Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64 Cu PET/CT study in healthy humans.

BACKGROUND AND AIMS: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. APPROACH AND RESULTS: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04. CONCLUSIONS: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.

Clinical characteristics and prognosis of early diagnosed Wilson's disease: A large cohort study.

BACKGROUND AND AIMS: Few studies have focused on the outcomes of Wilson's disease (WD) diagnosed before age of 5 years. This study aimed to summarize the clinical features of early diagnosed WD and analyse treatment outcomes and the risk factors associated with treatment failure. METHODS: A total of 139 children confirmed with WD before 5 years were enrolled in this study. Only patients with follow-up over 1 year were analysed with Kaplan-Meier survival analysis. The composite outcomes included death, progression to liver failure or acute hepatitis, development of renal or neurological symptoms and persistent elevation of alanine aminotransferase (ALT). The treatment failure was defined as occurrence of at least one of above outcomes. RESULTS: Among 139 WD patients at diagnosis, two (1.4%) WD patients presented with symptomatic liver disease, whereas 137 (98.6%) were phenotypically asymptomatic, including 135 with elevated ALT and 2 with normal liver function. Median serum ceruloplasmin (Cp) was 3.1 mg/dL, and urinary copper excretion was 87.4 µg/24-h. There were 71 variants identified in the the copper-transporting ATPase beta gene, and 29 were loss of function (LOF). 51 patients with LOF variant were younger at diagnosis and had lower Cp than 88 patients without LOF. Among 93 patients with over 1 year of follow-up, 19 (20.4%) received zinc monotherapy, and 74 (79.6%) received a zinc/D-penicillamine combination therapy. 14 (15.1%) patients underwent treatment failure, and its occurrence was associated with poor compliance (p < .01). CONCLUSIONS: Cp is a reliable biomarker for early diagnosis, and zinc monotherapy is an effective treatment for WD during early childhood. Good treatment compliance is critical to achieve a favourable outcome.

A case of Wilson's disease combined with intracranial lipoma and dysplasia of the corpus callosum with review of the literature.

BACKGROUND: Wilson's disease (WD) is an inherited disorder of copper metabolism. Agenesis of the corpus callosum is the complete or partial absence of the major united fiber bundles connecting the cerebral hemispheres. Intracranial lipoma is an adipose tissue tumor resulting from an abnormal embryonic development of the central nervous system. The simultaneous occurrence of these three disorders is rare and has not been reported. This report focuses on the pathogenesis and association between the three disorders and highlights the importance of recognizing and effectively managing their coexistence. CASE PRESENTATION: The purpose of this study was to present a patient with coexisting WD, intracranial lipoma, and corpus callosum dysplasia. We reviewed a female patient hospitalized in 2023 with clinical manifestations of elevated aminotransferases and decreased ceruloplasmin, as well as genetic testing for an initial diagnosis of Wilson's disease. Subsequently, a cranial MRI showed corpus callosum dysplasia with short T1 signal changes in the cerebral falx, leading to a final diagnosis of Wilson's disease combined with intracranial lipoma and corpus callosum dysplasia. The patient's WD is currently stable after treatment with sodium dimercaptosulfonamide (DMPS) and penicillamine, and the patient's abnormal copper metabolism may promote the growth of intracranial lipoma. CONCLUSION: The pathogenesis of WD combined with intracranial lipoma and corpus callosum dysplasia is complex and clinically rare. The growth of intracranial lipomas may be associated with abnormal copper metabolism in WD. Abnormal copper metabolism affects lipid metabolism and triggers inflammatory responses. Therefore, early diagnosis and treatment are beneficial for improvement. Each new case of this rare co-morbidity is important as it allows for a better assessment and understanding of these cases' more characteristic clinical manifestations, which can help estimate the course of the disease and possible therapeutic options.

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.

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.

Challenging diagnosis of Wilson's disease: A case report.

