (see Video 1). She had repeated falls and speech difficulties and became functionally impaired. WD, spinocerebellar ataxia, generalized dystonia, leukodystrophy, and other neurodegenerative disorders were initially considered in the differential diagnosis.

Laboratory investigations demonstrated decreased serum ceruloplasmin levels. An increase in 24-hour urinary copper levels is indicative of WD (see Table 1). Kayser-Fleischer rings were observed upon slit lamp examination. The presence of bilateral frontoparietal and basal ganglia hypodensities on computed tomography (CT) brain accentuates the neurological impact of copper accumulation. A magnetic resonance imaging (MRI) of the brain shows hyperintensities in a fluid-attenuated inversion-recovery (FLAIR) image as shown in Figure 1. Normal electroencephalography (EEG) findings excluded epileptic activity. The patient’s liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and alkaline phosphatase, were within normal ranges. A liver biopsy was not done because the patient’s parents had not given their consent for that invasive procedure. Ultrasonography of the abdomen was normal. Genetic testing for mutation analysis was not done due to financial constraints. The diagnosis of WD was established using the Leipzig Score, which considers a combination of clinical, biochemical, and imaging findings. The patient’s low ceruloplasmin levels, high urinary copper, presence of Kayser-Fleischer rings, and characteristic MRI findings were pivotal in confirming the diagnosis.

Figure 1 MRI of the brain. FLAIR image of MRI brain. Arrows show hyperintensities in the basal ganglia and brainstem. Notably, the white matter is also affected, which could be due to WD or other etiologies. MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion-recovery; WD, Wilson’s disease.

Treatment with d-penicillamine and oral zinc led to gradual improvement of the patient’s condition within 3 weeks, following established guidelines (5). The neurological symptoms were attributed to WD. Lifelong therapy is required for WD, with d-penicillamine typically starting at 250 to 500 mg/day and potentially increasing to 1,000 to 1,500 mg in divided doses (6). All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

WD is known for its diverse clinical presentations, ranging from hepatic to neurological symptoms. This case highlights the diagnostic challenge of WD presenting predominantly with neurological symptoms and no overt hepatic involvement (7). The absence of definitive hepatic impairment, as seen in our patient, adds to the complexity of diagnosing WD, where the liver typically plays a central role in symptomatology.

Recent reports by Sapuppo et al. [2020] and Ortiz et al. [2020] describe similar cases of WD presenting with neurological symptoms and minimal or asymptomatic hepatic involvement (2,8). These cases support the notion that WD can manifest with mild or even absent hepatic symptoms, emphasizing the importance of considering WD in patients with unexplained neurological signs. In our patient, despite the significant neurological impairment, comprehensive hepatic evaluations were limited. This case adds to the literature by illustrating a WD manifestation characterized by dystonia, choreiform movements, scanning speech, and action tremors, all in the absence of clear hepatic involvement (7). This underscores the heterogeneity of WD presentations and the necessity for a high index of suspicion in similar cases.

Due to difficulties in diagnosing WD, the Leipzig (Ferenci) score was devised by a group of experts to help diagnose patients. It comprises many key investigations for making the diagnosis of WD and applies to the adult population (4). The Leipzig score was calculated for our patient and it was more than 4 confirming our diagnosis.

The brain MRI of our patient showed hyperintensities in the basal ganglia, brainstem, and white matter. While white matter involvement in WD is less common, it has been reported (4). Typical MRI findings in WD include hyperintensities on T2-weighted images in the basal ganglia, thalamus, brainstem, and cerebellum. The ‘face of the giant panda’ sign, characterized by a hyperintense midbrain surrounded by a hypointense area, is pathognomonic for WD and helps differentiate it from other neurodegenerative disorders (9). Damage in the basal ganglia disrupts inhibitory pathways, leading to excessive motor output and abnormal movements such as dystonia (10,11). Elevated copper levels, which damage the blood-brain barrier and accumulate in brain regions like the striatum and globus pallidus, contribute to neuronal damage and abnormal movements through oxidative stress and lipid peroxidation (12). These structural and functional changes are evident on MRI and are crucial for diagnosing WD (13).

In WD, all first-degree relatives must be screened with biochemical markers, including liver function tests, serum copper and ceruloplasmin concentrations, urinary copper analysis, and slit-lamp examination for identification of the Kayser-Fleischer ring. There is a 25% probability of finding a homozygote among the siblings (3). A limitation of this case report is the absence of elastography or fibroscan assessments, which could have provided additional insight into hepatic involvement.

The clinical variability in WD presentations necessitates a thorough and individualized diagnostic approach. Clinicians should be aware of the potential for isolated neurological presentations and conduct appropriate screenings, including serum ceruloplasmin, urinary copper levels, and slit-lamp examination for Kayser-Fleischer rings, even when liver function tests are normal. Early diagnosis and treatment are crucial for managing symptoms and preventing disease progression.

Conclusions

This case underscores the importance of recognizing WD even in the absence of definitive hepatic impairment. It highlights the necessity for a comprehensive diagnostic approach, considering both neurological and hepatic evaluations. The report adds to existing literature by showcasing a case with predominant neurological symptoms, emphasizing the need for vigilance in diagnosing and managing WD across its diverse clinical spectrum.

Acknowledgments

We thank the patient for consenting to the publication of this case report. We also acknowledge the healthcare team involved in the patient’s care.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jxym.amegroups.com/article/view/10.21037/jxym-24-35/rc

Peer Review File: Available at https://jxym.amegroups.com/article/view/10.21037/jxym-24-35/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jxym.amegroups.com/article/view/10.21037/jxym-24-35/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dusek P, Litwin T, Członkowska A. Neurologic impairment in Wilson disease. Ann Transl Med 2019;7:S64. [PubMed]
2. Ortiz JF, Morillo Cox Á, Tambo W, et al. Neurological Manifestations of Wilson's Disease: Pathophysiology and Localization of Each Component. Cureus 2020;12:e11509. [PubMed]
3. Kumar MK, Kumar V, Singh PK. Wilson's Disease with Neurological Presentation, without Hepatic Involvement in Two Siblings. J Clin Diagn Res 2013;7:1476-8. [PubMed]
4. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003;23:139-42. [PubMed]
5. Roberts EA, Schilsky MLAmerican Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089-111. [PubMed]
6. Scheiber IF, Brůha R, Dušek P. Pathogenesis of Wilson disease. Handb Clin Neurol 2017;142:43-55. [PubMed]
7. Patil M, Sheth KA, Krishnamurthy AC, et al. A review and current perspective on Wilson disease. J Clin Exp Hepatol 2013;3:321-36. [PubMed]
8. Sapuppo A, Pavone P, Praticò AD, et al. Genotype-phenotype variable correlation in Wilson disease: clinical history of two sisters with the similar genotype. BMC Medical Genetics 2020;21:128. [PubMed]
9. Rędzia-Ogrodnik B, Członkowska A, Antos A, et al. Pathognomonic neuroradiological signs in Wilson's disease - Truth or myth? Parkinsonism Relat Disord 2023;107:105247. [PubMed]
10. Yu XE, Gao S, Yang RM, et al. MR Imaging of the Brain in Neurologic Wilson Disease. AJNR Am J Neuroradiol 2019;40:178-83. [PubMed]
11. Svetel M, Kozić D, Stefanova E, et al. Dystonia in Wilson's disease. Mov Disord 2001;16:719-23. [PubMed]
12. Huster D. Wilson disease. Best Pract Res Clin Gastroenterol 2010;24:531-9. [PubMed]
13. Langner C, Denk H. Wilson disease. Virchows Arch 2004;445:111-8. [PubMed]