Phenotypic polymorphism in Wilson’s disease – between genetics and epigenetics

Background: Wilson’s disease is a rare, autosomal recessive genetic disorder that affects the biliary excretion of copper and its toxic accumulation in various tissues, especially the liver and brain. It is widespread throughout the world, with a high prevalence in socio-culturally isolated communities. The course of the disease and the age of onset depend on the site of mutation in the gene and the degree of functional impairment of the ATP7B protein. The presence of the compound heterozygous patient complicates the comparative genetic and clinical evaluation. Therefore, it is necessary to analyze Wilson’s variants in both the homozygous and the compound-heterozygous conditions to better understand the genotype-phenotype correlations and the incomplete penetrance observed in this disorder. Outlining clear phenotype-genotype associations is difficult due to a large number of mutations and different clinical presentations, but the involvement of epigenetic factors, modifying genes, environmental and lifestyle factors could explain the differences in evolution and onset in members of the same family and not only. Conclusions: Wilson’s disease is a genetically and clinically complex disorder. Although the results of genotype-phenotype correlation studies are not well defined, and in some cases are completely contradictory, some peculiarities related to the age of onset, sex, clinical phenotype, and the evolution of the disease have been highlighted. The interaction between genetic mutations and epigenetic factors may explain the phenotypic variability, but needs further study

The diagnostic challenges of Wilson’s disease related to copper findings

Introduction. Wilson’s disease - a genetic disorder due to mutations of the ATP7B gene which causes disturbance of copper metabolism and its accumulation in various tissues, especially the liver and brain. Deviations in parameters of copper metabolism are not exclusively attributed to Wilson’s disease. Complex biochemical processes are involved in copper homeostasis. Disruptions in these processes lead to separately described diseases contrary to the ATP7B defect. Aim of study. To analyze the bibliographic data regarding the changes in copper homeostasis and the differential diagnosis of Wilson's disease related to its findings. Methods and materials. An advanced search was performed in the PubMed, Medline, and ScienceDirect databases, taking into account relevant articles, published in the last 10 years. The search English terms used were: “human copper metabolism”, “inherited disorders”, “serum ceruloplasmin”, “serum cooper”, “serum” “free” “copper”, “24-hour urinary copper”, “hepatic cooper”. Results. A single biochemical test is not sufficient to establish a diagnosis of Wilson's disease. Typical findings include low serum ceruloplasmin and serum copper, high copper urinary excretion in 24-hour and high hepatic copper content. The decrease of serum ceruloplasmin is not 100% sensitive or specific, and it must be differentiated from over cases, as well malabsorption, autoimmune hepatitis, celiac disease, familial aceruloplasminemia, MEDNIK syndrome, Menkes disease, etc. Serum copper (which includes copper incorporated in ceruloplasmin) is usually decreased in proportion to the decreased serum ceruloplasmin. Hypocupremia can occur in insufficient oral intake, an increased zinc uptake, taking valproic acid, idiopathic cases. In some situations, it may be within normal range or markedly elevated, that's why the serum “free” copper was proposed as a diagnostic test for Wilson's disease. However, it is recommended to be used as a pharmacotherapy monitoring test rather than a diagnostic test. Interpreting 24-hour urinary copper excretion can be difficult due to the overlap with findings in other types of liver disease (e.g. autoimmune hepatitis, chronic active liver disease, or cholestasis), incorrect urine collection, and copper contamination of the collection device, while in case of impaired kidney function, the test is not applicable. Hepatic copper accumulation is the hallmark of Wilson’s disease, but it can be misinterpreted due to inhomogeneous distribution of copper, long-standing cholestatic disorders, in idiopathic copper toxicosis syndromes such as Indian childhood cirrhosis. Conclusion. Numerous conditions can influence copper homeostasis, including several genetic diseases. Not a single test is specific per se and, thus, a range of tests has to be applied. The diagnostic finding can only be interpreted plausibly in context with other findings (clinically and laboratory) to avoid false-positive or false-negative results

