Wilson disease: Clinical manifestations, diagnosis, and treatment

Schilsky, Michael L.

doi:10.1002/cld.349

Cited by 45 publications

(59 citation statements)

References 12 publications

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“…Pathogenic variants in ATP7A and ATP7B manifest as Menkes and Wilson disease, respectively (Bull et al, 1993, Vulpe et al, 1993. In line with our model, neither disorder is characterized by immune suppression or neutropenia, even though severe liver pathology is a hallmark of Wilson disease (Schilsky, 2014). Mitochondrial signaling has previously been shown to promote cellular copper efflux (Leary et al, 2007, Leary et al, 2013, and the most severe leukopenias in our hep models coincide with higher levels of copper in the circulation.…”

Section: Discussionsupporting

confidence: 84%

Mitochondrial dysfunction triggers secretion of the immunosuppressive factor α-fetoprotein

Hossain

et al. 2021

Preprint

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Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identify a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that results in atrophy of the spleen and thymus and causes a peripheral white blood cell deficiency. We demonstrate that the leukopenia is caused by α-fetoprotein, which requires copper and the cell surface receptor CCR5 to promote white blood cell death. We further show that α-fetoprotein expression is upregulated in several cell types upon inhibition of oxidative phosphorylation, including a muscle cell model of Barth syndrome. Collectively, our data argue that α-fetoprotein secreted by bioenergetically stressed tissue suppresses the immune system, an effect which may explain the recurrent infections that are observed in a subset of mitochondrial diseases or in other disorders with mitochondrial involvement.

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Section: Discussionsupporting

confidence: 84%

Mitochondrial dysfunction triggers secretion of the immunosuppressive factor α-fetoprotein

Hossain

et al. 2021

Preprint

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“…To reduce it to normal levels, there are different strategies currently used as WD treatment involving removal of excess Cu by the administration of Cu chelators such as D-penicillamine (D-PCA; with very severe side effects such as immunological disturbances, skin defects, joint disorders and worsened neurological manifestations), Trientine (with lower side effects compared to D-penicillamine) and the novel chelating agents such as tetrathimolybdate (TTM; blocks Cu absorption) or choline tetrathiomolybdate (CTTM; a more stable salt formulation of tetrathiomolybdate) that are being currently evaluated (Chang et al 2013 ; Schilsky 2014 ; Weiss 2016 ). After Cu detoxification, re-accumulation of Cu in tissues are prevented by a “maintenance therapy” throughout life in which patients use lowered dosages (25–33% of the initial dose) of above mentioned chelators/agents or zinc salts (prevents intestinal Cu absorption but increases metallothionein, an heavy-metal scavenger) but also maintain a low copper diet (Schilsky 2014 ). However, some of the agents described above have been reported to cause significant problems when they are used long-term (Roberts et al 2008 ), therefore new drugs with less side effects are desired.…”

Section: Introductionmentioning

confidence: 99%

The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations

Ariöz

Wittung-Stafshede

2017

Biometals

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Wilson Disease (WD) is a hereditary genetic disorder, which coincides with a dysfunctional copper (Cu) metabolism caused by mutations in ATP7B, a membrane-bound P 1B -type ATPase responsible for Cu export from hepatic cells. The N-terminal part (* 600 residues) of the multi-domain 1400-residue ATP7B constitutes six metal binding domains (MBDs), each of which can bind a copper ion, interact with other ATP7B domains as well as with different proteins. Although the ATP7B's MBDs have been investigated in vitro and in vivo intensively, it remains unclear how these domains modulate overall structure, dynamics, stability and function of ATP7B. The presence of six MBDs is unique to mammalian ATP7B homologs, and many WD causing missense mutations are found in these domains. Here, we have summarized previously reported in vitro biophysical data on the MBDs of ATP7B and WD point mutations located in these domains. Besides the demonstration of where the research field stands today, this review showcasts the need for further biophysical investigation about the roles of MBDs in ATP7B function. Molecular mechanisms of ATP7B are important not only in the development of new WD treatment but also for other aspects of human physiology where Cu transport plays a role.

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“…Hepatic manifestations include asymptomatic transaminitis, acute or chronic hepatitis, fulminant hepatic failure and/or cirrhosis, while neurologic symptoms vary from mild tremors, articulating problems, dysarthria, Parkinson-like features, seizures and cognitive dysfunction. Some patients have mixed hepato-neurologic presentation[ 1 ]. Ophthalmologic involvement with Kaiser-Fleischer (KF) rings is common.…”

Section: Introductionmentioning

confidence: 99%

Wilson’s disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance

Barada

Haddad

Katerji

et al. 2017

WJG

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AIMTo determine the phenotypes and predominant disease-causing mutations in Lebanese patients with Wilson’s disease, as compared to regional non-European data.METHODSThe clinical profile of 36 patients diagnosed in Lebanon was studied and their mutations were determined by molecular testing. All patients underwent full physical exam, including ophthalmologic slit-lamp examination ultrasound imaging of the liver, as well as measurement of serum ceruloplasmin and 24-h urinary-Cu levels. In addition, genetic screening using PCR followed by sequencing to determine disease-causing mutations and polymorphisms in the ATP7B gene was carried on extracted DNA from patients and immediate family members. Our phenotypic-genotypic findings were then compared to reported mutations in Wilson’s disease patients from regional Arab and non-European countries.RESULTSPatients belonged to extended consanguineous families. The majority were homozygous for the disease-causing mutation, with no predominant mutation identified. The most common mutation, detected in 4 out of 13 families, involved the ATP hinge region and was present in patients from Lebanon, Egypt, Iran and Turkey. Otherwise, mutations in Lebanese patients and those of the region were scattered over 17 exons of ATP7B. While the homozygous exon 12 mutation Trp939Cys was only detected in patients from Lebanon but none from the regional countries, the worldwide common mutation H1069Q was not present in the Lebanese and was rare in the region. Pure hepatic phenotype was predominant in patients from both Lebanon and the region (25%-65%). Furthermore, the majority of patients, including those who were asymptomatic, had evidence of some hepatic dysfunction. Pure neurologic phenotype was rare.CONCLUSIONFindings do not support presence of a founder effect. Clinical and genetic screening is recommended for family members with index patients and unexplained hepatic dysfunction.

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Wilson disease: Clinical manifestations, diagnosis, and treatment

Cited by 45 publications

References 12 publications

Mitochondrial dysfunction triggers secretion of the immunosuppressive factor α-fetoprotein

Mitochondrial dysfunction triggers secretion of the immunosuppressive factor α-fetoprotein

The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations

Wilson’s disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance

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