Wilson's disease is arare inherited disorder of copper met abolism. If le f t untre ated, i t can turn into a multi systemic disease with copper deposition in the liver, brain, a nd other tissues. Diagnosi s of Wilson's is delayed in Pak ist an by many ye a rs on average due to va riabl e presen tations. In ad olescents, the initial s igns a re more likely to b e neuropsychiatric. Here we present a case of Wilso n's disease that pre sented initially with he patic symptoms and did not have signs specific to the di sea s e such as Kayser-Fleischer rings. Our case was diagnosed to be Wilson's Disease on ly on further investigat ions and s ubsequently the patient was treated with chela tion therapy using D-Penicillamine.Wilson's Disease should be kept in mind as a differential diagno sis in adolesce nt patients that present with unexplained acute liver failure and cytopenias without any neurological symptoms, as a missed diagnosis can prove to be fatal.

Neurological worsening in Wilson disease - clinical classification and outcome.

BACKGROUND & AIMS: Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. METHODS: From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. RESULTS: Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. CONCLUSIONS: In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. IMPACT AND IMPLICATIONS: In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.

Analysis of risk factors for neurological symptoms in patients with purely hepatic Wilson's disease at diagnosis.

OBJECTIVE: To analyze and explore the risk factors for neurological symptoms in patients with purely hepatic Wilson's disease (WD) at diagnosis. METHODS: This retrospective study was conducted at the First Affiliated Hospital of the Guangdong Pharmaceutical University on 68 patients with purely hepatic WD aged 20.6 ± 7.2 years. The physical examinations, laboratory tests, color Doppler ultrasound of the liver and spleen, and magnetic resonance imaging (MRI) of the brain were performed. RESULTS: The elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels and 24-h urinary copper level were higher in the purely hepatic WD who developed neurological symptoms (NH-WD) group than those in the purely hepatic WD (H-WD) group. Adherence to low-copper diet, and daily oral doses of penicillamine (PCA) and zinc gluconate (ZG) were lower in the NH-WD group than those in the H-WD group. Logistic regression analysis showed that insufficient doses of PCA and ZG were associated with the development of neurological symptoms in patients with purely hepatic WD at diagnosis. CONCLUSION: The development of neurological symptoms in patients with purely hepatic WD was closely associated with insufficient doses of PCA and ZG, and the inferior efficacy of copper-chelating agents. During the course of anti-copper treatment, the patient's medical status and the efficacy of copper excretion should be closely monitored.

Early neurological deterioration in Wilson's disease: a systematic literature review and meta-analysis.

INTRODUCTION: Neurological deterioration, soon after anti-copper treatment initiation, is problematic in the management of Wilson's disease (WD) and yet reports in the literature are limited. The aim of our study was to systematically assess the data according to early neurological deteriorations in WD, its outcome and risk factors. METHODS: Using PRISMA guidelines, a systematic review of available data on early neurological deteriorations was performed by searching the PubMed database and reference lists. Random effects meta-analytic models summarized cases of neurological deterioration by disease phenotype. RESULTS: Across the 32 included articles, 217 cases of early neurological deterioration occurred in 1512 WD patients (frequency 14.3%), most commonly in patients with neurological WD (21.8%; 167/763), rarely in hepatic disease (1.3%; 5/377), and with no cases among asymptomatic individuals. Most neurological deterioration occurred in patients treated with d-penicillamine (70.5%; 153/217), trientine (14.2%; 31/217) or zinc salts (6.9%; 15/217); the data did not allow to determine if that reflects how often treatments were chosen as first line therapy or if the risk of deterioration differed with therapy. Symptoms completely resolved in 24.2% of patients (31/128), resolved partially in 27.3% (35/128), did not improve in 39.8% (51/128), with 11 patients lost to follow-up. CONCLUSIONS: Given its occurrence in up to 21.8% of patients with neurological WD in this meta-analysis of small studies, there is a need for further investigations to distinguish the natural time course of WD from treatment-related early deterioration and to develop a standard definition for treatment-induced effects.

Significant heterogeneity in the diagnosis and long-term management of Wilson disease: Results from a large multicenter Spanish study.

