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Manganese And Its Unimportance In Health
- Thread starter Amazoniac
- Start date
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- Tags
- manganese unimportantium
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Amazoniac
Member
- Dietary manganese affects the concentration, composition and sulfation pattern of heparan sulfate glycosaminoglycans in Sprague-Dawley rat aorta
- Interrelationship between manganese, vitamin B1 and the level of pyruvic acid
(only abstract available, the rest wasn't published because the author had to stop pointing the AK-47 at the publisher to instead contain a road rager; firing wasn't necessary, everyone froze in the meantime)
Abstract said:
- Interrelationship between manganese, vitamin B1 and the level of pyruvic acid
(only abstract available, the rest wasn't published because the author had to stop pointing the AK-47 at the publisher to instead contain a road rager; firing wasn't necessary, everyone froze in the meantime)
Abstract said:
OP
Amazoniac
Member
Mito's post reminded me to share this:
- Intestinal response to dietary manganese depletion in Drosophila
- Intestinal response to dietary manganese depletion in Drosophila
Abstract said:
Perry Staltic
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- Joined
- Dec 14, 2020
- Messages
- 8,186
Not trying to be a spoiler, but as we all know, balance is everything. Manganese has an interesting history of neurotoxicity in certain professions, like manganese mining, welding, pottery (manganese glazes). Search "manganese poisoning", "manganese madness" and Mark Purdy (maybe Purdey) who developed the hypothesis that Phosmet, the organophosphate pesticide that used to be poured along the spines of cows fed with manganese-rich feeds, deformed prions in cows' brains due to a Cu/Mn imbalance.
OP
Amazoniac
Member
@Amazoniac Do you have any information regarding its role in excretion of copper? I heard somewhere that manganese is needed to pee out the excess copper, but couldn't find the text now.
Interesting. What’s another goor source ?
Which one? There’s sugar cane molasses in stores here
Wow. You still eat that much of it ?
Wow. You still eat that much of it ?
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Amazoniac
Member
OP
Amazoniac
Member
One of the early observations that it affects crapohydrate metabolism, a case that responded remarkably well to this toxin before partial pancreatectomy:
- Manganese-induced hypoglycaemia
- Manganese-induced hypoglycaemia
"After the patient claimed that an infusion of lucerne (alfalfa) controlled his diabetes better than insulin, an infusion was found to lower his blood-sugar, sometimes with hypoglycaemic symptoms, including coma. Because of the high content of manganese in lucerne, 5 to 10 mg. of manganese chloride was given by mouth, and was found to produce similar effects on the blood-sugar on all occasions. Oral manganese controlled the diabetes no less satisfactorily than soluble insulin."
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Amazoniac
Member
- Bile salts: structure, function, synthesis, and enterohepatic circulation | Nicola Tazzini
- Essential trace metals in man: Manganese - A Study in Homeostasis
- A missense variant in SLC39A8 confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity
- Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy
"Our analyses reveal that BA composition regulates the expression of Slc30a10 and cellular Mn efflux. SLC30A10 is one of three transporters identified thus far to be critical for whole-body Mn homeostasis in humans and mice (34, 35, 39, 40, 52, 54,–56). We found that BA pools low in 12HBAs, which have increased abundance of the non-12HBA LCA, act primarily via VDR to promote Slc30a10 expression. We also found that ileal Slc30a10 was inducible by LCA and the VDR agonist calcitriol, indicating that LCA and VDR signaling modulate intestinal Mn transport. A model is shown in Fig. 6."
"Although LCA made up <1% of the BA pools in our studies, the LCA concentration in the low-12HBA pools was 9 μM. As a point of reference, in the duodenum of healthy adult humans, the total bile acid concentration is 20 mM, and LCA makes up 1–3% of the pool, ∼200-600 μM (25, 46, 47). Although LCA is partly sulfated and excreted, a portion is taken up into enterocytes (48, 49)."
