Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update.

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.

Relapse following withdrawal of D-penicillamine from combination (D-penicillamine + zinc) therapy in hepatic Wilson disease.

OBJECTIVES: Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D-pen from combination (D-pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD. METHODS: Hepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24-h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin-bound-copper (NCC) <15 mcg/dL. After D-pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier. RESULTS: Forty-five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D-pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox-regression, ALT at D-pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014-1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity. CONCLUSION: Incidence of relapse after withdrawal of D-pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D-pen stoppage, predicts future relapse.

Exploring the Content Validity of the Unified Wilson Disease Rating Scale: Insights from Qualitative Research.

INTRODUCTION: Wilson disease (WD) is a rare metabolic disorder of impaired copper transport manifesting in hepatic, neurological, and psychiatric symptoms. To evaluate the clinical symptoms of WD in clinical trials, a group of clinicians created the Unified Wilson Disease Rating Scale (UWDRS). Content validity of this scale has not been established. The aim of this study was to evaluate the content validity of the UWDRS Part II from the patient perspective. METHODS: This study utilized multiple qualitative research methods including concept elicitation interviews, concept/instrument mapping, and cognitive debriefing interviews. RESULTS: Concept elicitation interviews with a sample of patients with WD and one or more neurological signs/symptoms identified several signs, symptoms, and impacts related to neurological dysfunction, strengthening our understanding of the importance of the neurological aspects of the WD patient experience. Mapping neurological concepts to Part II and III items of the UWDRS showed complete coverage of all salient neurological concepts and near complete coverage of all neurological concepts reported by patients in concept elicitation interviews. Item debriefing of Part II of the UWDRS revealed that patients generally found the items clear and personally relevant to their experience with WD. CONCLUSION: Overall, the findings from this study provide evidence for the content validity of the UWDRS Part II and supportive evidence for the content validity of Part III. The UWDRS should be used in conjunction with additional clinical outcomes assessments, specifically those evaluating the hepatic and psychiatric signs/symptoms of WD, to provide a comprehensive evaluation of the WD patient experience.

Assessment and factors affecting quality of life among patients with Wilson's disease.

Wilson's disease is caused by abnormal copper metabolism resulting in deposition in various organs, including the brain, liver, and cornea, thus disrupting organ function. It is characterized by encephalopathy, extrapyramidal symptoms, progressive liver failure, and copper ring deposition in the cornea. Management of this disease should include quality of life maintenance; however, relevant studies on this topic are lacking. This study aimed to assess the factors affecting the quality of life (QoL) of patients with Wilson's disease. A cross-sectional survey using convenience sampling was conducted between July 2020 and March 2021 at the hospital. Data on patient characteristics, 36-item Short-Form General Health Survey, Uniform Wilson Disease Rating Scale, and Hamilton Depression Rating Scale scores were collected. Associations among quality of life depression, anxiety, and Wilson's disease progression were examined using Pearson correlation analysis. Factors affecting the quality of life of patients, including depression, anxiety, liver function, clinical symptoms, diet, liver function, brain magnetic resonance imaging (MRI) findings, disease duration, Barthel Index, and Morse scores were examined using multivariate linear regression analysis. This study included 134 patients with Wilson's disease whose mean age was 29.12 ± 8.59 years. The mean QoL score in the patient group was 71.38 ± 9.55 points and was negatively correlated with anxiety (r = - 0.883, P = 0.000), depression (r = - 0.852 P = 0.000), and clinical symptoms (r = - 0.542, P = 0.000) scores. Anxiety, depression, and clinical symptoms severity are vital factors for the QoL of patients with Wilson's disease. The study provides foundational evidence to design novel interventions, including symptom management, diet, and self-care ability, which can help in improving the quality of life in patients with Wilson's disease and decreasing the burden associated with this disease.

Construction of a nomogram for predicting compensated cirrhosis with Wilson's disease based on non-invasive indicators.