There is uncertainty regarding Wilson's disease (WD) management. OBJECTIVES: To assess, in a multicenter Spanish retrospective cohort study, whether the approach to WD is homogeneous among centers. METHODS: Data on WD patients followed at 32 Spanish hospitals were collected. RESULTS: 153 cases, 58% men, 20.6 years at diagnosis, 69.1% hepatic presentation, were followed for 15.5 years. Discordant results in non-invasive laboratory parameters were present in 39.8%. Intrahepatic copper concentration was pathologic in 82.4%. Genetic testing was only done in 56.6% with positive results in 83.9%. A definite WD diagnosis (Leipzig score ≥4) was retrospectively confirmed in 92.5% of cases. Chelating agents were standard initial therapy (75.2%) with frequent modifications (57%), particularly to maintenance zinc. Enzyme normalization was not achieved by one third, most commonly in the setting of poor compliance, lack of genetic mutations and/or presence of cardiometabolic risk factors. Although not statistically significant, there were trends for sex differences in number of diagnosed cases, age at diagnosis and biochemical response. CONCLUSIONS: Significant heterogeneity in diagnosis and management of WD patients emerges from this multicenter study that includes both small and large reference centers. The incorporation of genetic testing will likely improve diagnosis. Sex differences need to be further explored.

Nonparametric regression with right-censored covariate via conditional density function.

Censoring often occurs in data collection. This article, considers nonparametric regression when the covariate is censored under general settings. In contrast to censoring in the response variable in survival analysis, regression with censored covariates is more challenging but less studied in the literature, especially for dependent censoring. We propose to estimate the regression function using conditional hazard rates. The asymptotic normality of our proposed estimator is established. Both theoretical results and simulation studies demonstrate that the proposed method is more efficient than the estimation based on complete observations and other methods, especially when the censoring rate is high. We illustrate the usefulness of the proposed method using a data set from the Framingham heart study and a data set from a randomized placebo-controlled clinical trial of the drug D-penicillamine.

Rare co-occurrence of multiple sclerosis and Wilson's disease - case report.

BACKGROUND: Wilson's disease is a hereditary disorder of copper metabolism resulting mainly in hepatic, neurological, and psychiatric symptoms. Multiple sclerosis (MS) is an immune-mediated demyelinating disease affecting the central nervous system (CNS). The co-occurrence of these two, although not unheard of in literature, is still considered to be very rare and can give rise to diagnostic difficulties. Also, comorbidity in MS highly influences quality of life and disease progression, which makes the timely diagnosis and treatment of these conditions essential. CASE PRESENTATION: The aim of this study is to present a patient exhibiting symptoms of both MS and Wilson's disease, as well as to conduct a detailed review of previously reported cases. The patient's neurological symptoms (sensory disorder) as well as MRI and CSF findings were characteristic for MS. The diagnosis of MS preceded that of Wilson's disease and was relatively mild in course. Currently, the patient receives cladribine as an immunomodulatory treatment after escalation from glatiramer acetate therapy. Apart from one episode of acute hepatic decompensation, during which transfusion, albumin supplementation and diuretic treatment was necessary, Wilson's disease manifested as chronic impairment of liver function. The diagnosis of Wilson's disease was established by the analysis of serum coeruloplasmin levels, histological examination and genetic findings. Continuous oral penicillamine therapy led to the slow normalization of hepatic function and significant amelioration of the patient's symptoms. Correlating with cases previously reported, the course of MS was relatively mild, and like in three out of four other known cases, the symptoms of Wilson's disease were mostly restricted to hepatic dysfunction. CONCLUSION: The case presented in our report is similar to those reported before. The co-occurrence of the two diseases seems to be more a coincidence than a sharing of common factors in their pathogenesis; however, they are considered to influence one another. Regarding rare co-occurrences such as this one, every new case is of high importance, as it enables a better evaluation and understanding of the clinical presentations that are more characteristic of these cases, thus aiding the estimation of disease course as well as possible therapeutic choices.

Antioxidants for Treatment of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis.

