Clinical Manifestations Of Wilson's Disease Research Articles

The role of intestine in metabolic dysregulation in murine Wilson disease.

The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, but little is known about other tissue involvement regarding metabolic changes in WD. In vitro studies suggested that the loss of intestinal ATP7B affects metabolic dysregulation in WD. We tested this hypothesis by evaluating the gut microbiota and lipidome in 2 mouse models of WD and by characterizing a new mouse model with a targeted deletion of Atp7b in the intestine. Cecal content 16S sequencing and untargeted hepatic and plasma lipidome analyses in the Jackson Laboratory toxic-milk and the Atp7b null global knockout mouse models of WD were profiled and integrated. Intestine-specific Atp7b knockout mice (Atp7bΔIEC) were generated and characterized using targeted lipidome analysis following a high-fat diet challenge. Gut microbiota diversity was reduced in animal models of WD. Comparative prediction analysis revealed amino acid, carbohydrate, and lipid metabolism functions to be dysregulated in the WD gut microbial metagenome. Liver and plasma lipidomic profiles showed dysregulated triglyceride and diglyceride, phospholipid, and sphingolipid metabolism in WD models. However, Atp7bΔIEC mice did not show gut microbiome differences compared to wild type. When challenged with a high-fat diet, Atp7bΔIEC mice exhibited profound alterations to fatty acid desaturation and sphingolipid metabolism pathways as well as altered APOB48 distribution in intestinal epithelial cells. Gut microbiome and lipidome underlie systemic metabolic manifestations in murine WD. Intestine-specific ATP7B deficiency affected both intestinal and systemic response to a high-fat challenge but not the microbiome profile, at least at early stages. WD is a systemic disease in which intestinal-specific ATP7B loss and diet influence the phenotype and the lipidome profile.

THU-382 - Online education yields significant gains in gastroenterologists’ knowledge of clinical manifestations of Wilson disease

THU-382 - Online education yields significant gains in gastroenterologists’ knowledge of clinical manifestations of Wilson disease

Genetics and epigenetic factors of Wilson disease.

Wilson disease (WD) is a complex condition due to copper accumulation mainly in the liver and brain. The genetic base of WD is represented by pathogenic mutations of the copper-transporting gene ATP7B with consequent lack of copper excretion through the biliary tract. ATP7B is the only gene so far identified and known to be responsible for the development of the disease. Our understanding of the disease has been evolving as functional studies have associated specific disease-causing mutations with specific copper-transporter impairments. The most frequent variant in patients of European descent is the H1069Q missense mutation and it has been associated with protein misfolding, aberrant phosphorylation of the P-domain, and altered ATP binding orientation and affinity. Conversely, there is much less understanding of the relation between the genotype and the clinical manifestations of WD. WD is characterized by a highly varied and unpredictable presentation with different combined hepatic, neurological, and psychiatric symptoms. Several studies have attempted to correlate genotype and phenotype but the most recent evidences on larger populations failed to identify a relation between genotype and clinical presentations. Given that so far also modifier genes have not shown convincing association with WD, there is growing interest to identify epigenetic mechanisms of gene expression regulation as underlying the onset and progression of WD phenotype. Evidence from animal models indicated changes in methionine metabolism regulation with possible effects on DNA methylation. Mouse models of WD have indicated transcript level changes of genes related to DNA methylation in fetal and adult livers. And finally, evidence is accumulating regarding DNA methylation changes in patients with WD. It is unexplored how ATP7B genetic mutations combine with epigenetic changes to affect the phenotype. In conclusion, WD is a genetic disease with a complex regulation of its phenotype that includes molecular genetics and epigenetic mechanisms.

Clinical manifestations of Wilson disease in organs other than the liver and brain.

