Two-year follow-up after chelating therapy in a patient with adult-onset parkinsonism and hypermanganesaemia due to SLC30A10 mutations

Mammarella, Lara Di Toro; Mignarri, Andrea; Battisti, Carla; Monti, Lucia; Bonifati, Vincenzo; Rasi, F; Federico, Antonio

doi:10.1007/s00415-013-7187-5

Cited by 22 publications

(16 citation statements)

References 6 publications

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“…However, this group disagrees with others that have found blood Mn concentrations to be reflective of brain Mn levels, as this patient showed only a slight increase in blood Mn levels before his death, while postmortem brain tissue showed extremely elevated levels. 113, 115, 116 Our preliminary data showed that WT SLC30A10 is localized on cell surface and the mutants in the endoplasmic reticulum (ER) in HeLa cells; expression of WT SLC30A10 enhances Mn efflux, increases viability of HeLa cells upon Mn exposure and protects GABAergic AF5 neural progenitor cells and primary midbrain neurons from Mn-induced neurodegeneration. 117 Together, these studies collectively identify SLC30A10 as a novel Mn exporter in humans, that when mutated, can result in Parkinsonism and manganism pathophysiology.…”

Section: Mn Transporters: Regulation Of Mn Levelsmentioning

confidence: 93%

Manganese-induced neurotoxicity: from C. elegans to humans

Chen

Chakraborty

Peres

et al. 2014

Toxicology Research

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Manganese (Mn) is one of the most abundant metals on the earth. It is required for normal cellular activities, but overexposure leads to toxicity. Neurons are more susceptible to Mn-induced toxicity than other cells, and accumulation of Mn in the brain results in Manganism that presents with Parkinson's disease (PD)-like symptoms. In the last decade, a number of Mn transporters have been identified, which improves our understanding of Mn transport in and out of cells. However, the mechanism of Mn-induced neurotoxicity is only partially uncovered, with further research needed to explore the whole picture of Mn-induced toxicity. In this review, we will address recent progress in Mn-induced neurotoxicity from C. elegans to humans, and explore future directions that will help understand the mechanisms of its neurotoxicity.

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Section: Mn Transporters: Regulation Of Mn Levelsmentioning

confidence: 93%

Manganese-induced neurotoxicity: from C. elegans to humans

Chen

Chakraborty

Peres

et al. 2014

Toxicology Research

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“…Both parkinsonian and dystonic features can dramatically approve after such infusions but successful treatment response may depend on early diagnosis and initiation of treatment. 80,83 …”

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

803

534

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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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“…Ferrous fumarate has been used to reduce intestinal Mn absorption and relieve hypermanganesemia in patients with HMDPC [22,28,29]. Therefore, we exposed mutant embryos to Mn in the presence or absence of ferrous fumarate at 5 dpf and examined their phenotype the following day.…”

Section: Resultsmentioning

confidence: 99%

“…Although chelation therapy improves the neurological symptoms, reduces serum Mn accumulation, and prevents further hepatic pathology [18,28], it has the disadvantage of requiring strict monitoring of other essential minerals, including zinc, copper, and selenium [22]. Moreover, intravenous EDTA-CaNa 2 and close patient monitoring are generally not available in most regions with inadequate medical resources [26].…”

Section: Introductionmentioning

confidence: 99%

Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis

Xia

Wei

et al. 2017

PLoS Genet

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Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn) efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC). However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca2+ transporting 1) protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC.

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Two-year follow-up after chelating therapy in a patient with adult-onset parkinsonism and hypermanganesaemia due to SLC30A10 mutations

Cited by 22 publications

References 6 publications

Manganese-induced neurotoxicity: from C. elegans to humans

Manganese-induced neurotoxicity: from C. elegans to humans

Wilson's disease and other neurological copper disorders

Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis

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