INTRODUCTION: Increasing evidence has shown that oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD). Oxidative stress impairs muscle function, reduces regenerative capacity, and leads to atrophy and muscle weakness. The present study aimed to evaluate the effectiveness and safety of antioxidants in treatment of DMD patients. METHODS: Medline, Embase, EBSCOhost, and Cochrane Library databases were searched using relevant keywords regarding DMD and antioxidants. The risk of bias for all included studies was assessed using the Cochrane risk of bias tool. The effectiveness of antioxidants in improving pulmonary function and muscle strength in DMD patients and their rate of adverse events was evaluated by meta-analysis. RESULTS: A total of nine eligible studies were identified. Among these, two studies involving 85 patients compared idebenone with placebo. Pooled data showed a significant improvement in pulmonary function after idebenone treatment. Flavonoids- and omega 3-based compounds (FLAVOMEGA) significantly improved muscle strength. Two studies evaluated coenzyme Q10 (CoQ10) and reported clinical improvement in physical activity. The remaining four studies evaluated pentoxifylline, superoxide dismutase, vitamin E combination with penicillamine and penicillamine alone, respectively, and found no significant differences between the intervention and placebo groups, measured by pulmonary function, muscle strength, movement function, or quality of life. Most adverse events were mild, while the rates of dropout and serious adverse events were low with respect to antioxidants. CONCLUSIONS: Idebenone appeared to be safe and effective in improving pulmonary function in DMD patients, while pentoxifylline, superoxide dismutase, penicillamine, or a combination of vitamin E with penicillamine did not show a significant therapeutic effect. CoQ10 and FLAVOMEGA might be beneficial in improving muscle strength or physical activity in DMD patients. However, additional trials with more participants are warranted in the future.

Characteristics, Treatment, and Prognosis of Elemental Mercury Intoxication in Children: A Single-Center Retrospective Study.

OBJECTIVES: Mercury exposure is common and can be toxic, especially in children. Children are often drawn to elemental mercury because of its density, color, and proclivity to form beads. METHODS: We present data on 49 children with mercury intoxication (MI) and 60 children with mercury exposure from Turkey. RESULTS: The most common source of mercury was broken thermometer in schools. Inhaling mercury vapor was the most common route of exposure. The median exposure time was 6 (6-16) hours in the MI group, and the time to 1st symptoms was 10 (0-24) hours. In the MI group, the median blood mercury level was 21 µg/L (13-32.3), the median spot urine mercury level was 40 µg/L (7.66-78), and the median 24-hour urine mercury level was 25.8 µg/L (11-64). The most common symptoms in patients with MI were malaise, muscle pain, muscle cramps, abdominal pain, nausea, headache, and decreased appetite. The patients were treated with n-acetyl cysteine, 2,3-dimercaptopropane sulfonic acid, D-penicillamine, and meso 2,3-dimercaptosuccinic acid. A positive correlation was found between exposure time and urinary mercury level in the MI group (r = 0.793, P < 0.001). A positive moderate correlation was found between exposure time and blood level in the mercury exposure group (r = 0.535, P < 0.00). The neurological and systemic examinations of patients were all normal at the 1st follow-up visit 1 month after discharge. CONCLUSIONS: Diagnosis, removal of the exposure source, and use of chelation therapy can result in complete resolution of the signs and symptoms of MI.

Gynecological history to diagnosis and pregnancy outcomes in diagnosed Wilson's disease patients under therapy - A bicentric matched-control cohort study.

