Assessment of cardiac function and electrocardiographic findings in patients with Wilson's disease.

BACKGROUND: This study evaluated cardiac function using tissue Doppler echocardiography and assessed electrocardiographic findings in children diagnosed with Wilson's disease. METHOD: Asymptomatic patients with a diagnosis of Wilson's disease (n = 43) were compared to healthy controls (n = 37) that were age and gender matched. RESULTS: The standard electrocardiographic and conventional echocardiographic examinations were similar in both groups. The left ventricular ejection fraction, shortening fraction, and diastolic function were not significantly different between the two groups. The Tei index for mitral lateral, mitral septal, tricuspid lateral, tricuspid septal, and inter-ventricular septum on tissue Doppler echocardiography was higher in the patient group, yet it did not reach statistical significance. Mitral lateral and septal systolic annular velocity values were significantly lower in the patient group when compared to the control group (p = 0.02 and 0.04, respectively). Also, mitral lateral and septal isovolumetric contraction time values were higher in the patient group (p = 0.04). Although the left ventricular values were not significantly different, relative left ventricular wall thickness was higher in the patient group when compared to the control group, and concentric remodelling in the left ventricle was found in 7 (16%) of 42 patients. QT interval (p = 0.02) and P-wave dispersion values (p = 0.04) were significantly higher in the patient group compared to the control group, and these tend to predict arrhythmias. CONCLUSION: Our study based on the tissue Doppler echocardiography assessment indicated a subclinical systolic, rather than diastolic, dysfunction in the myocardium with increased QT interval and P-wave dispersion, despite the young age of the patients and short disease duration.

Work ability assessment in a patient with Wilson's disease.

Wilson's disease (WD) is a rare, progressive autosomal recessive disorder characterised by impaired transport and excessive accumulation of copper in the liver, brain, and other tissues. The disease is diagnosed based on clinical manifestations and screening tests results. Work ability assessment of patients with WD is based on the analysis of liver, kidney, neurological, and cognitive impairments, and takes into account patient's level of education.This article presents a case with a 48-year-old male patient, who was admitted for work ability assessment due to polymorphic symptoms. The patient had been working as a salesman for 28 years. A detailed interview and examination by occupational health and other medical specialists revealed that the patient had been suffering from Wilson's disease from the age of 13, and had now developed hepatic manifestations (compensated liver cirrhosis with portal hypertension), neurological manifestations (dystonia, dysarthria, muscle weakness, vertigo), and psychiatric manifestations (depression, insomnia, cognitive impairment) of the disease, including problems partially caused by long-lasting treatment with copper chelating agents (neurological and haematological manifestations). There were no ocular manifestations of Wilson's disease (Kayser-Fleischer rings or sunflower cataract).The patient was assessed as having drastically diminished general work ability, dominantly due to neurological and psychiatric impairments caused by Wilson's disease.

A clinical assessment of Wilson disease in patients with concurrent liver disease.

GOALS: To investigate variations in clinical epidemiology of Wilson disease in patients with concurrent liver disease and the effect of coexisting disease on current diagnostic algorithms. BACKGROUND: Wilson disease is a rare disorder and few studies exist on diagnosis and natural history. Currently available tools have limited efficacy in complex patients, and the presence of coexisting diseases may further limit their use. More in-depth analyses of Wilson disease among complex patients with concurrent diseases will help improve algorithms for earlier diagnosis and treatment. STUDY: A retrospective cohort study using data from a large tertiary-care center to carry out a clinical assessment of Wilson disease among patients with coexisting liver disease. RESULTS: Forty-two Wilson disease patients were identified; 9 had comorbid liver diseases. The average age of diagnosis was significantly older in patients with concurrent liver disease compared with those without underlying disease (49.1 y vs. 26.8 y, P<0.0001). Patients with concurrent liver disease had more evidence of cirrhosis at presentation (9/9, 100% vs. 15/33, 45.5%), and showed greater mortality (4/8, 50% vs. 4/29, 13.8%, P=0.0222). Without mutation analysis data, a definitive diagnosis of Wilson disease using Leipzig criteria was made in 44% of patients with concurrent liver diseases. CONCLUSIONS: Patients with concurrent liver diseases were diagnosed with Wilson disease at significantly older ages, presented with more liver cirrhosis, and showed greater mortality. Mutation analysis is crucial for definitive diagnosis among complex cohorts and those with intermediate Leipzig scores.

A novel Global Assessment Scale for Wilson's Disease (GAS for WD).

