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Congenital erythrocytosis recognizes heterogeneous genetic basis and despite the use of NGS technologies, more than 50% of cases are still classified as idiopathic. Herein, we describe the case of a 3-year-old boy with a rare metabolic disorder due to SLC30A10 bi-allelic mutations and characterized by hypermanganesemia, congenital erythrocytosis and neurodegeneration, also known as hypermanganesemia with dystonia 1 (HMNDYT1). The patient was treated with iron supplementation and chelation therapy with CaNa2EDTA, resulting in a significative reduction of blood manganese levels and erythrocytosis indexes. Although it couldn't be excluded that the patient's developmental impairment was part of the phenotypic spectrum of the disease, after three months from starting treatment no characteristic extrapyramidal sign was detectable. Our findings suggest the importance of assessing serum manganese levels in patients with unexplained polycythemia and increased liver enzymes. Moreover, we highlight the importance of extended genetic testing as a powerful diagnostic tool to uncover rare genetic forms of congenital erythrocytosis. In the described patient, identifying the molecular cause of erythrocytosis has proven essential for proper clinical management and access to therapeutic options.

BackgroundManganese (Mn) is an essential trace metal necessary for good health; however, excessive amounts in the body are neurotoxic. To date, three genes (SLC30A10, SLC39A8, and SLC39A14) have been discovered to cause inborn errors in Mn metabolism in humans. As very rare diseases, the clinical features require further clarification.MethodsA male Chinese patient who mainly presented with hypermanganesemia and progressive parkinsonism–dystonia was recruited for this study. We collected and analyzed clinical information, performed whole-exome sequencing (WES), and reviewed the relevant literature.ResultsThe motor-developmental milestones of the patient were delayed at the age of 4 months, followed by rapidly progressive dystonia. The patient displayed elevated Mn concentrations in blood and urine, and brain magnetic resonance imaging (MRI) showed symmetrical hyperintensity on T1-weighted images and hypointensity on T2-weighted images in multiple regions. A novel homozygous variant of the SLC39A14 gene (c.1058T > G, p.L353R) was identified. The patient was treated with disodium calcium edetate chelation (Na2CaEDTA). Three months later, mild improvement in clinical manifestation, blood Mn levels, and brain MRI was observed. To date, 15 patients from 10 families have been reported with homozygous mutations of SLC39A14, with a mean age of onset of 14.9 months. The common initial symptom is motor regression or developmental milestone delay, with a disease course for nearly all patients involving development of progressive generalized dystonia and loss of ambulation before treatment. Additionally, hypermanganesemia manifests as Mn values ranging from 4- to 25-fold higher than normal baseline levels, along with brain MRI results similar to those observed in the recruited patient. Nine SLC39A14 variants have been identified. Seven patients have been treated with Na2CaEDTA, and only one patient achieved obvious clinical improvement.ConclusionWe identified a novel SLC39A14 mutation related to autosomal recessive hypermanganesemia with dystonia-2, which is a very rare disease. Patients present motor regression or delay of developmental milestones and develop progressive generalized dystonia. Chelation therapy with Na2CaEDTA appears to effectively chelate Mn and increase urinary Mn excretion in some cases; however, clinical response varies. The outcome of the disease was unsatisfactory. This study expands the genetic spectrum of this disease.