INTRODUCTION: most studies narrowly focus on pregnancy outcome comparisons between Wilson's disease (WD) patients on and off treatment. We aimed to identify menses irregularities in untreated WD, and to evaluate pregnancy outcomes in treated WD patients as compared to matched controls (with and without liver disease). METHODS: females with WD, hepatitis C (liver disease controls), and other gastrointestinal conditions (controls without liver disease) were identified at two tertiary hospital gastroenterology departments. Gynecological and obstetric data were retrospectively collected. A comparison of gynecological and obstetric outcomes was performed between the groups, and regression models were used to further assess obstetric outcomes. RESULTS: a total of 18 females with WD were identified, comprising 19 pregnancies under treatment in 11 patients, and 20 females were included in each control group. Age and liver disease stage were adjusted between groups. The incidence of menses irregularities was higher for WD (late menarche, 83 % vs. 10 % vs. 10 %, p < 0.01; irregular cycles, 100 % vs. 20 % vs. 20 %, p < 0.01; amenorrhea, 67 % vs. 10 % vs. 5 %, p < 0.01). Logistic regression models identified WD as a predictor of miscarriage and low birth weight (OR: 6.0; CI: 1.1-33.3; p < 0.05) but not of birth defects. Neither therapies (D-penicillamine 300 mg or zinc acetate 150 mg) nor disease presentation (hepatic and/or neurological) were associated with obstetric complications in WD subjects. CONCLUSION: there was a higher incidence of menses irregularities in untreated females with WD. In addition, our data suggest that treated WD still carries a higher risk of spontaneous abortion and low birth weight when compared to matched control groups with and without liver disease.

Adherence to treatment, a challenge even in treatable metabolic rare diseases: A cross sectional study of Wilson's disease.

Wilson's disease (WD), a rare genetic disorder responsible for copper accumulation in the body, is fatal if left untreated. Although there are effective treatments, adherence to treatment tends to be low. We evaluated the medication adherence of 139 patients using the Morisky scale. Adherence was correlated with age at diagnosis and at inclusion in the study, the form of the disease, the treatment, the duration of treatment, delivery and storage problems, depression, anxiety, the level of education, and the biological data. 32.4% of the patients had low adherence; their levels of exchangeable copper were significantly higher than those of the patients with high or medium adherence (P = .049). The average age of the patients at the time of the study was significantly higher in those with high adherence than in those with medium or low adherence (P = .043). 75.9% of the patients with high adherence had a neurological form and 26.7% of the patients with low adherence were asymptomatic (P = .0090). The duration of treatment was significantly longer in the patients with high adherence than in those with medium or low adherence (P = .0192). The type of treatment (chelators or zinc) had no impact on the level of adherence. Forty-four percent of the patients experienced problems dispensing and storing medications. Despite the availability of effective treatments for this rare disease, adherence problems occur with Wilson's disease in particular in asymptomatic patients. Although different factors are involved, sustained multidisciplinary management on a case-by-case basis is necessary.

Long-Term Urinary Copper Excretion on Chelation Therapy in Children with Wilson Disease.

OBJECTIVES: In Wilson disease (WD), 24-hour urinary copper excretion (UCE) is recommended to be used for diagnosis. It may be a useful tool to assess the efficacy of treatment during follow-up; however, there are limited data regarding the cutoff value of 24-hour UCE during follow-up in children. Therefore, we aim to evaluate the clinical use of 24-hour UCE during follow-up in children with WD. PATIENTS AND METHODS: Medical records of children diagnosed with WD at Kings' College Hospital from 2005 to 2018 were retrospectively reviewed. The UCE, serum copper, and ceruloplasmin levels, tested during follow-up, were statistically analyzed. RESULTS: Over the median duration of 7 years (range 1.4-14.4), 28 patients (age ranged 3.8-17.3 years) had UCE tests during follow-up. Of those, 21 patients had at least one 24-hour UCE test and 7 children had only spot UCE tests. In comparison with the level of 24-hour UCE collected at the first visit after penicillamine challenge test, the median excretion rate was significantly reduced over the follow-up period (P < 0.001), from 26.2 to 8.9 µmol/day following 1-2 years of therapy (P = 0.15), then reduced significantly to 2.2 µmol/day after 3-4 years (P = 0.009), and 5.6 µmol/day at >5 years of follow-up (P = 0.003). CONCLUSIONS: Our study suggests that within 1 year of treatment, the level of nonceruloplasmin-bound copper concentration (NCC) drops to <0.8 µmol/L. In the absence of progressive liver disease or signs of copper deficiency, 24-hour UCE decreases to ≤8 µmol/day and <6 µmol/day after 1 and 5 years of treatment, respectively.

