Do cytokines have any role in Wilson's disease?

Goyal, Madhu; Sinha, Sanjib; Patil, Shripad A.; Jayalekshmy, V.; Taly, AB

doi:10.1111/j.1365-2249.2008.03755.x

Cited by 15 publications

(7 citation statements)

References 17 publications

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“…Analysis of sphingolipids in 1 KO animal and age-matched control showed increased levels of ceramide, although a separate study is needed to determine significance of this pathway in mice and humans. Elevated levels of serum TNFa (31) and IL-1b (32) are found in patients with WD (as in our mouse model).…”

Section: Discussionsupporting

confidence: 71%

Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B−/− (Wilson disease) mice

et al. 2016

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Wilson disease (WD) is a hepatoneurologic disorder caused by mutations in the copper-transporter ATP7B. Copper accumulation in the liver is a hallmark of WD. Current therapy is based on copper chelation, which decreases the manifestations of liver disease, but often worsens neurologic symptoms. We demonstrate that in Atp7b−/− mice, an animal model of WD, liver function can be significantly improved without copper chelation. Analysis of transcriptional and metabolic changes in samples from WD patients and Atp7b−/− mice identified disregulation of nuclear receptors (NR), especially the LXR/RXR heterodimer, as an important event in WD pathogenesis. Treating Atp7b−/− mice with the LXR agonist T0901317 ameliorated disease manifestations despite significant copper overload. Genetic markers of liver fibrosis and inflammatory cytokines were significantly decreased, lipid profiles normalized and liver function and histology was improved. In conclusion, the results demonstrate the major role of an altered nuclear receptor function in the pathogenesis of WD; and suggest that modulation of nuclear receptor activity should be explored as a supplementary approach to improving liver function in WD.

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Section: Discussionsupporting

confidence: 71%

Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B−/− (Wilson disease) mice

et al. 2016

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“…However, the cause and effect relationship of elevated cytokines to the ongoing process in WD could not be to ascertained. [24] Thus, the mechanisms whereby copper deposition leads to tissue damage remains largely unanswered.…”

Section: Geneticsmentioning

confidence: 99%

Wilson′s disease: An Indian perspective

2009

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Wilson's disease (WD) is an autosomal recessive disease involving a defect of copper transport by the hepatic lysosomes. It leads to excess copper deposition in the liver, the brain, the kidneys and the skeletal system, affecting most commonly children or young adults and running an invariably fatal course if not adequately treated by de-coppering therapy. The last century has witnessed several changes, notable among these are: Increased awareness, improved diagnostic facilities leading to earlier recognition even in the pre-symptomatic phase, clear distinction from its mimics, aggressive therapeutic approaches owing to availability of effective treatment and an overall reduction in the morbidity and mortality. It is widely acknowledged that the disease is not as rare as once believed. Sir SAK Wilson published his landmark article in 1912, but it was only in 1968 that the first patient of WD was reported from our country. Publications from India on WD have focused on phenotypic characterization, documentations of lesser recognized aspects of the disease e.g. seizures, behavior abnormality, speech and cognitive impairment, sub-clinical affection of visual pathway, heart and autonomic function and pre-symptomatic detection. Attempts have been made to understand the clinical heterogeneity of the disease through identification of biochemical and immunological markers, magnetic resonance imaging, neuropathological study and genetic analysis for novel and/or known mutations. Assessment of impairment and severity and effect of various therapeutic interventions namely zinc sulphate on the long-term outcome and quality of life have also been studied. Nevertheless, clinicians often face difficulties in long-term care of these patients. Diagnostic errors leading to delay in diagnosis and initiation of treatment are common, even in patients with positive family history. There is no consensus regarding therapeutic protocols since the use of penicillamine, once a 'gold standard' for treatment, has been debated by experts. Mortality and morbidity of this potentially treatable disease and nonavailability of medications to the poor patients remain a major area of concern.

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“…The change of levodopa dose was the most significant change in the antiparkinson treatment scheme, as well as the introduction of other drugs affecting the level of inflammatory cytokines. However, it is hard to draw conclusions from the observed cytokine dynamics data in a single patient because IL and TNF levels in PD patients are highly variable and only future correlation analysis may reveal the relations [57,58].…”

Section: Case Reportmentioning

confidence: 99%

Case of Early-Onset Parkinson’s Disease in a Heterozygous Mutation Carrier of the ATP7B Gene

Ilyechova

Miliukhina

Karpenko

et al. 2019

JPM

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In this paper, we report a clinically proven case of Parkinson’s disease (PD) with early onset in a patient who is a heterozygous mutation carrier of ATP7B (the Wilson’s disease gene). The patient was observed from 2011 to 2018 in the Center for Neurodegenerative Diseases, Institute of Experimental Medicine (St. Petersburg, Russia). During this period, the patient displayed aggravation of PD clinical symptoms that were accompanied by a decrease in the ceruloplasmin concentration (from 0.33 to 0.27 g/L) and an increase in serum nonceruloplasmin copper, which are typical of the late stages of Wilson’s disease. It was found that one of the alleles of exon 14 in the ATP7B gene, which partially codes of the nucleotide-binding domain (N-domain), carries a mutation not previously reported corresponding to Cys1079Gly substitution. Alignment of the ATP7B N-domain amino acid sequences of representative vertebrate species has shown that the Cys at 1079 position is conserved throughout the evolution. Molecular dynamic analysis of a polypeptide with Cys1079Gly substitution showed that the mutation causes profound conformational changes in the N-domain, which could potentially lead to impairment of its functions. The role of ATP7B gene mutations in PD development is discussed.

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Do cytokines have any role in Wilson's disease?

Cited by 15 publications

References 17 publications

Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B−/− (Wilson disease) mice

Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B−/− (Wilson disease) mice

Wilson′s disease: An Indian perspective

Case of Early-Onset Parkinson’s Disease in a Heterozygous Mutation Carrier of the ATP7B Gene

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