Importance: Hypermanganesemia with dystonia type 2 is a rare autosomal recessive neurodegenerative disorder characterized by the loss of previously acquired milestones, dystonia, parkinsonian features, a high serum manganese level, and characteristic neuroimaging findings such as bilateral and symmetrically increased T1 and decreased T2/fluid-attenuated inversion recovery signal intensity in the basal ganglia. This condition is secondary to a mutation in the SLC39A14 gene. Objective: To present a series of three cases of hypermanganesemia with dystonia type 2, which was genetically confirmed secondary to a mutation in the SLC39A14 gene, and to describe the treatment and clinical course in these cases. Design: A retrospective case series. Setting: University, Tertiary hospital. Participants: Three unrelated pediatric patients with hypermanganesemia with dystonia type 2, genetically confirmed to be secondary to a mutation in the SLC39A14 gene. Exposures: Chelation therapy using calcium disodium edetate. Main outcome(s) and measure(s): The response to chelation therapy based on clinical improvements in motor and cognition developments. Results: All three patients were started on chelation therapy using calcium disodium edetate, and two of them showed an improvement in their clinical course. The chelation therapy could alter the course of the disease and prevent deterioration in the clinical setting. Conclusions and Relevance: Early diagnosis and intervention with chelating agents, such as calcium disodium edetate, will help change the outcome in patients with hypermanganesemia with dystonia type 2. This finding highlights the importance of early diagnosis and treatment in improving the outcomes of patients with treatable neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital portosystemic shunt (CPSS) is a rare malformation that leads to hyperammonemia, hypermanganesemia, and various symptoms. CPSSs are divided into intrahepatic and extrahepatic shunts. In patients with persistent CPSS including an intrahepatic portosystemic shunt (IPSS), early intervention to occlude the shunt reverses the associated complications. Case presentation The patient was a 1-year-and-7-month-old girl. She presented with hypergalactosemia and elevation of blood ammonia level (75 μg/dL) and total bile acid levels (68.2 μmol/L) during the neonatal period. Two IPSSs were detected using ultrasound and enhanced computerized tomography. Magnetic resonance imaging (MRI) at 1 year and 3 months of age showed abnormally high signal intensity in the pallidum of her brain. Spontaneous closure was not observed. We performed a right hepatectomy at 1 year and 7 months of age. The portal vein pressure was 16 mmHg after temporary occlusion of the right portal vein. Blood ammonia and serum manganese levels decreased immediately after the operation. The abnormal signal on brain MRI disappeared. She had a favorable course with no sign of recurrence of IPSS 5 years postoperatively. Conclusion Liver resection for an IPSS to control the symptoms of a portosystemic shunt is reasonable in a child for whom interventional radiological treatment is not indicated.

Importance: Hypermanganesemia with dystonia type 2 is a rare autosomal recessive neurodegenerative disorder characterized by the loss of previously acquired milestones, dystonia, parkinsonian features, a high serum manganese level, and characteristic neuroimaging findings such as bilateral and symmetrically increased T1 and decreased T2/fluid-attenuated inversion recovery signal intensity in the basal ganglia. This condition is secondary to a mutation in the SLC39A14 gene. Objective: To present a series of three cases of hypermanganesemia with dystonia type 2, which was genetically confirmed secondary to a mutation in the SLC39A14 gene, and to describe the treatment and clinical course in these cases. Design: A retrospective case series. Setting: University, Tertiary hospital. Participants: Three unrelated pediatric patients with hypermanganesemia with dystonia type 2, genetically confirmed to be secondary to a mutation in the SLC39A14 gene. Exposures: Chelation therapy using calcium disodium edetate. Main outcome(s) and measure(s): The response to chelation therapy based on clinical improvements in motor and cognition developments. Results: All three patients were started on chelation therapy using calcium disodium edetate, and two of them showed an improvement in their clinical course. The chelation therapy could alter the course of the disease and prevent deterioration in the clinical setting. Conclusions and Relevance: Early diagnosis and intervention with chelating agents, such as calcium disodium edetate, will help change the outcome in patients with hypermanganesemia with dystonia type 2. This finding highlights the importance of early diagnosis and treatment in improving the outcomes of patients with treatable neurodegenerative disorders.

Abstract 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 is an essential element that is ubiquitously present in our diet and water supply. It is a cofactor for several critical physiological processes. Elevated blood levels of Manganese secondary to SLC30A10 gene mutation presents distinctly with dystonia, polycythemia, chronic liver disease and a characteristic high T1 signal in basal ganglia on brain MRI. The primary treatment for this condition is chelation along with iron therapy. We report a previously healthy boy with compound heterozygous SLC30A10 gene mutations who had a unique clinical presentation with prominent seizures, polycythemia, and characteristic T1 hyperintensity in basal ganglia. Seizures have not been previously reported to be associated with this specific mutation.

