Inherited manganese disorders and the brain: What neurologists need to know

Dipti Kapoor; Divyani Garg; Suvasini Sharma; Vinay Goyal

doi:10.4103/aian.AIAN_789_20



AIAN REVIEW

Year : 2021 \| Volume : 24 \| Issue : 1 \| Page : 15-21

Inherited manganese disorders and the brain: What neurologists need to know

Dipti Kapoor¹, Divyani Garg², Suvasini Sharma¹, Vinay Goyal³
¹ Department of Pediatrics (Neurology Division), Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India
² Department of Neurology, Lady Hardinge Medical College and Smt. Sucheta Kriplani Hospital, New Delhi, India
³ Institute of Neurosciences, Medanta Medicity, Gurgaon, Haryana, India

Date of Submission	22-Jul-2020
Date of Acceptance	28-Jul-2020
Date of Web Publication	05-Feb-2021

Correspondence Address:
Dr. Suvasini Sharma
Department of Pediatrics (Neurology Division), Lady Hardinge Medical College and Kalawati Saran Childrenfs Hospital, New Delhi
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/aian.AIAN_789_20

Abstract

Although acquired manganese neurotoxicity has been widely reported since its first description in 1837 and is popularly referred to as “manganism,” inherited disorders of manganese homeostasis have received the first genetic signature as recently as 2012. These disorders, predominantly described in children and adolescents, involve mutations in three manganese transporter genes, i.e., SLC30A10 and SLC39A14 which lead to manganese overload, and SLC39A8, which leads to manganese deficiency. Both disorders of inherited hypermanganesemia typically exhibit dystonia and parkinsonism with relatively preserved cognition and are differentiated by the occurrence of polycythemia and liver involvement in the SLC30A10-associated condition. Mutations in SLC39A8 lead to a congenital disorder of glycosylation which presents with developmental delay, failure to thrive, intellectual impairment, and seizures due to manganese deficiency. Chelation with iron supplementation is the treatment of choice in inherited hypermanganesemia. In this review, we highlight the pathognomonic clinical, laboratory, imaging features and treatment modalities for these rare disorders.

Keywords: Inherited hypermanganesemia, manganese transport, SLC30A10, SLC39A14, SLC39A8

How to cite this article:
Kapoor D, Garg D, Sharma S, Goyal V. Inherited manganese disorders and the brain: What neurologists need to know. Ann Indian Acad Neurol 2021;24:15-21

How to cite this URL:
Kapoor D, Garg D, Sharma S, Goyal V. Inherited manganese disorders and the brain: What neurologists need to know. Ann Indian Acad Neurol [serial online] 2021 [cited 2021 Mar 4];24:15-21. Available from: https://www.annalsofian.org/text.asp?2021/24/1/15/308709

Introduction

Manganese (Mn) transport disorders or transportopathies are inherited disorders leading to excess or deficiency of Mn and have been reported to occur as a result of mutations in SLC30A10, SLC39A14, and SLC39A8 genes, This review highlights pathogenesis, clinical presentation, and treatment of Mn transporter defects [Table 1]. We also intend to sensitize the treating clinicians and neurologists so as when to suspect and investigate for these disorders, including genetic testing, in order to initiate appropriate therapy before there is a profound progression of the disease process.