"Similar to BAs, a significant portion of Mn undergoes enterohepatic cycling (57, 58). Thus, enterocytes are exposed to luminal Mn from two sources: bile and diet. In adult humans, only about 3–5% of ingested Mn is absorbed (31), indicating robust regulation of intestinal Mn absorption. Obstructing the bile duct results in reduced excretion rates of intravenously administered 54Mn in rats (59), highlighting the importance of Mn clearance by the liver and final excretion in the feces. But the intestine appears to play an important role in Mn homeostasis as well, especially when liver excretion has been saturated (60). Whereas deletion of Slc30a10 only in hepatocytes is insufficient to cause hypermanganesemia, combined deletion in the liver and gastrointestinal tract causes severe hypermanganesemia and neurotoxicity (39, 41), mimicking the whole-body Slc30a10 knockout mice, although less severe (39, 40). These findings support the notion that intestine and hepatobiliary excretion systems both participate in Mn homeostasis."
"We identified BA composition, especially LCA abundance, as a modulator of Slc30a10 expression in vitro, ex vivo, and in the mouse ileum. We also showed that VDR is the primary mediator of this signaling pathway. This is consistent with a previous report showing VDR activation inducing SLC30A10 in Caco-2 cells and that this requires the VDR element in SLC30A10's promoter region (45 [⇈]). Claro da Silva et al. (45) previously reported increased SLC30A10 mRNA levels in half of duodenal biopsies from volunteers administered oral calcitriol (0.5 µg for 10 days). However, ileal biopsies were not reported, and the ileum is expected to be the primary site of uptake of bile acids into enterocytes (49). Our data show that Slc30a10 expression is induced by LCA and calcitriol in vivo in the mouse ileum."
"In our experiments, Slc30a10 induction was not completely abrogated upon removal of LCA from BA pools or deletion of VDR. Thus, other BAs and nuclear receptors might also contribute to BA-dependent induction of Slc30a10."
"Another Mn transporter is SLC39A8. This protein is highly expressed in the liver, where it is critical for Mn uptake from bile into hepatocytes (53). The localization and physiological relevance of SLC39A8 in the intestine has not been reported. We found that gut organoids treated with [low 12HBA] pools up-regulated Slc39a8 mRNA expression more strongly than [high 12HBA] pools(Fig. 4C). Caco-2 cells also showed increased SLC39A8 expression upon H10, but not H90, treatment (Fig. 4D). Further analyses showed that, similar to Slc30a10, Slc39a8 mRNA expression was blunted upon removal of LCA from BA pools and in gut organoids from VDR–/– mice, whereas removal of CDCA from BA pools had no effect (Fig. 4, E–G). These data support the possibility that both Slc30a10 and Slc39a8 are regulated by LCA-to-VDR signaling."
"Some researchers have reported that patients with type 2 diabetes have plasma or serum Mn at levels higher than controls, whereas others have reported the opposite (73,–76). Because Mn levels must be maintained within a small range (31, 44), it makes sense that both deficiency and excess of Mn would lead to negative consequences. Accordingly, a recent report showed a U-shaped relationship between plasma Mn and the odds ratio for type 2 diabetes (77). When interpreting the previous findings, it should be noted that the most accurate circulating Mn levels are obtained from whole blood, not serum or plasma, because over 60% of blood Mn is found in erythrocytes (78)."
"This work demonstrates that BAs and BA pool composition also regulate metal homeostasis, which may be relevant for health and disease."
"Although LCA made up <1% of the BA pools in our studies, the LCA concentration in the low-12HBA pools was 9 μM. As a point of reference, in the duodenum of healthy adult humans, the total bile acid concentration is 20 mM, and LCA makes up 1–3% of the pool, ∼200-600 μM (25, 46, 47). Although LCA is partly sulfated and excreted, a portion is taken up into enterocytes (48, 49)."
"Similar to BAs, a significant portion of Mn undergoes enterohepatic cycling (57, 58). Thus, enterocytes are exposed to luminal Mn from two sources: bile and diet. In adult humans, only about 3–5% of ingested Mn is absorbed (31), indicating robust regulation of intestinal Mn absorption. Obstructing the bile duct results in reduced excretion rates of intravenously administered 54Mn in rats (59), highlighting the importance of Mn clearance by the liver and final excretion in the feces. But the intestine appears to play an important role in Mn homeostasis as well, especially when liver excretion has been saturated (60). Whereas deletion of Slc30a10 only in hepatocytes is insufficient to cause hypermanganesemia, combined deletion in the liver and gastrointestinal tract causes severe hypermanganesemia and neurotoxicity (39, 41), mimicking the whole-body Slc30a10 knockout mice, although less severe (39, 40). These findings support the notion that intestine and hepatobiliary excretion systems both participate in Mn homeostasis."