Wilson disease (WD) is an inherited genetic disorder that is caused by copper metabolism disturbances with main hepatic, neurological, and psychiatric presentation. Deposits of copper accumulate in different organs and may cause a broad range of clinical manifestations. Patients with WD may present with ophthalmological symptoms, or renal, cardiac and osteoarticular involvement. The most common ophthalmological sign as a result of copper accumulation is the Kayser-Fleischer corneal ring, whereas sunflower cataracts are observed rarely. Retinal degeneration, present in WD patients, may serve as a marker of neurodegeneration. Osteoarticular involvement is quite common and includes osteopenia, osteoporosis and arthropathy, which may lead to bone fractures and joint problems mainly affecting knees and wrists. Renal disturbances include tubular dysfunction and renal calculi. A recent cardiac study has shown a higher risk of atrial fibrillation and heart failure in WD patients than in non-WD patients. Autonomic system dysfunction is also observed, but involvement is subclinical in most cases. Another manifestation of WD concerns endocrine system disturbances, which can lead to recurrent abortions, infertility, growth disruption, and parathyroid failure. However, it is possible to become pregnant for females with mild WD symptoms and for those who are compliant with therapy. Hematologic disturbances are frequent and may include acute hemolytic anemia, leucopenia, anemia and low platelet count. Other observed symptoms include lipomas and characteristic of WD skin changes like hyperpigmentation of the legs, xerosis or azure lunulae of the nails. In this paper, we present some of the less common, but nevertheless, important manifestations of WD.

Chapter 13 - Other organ involvement and clinical aspects of Wilson disease

Wilson disease (WD) is a rare disorder of copper metabolism that presents mainly with hepatic and neuropsychiatric features. Copper accumulates not only in the liver and brain, but also in other organs. Liver injury can also be the cause of secondary impairment of other tissues. Therefore, the clinical manifestation of WD may be renal, cardiac, skin, osteoarticular, or endocrinologic and include other organ disturbances. Renal abnormalities include tubular dysfunction (e.g., renal tubular acidosis, aminoaciduria) and nephrolithiasis. Bone demineralization is a common manifestation in patients with WD. Cardiac injury may include arrhythmia, cardiomyopathy, and autonomic dysfunction. Different endocrine system manifestations, such as infertility or repeated miscarriages, growth and puberty disturbances, and hypoparathyroidism, are observed. Other important clinical aspects of WD include pancreas involvement, immunologic abnormalities, the presence of lipomas, and skin changes. Although other organ involvement is not common in WD and usually not severe, delayed diagnosis may lead to irreversible changes in organs and tissues. Therefore, awareness of other possible WD presentations is important in the differential diagnosis of WD.

Intragenic Deletions in ATP7B as an Unusual Molecular Genetics Mechanism of Wilson's Disease Pathogenesis.

Wilson’s disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B resulting in copper overload in the liver and brain. Direct sequencing is routinely used to confirm WD diagnosis; however, partial and whole gene deletions in the heterozygous state cannot be detected by exon amplification since the normal allele will mask its presence. The aim of the present work was to search for unusual mutational events in the unexplained WD cases and to provide insight into the mechanisms. Out of 1420 clinically and biochemically confirmed WD samples received between 2000 and 2014 for routine mutation analysis, we were unable to detect mutant alleles in 142 samples, after extensive sequencing analysis. We used selective amplification and MLPA to identify the partial gene deletions and identified three different partial gene deletions in seven different families. All three deletions were fully characterized at the DNA sequence level. We report the first hemizygous case with WD due to intragenic deletion in the ATP7B (c.3134_3556+689del). This novel deletion resulted from an excision event mediated by consensus sequences in an AluSq2 repeat element and could be traced to micro homologous end joining (MMEJ). Finally, we determined the prevalence of the three deletions in DNA samples from a multinational group of WD patients. Our results emphasize the need for searching mutant alleles beyond routine methods and highlight that large ATP7B deletions are rare, but account for a detectable proportion in some WD patients. Screening for gene aberrations will further improve mutation detection in patients with unidentified ATP7B mutations presenting with clinical manifestations of WD.

Direct sequencing of mutations in the copper-transporting P-type adenosine triphosphate (ATP7B) gene for diagnosis and pathogenesis of Wilson's disease.