Table 1: Prominent characteristics of inherited defects of manganese transport

Click here to view

Manganese in health and disease

Mn is a naturally occurring essential trace metal which serves as a cofactor for multiple enzymes including transferases, lyases, hydrolases, ligases, isomerases, and oxidoreductases, thereby catalyzing numerous physiological processes, including regulation of immune function, blood sugar and cellular energy, reproduction, digestion, bone growth, blood coagulation and homeostasis, defense against reactive oxygen species, and neuronal and glial cell function such as neurotransmitter synthesis.^{[1],[2],[3],[4],[5]} Foods rich in Mn include legumes, seafood, leafy green vegetables, rice, nuts, whole grain, seeds, chocolate, tea, spices, soybean, and some fruits such as pineapple and acai.^[4] Most dietary supplements and multivitamin preparations contain Mn. Occupational exposure to Mn occurs in activities involving mining, welding, battery manufacture, and with the use of fungicides containing the metal in its composition, such as maneb and mancozeb.^{[3],[6],[7],[8],[9],[10]} The levels of Mn in the environment may also increase secondary to the use of the gasoline additive methylcyclopentadienyl manganese tricarbonyl (MMT).^[11] Drug abuse of the injectable drug methcathinone may lead to Mn toxicity due to the use of potassium permanganate in the synthesis process.^[12] Mn is also present in significant concentrations in both neonatal and infant formulas and total parenteral nutrition (TPN), which may cause Mn accumulation when given for prolonged periods of time.^{[13],[14],[15]} Patients with liver failure or hepatic encephalopathy can develop Mn toxicity as it is excreted in the bile.^[14] Iron (Fe) deficiency, one of the most common nutritional deficiencies, can also hypothetically result in Mn toxicity as Fe and Mn compete for similar transport protein and decreased Fe levels might lead to an accumulation of Mn to toxic levels over time.^{[16],[17],[18]}

Search methodology

We have conducted a narrative review using PubMed database which was searched and all published data available on inherited disorders of Manganese transport up to June 2020 was reviewed, using the search terms “manganese transport,” “inherited hypermanganesemia,” “manganese homeostasis,” “manganese transportopathies,” and “hereditary manganese diseases.” All types of studies including reviews, case series, and case reports were included in the review. The abstracts were screened for relevance to the review topic.

Determinants of Mn homeostasis

The homeostasis of Mn levels in our body is crucially regulated through intestinal absorption and hepatobiliary secretion of the metal into the gastrointestinal tract.^[19] The nervous system is the primary target for excessive Mn. Normal physiological Mn concentration of Mn in the human brain is estimated to be 5.32–14.03 ng Mn/mg protein and 15.96–42.09 ng Mn/mg protein is the estimated pathophysiological threshold.^[20],[21] Excessive levels of Mn are toxic causing oxidative stress, impaired mitochondrial function, impaired autophagy, and neuronal apoptosis.^[22]

Understanding of in vivo Mn homeostasis has dramatically expanded over the past decade with the recognition of inherited disorders of Mn transport. The uptake of Mn²⁺ into the cells is facilitated by a number of membrane transporters such as the divalent metal transporter 1 (DMT1/SLC11A2), ZRT/IRT-like proteins ZIP8 (SLC39A8) and ZIP14 (SLC39A14), the dopamine transporter (DAT), and calcium channels' choline and citrate transporters. Mn²⁺ is oxidized in the blood by ceruloplasmin to Mn³⁺ which binds to transferrin (Tf) and is subsequently internalized through transferrin/transferrin receptor (Tf/TfR)-mediated endocytosis. Within the endosome, Mn³⁺ is again reduced to Mn²⁺ and uptake into the cytoplasm occurs via the DMT1 transporter. Manganese efflux and export from the cytosol is mediated by the membrane-localized transporters ferroportin (Fpn or SLC40A1) and the solute carrier family 30 member 10 (SLC30A10).^{[23],[22],[24]} Within the cell cytosol, Mn gets shuttled via a number of organelle-specific transporters.^{[25],[26],[27],[28]} Iron (Fe) competes with Mn for binding and uptake at a number of transporters including the Tf/TfR complex, DMT1, and ferroportin.^[29] Recently mutations in several transporter proteins with affinity to Mn (i.e., ATP13A2, ATP13A1, DMT-1 and Fpn) have been described and might have implications on Mn homeostasis on subcellular level; however, blood manganese levels tend to remain unaffected with no evidence of excessive Mn deposition.^{[30],[31],[32]}

Pathophysiology

Excess Mn shows predilection to accumulate in the basal ganglia, especially in the striatum (caudate nucleus, putamen and nucleus accumbens), globus pallidus (GP), and the substantia nigra (SN), an intricate network of neurotransmitters.^[33],[34] Exposure to excessive Mn can lead to disruption of harmony among various neurotransmitter functions, causing behavioral alterations including hypoactivity, cognitive impairments, and altered sensorimotor function. These complex physiological imbalances lead to a distinct neurodegenerative extrapyramidal syndrome known as manganism. The symptoms include initial cognitive and psychiatric disturbances followed by a movement disorder resembling Parkinson's disease with limb rigidity, dystonia, and a characteristic high-stepping gait.^[23],[22] Mn, being a paramagnetic metal, leads to characteristic deposition and MRI brain appearances with pronounced hyperintensity of the globus pallidus on T1-weighted and hypointensity on T2-weighted images^[35] [Figure 1].