"We identified BA composition, especially LCA abundance, as a modulator of Slc30a10 expression in vitro, ex vivo, and in the mouse ileum. We also showed that VDR is the primary mediator of this signaling pathway. This is consistent with a previous report showing VDR activation inducing SLC30A10 in Caco-2 cells and that this requires the VDR element in SLC30A10's promoter region (45 [⇈]). Claro da Silva et al. (45) previously reported increased SLC30A10 mRNA levels in half of duodenal biopsies from volunteers administered oral calcitriol (0.5 µg for 10 days). However, ileal biopsies were not reported, and the ileum is expected to be the primary site of uptake of bile acids into enterocytes (49). Our data show that Slc30a10 expression is induced by LCA and calcitriol in vivo in the mouse ileum."
"In our experiments, Slc30a10 induction was not completely abrogated upon removal of LCA from BA pools or deletion of VDR. Thus, other BAs and nuclear receptors might also contribute to BA-dependent induction of Slc30a10."
"Another Mn transporter is SLC39A8. This protein is highly expressed in the liver, where it is critical for Mn uptake from bile into hepatocytes (53). The localization and physiological relevance of SLC39A8 in the intestine has not been reported. We found that gut organoids treated with [low 12HBA] pools up-regulated Slc39a8 mRNA expression more strongly than [high 12HBA] pools
"Some researchers have reported that patients with type 2 diabetes have plasma or serum Mn at levels higher than controls, whereas others have reported the opposite (73,–76). Because Mn levels must be maintained within a small range (31, 44), it makes sense that both deficiency and excess of Mn would lead to negative consequences. Accordingly, a recent report showed a U-shaped relationship between plasma Mn and the odds ratio for type 2 diabetes (77). When interpreting the previous findings, it should be noted that the most accurate circulating Mn levels are obtained from whole blood, not serum or plasma, because over 60% of blood Mn is found in erythrocytes (78)."
"This work demonstrates that BAs and BA pool composition also regulate metal homeostasis, which may be relevant for health and disease."
- Essential trace metals in man: Manganese - A Study in Homeostasis
"Without exception, all human tissues contain manganese, according to emission spectroscopy. Concentrations are remarkably constant throughout most of life (Table 1). There is no tendency for decrease or accumulation to occur with aging."
"Highest concentrations of manganese (means of 68-180 p.p.m. ash) occurred in two organs with several specialized metabolic activities, including the excretion of this metal, i.e., the pancreas and the liver, and in organs concerned with transport across membranes: the kidney and the large and small intestines (Tables 1 and 2). Lowest concentrations (25 p.p.m.) occurred in organs and tissues with fewer metabolic activities : aorta, heart, diaphragm, muscle, bladder, brain, esophagus, larynx, trachea, lung, spleen, skin, ovary, prostate, testes, uterus, thyroid and bone. Differences in concentrations between the two groups of tissues are significant, as is also the case for potassium, calcium, phosphorus, copper and zinc, but not for magnesium [12]. Intermediate concentrations (36-48 p.p.m.) were found in adrenal, stomach and omentum, the last also concerned with transport."
"InTable 3 are shown concentrations of manganese in nine organs according to geographic origin of the subjects supplying the tissues. In general there was little deviation from place to place and no definite signs of manganese deficiency in any area."
"In spite of the relative constancy of the levels of manganese specific for each organ and tissue, data were tested by computer to ascertain whether or not a linear relationship between the concentration of manganese and those of other elements, trace and bulk, existed. Choosing coefficients of correlation of 0.50 or more and of 0.30-o. 50 and probabilities of chance occurrence (P) of 0.001 or less, a number of such relationships were shown to exist (Table 4)."