BACKGROUND: Wilson's disease (WD) often leads to liver fibrosis and cirrhosis, and early diagnosis of WD cirrhosis is essential. Currently, there are few non-invasive prediction models for WD cirrhosis. The purpose of this study is to non-invasively predict the occurrence risk of compensated WD cirrhosis based on ultrasound imaging features and clinical characteristics. METHODS: A retrospective analysis of the clinical characteristics and ultrasound examination data of 102 WD patients from November 2018 to November 2020 was conducted. According to the staging system for WD liver involvement, the patients were divided into a cirrhosis group (n = 43) and a non-cirrhosis group (n = 59). Multivariable logistic regression analysis was used to identify independent influencing factors for WD cirrhosis. A nomogram for predicting WD cirrhosis was constructed using R analysis software, and validation of the model's discrimination, calibration, and clinical applicability was completed. Due to the low incidence of WD and the small sample size, bootstrap internal sampling with 500 iterations was adopted for validation to prevent overfitting of the model. RESULTS: Acoustic Radiation Force Impulse (ARFI), portal vein diameter (PVD), and serum albumin (ALB) are independent factors affecting WD cirrhosis. A nomogram for WD cirrhosis was constructed based on these factors. The area under the ROC curve (AUC) of the model's predictive ability is 0.927 (95% CI: 0.88-0.978). As demonstrated by 500 Bootstrap internal sampling validations, the model has high discrimination and calibration. Clinical decision curve analysis shows that the model has high clinical practical value. ROC curve analysis of the model's rationality indicates that the model's AUC is greater than the AUC of using ALB, ARFI, and PVD alone. CONCLUSION: The nomogram model constructed based on ARFI, PVD, and ALB can serve as a non-invasive tool to effectively predict the risk of developing WD cirrhosis.

[Huangpu Tongqiao Capsule improves cognitive impairment in rats with Wilson disease by inhibiting endoplasmic reticulum stress-mediated apoptosis pathway].

OBJECTIVE: To investigate the neuroprotective effect of Huangpu Tongqiao Capsule (HPTQ) in a rat model of Wilson disease (WD) and explore the underlying mechanisms. METHODS: SD rat models of WD were established by feeding of coppersupplemented chow diet and drinking water for 12 weeks, and starting from the 9th week, the rats were treated with low-, moderate- and high-dose HPTQ, penicillamine, or normal saline by gavage on a daily basis for 3 weeks. Copper levels in the liver and 24-h urine of the rats were detected, and their learning and memory abilities were evaluated using Morris water maze test. HE staining was used to observe morphological changes of CA1 region neurons in the hippocampus, and neuronal apoptosis was detected with TUNEL staining. Hippocampal expressions of endoplasmic reticulum stress (ERS)-mediated apoptosis pathway-related proteins GRP78, CHOP, caspase-12, cleaved caspase-9, and cleaved caspase-3 at both the mRNA and protein levels were detected using RT-qPCR, immunofluorescence assay or Western blotting. RESULTS: Compared with normal control rats, the rat models with copper overload-induced WD exhibited significantly increased copper levels in both the liver and 24-h urine, impaired learning and memory abilities, obvious hippocampal neuronal damage in the CA1 region and increased TUNEL-positive neurons (P<0.01), with also lowered mRNA and protein expressions of GRP78, CHOP, caspase-12, cleaved caspase-9, and cleaved caspase-3 in the hippocampus (all P<0.01). Treatments with HPTQ and penicillamine significantly lowered copper level in the liver but increased urinary copper level, improved learning and memory ability, alleviated neuronal damage and apoptosis in the hippocampus, and decreased hippocampal expressions of GRP78, CHOP, caspase-12, cleaved caspase-9, and cleaved caspase-3 in the rat models (P<0.01 or 0.05). CONCLUSION: HPTQ Capsule has neuroprotective effects in rat models of WD possibly by inhibiting ERS-mediated apoptosis pathway.

Prevalence, Incidence, and Treatment Pattern of Wilson's Disease Using National Health Insurance Data From 2010-2020, Korea.

BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder in which copper (Cu) accumulates in organs, particularly in the liver and central nervous system. This study aimed to investigate the prevalence, incidence, and treatment patterns of WD patients in Korea. METHODS: National Health Insurance System (NHIS) claims data from 2010 to 2020 were analyzed. patients with WD as a primary or additional diagnosis at least once were identified using the International Classification of Diseases (ICD)-10 disease code E83.0 and a record for a registration program for rare intractable diseases in Korea. RESULTS: The average age- and sex-adjusted prevalence and incidence of WD between 2010 and 2020 were 3.06/100,000 and 0.11/100,000, respectively. The mean age of the patients with newly diagnosed WD was 21.0 ± 15.9 years. Among the 622 WD incident cases during the study period, 19.3% of the patients had liver cirrhosis and 9.2% had received liver transplantation. Psychological and neurological diseases were present in 40.7% and 48.1% of the patients, respectively. Regarding the diagnosis of WD, liver biopsy was performed in only 51.6% of new cases. D-penicillamine, trientine, or zinc were prescribed in 81.5% of the incident cases, and the treatment uptake rates decreased with increasing age. CONCLUSION: The prevalence of WD in Korea is 3.06/100,000 and approximately 1,800 patients use medical services annually. A significant proportion of patients are diagnosed at the cirrhotic stage and not treated with Cu-chelating therapeutics, suggesting the need for early diagnosis and adequate treatment to improve prognosis.

Burden of Wilson Disease among patients and care partners in the United States: results from a cross-sectional survey.

OBJECTIVE: This study assessed the burden of Wilson Disease (WD) among patients and care partners (WD-CPs) in the US and compared it to a US general population of adults (GPs) and care partners (GP-CPs). METHODS: This cross-sectional, self-reported survey included patients with WD and WD-CPs aged ≥18 years recruited through the Wilson Disease Association (WDA), while data for GPs and GP-CPs were obtained from the 2022 National Health and Wellness Survey. GPs and GP-CPs were propensity score matched (3:1) with WD patients and WD-CPs for demographics and health characteristics. Bivariate analysis evaluated differences in comorbidity burden and health-related outcomes of the WD cohorts compared to matched GP cohorts. RESULTS: Thirty-seven patients with WD and 53 WD-CPs completed the survey. Most patients reported some treatment burden (73.3%), experienced sleep problems (60%), and visited a healthcare provider (HCP) in the past 6 months (91.9%). Compared with matched GPs, patients with WD had a significantly higher mortality risk (p < .001) and reported greater rates of chronic liver disease, cirrhosis (both, p < .001), migraines (p = .032), non-alcoholic steatohepatitis (p = .004), sleep problems (p = .009) and HCP visits (p = .002). Most WD-CPs (75.5%) reported high burden of caring (mean ZBI-12 score, 26.5) and more negative impact on esteem than GP-CPs. CONCLUSION: This study highlights the burden of WD experienced by patients and WD-CPs, with patients experiencing high treatment burden, comorbidity burden and healthcare resource utilization, and WD-CPs experiencing high impact of caring, including impact on employment and self-esteem.

Wilson Disease (WD) is a rare genetic disorder that results from copper building up in the liver and the central nervous system. The management of WD has been consistent for the past 50 years. We surveyed patients with WD and family members of patients with WD ("care partners," hereby referred to as WD-CPs) residing in the US, to understand the burden of WD. We also used data from the 2022 National Health and Wellness Survey to compare patients with and WD-CPs to a sample of adults and care partners of adults in the general population (hereby referred to as GP and GP-CPs). The study found that the majority of the patients with WD reported some treatment burden (73.3%), experienced sleep problems (60.0%), and visited a healthcare provider (HCP) in the past 6 months (91.9%). Compared to GPs, patients with WD had a significantly higher risk of dying in the next 10 years and reported greater rates of other health conditions (chronic liver disease, cirrhosis, migraines, and non-alcoholic steatohepatitis), sleep problems, and visits to healthcare providers in the last 6 months. The majority of WD-CPs (75.5%) reported high burden of caring and more negative impact on their self-esteem than GP-CPs. Overall, this study highlights the burden of WD and suggests the need for more effective treatments that can reduce this burden.