Figure 1: (a-c). T1-weighted MRI (axial section) brain showing hyperintensities in bilateral caudate, globus pallidus, and lentiform nucleus (a), dorsal pons with sparing of ventral pons (b), and cerebellar white matter (c). (d-f). T2-weighted MRI (axial section) showing hypointensities in bilateral basal ganglia (d), midbrain (e), and pons (f)

Click here to view

Historical aspects

The first disorder of inherited Mn transport was reported in 2012 leading to Mn neurotoxicity characterized by dystonia, in association with polycythemia and cirrhosis of the liver, attributable to homozygous mutations in the SLC30A10 gene.^[36],[37] Prior to this in 2008, Tuschl et al. had described a clinical study of a patient who was later shown to harbor SLC30A10 mutations. This was a 12-year-old female born to consanguineous parentage who developed gait abnormality and dystonia. MRI revealed Mn deposition in the basal ganglia, anterior pituitary, and cerebellar white matter. Liver biopsy revealed the presence of cirrhosis and elevated Mn levels. Preceding even these descriptions, Gospe et al. in 2000 described a similar case. In 2016, another inherited disorder leading to hypermanganesemia was described attributable to SLC39A14 mutations.^[38],[39] This was shown to differ from the SLC30A10 condition by the absence of polycythemia and liver involvement. In 2015, mutations in SLC39A8 were reported to lead to Mn and Zinc (Zn) deficiency.^[40],[41]

Hypermanganesemia with dystonia 1 (HMNDYT1)-SCL30A10 deficiency OMIM#618320

The bi-allelic mutation in Mn transporter gene SCL30A10 leads to the systemic accumulation and Mn neurotoxicity. SLC30A10 belongs to the SLC30 family of metal transporters, expressed at the cell membrane where they are responsible for efflux of Zn and Mn from the cytosol. This gene is specifically expressed in liver, gastrointestinal tract, and brain.^[36] The clinical manifestations include a distinct syndrome of hypermanganesemia, polycythaemia, dystonia, chronic liver disease (ranging from asymptomatic steatosis to cirrhosis with liver insufficiency), and depletion of iron stores. Recently, Mn deposition in thyroid gland leading to reduced thyroxine production and hypothyroidism in mice model with knocked out SCL30A10 gene has been reported, giving rise to speculation that thyroid gland might be one of the unexplored targets in the disease pathology.^[42]

The neurological manifestations start appearing in early childhood with progressive difficulty in walking and in conducting fine hand movements. The child soon develops dystonia in limbs with a characteristic high-stepping gate, also described as “cock-walk gait.” Involvement of white matter can cause spasticity and pyramidal tract signs. However, cognition tends to remain intact. A late-onset form presenting as L-DOPA unresponsive Parkinsonism in adults has also been reported.^[36]

Investigations reveal dramatically raised blood Mn levels, usually ten times that of normal. Brain MRI shows deposition of Mn, evident in the basal ganglia, particularly the globus pallidus and striatum with pronounced hyperintensity of T1-weighted imaging with or without corresponding hypointensity on T2-weighted imaging.^{[36],[37],[43],[44],[45],[46],[47]} The additional involvement of the white matter occurs in the cerebrum and cerebellum, midbrain, dorsal pons, and medulla with a pathognomonic sparing of the ventral pons. The histopathological examination in post-mortem sample reportedly shows severe neuronal loss and vacuolated myelinopathy in the globus pallidus.^[46] The accumulation of Mn in the liver can lead to hepatotoxicity; however, the clinical presentation ranges from mild liver disease (steatosis) to severe disease (cirrhosis). The occurrence of polycythemia in majority of the patients has been attributed to the induction of erythropoietin gene expression via stabilization of the hypoxia-inducible factor 1 alpha and a chemical “hypoxia.”^[47] Moreover, since Mn and Fe compete for binding at several transporters, it leads to depletion of iron stores in individuals with SLC30A10 mutations who show an increased total iron-binding capacity and a low ferritin.^[36],[37] Hence, there is juxtaposition of polycythemia in the setting of iron deficiency.