Фенотипическая и генотипическая диагностика болезни Вильсона: клинический случай

Summary. Wilson’s disease is a rare genetic disease determined by a mutation of the ATP7B gene, which leads to reduced biliary excretion of copper and its storage in various tissues. Although it is a monogenic disorder, the disease is characterized by extraordinary clinical and genetic diversity. The given article tells about a young man diagnosed with Wilson’s disease. The patient was evaluated according to international protocols: clinical, hematological, biochemical, ophthalmological, imaging, endoscopic and genetic. Thus, according to the results of all investigations, a Leipzig score ≥ 4 points was established, which is valid for a definite diagnosis of Wilson’s disease. The peculiarities of this clinical case are the early onset of the disease with primary manifestations of advanced liver disease, the delay in establishing the diagnosis, the compound heterozygous status, the low compliance of the patient, and the refusal to accept the presence of a genetic disease by the family.Rezumat. Boala Wilson reprezinta o maladie genetica rară determinata de o mutația genei ATP7B, ce duce la reducerea excreției biliare a cuprului și depozitarea lui în diferite țesuturi. Deși, este o tulburare monogenică, boala se caracterizează printr-o diversitate clinică și genetică extraordinară. Articolul dat relatează despre un tânar diagnosticat cu boala Wilson. Bolnavul a fost evaluat conform protocoalelor internaționale: clinic, hematologic, biochimic, oftalmologic, imagistic, endoscopic și genetic. Astfel, conform rezultatelor tuturor investigațiilor s-a stabilit un scor Leipzig ≥ 4 puncte, ce este valabil pentru un diagnostic cert de boală Wilson. Particularitățile acestui caz clinic sunt debutul precoce a bolii cu manifestări primare de boală hepatică avansată, întârzierea stabilirii diagnosticului, statutul de heterozigot compus, complianța redusă a pacientului și refuzul de a accepta prezența unei boli genetice de către familie.Резюме. Болезнь Вильсона — редкое генетическое заболевание, определяемое мутацией гена ATP7B, что приводит к снижению экскреции меди с желчью и ее депонированию в различных тканях. Хотя это моногенное заболевание, заболевание характеризуется необычайным клиническим и генетическим разнообразием. В данной статье рассказывается о молодом человеке с диагнозом болезнь Вильсона. Пациент был оценен в соответствии с международными протоколами: клиническим, гематологическим, биохимическим, офтальмологическим, ультразвуковое исследование, эндоскопическим и генетическим. Таким образом, по результатам всех исследований была установлена Лей пцигская оценка ≥ 4 балла, что справедливо для достоверного диагноза болезни Вильсона. Особенностью данного клинического случая является раннее начало заболевания с первичными проявлениями запущенного заболевания печени, задержка в установлении диагноза, компаунд-гетерозиготный статус, низкая комплаентность больного и отказ принять наличие генетического заболевания. семьей

Wilson's disease: clinical evolution of moldovan patients

Discipline of Gastroenterology, State University of Medicine and Pharmacy “Nicolae Testimitanu”, str. Stefan cel Mare 165, Chisinau, Republic of Moldova, IMSP, Institute of Mother and Child, Genetic Center of Excellence in the Republic of Moldova, Laboratory of Human Molecular GeneticsIntroduction. Wilson's disease (WD) is an autosomal recessive genetic disorder associated with a high mortality and disability rate. WD manifests as chronic liver disease and/or neurological impairment due to accumulation of copper in several tissues, principally in the liver and brain (Fig.1). Early diagnosis and therapy can result in a good prognosis of WD. Purpose. To analyze the clinical and laboratory evolutions of WD and the effects of the standard treatments in Moldovan patients with WD. Material and methods. 15 patients (6 females and 9 males) with WD were evaluated retrospectively between 2018-2021. (Fig.2) Results. The median age at diagnosis was 22 years (2 – 36 years). The distribution by clinical fenotypes is presented in Tab.1 Fibrosis analysis (by Fibroscan) revealed that: 6 patients - F2, 2 - F4, 2 - steatosis, 1 - F0. The treatment consisted of D-penicillamine associated with pyridoxine for all patients. At the end of the study, all treated hepatic patients were asymptomatic. (Fig.3) Conclusions. The study suggests that Wilson's disease must be ruled out in children older than two years presenting with abnormal levels of hepatic enzymes because of the heterogeneity of symptoms and the encouraging treatment results obtained so far