Wilson's disease (WD) is an inherited disorder of copper metabolism. Despite being treatable, patients with WD suffer severe disabilities due to delay in initiation and difficulty in monitoring treatment. We propose a two tier, Global Assessment Scale for Wilson's Disease (GAS for WD) that grades the multisystemic manifestations of the disease. Tier 1 scores the global disability in four domains: Liver, Cognition and behavior, Motor, and Osseomuscular. Tier 2 is multidimensional scale for a fine grained evaluation of the neurological dysfunction. We prospectively validated this scale in 30 patients with WD. Both tiers had a high inter-rater reliability (Intraclass correlation coefficient ICC (A, 2) = 0.96-1.0). Tier 2 items were internally consistent (Cronbach's alpha = 0.89) and factorial analysis showed that 90.3% of the Tier 2 total score variance was determined by seven factors. Scores of both tiers were commensurate with the disease burden as assessed by standard disability scales (Child Pugh, UPDRS, SS3, and CGI) and satisfied criteria for validity. Longitudinal follow-up over 1.5 years showed that the scale was sensitive to clinical change. This suggests that GAS for WD is a practical tool with potential applications in management of patients, and in testing and comparison of treatment regimens.

Withdrawal of penicillamine from zinc sulphate-penicillamine maintenance therapy in Wilson's disease: promising, safe and cheap.

BACKGROUND: Penicillamine, once considered the cornerstone of treatment for Wilson disease (WD), is rather expensive and toxic, and often causes neurological worsening. Zinc sulphate, aiming at the treatment of free-copper toxicosis, has emerged as effective, safe and cheap alternative. AIM: To assess the effect of withdrawal of penicillamine from maintenance treatment with penicillamine and zinc sulphate. PATIENTS AND METHODS: 45 patients of WD (M:F: 28:17; age at diagnosis: 13.5+/-63 years), on both penicillamine (P) and zinc sulphate (Zn), couldn't continue penicillamine due to financial constraints. Their clinical data, disability and impairment scores (Schwab and England (S&E) score, Neurological Symptom Score (NSS), and Chu staging) and follow-up data of patients maintained only on zinc sulphate were recorded. RESULTS: Majority of patients (84.4%) had neuropsychiatric manifestations. The mean duration of treatment with penicillamine (P) and zinc sulphate (P+Zn), before stopping penicillamine, was 107.4+/-67.3 months. 40 patients improved variably, while the rest didn't. They received only zinc sulphate for 27.2+/-8.5 months (range: 12 to 34) and 44 patients (97.7%) remained status quo or improved marginally. Only one patient reported worsening in dysarthria. Their disability and impairment scores during combination (penicillamine and zinc sulphate) and Zn alone were: Chu (1.3+/-0.5 vs. 1.5+/-1.9; p=0.4), NSS (1.8+/-3.1 vs. 1.5+/-2.3; p=0.03) and S&E (96.4+/-5.6 vs. 98.6+/-3.5; p=0.03). There were no adverse effects. CONCLUSIONS: Withdrawal of penicillamine from zinc sulphate/penicillamine maintenance therapy for patients with Wilson's disease was effective, safe and economic, for almost all patients. This retrospective study reiterates that zinc sulphate may be used as a preferred mode of treatment for patients with Wilson's disease.

Three atypical cases of Wilson disease: assessment of the Leipzig scoring system in making a diagnosis.

BACKGROUND/AIMS: The diagnosis of this condition in the absence of any neurological findings may pose a dilemma. In 2001, experts from The 8th International Conference on Wilson disease (WD) and Menkes disease in Leipzig, Germany proposed a scoring system that may facilitate diagnosis of WD. METHODS/RESULTS: Three patients were identified as having an atypical presentation of WD as they all presented after the age 40. Two of the three presented with established cirrhosis, and none had any neuropsychiatric manifestations. All three patients fulfilled the Leipzig diagnostic criteria proposed by EASL prior to confirmatory mutation analysis. Patient A died of liver failure despite treatment. Patients B and C have remained with stable liver disease on chelation therapy. CONCLUSIONS: We believe these patients represent a group most likely to be missed in the diagnostic work-up of liver disease due to a combination of atypical features such as older age of onset, presence of other confounders for liver disease, and sometimes absence of Kayser-Fleischer rings. The Leipzig scoring system proposed in 2003 was helpful in support of an initial diagnosis of Wilson disease in these patients, validated later by genetic testing.

Constantin von Economo's contribution to the understanding of movement disorders.