Chelating treatment with CaNa2 ethylenediaminetetraacetic acid (EDTA) has been shown to effectively reduce Mn accumulation, ameliorate neurological symptoms, and prevent liver disease progression.^[47] In the majority of the cases, Mn chelation leads to resolution of polycythemia and normalization of serum iron indices. However, blood Mn levels often do not normalize, but get stabilized.^[45],[48] EDTA-CaNa2 is given intravenously as a 5 to 8 day course every 4 weeks with close monitoring of calcium and other trace metal levels such as zinc (Zn), copper (Cu), and selenium (Se) in order to detect fluctuations in serum levels.^[49] Effect of this chelator on Mn levels can be estimated by observing reduction in T1 hyperintensity on MRI brain. Although chelation therapy with EDTA-CaNa2 has shown promising results, the need of intravenous administration significantly adds to the burden of the disease. The role of orally administered chelators like 2, 3-dimercaptosuccinic acid and d-penicillamine in halting disease progression still remains to be determined.^[44],[50] Supplementation with iron alone has also been shown to improve clinical symptoms to some extent and reduce Mn levels.^[51] However, the synergistic action of orally supplemented iron is hypothesized to occur in addition to chelation therapy. Iron can act as a competitive ligand at Mn transporters leading to reduction of Mn absorption, stabilization of Mn levels, and further clinical improvement. However, iron therapy warrants stringent monitoring of iron parameters with the aim to keep iron levels at the high end of normal without causing iron toxicity.^{[36],[37],[42],[48]} Treatment options used so far in inherited hypermanganesemia are outlined in [Table 2].

Table 2: Treatment options in inherited hypermanganesemia

Click here to view

Hypermanganesemia with dystonia 2 (HMNDYT2)- SCL39A14 deficiency

OMIM# 608736

Mutations in SCL39A14 gene leading to Mn-induced neurotoxicity were first reported in the year 2016 by Tuschl et al.^[39] SLC39A14 is a part of the solute carrier 39 family present at the cell membrane that has been shown to facilitate influx of Mn, Fe, Zn, and Cadmium into the cytosol.^{[52],[53],[54],[55]} However, mutations leading to loss of function of this gene predominantly disturb Mn homeostasis, having little effect on other metals.^[55],[56] Clinical symptoms start becoming evident early in life and included loss of developmental milestones, progressive dystonia, and bulbar dysfunction. Around the age of 10 years, most patients develop severe, generalized dystonia that seems resistant to treatment, spasticity, limb contractures, and scoliosis and loss of locomotor abilities. Some patients might also show features of parkinsonism, such as hypomimia, tremor, and bradykinesia.^[39] In contrast to SCL30A10 deficiency, these patients have an earlier onset of symptoms and absence of polycythemia and liver involvement. Although Mn levels are raised about 3–25 times the normal limit, iron indices tend to remain in a normal range. The absence of Mn accumulation in liver in affected individuals can be explained by the fact that SLC39A14 is mainly required for Mn uptake into the liver for subsequent biliary excretion, and that the build-up of Mn in the brain occurs secondary due to impaired hepatic uptake of the metal. Neuroimaging reveals MRI brain appearances identical to those seen in HMNDYT1. Post-mortem examination of one affected individual had shown marked neuronal loss in the globus pallidus, while relative preservation of neurons in the caudate, putamen, thalamus, and cerebral cortex. Patchy loss of myelin associated with coarse vacuoles in the cerebral and cerebellar white matter, and axonal loss were also observed.^[39]