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.

Background: Congenital portosystemic shunt (CPSS) is a rare malformation that leads to hyperammonemia, hypermanganesemia, and various symptoms. CPSSs are divided into intrahepatic and extrahepatic shunts. In patients with persistent CPSS including an intrahepatic portosystemic shunt (IPSS), early intervention to occlude the shunt reverses the associated complications. Case presentation: The patient was a 1-year-and-7-month-old girl. She presented with hypergalactosemia and elevation of blood ammonia level (75 μg/dL) and total bile acid levels (68.2 μmol/L) during the neonatal period. Two IPSSs were detected using ultrasound and enhanced computerized tomography. Magnetic resonance imaging (MRI) at 1 year and 3 months of age showed abnormally high signal intensity in the pallidum of her brain. Spontaneous closure was not observed. We performed a right hepatectomy at 1 year and 7 months of age. The portal vein pressure was 16 mmHg after temporary occlusion of the right portal vein. Blood ammonia and serum manganese levels decreased immediately after the operation. The abnormal signal on brain MRI disappeared. She had a favorable course with no sign of recurrence of IPSS 5 years postoperatively. Conclusion: Liver resection for an IPSS to control the symptoms of a portosystemic shunt is reasonable in a child for whom interventional radiological treatment is not indicated. [ABSTRACT FROM AUTHOR]

Purpose: A congenital extrahepatic portosystemic shunt (CEPS) associated with hyperammonemia requires occlusion of the shunt vessels. We evaluated the effectiveness and safety of laparoscopic ligation of a CEPS in children with hyperammonemia.Methods: The subjects of this retrospective study were seven children with hyperammonemia who underwent laparoscopic ligation of a CEPS. Their median age was 5.2 years (range 1-16 years). Before the laparoscopic procedure, a catheter was inserted through the femoral vein and placed in the portal vein via the shunt vessel. The shunt vessel was dissected and taped laparoscopically. After measuring the portal vein pressure under temporal occlusion, the shunt vessels were ligated.Results: The types of shunts according to location were patent ductus venosus (n = 2), splenorenal shunt (n = 2), gastrorenal shunt (n = 2), and superior mesenteric vein-inferior vena cava shunt (n = 1). Laparoscopic ligation of the shunt vessel was completed uneventfully in all patients. The median portal vein pressure was 19 mmHg after ligation. The median preoperative blood ammonia level was 94 µg/dL (range 71-259 µg/dL), which decreased after ligation in all patients. There was no incidence of postoperative liver failure.Conclusion: Laparoscopic ligation of a CEPS is safe and effective for children with hyperammonemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential element in trace quantity but large amounts are toxic. A novel hereditary disorder encompassing high blood Mn levels, dystonia, polycythemia, distinctive T1 hyperintense signals in the basal ganglia onmagnetic resonance imaging (MRI) brain, and chronic liver disease was recently described. The disorder is caused by mutations in a Mn transporter encoding gene SLC30A10. We are reporting the clinical features of this rare disorder in two Saudi brothers. The older brother presented with progressive gait difficulties, hypotonia, intermittent dystonia, polycythemia, and characteristic T1-hyperintense lesions on MRI brain. SLC30A10 sequencing identified a novel missense mutation. The younger brother was identified in presymptomatic phase on family screening. Chelation therapy with disodium calcium edetate (ethylenediaminetetraacetic acid, EDTA) led to stabilization of gait, reduction in Mn levels, and resolution of polycythemia.We wish to highlight the atypical neurologic presentation, a novel missense mutation, and beneficial effect of EDTA in this rare disease. [ABSTRACT FROM AUTHOR]