Phenotype and molecular characterization of Wilson's disease in Morocco.

BACKGROUND AND STUDY AIMS: In Morocco the prevalence of Wilson disease (WD) and the spectrum of mutations are not known. The aim of the present study was to estimate the prevalence of WD in Morocco, to evaluate the phenotype among a large cohort of WD patients, and to characterize ATP7B variants in a subgroup of WD patients. PATIENTS AND METHODS: We collected data from 226 patients admitted to five university hospital centers in Morocco between 2008 and 2020. The diagnosis was based on clinical manifestations, function tests and biochemical parameters. The genotype was characterized in 18 families diagnosed at the University Hospital Center of Marrakesh, by next generation sequencing. RESULTS: The mean annual prevalence in Morocco was 3.88 per 100,000 and the allele frequency was 0.15 %. Among the 226 patients included (121 males and 105 females), 196 were referred for a hepatic or neurological involvement and 30 were asymptomatic. The mean age at diagnosis was 13 ± 5.1 years (range: 5 - 42 years). Consanguinity was found in 63.3 % of patients. The mean duration of illness was 2.8 ± 1.9 years. Kayser-Fleischer rings were found in 131 (67.9 %) of 193 patients. Among the 196 symptomatic patients, 141/159 (88.7 %) had low serum ceruloplasmin (<0.2 g/L) and a high 24-hours urinary copper (>100 µg/day) was found in 173/182 (95.1 %) patients. The initial treatment was D-penicillamine in 207 patients, zinc acetate in five, zinc sulfate in five, and nine patients were not treated; 60/207 (29 %) patients have stopped treatment. A total of 72 patients died; the mortality rate was 31.9 %. Eight different ATP7B variants were identified among the 18 patients studied, of which two were novel (p.Cys1104Arg and p.Gln1277Hisfs*52), and six previously published (p.Gln289Ter, p.Cys305Ter, p.Thr1232Pro, p.Lys1020Arg, p.Glu583ArgfsTer25 and c.51+4A>T). All informative patients were homozygous for the disease-causing mutation. CONCLUSION: In Morocco, a high prevalence due to consanguinity and a high mortality rate due to the difficulty of diagnosis and lack of treatment were observed in WD patients. NGS sequencing identified new ATP7B variants in WD patients from Morocco.

Neurological Deterioration in Wilson's Disease-Types, Etiology, Course, and Management.

Wilson's disease (WD) is an inherited disorder of copper metabolism in which pathological copper accumulation, mainly in the liver and the brain, leads to hepatic and/or neuropsychiatric signs and symptoms. Chelators and zinc salts can successfully induce negative copper balance in many patients; however, neurological deterioration may still be observed. This phenomenon can be divided into: (1) early 'paradoxical' neurological deterioration, which usually develops in the first 6 months of anti-copper treatment and may be commonly related to drug type, or (2) late neurological deterioration, which mostly occurs after 6 months of treatment and is often related either to non-compliance with treatment, overtreatment resulting in copper deficiency, or adverse drug reactions. Another explanation, especially for early neurological deterioration, is natural WD progression, which can be difficult to differentiate from drug-related deterioration, but usually leads to a worse outcome. There is still no consensus on how to define neurological deterioration in WD using scales or biomarkers, how to distinguish it from the natural disease progression, its risk factors, and optimal management. This narrative review, based on the current literature, aims to provide definitions, prevalence, pathological mechanisms and factors related to neurological deterioration, and also proposes schemes for diagnosis and treatment.

Systemic lupus erythematosus combined with Wilson's disease: a case report and literature review.