Treatment with EDTA-CaNa2 according to the protocol used in HMNDYT1 has been observed to be less effective with only marginal improvement in neurological symptoms.^[39],[57] This could be explained by the differences in disease severity. It seems likely in this condition, since the onset is very early and progression is rapid, the treatment becomes potentially ineffective as neurodegeneration has already reached an irreversible stage. In addition, the genotype might play a role in treatment response.^[39] The two oral chelators, 2, 3-dimercaptosuccinic acid and d-penicillamine, also failed to show a clinical response in this disorder in one patient.^[57] It has been reported that dietary Mn restriction in the form of 2 to 3 “Mn free days” per week might have a synergistic effect along with chelation therapy in improving the neurologic symptoms.^[57] This entails the use of an Mn depleted formula in conjunction with a multivitamin free of Mn on the “Mn free” days. However, designing an Mn-free or low Mn diet is challenging due to the ubiquitous occurrence of the metal in food items.

Congenital disorder of glycosylation 2N (CDG2N)-SLC39A8 deficiency (OMIM#616721)

Mutations in SLC39A8, an Mn uptake transporter, were first reported to cause an inherited disorder of Mn and Zn deficiency in the year 2015.^[40],[58] Patients with a bi-allelic mutation leading to loss of function show an abnormal glycosylation pattern consistent with a type II congenital disorder of glycosylation. This could be attributed to the impaired function of Mn-dependent enzymes such as the β-1,4-galactosyltransferase required for the galactosylation of glycoproteins.^{[40],[58],[59]} Dysfunction of the mitochondrial MnSOD, another Mn dependent enzyme, can lead to Leigh-like mitochondrial disease characterized by elevated CSF lactate and abnormal respiratory chain enzymology.^[59] Systemic Mn deficiency causes developmental delay, intellectual disability, failure to thrive, short stature, dwarfism, cranial asymmetry, seizures, hypotonia, dystonia, strabismus, and deafness. Characteristically, blood Mn levels are low. MRI brain imaging is nonspecific, showing cerebellar and/or cerebral atrophy in majority of the patients and hyperintensity of the basal ganglia on T2-weighted MR imaging in some patients.^[59]

Oral Mn supplementation appears to be an effective treatment strategy. It has shown to cause improvement in the locomotor function and hearing along with normalization of Mn-dependent enzyme functions.^[60] Initial galactose priming to normalize glycosylation pattern has not shown to be as effective as the resolution of Mn deficiency by supplementation. However, regular monitoring of blood Mn levels and brain MRI changes are imperative to avoid Mn toxicity in these patients.^[60]

Conclusions

In this review, we have summarized the key features of inherited Mn defects. The discovery and knowledge about the inherited disorders of Mn metabolism has improved our understanding about the intricate Mn homeostasis in the human body. Since these inherited Mn transporter defects form an important differential diagnosis in children with unexplained developmental delay or a movement disorder, determination of blood Mn level can serve as a simple and cost-effective screening test in the routine neurological work-up of such patients with supportive ancillary features. Diagnostic clues of Mn toxicity include the constellation of dystonia, Parkinsonism, polycythaemia, and liver disease, and abnormal brain MRI findings in the form of T1 hyperintensities in the basal ganglia in the case of hypermanganesemia. Early diagnosis is crucial to identify the disorder, initiate appropriate treatment, and avoid irreversible disease progression.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

[61]