Pediatric Wilson's Disease: Phenotypic, Genetic Characterization and Outcome of 182 Children in France.

OBJECTIVES: To describe a cohort of Wilson disease (WD) pediatric cases, and to point out the diagnostic particularities of this age group and the long-term outcome. METHODS: Clinical data of 182 pediatric patients included in the French WD national registry from 01/03/1995 to 01/06/2019 were gathered. RESULTS: Diagnosis of WD was made at a mean age of 10.7 ±â€Š4.2 years (range 1-18 years). At diagnosis, 154 patients (84.6%) had hepatic manifestations, 19 (10.4%) had neurological manifestations, and 9 patients (4.9%) were asymptomatic. The p.His1069Gln mutation was the most frequently encountered (14% of patients).Neurological patients were diagnosed at least 1 year after they presented their first symptoms. At diagnosis, the median urinary copper excretion (UCE) was 4.2 µmol/24 hours (0.2-253). The first-line treatment was d-penicillamine (DP) for 131 (72%) patients, zinc salts for 24 (13%) patients, and Trientine for 17 (9%) patients. Liver transplantation was performed in 39 (21.4%) patients, for hepatic indications in 33 of 39 patients or for neurological deterioration in 6 of 39 patients, mean Unified Wilson's Disease Rating Scale of the latter went from 90 ±â€Š23.1 before liver transplantation (LT) to 26.8 ±â€Š14.1 (P < 0.01) after a mean follow-up of 4.3 ±â€Š2.5 years. Overall survival rate at 20 years of follow-up was 98%, patient and transplant-free combined survival was 84% at 20 years. CONCLUSION: Diagnosis of WD can be challenging in children, particularly at the early stages of liver disease and in case of neurological presentation; hence the support of clinical scores and genetic testing is essential. Diagnosis at early stages and proper treatment ensure excellent outcomes, subject to good long-term treatment compliance. LT is a valid option for end-stage liver disease not responding to treatment and can be discussed for selected cases of neurological deterioration.

Neurological features and outcomes of Wilson's disease: a single-center experience.

Wilson's disease (WD) is an autosomal recessive genetic disorder of copper metabolism, and WD patients can present with neurologic symptoms. We aimed to report the general characteristics and prognosis of a Turkish series of WD patients with neurological manifestations. A total of 12,352 patients were screened from the patient database, and 53 WD patients were included. Patients were classified based on the predominant neurological syndrome type including tremor, dystonia, parkinsonism, or discrete neurological signs and were classified as having "good outcome," "stable," and "poor outcome" according to their treatment response. There were 32 male and 21 female patients, aged 20-66 years. The mean follow-up was 11.3 ± 4.56 years. Sixty-two percent of patients presented predominantly with neurological symptoms. Neurological WD diagnosis was established after a mean time delay of 2.3 years from the WD diagnosis. The most common neurological manifestation was dystonia, followed by tremor and parkinsonism. Fifteen patients had a family history of WD. Consanguinity was present in 20 patients. Patients were treated with D-penicillamine, trientine, zinc salts, or their combinations. Besides the main treatments, 41 patients were on symptomatic treatment for neurologic symptoms. Thirty-six patients had a "good outcome," five patients were stable, and six patients had "poor outcome." Post-chelation neurological worsening was observed in 11 patients. WD should be considered in differential diagnosis in any patient with unexplained neurologic symptoms. Early diagnosis is important, and appropriate treatment should be promptly initiated to prevent progressive and irreversible damage, with good prognosis and stable disease in the majority of the patients with treatment compliance.

[Advances in the treatment of Wilson Disease].

Wilson Disease is kind of an autosomal recessive genetic disease. Early diagnosis and timely treatment are very important for prognosis. This article reviews the treatment of Wilson Disease, focusing on penicillamine, sodium dimercaptopropane sulfonate, ammonium tetrathiomolybdate and zinc, liver transplantation and gene therapy. At the same time, the problems of medication adherence and follow-up evaluation in patients with Wilson Disease are also discussed.