Background: Manganese (Mn) is an essential trace metal necessary for good health; however, excessive amounts in the body are neurotoxic. To date, three genes ( SLC30A10 , SLC39A8 , and SLC39A14 ) have been discovered to cause inborn errors in Mn metabolism in humans. As very rare diseases, the clinical features require further clarification., Methods: A male Chinese patient who mainly presented with hypermanganesemia and progressive parkinsonism-dystonia was recruited for this study. We collected and analyzed clinical information, performed whole-exome sequencing (WES), and reviewed the relevant literature., Results: The motor-developmental milestones of the patient were delayed at the age of 4 months, followed by rapidly progressive dystonia. The patient displayed elevated Mn concentrations in blood and urine, and brain magnetic resonance imaging (MRI) showed symmetrical hyperintensity on T1-weighted images and hypointensity on T2-weighted images in multiple regions. A novel homozygous variant of the SLC39A14 gene (c.1058T > G, p.L353R) was identified. The patient was treated with disodium calcium edetate chelation (Na 2 CaEDTA). Three months later, mild improvement in clinical manifestation, blood Mn levels, and brain MRI was observed. To date, 15 patients from 10 families have been reported with homozygous mutations of SLC39A14 , with a mean age of onset of 14.9 months. The common initial symptom is motor regression or developmental milestone delay, with a disease course for nearly all patients involving development of progressive generalized dystonia and loss of ambulation before treatment. Additionally, hypermanganesemia manifests as Mn values ranging from 4- to 25-fold higher than normal baseline levels, along with brain MRI results similar to those observed in the recruited patient. Nine SLC39A14 variants have been identified. Seven patients have been treated with Na 2 CaEDTA, and only one patient achieved obvious clinical improvement., Conclusion: We identified a novel SLC39A14 mutation related to autosomal recessive hypermanganesemia with dystonia-2, which is a very rare disease. Patients present motor regression or delay of developmental milestones and develop progressive generalized dystonia. Chelation therapy with Na 2 CaEDTA appears to effectively chelate Mn and increase urinary Mn excretion in some cases; however, clinical response varies. The outcome of the disease was unsatisfactory. This study expands the genetic spectrum of this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Zhang, Zhu, Wang, Hao, Zhang, Zhao and Bao.)

Background: The first gene causing early-onset generalized dystonia with brain manganese accumulation has recently been identified. Mutations in the SLC30A10 gene, encoding a manganese transporter, cause a syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia. Methods: We present 10-year longitudinal clinical features, MRI data, and treatment response to chelation therapy of the originally described patient with a proven homozygous mutation in SLC30A10. Results: The patient presented with early-onset generalized dystonia and mild hyperbilirubinemia accompanied by elevated whole-blood manganese levels. T1-sequences in MRI showed hyperintensities in the basal ganglia and cerebellum, characteristic of manganese deposition. Treatment with intravenous disodium calcium edetate led to clinical improvement and reduction of hyperintensities in brain imaging. Conclusions: We wish to highlight this rare disorder, which, together with Wilson's disease, is the only potentially treatable inherited metal storage disorder to date, that otherwise can be fatal as a result of complications of cirrhosis. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Manganese intoxication leads to the accumulation of manganese in the brain, mostly in the globus pallidus, which clinically manifests as a L-DOPA - resistant parkinsonian syndrome with specific symptoms, such as spastic-hypokinetic dysarthria and postural instability. A new kind of manganese poisoning associated with drug abuse has been reported in Eastern European countries., A Case Report: We present an adult patient with neurological abnormalities secondary to manganese intoxication related to the abuse of psychoactive substances. High serum levels of manganese, hyperintense lesions on T1-weighted magnetic resonance imaging (MRI), and parkinsonism in this case confirmed the diagnosis. MRI results showed accumulation of manganese in the basal ganglia which caused an increased signal in this area of the brain on T1 weighted sequence. This is the second case reported with diffuse high signal intensity of the entire white matter due to manganese and ephedron neurointoxication. To the best of our knowledge, this is the first time such extensive pathological changes to cerebellar white matter, located near the fourth ventricle, have been described., Conclusions: We suggest that chronic exposure to manganese and ephedron damaged the white matter in the cerebral hemispheres and continued to affect the periventricular area of the fourth ventricle, causing continuous changes to the white matter., (© 2021 MEDPRESS.)