References

1.	Clayton PT. Inherited disorders of transition metal metabolism: An update. J Inherit Metab Dis 2017;40:519-29.
2.	Chen P, Parmalee N, Aschner M. Genetic factors and manganese induced neurotoxicity. Front Genet 2014;5:265.
3.	da Silva CJ, da Rocha AJ, Mendes MF, Sabatini AP, Braga dM, Jeronymo S. Brain manganese deposition depicted by magnetic resonance imaging in a welder. Arch Neurol 2008;65:983.
4.	Li L, Yang X. The essential element manganese, oxidative stress, and metabolic diseases: Links and interactions. Oxidative Med Cell Longev 2018;2018:7580707.
5.	Santos D, Batoreu MC, Almeida I, Ramos R, Sidoryk-Wegrzynowicz M, Aschner M, et al. Manganese alters rat brain amino acids levels. Biol Trace Elem Res 2012;150:337-41.
6.	Baker MG, Simpson CD, Stover B, Sheppard L, Checkoway H, Racette BA, et al. Blood manganese as an exposure biomarker: State of the evidence. J Occup Environ Hyg 2014;11:210-7.
7.	Aschner M, Erikson K, Hernández E, Tjalkens R. Manganese and its role in Parkinson's disease: From transport to neuropathology. Neuro Mol Med 2009;11:252-66.
8.	Josephs KA, Ahlskog JE, Klos KJ, Kumar N, Fealey RD, Trenerry MR, et al. Neurologic manifestations in welders with pallidal MRI T1 hyperintensity. Neurology 2005;64:2033-9.
9.	Sriram K, Lin GX, Jefferson AM, Stone S, Afshari A, Keane MJ, et al. Modifying welding process parameters can reduce the neurotoxic potential of manganese-containing welding fumes. Toxicology 2015;328:168-78.
10.	Cersosimo MG, Koller WC. The diagnosis of manganese-induced parkinsonism. Neuro Toxicol 2006;27:340-6.
11.	Au C, Benedetto A, Anderson J, Labrousse A, Erikson K, Ewbank JJ, et al. SMF-1, SMF-2 and SMF-3 DMT1 orthologues regulate and are regulated differentially by manganese levels in C. elegans. PLoS One 2009;4:e7792.
12.	Gulson B, Mizon K, Taylor A, Korsch M, Stauber J, Davis JM, et al. Changes in manganese and lead in the environment and young children associated with the introduction of methylcyclopentadienyl manganese tricarbonyl in gasoline–preliminary results. Environ Res 2006;100:100-14.
13.	Stepens A, Logina I, Liguts V, Aldiņš P, Ekšteina I, Platkājis A, et al. A parkinsonian syndrome in methcathinone users and the role of manganese. N Engl J Med 2008;358:1009-17.
14.	Alves G, Thiebot J, Tracqui A, Delangre T, Guedon C, Lerebours E. Neurologic disorders due to brain manganese deposition in a jaundiced patient receiving long-term parenteral nutrition. J Parenter Enteral Nutr 1997;21:41-5.
15.	Iinuma Y, Kubota M, Uchiyama M, Yagi M, Kanada S, Yamazaki S, et al. Whole-blood manganese levels and brain manganese accumulation in children receiving long-term home parenteral nutrition. Pediatr Surg Int 2003;19:268-72.
16.	Zeron HM, Rodriguez MR, Montes S, Castaneda CR. Blood manganese levels in patients with hepatic encephalopathy. J. Trace Elements Med Biol 2011;25:225-9.
17.	Fitsanakis VA, Zhang N, Avison MJ, Erikson KM, Gore JC, Aschner M. Changes in dietary iron exacerbate regional brain manganese accumulation as determined by magnetic resonance imaging. Toxicol Sci 2011;120:146-53.
18.	Smith EA, Newland P, Bestwick KG, Ahmed N. Increased whole blood manganese concentrations observed in children with iron deficiency anaemia. J Trace Elem Med Biol 2012;27:65-9.
19.	Aschner JL, Aschner M. Nutritional aspects of manganese homeostasis. Mol Asp Med 2005;26:353-62.
20.	Bowman AB, Aschner M. Considerations on manganese (Mn) treatments for in vitro studies. Neurotoxicology 2014;41:141-2.
21.	Zogzas CE, Mukhopadhyay S. Inherited disorders of manganese metabolism. Adv Neurobiol 2017;18:35-49.
