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Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system

Marti-Sanchez, L; Ortigoza-Escobar, JD; Darling, A; Villaronga, M; Baide, H; Molero-Luis, M; Batllori, M; ... Duenas, P; + view all (2018) Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system. Orphanet Journal of Rare Diseases , 13 , Article 28. 10.1186/s13023-018-0758-x. Green open access

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Abstract

Background The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these disorders. We aimed to explore further biomarkers of Mn deposition in the central nervous system in two siblings presenting with acute dystonia and hypermanganesemia due to mutations in SLC39A14. These biomarkers may help clinicians to establish faster and accurate diagnosis and to monitor disease progression after chelation therapy is administered. Results A customized gene panel for movement disorders revealed a novel missense variant (c.311G > T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na2CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued. Conclusions Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na2CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.

Type: Article
Title: Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s13023-018-0758-x
Publisher version: https://doi.org/10.1186/s13023-018-0758-x
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, Medicine, Research & Experimental, Research & Experimental Medicine, Manganese homeostasis, SLC39A14, SLC30A10, Dystonia, Pallidum, Hypermanganesemia, METAL-ION TRANSPORTER, MANGANESE ACCUMULATION, SLC30A10 MUTATIONS, HEPATIC CIRRHOSIS, ICP-MS, POLYCYTHEMIA, DYSTONIA, DEFICIENCY, DISORDER, ZIP14
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10043427
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