Wilson disease is a rare genetic disorder in which impaired copper excretion results in toxic copper levels and tissue damage. Manifestations are primarily hepatic and/or neuropsychiatric, with a ...variety of neurological phenotypes. The aim of this study was to characterize neurological signs of Wilson disease in newly diagnosed patients and to determine whether they correlated with disability, liver function, and copper metabolism.
Fifty-three treatment-naïve patients recently diagnosed with Wilson disease who exhibited neurological symptoms were included. Neurological manifestations were characterized by examination in terms of symptom type and degree of neurological impairment (Unified Wilson's Disease Rating Scale UWDRS Part III) and correlated with degree of disability (UWDRS Part II), abnormalities in copper parameters and hepatic status.
Most patients (62.3%) exhibited tremor and ataxia, whereas 15.1% were dystonic, and 11.3% had parkinsonism. Discrete or unclassified signs only were observed in 11.3% of patients. A good correlation between disability (UWDRS Part II) and neurological impairment (UWDRS Part III) was observed (Pearson r = 0.84). However, there was a lack of correlation when either disability or neurological impairment were analyzed with copper parameters or liver impairment.
The predominant neurological manifestations in this cohort of newly diagnosed Wilson disease patients were ataxia and tremor. Neurological impairment measured was highly correlated with the level of disability. However, hepatic manifestations of Wilson disease and copper levels did not appear to be correlated with neurological status and disability. These results highlight the challenges faced when assessing Wilson disease with its highly variable symptomatology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Wilson’s disease (WD) is a genetic disorder with copper accumulation in various tissues leading to related clinical symptoms (mainly hepatic and neuropsychiatric) which can be in 85% of patients ...successfully treated with anti-copper agents. However, during WD treatment neurological deterioration may occur in several patients. D-penicillamine (DPA) is one of the most frequently used drugs in WD treatment. Despite its efficacy, DPA can produce many adverse drug reactions, which should be recognized early. We present the case of a 51-year-old man diagnosed with the hepatic form of WD and initially treated with DPA in whom after 15 months of treatment, diplopia and evening ptosis occurred. WD treatment non-compliance as well as overtreatment were excluded. Supported by neurological symptoms, a positive edrophonium test, and high serum levels of antibodies against acetylcholine receptors (AChR-Abs), as well as low concentrations of antibodies against muscle-specific kinase (MuSK-Abs), the diagnosis of myasthenia gravis (MG), induced by DPA, was established. DPA was stopped; zinc sulfate for WD and pyridostigmine for MG symptoms were introduced. Diplopia and ptosis subsided after a few days, which supported our diagnosis. During a follow-up visit after 6 months, the patient did not present any MG symptoms. AChR-Abs level gradually decreased and MuSK-Abs were no longer detected. Pyridostigmine was stopped, and within 9 months of follow-up, the neurological symptoms of MG did not reoccur. The authors discussed the patient’s neurological deterioration, performed a systematic review of DPA-induced MG in WD and concluded that MG is a rare and usually reversible complication of DPA treatment. DPA-induced MG generally occurs 2–12 months after treatment initiation and ocular symptoms predominate. Response to pyridostigmine treatment is good and MG symptoms usually reverse within one year after DPA treatment cessation. However, symptoms may persist in some cases where DPA treatment is only a trigger factor for MG occurrence.
Purpose
Wilson’s disease (WD) is an autosomal recessive disorder of
ATP7B
gene leading to impaired copper metabolism. Brain imaging, such as magnetic resonance (MR) and transcranial sonography (TCS) ...in WD patients, shows changes mostly in the basal ganglia. Heterozygotic carriers of one faulty
ATP7B
gene should not exhibit symptoms of WD, but one in three heterozygotes has copper metabolism abnormalities. This study examined heterozygote
ATP7B
mutation carriers using TCS to assess any basal ganglia changes compared with healthy controls.
Methods
Heterozygote carriers and healthy volunteers underwent the same standard MR and TCS imaging protocols. Heterozygotes were followed for 5 years and monitored for the development of neurological symptoms.
