Hypermanganesemia due to mutations in SLC39A14 : further insights into Mn deposition in the central nervous system
Marti-Sanchez, L. (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Ortigoza Escobar, Juan Dario (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Darling, Alejandra (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Villaronga, M. (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Baide, H. (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Molero-Luis, M. (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Batllori, M. (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Vanegas, M. I. (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Muchart, J. (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Aquino, Lourdes (Hospital de Mataró (Catalunya). Departament de Pediatria)
Artuch, R. (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Macaya Ruiz, Alfons (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Kurian, M. A. (Great Ormond Street Institute of Child Health (Londres, Regne Unit))
Dueñas, Pérez (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Fecha:	2018
Resumen:	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. 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 NaCaEDTA 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. 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 NaCaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.
Ayudas:	Instituto de Salud Carlos III PI15-00287 Instituto de Salud Carlos III CM16-00084
Nota:	Altres ajuts: This work is funded by the European Regional Development Fund (FEDER) and the Fundació La Marató TV3 (20,143,130 to BPD). LMS has a grant from Fundació Sant Joan de Déu. MAK holds a Wellcome Intermediate Clinical Fellowship.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Manganese homeostasis ; SLC39A14 ; SLC30A10 ; Dystonia ; Pallidum ; Hypermanganesemia
Publicado en:	Orphanet Journal of Rare Diseases, Vol. 13 (january 2018) , ISSN 1750-1172

DOI: 10.1186/s13023-018-0758-x
PMID: 29382362

8 p, 1.3 MB

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