Inborn errors of copper metabolism

Summary The classic copper metabolism disorder, Wilson disease (WD), was first defined in 1912. Both early onset presentations in infancy and late onset manifestations in adults > 70 years are now well recognized. Modern biochemical and genetic prevalence studies suggest that WD may be considerably more common than previously appreciated. Early diagnosis of WD is crucial to ensure that patients can be started on adequate treatment but uncertainty remains about the best possible choice of medication. Direct genetic testing for ATP7B mutations is increasingly available to confirm the clinical diagnosis of WD. WD needs to be differentiated from other conditions that present clinically with hepatolenticular degeneration or share biochemical abnormalities with WD, such as reduced serum cerulo plasmin levels. Disordered copper metabolism is also implied in an increasing number of other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations, and the common late-onset neurodegenerative disorders Alzheimer’s disease and Parkinson’s disease.

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“…When fully progressed, the ATP7A -related motor neuron phenotype is reminiscent of type 2 Charcot-Marie-Tooth disease (CMT2). 74 …”

Section: Other Copper Transport Disorders and Related Diseasesmentioning

confidence: 99%

“…Cerebral MRI in affected subjects shows pronounced cerebellar hypoplasia and hypomyelination, reminiscent of Menkes disease. 74 …”

Section: Other Copper Transport Disorders and Related Diseasesmentioning

confidence: 99%

Wilson's disease and other neurological copper disorders

Bandmann

Weiss

Kaler

2015

The Lancet Neurology

741

512

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“…S2I). Neurodegeneration and cerebral arterial tortuosity are phenotypes present in all patients affected by Menkes disease (Kaler, 2013; Manara et al, 2017a; Manara et al, 2017b). These bioinformatic results demonstrate that genealogical proteomics datasets contain sufficient information to predict clinical traits which are diagnostic of genetic diseases of copper metabolism.…”

Section: Resultsmentioning

confidence: 99%

Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees

et al. 2018

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Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. We use triple-SILAC mass spectrometry to quantify proteomes from human pedigrees affected by mutations in ATP7A, which cause Menkes disease, a rare neurodegenerative and neurodevelopmental disorder stemming from systemic copper depletion. We identified 214 proteins whose expression was altered in ATP7A fibroblasts. Bioinformatic analysis of ATP7A-mutant proteomes identified known phenotypes and processes affected in rare genetic diseases causing copper dyshomeostasis, including altered mitochondrial function. We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes.

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“…MD-Patienten zeigen eine beeinträchtigte intestinale Kupferabsorption, die Kupfermangel und insuffiziente Ak-tivität der kupferabhängigen Enzyme zur Folge hat und zu einem komplexen, schnell lebensbedrohlichen, multisystemischen Syndrom führt [3,4]. MD-Patienten zeigen eine beeinträchtigte intestinale Kupferabsorption, die Kupfermangel und insuffiziente Ak-tivität der kupferabhängigen Enzyme zur Folge hat und zu einem komplexen, schnell lebensbedrohlichen, multisystemischen Syndrom führt [3,4].…”

Section: Trichoskopie Biochemische Und Radiologische Befundeunclassified

Pili torti, pale and elastic skin, and severe neurological impairment

Gironi

Peruzzi²,

Chierici

et al. 2017

J Deutsche Derma Gesell

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Patient bereits wegen zu geringer Gewichtszunahme und Hyperaktivität aufgenommen worden. Einen Monat danach entwickelte er eine Anämie (Hb 6,4 g/dL), eine Harnwegsinfektion und einen gastroösophagealen Reflux. Ab einem Alter von vier Monaten traten fokale Krampfanfälle mit episodischen Augenverdrehungen, Hand-und Fingermyoklonus sowie Hypertonie und Dyskinäsie des Schultergürtels auf; das EEG zeigte einen temporal-okzipitalen Fokus. InteressenkonfliktKeiner.

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Inborn errors of copper metabolism

Cited by 95 publications

References 31 publications

Wilson's disease and other neurological copper disorders

Wilson's disease and other neurological copper disorders

Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees

Pili torti, pale and elastic skin, and severe neurological impairment

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