22.	Tuschl K, Mills PB, Clayton PT. Manganese and the brain. Int Rev Neurobiol 2013;110:277-312.
23.	Peres TV, Schettinger MR, Chen P, Carvalho F, Avila DS, Bowman AB, et al. Manganese-induced neurotoxicity: A review of its behavioural consequences and neuroprotective strategies. BMC Pharmacol Toxicol 2016;17:57.
24.	Chen P, Chakraborty S, Mukhopadhyay S, Lee E, Paoliello MM, Bowman AB, et al. Manganese homeostasis in the nervous system. J Neurochem 2015;134:601-10.
25.	Christenson ET, Gallegos AS, Banerjee A. In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1. J Biol Chem 2018;293:3819-28.
26.	Cohen Y, Megyeri M, Chen OC, Condomitti G, Riezman I, Loizides-Mangold U, et al. The yeast p5 type ATPase, spf1, regulates manganese transport into the endoplasmic reticulum. PLoS One 2013;8:e85519.
27.	Leitch S, Feng M, Muend S, Braiterman LT, Hubbard AL, Rao R. Vesicular distribution of secretory pathway Ca (2)+-ATPase isoform 1 and a role in manganese detoxification in liver-derived polarized cells. Biometals 2011;24:159-70.
28.	Tan J, Zhang T, Jiang L, Chi J, Hu D, Pan Q, et al. Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome associated ATP13A2 protein. J Biol Chem 2011;286:29654-62.
29.	Fitsanakis VA, Zhang N, Garcia S, Aschner M. Manganese (Mn) and iron (Fe): Interdependency of transport and regulation. Neurotox Res 2010;18:124-31.
30.	Anazi S, Maddirevula S, Salpietro V, Asi YT, Alsahli S, Alhashem A, et al. Expanding the genetic heterogeneity of intellectual disability. Hum Genet 2017;136:1419-29.
31.	Choi EK, Nguyen TT, Iwase S, Seo YA. Ferroportin disease mutations influence manganese accumulation and cytotoxicity. FASEB J 2019;33:2228-40.
32.	Wolff NA, Garrick MD, Zhao L, Garrick LM, Ghio AJ, Thevenod F. A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Sci Rep 2018;8:211.
33.	Guilarte TR, Chen M-K, Mcglothan JL, Verina T, Wong DF, Zhou Y, et al. Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol 2006;202:381-90.
34.	Guilarte TR, Mcglothan JL, Degaonkar M, Chen M-K, Barker PB, Syversen T, et al. Evidence for cortical dysfunction and widespread manganese accumulation in the nonhuman primate brain following chronic manganese exposure: A 1H-MRS and MRI study. Toxicol Sci 2006;94:351-8.
35.	Li SJ, Jiang L, Fu X, Huang S, Huang YN, Li XR, et al. Pallidal index as biomarker of manganese brain accumulation and associated with manganese levels in blood: A meta-analysis. PLoS One 2014;9:e93900.
36.	Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, et al. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet 2012;90:467-77.
37.	Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, et al. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet 2012;90:457-66.
38.	Gospe SM, Caruso RD, Clegg MS, Keen CL, Pimstone NR, Ducore JM, et al. Paraparesis, hypermanganesaemia, and polycythaemia: A novel presentation of cirrhosis. Arch Dis Child. 2000;83:439-42.
39.	Tuschl K, Meyer E, Valdivia LE, Zhao N, Dadswell C, Abdul-Sada A, et al. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Commun 2016;7:11601.
40.	Boycott KM, Beaulieu CL, Kernohan KD, Gebril OH, Mhanni A, Chudley AE, et al. Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the Manganese and Zinc transporter gene SLC39A8. Am J Hum Genet 2015;97:886-93.
41.	Sreedharan S, Stephansson O, Schioth HB, Fredriksson R. Long evolutionary conservation and considerable tissue specificity of several atypical solute carrier transporters. Gene 2011;478:11-8.
42.	Liu C, Hutchens S, Jursa T, Shawlot W, Polishchuk EV, Polishchuk RS, et al. Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production. J Biol Chem 2017;292:16605-15.