Results
The study assessed 34 heterozygotes (21 women), with mean age of 43 years (range of 18 to 74 years) and 18 healthy controls (13 women), with mean age of 47 years (range of 20 to 73 years). Bilateral lenticular nucleus (LN) hyperechogenicity was found in 25 heterozygotes, but none of the controls (
p
< 0.001). Bilateral substantia nigra (SN) hyperechogenicity was found in 8 heterozygotes and one control; another 3 heterozygotes had unilateral SN hyperechogenicity (
p
= 0.039 for the right;
p
= 0.176 for the left). Heterozygotes had larger SN area on both sides compared with controls (
p
= 0.005 right;
p
= 0.008 left).
Conclusions
SN and LN hyperechogenicity were more frequent in heterozygotes than in controls, probably due to copper accumulation, but it remains unknown if this predisposes to brain neurodegeneration.
Abstract Wilson's disease (WD) is an inherited copper metabolism disorder. Gait disturbances may present with both extrapyramidal and cerebellar patterns. The frequencies of particular types of gait ...abnormalities have not been established; thus, the aim of the present study was to determine the occurrence of initial gait disturbances among our neurological WD patients. We analyzed 103 WD patients with neurological features at the time of diagnosis, between 2005 and 2014. The neurological and gait assessments were based on the Unified Wilson's Disease Score Scale (UWDRS), from which, we distinguished three main patterns of gait: dystonic, ataxic, or Parkinsonian. All types of gait impairment were assessed using four stages of severity (0 = normal, 4 = severe). We also obtained each patient's history of falls. Three patients had severe dystonia of limbs and were unable to stand or walk. Gait abnormalities were noted in 59% (59/100) of the remaining group of patients. The most common observed pattern was ataxic gait (45%; 27/59), which presented as impaired tandem in most cases. A mixed gait impairment was observed in 25% (15/59) of patients (ataxic, dystonic, and Parkinsonian, n = 8; ataxic and Parkinsonian, n = 7), a Parkinsonian gait in 18% (11/59), and a dystonic gait in 10% (6/59) of patients. Falls were noted in 35% of patients, but were occasionally observed in most cases. Gait disturbances are frequent in WD, and reflect the involvement of many brain structures.
Treatment of Wilson's disease (WD), an inherited disease characterized by copper overload, is lifelong and there is the possibility that copper deficiency (CD) may occur. We systematically reviewed ...the literature to describe treatment patterns, symptoms and outcomes associated with CD.
Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, the PubMed database was searched up to 6 April 2023.
Across 17 articles, 20 cases of CD were described, most commonly (15 cases) in WD patients treated with zinc salts (ZS), less often on combined chelator and ZS therapy (3 cases), molybdate salts plus ZS (1), or molybdate alone (1). CD symptoms occurred insidiously, including sideroblastic anemia, neutropenia, axonal sensory neuropathy, posterior cord myelopathy and increased ratio of epileptic seizures (or epilepsy). CD diagnosis was based on symptoms and severely reduced urinary copper excretion (<20 µg/24 h <0.3 µmol/24 h on ZS, or <100 µg/24 h <1.6 µmol/24 h on chelators) with low total serum copper and ceruloplasmin.
Awareness of CD and regular monitoring of copper metabolism is needed during WD treatment. Temporary cessation of anti-copper treatment usually reverses serum copper reductions as well as pancytopenia; however, some symptoms, especially neuropathy and myelopathy, may persist.