Abstract: Manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. This letter highlights the neurological manifestations and neuroimaging features of inherited manganism (IMn), an unusual and treatable inborn error of Mn homeostasis. Early-onset dystonia with “cock-walk” gait and hyperintense signal in basal ganglia, associated to polycythemia, chronic liver disease and hypermanganesemia, promptly suggest IMn, and a genetic evaluation should be performed. [Copyright &y& Elsevier]

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.)

The objective of the present study was to evaluate sex, menopause, pregnancy, and age-specific differences of blood manganese (Mn) levels in relation to iron status, and to assess the toxicological implications of these relationships. Females of childbearing age have higher concentrations of blood Mn than males because women have lower concentrations of ferritin. Previous studies indicated significant increases in blood Mn levels throughout pregnancy, and that the geometric mean of blood Mn was significantly higher in premenopausal women than postmenopausal women. This may be due to the enhanced absorption of Mn because of upregulation of iron absorption, which is especially important during late pregnancy. Mn concentrations are highest in infancy, decreased with age up to adolescence, and did not change during adulthood. Thus, the relationship of iron with Mn may be the major factor affecting blood Mn levels according to menstrual stage, reproductive status, menopausal factors, and age. However, Mn absorbed via the gastrointestinal system seems to be less neurotoxic than inhaled or parenteral Mn, due to the tight enterohepatic homeostatic control of this essential element. Furthermore, children and pregnant women had no adverse health effects from blood levels of Mn that were associated with adverse effects in adult workers. In conclusion, the differences between a physiological and a pathological hypermanganesemia complicate interpretation of the dose-response relationship.

Introduction: Manganese (Mn) toxicity is often observed in adult patients receiving long-term home parenteral nutrition (HPN), and differing recommendations on the safe level of Mn administration to these patients have been made in the literature over the past 10 years., Methods: This systematic review used the National Health and Medical Research Council (NHMRC) evidence hierarchy to assess the design and strength of individual studies (high I to low IV) and the overall grade of evidence (grade A high to grade D low)., Results: Eight studies met the inclusion criteria. Levels of evidence ranged from high (NHMRC II) to mid-level (III-3). A widespread recommendation in the literature for patients receiving long-term HPN is 55 µg (1 µmol) Mn/d., Conclusion: The recommendation of 55 µg (1 µmol) Mn/d is of moderate-strength evidence (NHMRC B grade). There is limited evidence to support not supplementing Mn to patients receiving long-term HPN. Further intervention studies providing high-level evidence (II and above) are required to determine the safety of not supplementing Mn to all patients receiving long-term HPN., (© 2015 American Society for Parenteral and Enteral Nutrition.)

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.)

Background: Long-term parenteral nutrition (PN) can be associated with micronutrient deficiency or toxicity depending on supplementation. Recently, hypermanganesemia and potential neurological toxicity were reported. The aim of this study was to assess the effect of manganese supplementation in a sample of patients on long-term PN receiving manganese (Mn) as part of a multi-trace element (TE) supplement., Methods: A convenience sample of 16 patients underwent clinical and blood biochemical measurements as well as magnetic resonance imaging (MRI) of the brain. Descriptive statistics were performed., Results: The mean daily Mn supplementation was 7.28 ± 0.97 µmol/d (400 ± 53 µg/d), which was within the American Medical Association Nutrition Advisory Group guidelines of 2.73-14.56 μmol/d (150-800 µg/d) but exceeded the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) 2002 recommendations of 1.09-1.82 µmol/d (60-100 µg/d). The mean whole blood Mn level was 1.38 ± 0.29 times the upper limit of normal (ULN), and 8 of 14 patients with blood measurements had Mn levels above ULN. On MRI, 81% of patients had high signals on T1-weighted images assumed to be Mn deposits in their basal ganglia. Two patients with positive MRI (15%) had a clinical diagnosis of Parkinson disease. Multiple neuropsychiatric complaints were reported, including depression (66%), lack of concentration (42%), memory disturbances (17%), and gait instability (8%)., Conclusion: These results suggest that Mn status is elevated in these patients. Manganese supplementation should be used with caution in patients receiving long-term PN, and attention should be paid to the Mn content of multi-TE supplements.