Constantin von Economo's (CvE) main scientific achievements were his studies on the cytoarchitectonics of the cerebral cortex, sleep, and encephalitis lethargica (EL). He found a close relationship between motor symptoms and psychiatric and behavioral disorders in EL and postencephalitic Parkinsonism and identified the underlying neuropathology in the diencephalon and the brainstem. In agreement with Tretiakoff's findings in Parkinson's disease, CvE related postencephalitic Parkinsonism to neuronal loss in the substantia nigra. Several of CvE's early, less well-known publications also deal with the basal ganglia and movement disorders. He demonstrated in rabbits that the substantia nigra modulates automatization, coordination, and succession of masticatory movements and swallowing. In a study on the effects of experimental lesions of the cerebral peduncle in cats and monkeys, CvE hypothesized a corticotegmental pathway that maintains motor functions after pyramidal tract lesions. Recent studies have identified this pathway, which ends in the pedunculopontine nucleus. In a study on posthemiplegic chorea, CvE discussed various pathophysiological hypotheses that partly resemble modern concepts of chorea. In a clinicopathological study on Wilson's disease, CvE traced the striofugal fibers and visualized the basal ganglia outflow pathways. CvE was an outstanding multidisciplinary movement disorder specialist who contributed substantially to modern basal ganglia research.

In vitro assessment of copper-induced toxicity in the human hepatoma line, Hep G2.

Copper, though essential, is highly toxic when present in excess, as in Wilson disease, a genetic disorder of hepatic copper metabolism. We hypothesized that mitochondria are a major target of copper-induced cytotoxicity in Wilson disease. We used the human hepatoma line Hep G2 to examine copper-mediated cytotoxicity and three different methods to assess organelle damage: MTT assay (mitochondria), neutral red (NR; lysosomes) and Trypan blue exclusion assay (TB; plasma membrane). For all assays, cells at approximately 60% confluence in microtitre plates were incubated with CuCl(2) (concentration range: 50-100-150-200 microM) for 24 or 48 h. Results were expressed as percent of untreated control. At 24 h, cytotoxicity as detected by NR assay was significantly higher at all concentrations of copper than for MTT or TB ( p<0.005 at all concentrations). Cytotoxicity as detected by MTT was higher than that detected by TB at all concentrations except at 200 microM (p<0.05 for 50 microM, p<0.005 for 100 microM, p = 0.001 for 150 microM). Results at 48 h were similar (NR versus others: p <0.001 MTT versus TB: NS except at 150 microM where p<0.01). We investigated reactive oxygen species (ROS) production in copper-associated hepatocytoxicity by incubating sub-confluent cells with 2('),7(')-dichlorodihydrofluorescein diacetate dye plus copper (concentration range: 0-200 microM) for 1-1.5 h. Copper, but not zinc, produced significant increases in ROS (p<0.001). In summary, Hep G2 lysosomes appeared more susceptible to Cu-mediated damage than mitochondria; the cell membrane was highly resistant to damage.

Liver transplantation for Wilson's disease: long-term results and quality-of-life assessment.

BACKGROUND: Wilson's disease associated with severe liver disease is effectively cured by orthotopic liver transplantation (OLT). However, there are also anecdotal reports of improved or resolved neurologic symptoms after OLT in patients with stable or normal liver function. Side effects with conventional chelating agents are common, and it has been suggested that OLT should be considered in patients with severe progressive neurologic symptoms. However, the decision to apply this therapeutic modality to a subgroup of patients without significant liver disease is a quality-of-life issue. METHODS: Long-term follow-up and quality-of-life data were obtained prospectively for 24 patients who underwent OLT between 1988 and 2000 for Wilson's disease associated with severe liver disease. In long-term survivors, quality of life was assessed using the 36-Item Short Form 36 Health Survey Questionnaire. RESULTS: One patient who had multiorgan failure before OLT died within 24 hr of surgery and two patients died within 1 year because of immunosuppressant-related complications. There have been no deaths or graft loss in patients who have undergone transplantation since 1994, and after a median follow-up of 92 months, all survivors have satisfactory graft function (5-year patient and graft survival, 87.5%), with quality-of-life scores (assessed in 86% of survivors) comparable to age- and sex-matched controls from the general population. CONCLUSIONS: The authors' results suggest that liver transplantation can be safely performed in patients with Wilson's disease, with excellent long-term results and quality of life. Further study of the utility of liver transplantation in the management of patients with severe neurologic symptoms is justified.

New knowledge of genetic pathogenesis of hemochromatosis and Wilson's disease.

Discovery of the gene for WD has greatly enhanced our understanding of this disorder at the cellular level and has set the stage for future testing of new modes of therapy. Improvements in analytic methods for detecting mutations in genomic DNA will someday enable a rapid and cost-effective method of screening for this disorder. Until then, the time-tested clinical and biochemical evaluation, including measurement of ceruloplasmin oxidase activity, slit-lamp examination for Kayser-Fleischer rings, and measurement of hepatic copper content, will continue to remain the standard for establishing the diagnosis of WD.