BACKGROUND: Systemic lupus erythematosus (SLE) and Wilson's disease (WD) are both systemic diseases that can affect multiple organs in the body. The coexistence of SLE and WD is rarely encountered in clinical practice, making it challenging to diagnose. CASE REPORT: We present the case of a 9-year-old girl who initially presented with proteinuria, haematuria, pancytopenia, hypocomplementemia, and positivity for multiple autoantibodies. She was diagnosed with SLE, and her blood biochemistry showed elevated liver enzymes at the time of diagnosis. Despite effective control of her symptoms, her liver enzymes remained elevated during regular follow-up. Laboratory tests revealed decreased serum copper and ceruloplasmin levels, along with elevated urinary copper. Liver biopsy revealed chronic active hepatitis, moderate inflammation, moderate-severe fibrosis, and a trend towards local cirrhosis. Genetic sequencing revealed compound heterozygous mutations in the ATP7B gene, confirming the diagnosis of SLE with WD. The girl received treatment with a high-zinc/low-copper diet, but her liver function did not improve. Upon recommendation following multidisciplinary consultation, she underwent liver transplantation. Unfortunately, she passed away on the fourth day after the surgery. CONCLUSIONS: SLE and WD are diseases that involve multiple systems and organs in the body, and SLE complicated with WD is rarely encountered in the clinic; therefore, it is easy to misdiagnose. Because penicillamine can induce lupus, it is not recommended. Liver transplantation is indicated for patients with liver disease who do not respond to medical treatment with WD. However, further research is needed to determine the optimal timing of liver transplantation for patients with SLE complicated with WD.

Assessment of sleep disturbance in patients with Wilson's disease.

BACKGROUND: Wilson's disease (WD) is frequently manifested with anxiety, depression and sleep disturbance; this investigation aimed to elucidate these manifestations and identify the influencing factors of sleep disturbance. METHODS: Sleep disturbance, anxiety and depression were compared in 42 WD and 40 age- and gender-matched healthy individuals. 27 individuals indicated a neurological form of the disease (NV), and 15 had a non-neurological variant (NNV). RESULTS: This investigation revealed that the Parkinson's disease sleep scale (PDSS) score of WD individuals was lower, whereas their Epworth Sleepiness Scale (ESS), Pittsburgh sleep quality index (PSQI), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD) scores were higher than the healthy individuals (p < 0.05). Furthermore, the WD subjects had markedly increased prevalence of poor sleep quality, anxiety, and depression than healthy individuals (p < 0.05). Subgroup analysis showed that NV subjects had significantly higher scores on the UWDRS, PSQI, HAMA, and HAMD scales than those in the NV group, as well as higher rates of EDS, anxiety, and depression (p < 0.05). In patients with sleep disturbance, we identified UWDRS, neurological variant, and depression as associated factors. The linear regression model demonstrated depression as the dominant risk factor. CONCLUSIONS: Depression is highly correlated with and is a determinant of sleep disturbance in WD patients.

Adherence to medical treatment for Wilson's disease in children and adolescents: a cohort study from Turkey.

BACKGROUND: This study aimed to assess medication adherence and demographic, clinical, and psychopathological parameters such as quality of life, depression, and anxiety levels that can affect pediatrics with Wilson's Disease (WD). METHODS: A prospective cohort study was conducted at an outpatient clinic in Turkey among pediatric patients (2 to 18 years) with WD between November 2022 and April 2023. The Medication Adherence Report Scale (MARS-5) as a subjective and Medication Possession Ratio (MPR) as an objective assessment were scored. Physical, genetic and biochemical parameters, the Pediatric Quality of Life Inventory (PedsQL) for both parents and patients, Childhood Depression Inventory, State Trait Anxiety Inventory were also administered. RESULTS: A total of 30 pediatric outpatients who were prescribed D-penicillamine (n = 27) or trientine (n = 3) as chelators and zinc (n = 29) and pyridoxine (n = 19) as supplements were included. Proteinuria (n = 3), skin rash (n = 2), and gastrointestinal upset (n = 2) were observed. When the correlation between MARS-5 and duration of follow-up was examined, a significant negative correlation was found (p = 0.014). According to MPRs, non-adherence rates (missed doses ≥ 20%) were 29.6%, 17.2% and 5.3% for D-penicillamine, zinc and pyridoxine, respectively. PedsQL scores were higher than those of parents, with a positive correlation between them (p < 0.001). Also, there was a significant positive correlation between PedsQL and State Anxiety Inventory (p < 0.001). Comparing the change in urinary copper levels between different levels of treatment knowledge, significant differences were observed between high- and low levels (p = 0.043). CONCLUSIONS: Overall, nonadherence rates were 23.3% based on MARS-5 and 5.3-29.6% based on MPR. It is essential to consider factors such as the duration of follow-up, biochemical parameters, treatment knowledge, quality of life and anxiety as potential influencers of medication adherence.