Wilson's disease (WD) is an inherited disorder of copper metabolism with clinical symptoms related to pathological copper accumulation, which are mainly hepatic and/or neuropsychiatric. The disease ...is potentially treatable with pharmacological agents (chelators or zinc salts). As such, key factors for a favorable treatment outcome are early diagnosis and anti-copper treatment initiation as well as appropriate treatment monitoring for safety and efficacy. Despite the generally favorable outcome in most treated patients, almost 10% of the general population of WD patients and about 25% of patients in the group with initial neurological phenotype of disease experience early neurological deterioration. In almost 50% of patients with neurological symptoms, the symptoms persist. A search for new treatment modalities (e.g., gene therapy, molybdenum salts) aims to prevent early neurological deterioration as well as improve treatment outcomes. In addition to evaluating the clinical signs and symptoms of the disease, serum biomarkers for diagnosis and treatment monitoring are very important for WD management. Sensitive serum biomarkers of copper metabolism and liver injury are well described. However, there is a need to establish blood-based biomarkers of central nervous system (CNS) injury to help identify patients at risk of early neurological deterioration and aid in their monitoring. Based on the available literature and studies of WD patients, the authors reviewed serum biomarkers of CNS involvement in WD, as well as their potential clinical significance.
CEL NAUKOWY: Głównym celem naukowym artykułu jest analiza kwestii, czy w świetle przepisów Konstytucji RP jakikolwiek podmiot spoza jej art. 10 mógłby równoważyć pozycję ustrojową legislatywy ...i egzekutywy – pełnić rolę „czwartej władzy”.
PROBLEM I METODY BADAWCZE: Podstawowym problemem badawczym jest próba odpowiedzi na pytania, czy według Konstytucji jakiś podmiot mógłby pełnić rolę „czwartej władzy”, a jeśli nie, to jak należy zmienić Konstytucję, aby wprowadzić do niej „czwartą władzę”. W artykule wykorzystano analizę instytucjonalno-prawną przepisów Konstytucji ze szczególnym uwzględnieniem: językowo-logicznej, systemowej, doktrynalnej oraz sądowej wykładni przepisów Konstytucji.
PROCES WYWODU: Merytoryczną część artykułu rozpoczynają uwagi o konstytucyjnej zasadzie podziału władzy. Następnie przedstawione są rozważania o pojęciu „czwartej władzy” z perspektywy konstytucyjno-prawnej oraz analiza przepisów Konstytucji nakierowana na odnalezienie podmiotu, który mógłby pełnić rolę „czwartej władzy”. Artykuł kończą propozycje wprowadzenia zmian do Konstytucji, które pozwolą suwerenowi, samorządowi terytorialnemu oraz organom kontroli państwowej i ochrony prawa równoważyć pozycję ustrojową legislatywy i egzekutywy.
WYNIKI ANALIZY NAUKOWEJ: W świetle przepisów Konstytucji RP żaden podmiot nie pełni roli „czwartej władzy”.
WNIOSKI, INNOWACJE, REKOMENDACJE: Potrzebne jest wprowadzenie do Konstytucji RP zmian wzmacniających pozycję ustrojową Narodu, samorządu terytorialnego, organów kontroli państwowej i ochrony prawa oraz prokuratury, które mogłyby pełnić rolę „czwartej władzy”.
Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving ...hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes.
WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9.
We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.
The reviewed scientific monograph is the first book devoted entirely to a very important issue: the evolution of the institution of the head of state in Poland from 1918 to 1997. The head of state in ...this period functioned in various constitutional-legal forms, both individual (Chief of State, President of the Republic of Poland, Chairman of the State National Council) and collegial (Presidium of the State National Council, State Council). These different legal regulations undoubtedly influenced the current construction of the provisions of the Constitution of the Republic of Poland of 1997 pertaining to the President of the Republic of Poland. The main advantage of the monograph, besides the insightful legal analyses, is the presentation of the constitutional practice and the historical background concerning the functioning of the head of state in the analysed period.
The reviewed scientific monograph is the first book devoted entirely to a very important issue: the evolution of the institution of the head of state in Poland from 1918 to 1997. The head of state in ...this period functioned in various constitutional-legal forms, both individual (Chief of State, President of the Republic of Poland, Chairman of the State National Council) and collegial (Presidium of the State National Council, State Council). These different legal regulations undoubtedly influenced the current construction of the provisions of the Constitution of the Republic of Poland of 1997 pertaining to the President of the Republic of Poland. The main advantage of the monograph, besides the insightful legal analyses, is the presentation of the constitutional practice and the historical background concerning the functioning of the head of state in the analysed period.
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