Update on the Diagnosis and Management of Wilson Disease

Roberts, Eve A.

doi:10.1007/s11894-018-0660-7

Cited by 48 publications

(28 citation statements)

References 86 publications

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“…Variants in MUTYH were detected in 3 individuals (in 1/90 of our cohort), and in the ATP7B gene in 4 individuals (in 1/70 of our cohort). The prevalence of heterozygous germline MUTYH and ATP7B variants in our cohort is comparable to that reported in the general population (1/100 and 2/100 for MUTYH and 1/90 for ATP7B variants) (Nielsen et al, 1993;Al-Tassan et al, 2002;Cleary et al, 2009;Win et al, 2017;Roberts, 2018). Since the guidelines of the ACMG recommend to only return bi-allelic pathogenic variants, carriers' status was checked in our study but was not reported.…”

Section: Discussionsupporting

confidence: 83%

Actionable Exomic Secondary Findings in 280 Lebanese Participants

2020

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The expanded use of NGS tests in genetic diagnosis enables the massive generation of data related to each individual, among which some findings are of medical value. Over the last three and a half years, 280 unrelated Lebanese patients, presenting a wide spectrum of genetic disorders were referred to our center for genetic evaluation by WES. Molecular diagnosis was established in 56% of the cases, as was previously reported. The current study evaluates secondary findings in these patients in 59 genes, linked to conditions mostly responsive to medical interventions, as per the ACMG guidelines. Our analysis allowed us to detect 19 pathogenic/likely pathogenic variants in 24 individuals from our cohort. Dominant actionable variants were found in 17 individuals representing 6% of the studied population. Genes associated with dominant cardiac diseases were the most frequently mutated: variants were found in 2.1% of our cohort. Genetic predisposition to cancer syndromes was observed in 1.07% of the cases. In parallel to dominant disease alleles, our analysis identified a recessive pathogenic disease allele in 2.5% of the individuals included in this study. Of interest, some variants were detected in different patients from our cohort thus urging the study of their prevalence in our population and the implementation, when needed, of specific genetic testing in the neonatal screening panel. In conclusion, here we report the first study estimating the actionable pathogenic variant load in the Lebanese population. Communicating current findings to the patients will enable them to benefit from a multi-disciplinary approach. Furthermore, tailoring the ACMG guidelines to the population is suggested, especially in highly consanguineous populations where the information related to recessive alleles might be highly beneficial to patients and their families.

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Section: Discussionsupporting

confidence: 83%

Actionable Exomic Secondary Findings in 280 Lebanese Participants

2020

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“…Ceruloplasmin is essential to iron transport and metabolism through its ferroxidase activity, which catalyzes the conversion of Fe 2+ to Fe 3+ . Ceruloplasmin plasma levels are of clinical relevance, mainly in the diagnosis of Wilson disease, a genetic condition caused by ATP7B pathogenic variants [7][8][9]. Changes in plasma copper levels and parameters of copper metabolism are connected to metabolic conditions, including obesity and fatty liver, and dietary factors [2,10].…”

Section: Introductionmentioning

confidence: 99%

Effects of Dietary Glucose and Fructose on Copper, Iron, and Zinc Metabolism Parameters in Humans

et al. 2020

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Alterations of transition metal levels have been associated with obesity, hepatic steatosis, and metabolic syndrome in humans. Studies in animals indicate an association between dietary sugars and copper metabolism. Our group has conducted a study in which young adults consumed beverages sweetened with glucose, fructose, high fructose corn syrup (HFCS), or aspartame for two weeks and has reported that consumption of both fructose- and HFCS-sweetened beverages increased cardiovascular disease risk factors. Baseline and intervention serum samples from 107 participants of this study were measured for copper metabolism (copper, ceruloplasmin ferroxidase activity, ceruloplasmin protein), zinc levels, and iron metabolism (iron, ferritin, and transferrin) parameters. Fructose and/or glucose consumption were associated with decreased ceruloplasmin ferroxidase activity and serum copper and zinc concentrations. Ceruloplasmin protein levels did not change in response to intervention. The changes in copper concentrations were correlated with zinc, but not with iron. The decreases in copper, ceruloplasmin ferroxidase activity, ferritin, and transferrin were inversely associated with the increases in metabolic risk factors associated with sugar consumption, specifically, apolipoprotein CIII, triglycerides, or post-meal glucose, insulin, and lactate responses. These findings are the first evidence that consumption of sugar-sweetened beverages can alter clinical parameters of transition metal metabolism in healthy subjects.

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“…Copper chelating agents with or without zinc supplementation are the mainstay of therapy in WD [ 20 ]. Whether these therapies are also efficacious in reversing nephritis in those with associated IgA-N is not very clear, although some studies have shown clear benefits [ 6 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

IgA vasculitis with nephritis in cirrhotic Wilson disease: Is there an association?

Acharya¹,

Xu²,

Clapp³

et al. 2020

CNCS

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Introduction: IgA vasculitis (IgA-V) predominantly involves skin, gastrointestinal (GI) tract, joints, and kidneys. Wilson disease (WD) is a hepatolenticular degenerative disease caused by ATP7B gene mutation. Case report: Here we describe an unusual association of IgA-V with nephritis (IgA-VN) in an 11-year-old child with WD. He presented with palpable purpura without arthritis and GI involvement. Renal function was normal. Urinalysis showed microscopic hematuria and tubular proteinuria. Evaluation showed transaminitis, hypoalbuminemia, IgA hyperglobulinemia, and coagulation abnormalities. Serum ceruloplasmin and copper were low and 24-hour urine copper was extremely elevated. Liver biopsy showed stage IV cirrhosis with increased quantitative liver copper content. Skin and renal biopsy showed IgA-positive leukocytoclastic vasculitis and mesangial hyperplasia with IgA deposition, respectively. Quantitative renal copper content was normal. Homozygous pathogenic variant c.3207C>A (p.His1069Gln) of ATP7B was detected. There were no Kayser-Fleischer rings in the eyes, and neuropsychiatric examination was normal. Treatment with zinc and trientine led to normalization of hepatic function and serum IgA level with resolution of the rash and maintenance of renal function. Conclusion: Defective hepatic processing and/or clearance of IgA/IgA immune complexes probably led to the IgA-mediated skin and renal injury. Further such reports will help augment our understanding on the pathophysiology of IgA-VN in WD.

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Update on the Diagnosis and Management of Wilson Disease

Cited by 48 publications

References 86 publications

Actionable Exomic Secondary Findings in 280 Lebanese Participants

Actionable Exomic Secondary Findings in 280 Lebanese Participants

Effects of Dietary Glucose and Fructose on Copper, Iron, and Zinc Metabolism Parameters in Humans

IgA vasculitis with nephritis in cirrhotic Wilson disease: Is there an association?

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