Taste and smell function in Wilson's disease.

OBJECTIVE: Wilson's disease (WD) is a metabolic disorder associated with abnormal copper metabolism that results in hepatic, psychiatric, and neurologic symptoms. No investigation of taste function has been made in patients with WD, although olfactory dysfunction has been evaluated. METHODS: Quantitative taste and smell test scores of 29 WD patients were compared to those of 790 healthy controls. Taste was measured using the 53-item Waterless Empirical Taste Test (WETT®) and smell using the 40-item revised University of Pennsylvania Smell Identification Test (R-UPSIT®). Multiple linear regression analysis controlled for age and sex. RESULTS: Average WETT® scores did not differ meaningfully between WD and control subjects (respective medians & IQRs = 32 [28-42] & 34 [27-41]); linear regression coefficient = 1.19, 95% CI [-0.81, 3.19], p = 0.242). In contrast, WD was associated with significantly reduced olfactory function [respective median (IQR) R-UPSIT® scores = 35 (33-37) vs. 37 (35-38); adjusted linear regression coefficient = -1.59, 95% CI [-2.34, -0.833]; p < 0.001)]. Neither olfaction nor taste were influenced by WD symptom subtype [23 (79.3%) were hepatic-predominant; 6 (20.7%) neurologic predominant]; R-UPSIT®, p = 0.774; WETT®, p = 0.912). No effects of primary medication or years since diagnosis (R-UPSIT®, p = 0.147; WETT®, p = 0.935) were found. Weak correlations were present between R-UPSIT® and WETT® scores for both control (r=0.187, p < 0.0001) and WD (r=0.237) subjects, although the latter correlation did not reach the 0.05 α level (p = 0.084). CONCLUSION: Although WD negatively impacts smell function, taste is spared. Research is needed to understand the pathophysiologic mechanisms responsible for this divergence.

Resolution of Wing-Beating Tremor and Magnetic Resonance Imaging Lesions in Wilson's Disease Following Penicillamine.

Background: The wing-beating tremor, characteristic of Wilson's disease (WD), is a disabling symptom that can be resistant to anti-copper and anti-tremor medications. Phenomenology Shown: This video illustrates severe bilateral wing-beating tremor, moderate head and lower limb tremors, mild cervical dystonia, and subtle cerebellar ataxia, with nearly resolution after penicillamine treatment. Educational Value: This case highlights a typical aspect of WD, emphasizing the importance of early detection and treatment, and its correlation with MRI findings. Highlights: This case highlights the typical wing-beating tremor in Wilson's disease and its correlation with the involvement of the dentato-rubro-thalamic pathway. The early diagnosis and initiation of treatment with penicillamine resulted in an excellent clinical and radiological response.

Bilateral optic atrophy in Wilson disease: A case report and literature review.

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The clinical manifestations of WD are complex and variable, with Kayser-Fleischer ring (K-F ring) and the sunflower cataract being the most common ocular findings. Visual impairment is rare in patients with WD. We report the case of a 17-year-old female with bilateral optic atrophy associated with WD and summarize the clinical features of previously reported cases of optic neuropathy in WD, Clinicians should be aware that WD is a rare cause of optic neuropathy and that optic neuropathy in patients with WD may need to be recognized and screened.