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Background: A genetic variant in the manganese transporter SLC30A10 (rs188273166, p.Thr95Ile) was associated with increased plasma alanine transaminase (ALT) in a recent genome-wide association study in the UK Biobank (UKB). The aims of the present study were to test the association of rs188273166 with ALT in an independent cohort, and to begin to assess the clinical, hepatic, and biochemical phenotypes associated with the variant., Methods: We included n = 334,886 white participants from UKB, including 14,462 with hepatic magnetic resonance imaging (MRI), and n = 113,612 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study combined., Results: Genotyping SLC30A10 p.Thr95Ile identified 816 heterozygotes in the UKB and 111 heterozygotes in the Copenhagen cohort. Compared to noncarriers, heterozygotes had 4 and 5 U/L higher levels of ALT in the UKB and Copenhagen cohort, respectively, and 3 U/L higher plasma aspartate transaminase and gamma-glutamyl transferase in the UKB. Heterozygotes also had higher corrected T1 on liver MRI, a marker of hepatic inflammation (p = 4 × 10 -7 ), but no change in MRI-quantified steatosis (p = 0.57). Plasma manganese was within the normal range in nine heterozygotes that provided new blood samples. SLC30A10 p.Thr95Ile heterozygotes had an eightfold increased risk of biliary tract cancer in UKB (p = 4 × 10 -7 ), but this association was not replicated in the Copenhagen cohort., Conclusions: SLC30A10 p.Thr95Ile was associated with elevated liver enzymes in two large general population cohorts, and with MRI-quantified hepatic inflammation. A rare genetic variant (p.Thr95Ile) in the manganese transporter SLC30A10 is associated with elevated plasma alanine transaminase (ALT) and higher corrected T1 on liver MRI, markers of liver inflammation. These data support that the variant may increase the risk of liver disease., (© 2022. Asian Pacific Association for the Study of the Liver.)

This inborn error of manganese metabolism has only recently been identified. A total of 28 affected individuals from ten families are known worldwide. Mutations in SLC39A14, encoding a Mn uptake transporter, have recently been recognized to cause excessive Mn concentrations in the blood which is believed to be neurotoxic and lead to a parkinsonian-like movement disorder caused by accumulation of Mn in the basal ganglia. We are reporting a new variant of SLC39A14 gene mutation (OMIM 608736 8p21.3) that has never been described in the literature so far. The index case is a 3-year-old female who was born at 30 weeks' gestation by emergency lower segment caesarean section, the second of twins, weighing 1.4 kg. Parents have a consanguineous marriage (first cousins) and have four healthy male children. She presented at 30 months of age with history of unsteady gait of 4 months duration and is progressively worsening. She became stiff and has lost all of her locomotor skills. Apart from low serum iron and iron deficiency anemia, her initial work up was unremarkable. T1-weighted MRI brain showed bilateral hyperintense signal in basal ganglia, mid-brain and pontine tegmentum giving rise to the characteristic eye-of-the-tiger sign. Genetic DNA evaluation (Whole Exome Sequencing WES) identified the homozygous missense variant c.1136.T in exon 7 of SLC39A14 gene which is associated with hypermanganesemia. Whole blood Mn was markedly raised at 150 nmol/L (8 mg/L) (normal 10 nmol/L, 0.7 mg/Bioscientia). This young girl has just started treatment with intravenous disodium calcium edetate and oral iron.

Background: Manganese is a critical trace element that not only has antioxidant properties, but also is essential for various metabolic pathways and neurotransmitters production. However, it can be toxic at high levels, particularly in the central nervous system. Manganese intoxication can be acquired, but an inherited form due to autosomal-recessive mutations in the SLC30A10 gene encoding a Mn transporter protein has also been reported recently. These mutations are associated with significant failure of manganese excretion and its storage in the liver, brain (especially basal ganglia), and other peripheral tissues, resulting in toxicity., Case Presentation: A 10-year-old boy from consanguineous parents presented with a history of progressive truncal instability, gait difficulty, and frequent falls for 2 months. He had dystonia, rigidity, ataxia, dysarthria, bradykinesia and a plethoric skin. Investigations showed polycythemia, low serum iron and ferritin levels, and increased total iron binding capacity. A brain MRI revealed symmetric hyperintensities in the basal ganglia and dentate nucleuses on TI images that were suggestive of brain metal deposition together with clinical manifestations. Serum calcium and copper levels were normal, while the manganese level was significantly higher than normal values. There was no history of environmental overexposure to manganese. Genetic testing showed a homozygous missense mutation in SLC30A10 (c.C1006T, p.His336Tyr) and Sanger sequencing confirmed a homozygous state in the proband and a heterozygous state in the parents. Regular treatment with monthly infusions of disodium calcium edetate and oral iron compounds resulted in decreased serum manganese and hemoglobin levels to normal values, significant resolution of MRI lesions, and partial improvement of neurological symptoms during 6 months of follow-up., Conclusion: The syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by SLC30A10 mutation is a treatable inherited metal deposition syndrome. The patient may only have pure neurological without hepatic manifestations. Although this is a rare and potentially fatal inborn error of metabolism, early diagnosis and continuous chelation therapy might improve the symptoms and prevent disease progression.

Manganese (Mn 2+ ) is extruded from the cell by the zinc transporter 10 (ZnT10). Loss of ZnT10 expression caused by autosomal mutations in the ZnT10 gene leads to hypermanganesemia in multiple organs. Here, combining fluorescent monitoring of cation influx in HEK293-T cells expressing human ZnT10 with molecular modeling of ZnT10 cation selectivity, we show that ZnT10 is exploiting the transmembrane Ca 2+ inward gradient for active cellular exchange of Mn 2+ In analyzing ZnT10 activity we used the ability of Fura-2 to spectrally distinguish between Mn 2+ and Ca 2+ fluxes. We found that ( a ) application of Mn 2+ -containing Ca 2+ -free solution to ZnT10-expressing cells triggers an influx of Mn 2+ , ( b ) reintroduction of Ca 2+ leads to cellular Mn 2+ extrusion against an inward Mn 2+ gradient, and ( c ) the cellular transport of Mn 2+ by ZnT10 is coupled to a reciprocal movement of Ca 2+ Remarkably, replacing a single asparagine residue in ZnT10 (Asp-43) with threonine (ZnT10 N43T) converted the Mn 2+ /Ca 2+ exchange to an uncoupled channel mode, permeable to both Ca 2+ and Mn 2+ The findings in our study identify the first ion transporter that uses the Ca 2+ gradient for active counter-ion exchange. They highlight a remarkable versatility in metal selectivity and mode of transport controlled by the tetrahedral metal transport site of ZnT proteins., (© 2019 Levy et al.)

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 Na 2 CaEDTA 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 Na 2 CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.

During the course of infection, many natural defenses are set up along the boundaries of the host-pathogen interface. Key among these is the host response to withhold metals to restrict the growth of invading microbes. This simple act of nutritional warfare, starving the invader of an essential element, is an effective means of limiting infection. The physiology of metal withholding is often referred to as "nutritional immunity," and the mechanisms of metal transport that contribute to this host response are the focus of this review., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)