43.	Quadri M, Kamate M, Sharma S, Olgiati S, Graafland J, Breedveld GJ, et al. Manganese transport disorder: Novel SLC30A10 mutations and early phenotypes. Mov Disord 2015;20:996-1001.
44.	Zaki MS, Issa MY, Elbendary HM, El-Karaksy H, Hosny H, Ghobrial C, et al. Hypermanganesemia with dystonia, polycythemia and cirrhosis in 10 patients: Six novel SLC30A10 mutations and further phenotype delineation. Clin Genet 2018;93:905-12.
45.	Gulab S, Kayyali HR, Al-Said Y. Atypical neurologic phenotype and novel SLC30A10 mutation in two brothers with hereditary hypermanganesemia. Neuropediatrics 2018;49:72-5.
46.	Lechpammer M, Clegg MS, Muzar Z, Huebner PA, Jin LW, Gospe SM Jr. Pathology of inherited manganese transporter deficiency. Ann Neurol 2014;75:608-12.
47.	Tuschl K, Mills PB, Parsons H, Malone M, Fowler D, Bitner-Glindzicz M, et al. Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia–a new metabolic disorder. J Inherit Metab Dis 2008;31:151-63.
48.	Stamelou M, Tuschl K, Chong WK, Burroughs AK, Mills PB, Bhatia KP, et al. Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: A new treatable disorder. Mov Disord 2012;27:1317-22.
49.	Tuschl K, Clayton PT, Gospe SM Jr, et al. Dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020; 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK100241.
50.	Mukhtiar K, Ibrahim S, Tuschl K, Mills P. Hypermanganesemia with dystonia, polycythemia and cirrhosis (HMDPC) due to mutation in the SLC30A10 gene. Brain Dev 2016;38:862-5.
51.	Avelino MA, Fusao EF, Pedroso JL, Arita JH, Ribeiro RT, Pinho RS, et al. Inherited manganism: The “cock-walk” gait and typical neuroimaging features. J Neurol Sci 2014;341:150-2.
52.	Girijashanker K, He L, Soleimani M, Reed JM, Li H, Liu Z, et al. Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: Similarities to the ZIP8 transporter. Mol Pharmacol 2008;73:1413-23.
53.	Jenkitkasemwong S, Wang CY, Mackenzie B, Knutson MD. Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 2012;25:643-55.
54.	Jeong J, Eide DJ. The SLC39 family of zinc transporters. Mol Asp Med 2013;34:612-9.
55.	Aydemir TB, Kim MH, Kim J, Colon-Perez LM, Banan G, Mareci TH, et al. Metal transporter Zip14 (Slc39a14) deletion in mice increases manganese deposition and produces neurotoxic signatures and diminished motor activity. J Neurosci 2017;37:5996-6006.
56.	Xin Y, Gao H, Wang J, Qiang Y, Imam MU, Li Y, et al. Manganese transporter SLC39A14 deficiency revealed its key role in maintaining manganese homeostasis in mice. Cell Discov 2017;3:17025.
57.	Rodan LH, Hauptman M, D'Gama AM, Qualls AE, Cao S, Tuschl K, et al. Novel founder intronic variant in SLC39A14 in two families causing manganism and potential treatment strategies. Mol Genet Metab 2018;124:161-7.
58.	Park JH, Hogrebe M, Gruneberg M, Duchesne I, von der Heiden AL, Reunert J, et al. SLC39A8 deficiency: A disorder of manganese transport and glycosylation. Am J Hum Genet 2015;97:894-903.
59.	Riley LG, Cowley MJ, Gayevskiy V, Roscioli T, Thorburn DR, Prelog K, et al. A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders. J Inherit Metab Dis 2017;40:261-9.
60.	Park JH, Hogrebe M, Fobker M, Brackmann R, Fiedler B, Reunert J, et al. SLC39A8 deficiency: Biochemical correction and major clinical improvement by manganese therapy. Genet Med 2017;20:259.
61.	Jiang Y-M, Mo X-E, Du F-Q, Fu X, Zhu X-Y, Gao H-Y, et al. Effective treatment of manganese-induced occupational parkinsonism with p-aminosalicylic acid: A case of 17-year follow-up study. J Occup Environ Med 2006;48:644-9.