Copper-transporting P-type adenosine triphosphatase (ATP7B) has been identified as the pathogenic gene in hepatolenticular degeneration, or Wilson's disease (WD). The aim of this study was to explore the correlation between genetic mutations and the clinical profile of WD, and to discuss the value of mutation examination in its diagnosis for providing a scientific basis for the development of a method to examine genetic mutations. Sixty-eight Chinese Han patients with WD and 20 controls were included in this study. The ATP7B gene in DNA extracted from patient blood samples was amplified by PCR and sequenced. These sequences were compared against corresponding gene sequences obtained from healthy controls to statistically analyze the genetic mutations. Five of the nineteen mutations in ATP7B were newly detected mutations; moreover, 8 of these mutations were polymorphic (2 were newly identified). The Arg778Leu and Pro992Leu mutations in exons 8 and 13 were detected at the highest mutation frequencies of 25.74 and 16.91%, respectively. The frequencies of all other mutations were below 5%. However, the clinical manifestations of WD did not differ significantly in patients with the Arg778Leu and Pro992Leu mutations. Therefore, these mutations were considered as hotspot mutations in Chinese WD patients. However, we observed no significant correlation between these genetic types and the clinical symptoms of WD. The correlation between the mutation genotype and disease phenotype remains to be elucidated. In conclusion, the highly sensitive and specific direct DNA sequencing method can be used to screen for the causative genes of WD.

Febrile Syndrome as a First Clinical Manifestation of Wilson Disease

Wilson disease (WD) is a rare autosomal recessive genetic disorder associated with copper metabolism. ATP7B protein function is reduced or absent. The classical clinical presentation with positivity for Kayser-Fleischer rings, neurological and hepatic manifestations is not the rule. About half of the patients presenting liver disease may have atypical clinical manifestations and do not possess two of the three classical criteria. Presentation of case: A 36 year-old male with atypical WD clinical presentation characterized by febrile syndrome and jaundice as the predominant manifestations of the disease.

Wilson Disease

The clinical manifestations of Wilson disease (WD) are varied and challenging. We conducted the current study to present the phenotypic characteristics and follow-up for a large cohort of patients with WD. We reviewed the medical records of 282 cases of WD (male:female ratio, 196:86) for clinical features, investigations, treatment, and outcome data. The clinical presentations were as follows: hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and "presymptomatic," 15 (5.3%). Mean age was 15.9 years. Presymptomatic patients and those with the hepatic form of WD were younger and patients with osseomuscular and psychiatric forms were older than neurologic patients. The mean duration of illness at the time of diagnosis was 28 months. Predominant neurologic features were as follows: parkinsonism, 62.3%; dystonia, 35.4%; cerebellar, 28%; pyramidal signs, 16%; chorea, 9%; athetosis, 2.2%; myoclonus, 3.4%; and behavioral abnormalities, 16%. Kayser-Fleischer (KF) rings were seen as follows: neurologic patients, 100%; hepatic patients, 86%; and presymptomatic patients, 59%. Positive family history was noted in 47% and consanguinity in 54%. Patients born of consanguineous parents had an earlier age of onset and shorter duration of illness before presentation. Serum ceruloplasmin was decreased in 93% and 24-hour urinary copper excretion was increased in 70% of patients. Neuroimaging (computed tomography/magnetic resonance imaging) and electrophysiologic abnormalities were seen in many patients. Overall, 195 patients were on D-penicillamine therapy and 182 on zinc sulphate. Follow-up data, available for 225 patients, for a mean duration of 46 months, revealed improvement in 176, no change in 20, and deterioration in 6. Twenty-three patients died. To conclude, despite increased awareness and recognition and significant inroads into therapeutic frontiers, follow-up remains poor in developing countries and a return to previous level of functioning is not universal.

Acquired Hepatocerebral Degeneration

Acquired hepatocerebral degeneration (AHD) is a neurologic syndrome occurring in the presence of chronic hepatic disease, which results in permanent neurologic aberrations. The syndrome shares many of the clinical manifestations of Wilson disease, however, distinction can be made with slit lamp examination and biochemical studies. Cranial magnetic resonance (MR) imaging of a patient with AHD revealed increased signal intensity in the dentate nuclei bilaterally on T2-weighted images indistinguishable from Wilson disease. The MR findings of Wilson disease as described in the literature are not specific and further investigation with slit lamp examination and biochemical studies is warranted to distinguish between the two entities.