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

Abstract

BackgroundThe 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.ResultsA 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.ConclusionsOur 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.

Brain manganese and the balance between essential roles and neurotoxicity

“…Post-mortem analyses of one patient showed evidence of neuronal degeneration in the globus pallidus (159). Additional descriptions of patients suffering from Mn toxicity due to mutations in SLC39A14 were reported in 2018 (161,162).…”

Intestine-specific deletion of metal transporter Zip14 (Slc39a14) causes brain manganese overload and locomotor defects of manganism

“…Mutations in the SLC39A14 gene encoding the ZIP14 transporter were found in patients with childhood-onset parkinsonism and dystonia with systemic and brain Mn accumulation (35). Since that discovery, there have been a number of case reports of similar symptoms in humans with ZIP14 mutations (17, 23, 31, 38). Whole-body Zip14 KO mice display phenotypes similar to those of human carriers of ZIP14 mutations, including spontaneous systemic and brain Mn overload, specifically in the globus pallidus, and motor dysfunction (3).…”

The intestinal metal transporter ZIP14 maintains systemic manganese homeostasis

“…Previous studies have shown that ZIP14 is capable of mediating the uptake of Mn in vitro (15). Highlighting the function of ZIP14 as a Mn transporter in vivo, homozygous mutations of ZIP14 result in Mn hyperaccumulation in the blood and other tissues of affected individuals without apparent effects on other metals (10,(16)(17)(18).…”