Exchangeable copper - a new diagnostic indicator for Wilson's disease

Introduction. Wilson”s disease (WD) biochemical markers continue to evolve. Classical tests have their own limits (tab.1), and they are often insufficient to diagnose or exclude WD. The free copper was proposed as a diagnostic test, but it was showed a large overlapping of this parameter between non-WD subjects and WD patients. New biomarkers are being investigated. Purpose. The paper aims to analyze the bibliographic data on the new tools for diagnostic in WD, like exchangeable copper (CuEXC). Material and methods. An advanced search was performed in the PubMed, and ScienceDirect databases, using the search English terms: ”Wilson's disease”, ”diagnostic test” and ”relative exchangeable copper”. Results. CuEXC is a new validated method for the direct determination of labile copper that can be correlated with the toxic fraction of copper and used to monitor treatment in Wilson patients. The relative exchangeable copper (REC) - the ratio of CuEXC/total serum copper is the best biomarker for the diagnosis of WD showing 100% sensitivity and 100% specificity. Studies confirm that a REC value >18.5% appears to be a highly discriminatory tool to differentiate WD between controls, presymptomatic patients, heterozygotes, and patients with non-Wilsonian liver disease, in cirrhosis and cholestasis, both in adults and in children. Family screening in asymptomatic subjects observed that REC determination significantly differentiated subjects non-WD from WD patients with a cutoff of 15%. Conclusions. CuEXC proved a helpful contribution in starting quickly the treatment without waiting for genetic testing results. Being a tool with high sensitivity and specificity, the determination of REC can be useful, reliable, rapid, and easy to set up to confirm or exclude WD in both adults and children, in carriers or asymptomatic patients

Correlation between neurological impairment and liver status in Wilson’s disease

Background: The most widely recognized aspect of the neuro-hepatic relation is hepatic encephalopathy, in which neurotransmission in the brain is altered. Of course, there are many conditions that affect both the liver and the nervous system, Wilson’s disease being one of the best known. The aim was to characterize the neurological manifestations of Wilson’s diseases in terms of symptom type and degree of neurological impairment and correlate these features with degree of abnormalities in copper metabolism, and hepatic status. Material and methods: 15 patients diagnosed with Wilson’s disease were characterized by examination in terms of symptoms including consciousness, activities of daily living as reported by the patient. The neurological manifestations were analyzed in relation to copper abnormalities and liver status. Results: Most patients (52.9%) exhibited tremor and ataxia, whereas 9.3% were dystonic, and 7.3% had Parkinsonism. Discrete signs were observed in 19.6% of patients. A positive correlation between neurological impairment and higher level of free cooper was observed (Pearson r=0.71). Poor correlation was identified between neurological impairment and hepatic disturbances. Conclusions: The neurological manifestations of Wilson’s disease did not appear to be correlated with hepatic status. These results draw our attention to the symptomatic variability of Wilson’s disease, and an individualized approach to each patient is essential

The spectrum of liver presentation in wilson's disease: a literature review

Introduction. Wilson's disease represents one of the genetic diseases that has lifelong treatment, which significantly improved the quality of life for patients and reduced the disabling complications associated with the lack of an early diagnosis. Material and methods. A structured search was performed in PubMed and HINARI, using English search terms: "Wilson's disease", "acute liver failure", "cirrhosis", "acute Wilsonian hepatitis", "hepatic manifestation", "chronic liver disease", "asymptomatic Wilson's disease", and "active chronic hepatitis". Results. Wilson's disease can occur at any age and can mimic the presence of other chronic liver diseases. The hepatic expression is highly variable, ranging from asymptomatic presentation to severe liver diseases, such as decompensated cirrhosis and acute liver failure. Any patient with transaminitis and abnormal parameters of cooper metabolism should be comprehensively and carefully evaluated to identify Wilson's disease early and to prevent misdiagnosis or unnecessary therapies. Confirmation of the diagnosis should not exclude the co-existence of other liver diseases. Conclusions. The use of validated and adapted scores for Wilson's disease may facilitate diagnosis, but they cannot be used in acute liver failure. Considering that WD presents itself with great phenotypic diversity and can evolve under the mask of other pathologies, it is necessary to carry out a careful differential diagnosis