Zinc acetate treatment in Wilson's disease.

OBJECTIVE: To briefly review the pathophysiology and diagnosis of Wilson's disease, and to evaluate the pharmacology, pharmacokinetics, clinical utility, adverse effects, dosing regimens, and pharmacoeconomics of zinc acetate therapy in Wilson's disease. DATA SOURCES: A MEDLINE search (December 1966-December 1996) of the English-language literature using the terms zinc and Wilson's disease was conducted to identify pertinent clinical trials, review articles, and case reports. Additional articles were selected from bibliographies of the reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Due to the rarity of the disease, all articles were considered for possible inclusion in this review. Single case reports are referenced, but were not selected for evaluation. DATA SYNTHESIS: Wilson's disease, an inherited disorder of copper metabolism, is fatal if untreated. The chelating drugs penicillamine and trientine have been the mainstay of therapy; however, adverse reactions of chelators often interfere with successful treatment. Recently, zinc acetate was approved in the US for maintenance therapy in patients initially treated with a chelating agent. Although studies evaluating large populations are lacking zinc therapy has demonstrated exceptional safety and efficacy over a period of 40 years. Zinc acetate can be used during pregnancy and for the treatment of presymptomatic patients, although data do not support its use as monotherapy in patients with acute neurologic or hepatic disease. CONCLUSIONS: Zinc acetate is an effective maintenance therapy for patients with Wilson's disease. Negligible toxicity, compared with that of previously approved treatments, is a major advantage.

Assessment of the hypothalamic-pituitary-testicular function in male patients with Wilson's disease.

Sixteen male patients with Wilson's disease were studied to detect potential endocrine dysfunctions. There was no clinical evidence of feminization in any of the patients, and the patient group spanned most pubertal stages. Gonadotropin, testosterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate, androstenedione, estradiol, prolactin, cortisol, thyrotropin, and free thyroxine levels were determined. Low or borderline luteinizing hormone (LH) levels were present in most of the patients. In six of the adult patients, a standard gonadotropin-releasing hormone (GnRH) test was performed. Five of the six patients had blunted LH and follicle-stimulating hormone (FSH) responses to GnRH. Increased androgen levels were found in eight of the patients. Sex hormone-binding globulin was normal in eight of nine tested patients. Three single-dose human chorionic gonadotropin (hCG) stimulation tests of six adult patients showed normal responses. Three other patients who had elevated baseline levels responded with modest increases. Since liver disease is usually associated with decreased androgen levels, it is difficult to account for the elevated androgen levels. Both increased androgen levels and copper accumulation in the hypophysis could be responsible for the blunted GnRH response.

Evoked potentials in assessment and follow-up of patients with Wilson's disease.

Treatment of 9 patients with Wilson's disease was prospectively studied with evoked potentials and magnetic resonance imaging (MRI). Oral penicillamine therapy led to a decrease in auditory brainstem (ABP) and somatosensory (SEP) conduction times in 6 and 4 neurologically symptomatic patients, respectively. ABP and SEP were normal in 3 other symptom-free patients. MRI showed cerebral lesions in 4 of 7 patients. Quantified indices of brain atrophy were unaffected by treatment. ABP and SEP may reveal a reversible component of the disease that cannot be detected by MRI, and may be a more sensitive measure of treatment efficacy.

Clinical assessment of 31 patients with Wilson's disease. Correlations with structural changes on magnetic resonance imaging.

Thirty-one patients with Wilson's disease were evaluated with detailed neurologic and medical examinations. Mean age (+/- SD) at onset was 21 +/- 5 years and at examination was 28 +/- 6 years. Of the 90% of patients who were first treated with penicillamine, 31% deteriorated initially despite therapy, and half never recovered to pretherapy baseline. At the time of our evaluations, the most common neurologic findings were dysarthria (97%), dystonia (65%), dysdiadochokinesia (58%), rigidity (52%), gait and postural abnormalities (42%), and tremor (32%). Chorea and dementia were rare. Twenty-two patients underwent magnetic resonance imaging. All but one of the 19 symptomatic patients had abnormal scans. The three asymptomatic patients had normal scans. Most lesions were seen in the caudate, putamen, subcortical white matter, midbrain, and pons. Generalized brain atrophy was also common. Lesions were less common in the thalamus, cerebellar vermis, midbrain tegmentum, globus pallidus, red nucleus, and dentate nucleus. Dystonia and bradykinesia correlated with putamen lesions, and dysarthria correlated with both putamen and caudate lesions.