"Highest concentrations of manganese (means of 68-180 p.p.m. ash) occurred in two organs with several specialized metabolic activities, including the excretion of this metal, i.e., the pancreas and the liver, and in organs concerned with transport across membranes: the kidney and the large and small intestines (Tables 1 and 2). Lowest concentrations (25 p.p.m.) occurred in organs and tissues with fewer metabolic activities : aorta, heart, diaphragm, muscle, bladder, brain, esophagus, larynx, trachea, lung, spleen, skin, ovary, prostate, testes, uterus, thyroid and bone. Differences in concentrations between the two groups of tissues are significant, as is also the case for potassium, calcium, phosphorus, copper and zinc, but not for magnesium [12]. Intermediate concentrations (36-48 p.p.m.) were found in adrenal, stomach and omentum, the last also concerned with transport."
"In
"In spite of the relative constancy of the levels of manganese specific for each organ and tissue, data were tested by computer to ascertain whether or not a linear relationship between the concentration of manganese and those of other elements, trace and bulk, existed. Choosing coefficients of correlation of 0.50 or more and of 0.30-o. 50 and probabilities of chance occurrence (P) of 0.001 or less, a number of such relationships were shown to exist (Table 4)."
- A missense variant in SLC39A8 confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity
- Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy
Wow.
Side Effects of Too Much Manganese:
Overexposure to Mn, usually in the workplace, causes manganism, a syndrome similar to Parkinson’s disease.
-- Manganism
-- Oxidative Stress
-- Inflammation
-- Impaired Cognition
-- ADHD
-- Brain Damage
-- Anxiety
-- Parkinson’s
-- Alzheimer’s
-- ALS
-- Early Puberty
-- May Impair Sleep
-- Bacterial Infection
-- Prion Disease
-- Heart Damage
-- Sense of Smell
-- Asthma
-- Infant Mortality
-- Cancer and Liver Disease Mortality
Ways to Combat Manganese Toxicity:
-- Iron
-- Calcium
-- Taurine
-- Magnesium
-- Vitamin E
-- Glutathione
-- NAC
-- Melatonin
-- Quercetin
-- Lemon balm
-- Milk thistle
-- Lycopene
-- Curcumin
labs.selfdecode.com
Overexposure to Mn, usually in the workplace, causes manganism, a syndrome similar to Parkinson’s disease.
-- Manganism
-- Oxidative Stress
-- Inflammation
-- Impaired Cognition
-- ADHD
-- Brain Damage
-- Anxiety
-- Parkinson’s
-- Alzheimer’s
-- ALS
-- Early Puberty
-- May Impair Sleep
-- Bacterial Infection
-- Prion Disease
-- Heart Damage
-- Sense of Smell
-- Asthma
-- Infant Mortality
-- Cancer and Liver Disease Mortality
Ways to Combat Manganese Toxicity:
-- Iron
-- Calcium
-- Taurine
-- Magnesium
-- Vitamin E
-- Glutathione
-- NAC
-- Melatonin
-- Quercetin
-- Lemon balm
-- Milk thistle
-- Lycopene
-- Curcumin
Manganese Toxicity Symptoms, Side Effects & Remedies - SelfDecode Labs
We all need a bit of manganese, but how much is too much? Read this post to learn about manganese toxicity symptoms and remedies.
labs.selfdecode.com
Rafael Lao Wai
Member
- Joined
- Jun 16, 2017
- Messages
- 1,790
Somewhere in the one of the first studies of the thread, they also say a 5 mg dose of manganese normalizes the heart. I'm getting interested in buying some manganese to see what effects I get. Seems like an interesting nutrient.
OP
Amazoniac
Member
- Arginine and manganese supplementation on the immune competence of broilers immune stimulated with vaccine against Salmonella Enteritidis
"Manganese (Mn) has been identified as an important element in supporting normal immune functions in broiler chickens (Kidd, 2004), as it interacts with heterophils and macrophages through plasma membrane cells that are involved in immune response (Hurley and Keen, 1987). Son et al. (2007), reported that Mn supplementation increased Natural Killer cell cytolytic capacity and macrophage cytotoxicity against tumor cells compared to control. They concluded that immune responsiveness after supplementation with magnesium (Mg) and Mn presented positive effects; however, the exact explanation of how the minerals modulate the immune response was not completely clarified. Additionally, Mn is a cofactor of arginase, a metallo-enzyme that converts Arg into ornithine (and urea) (Wu and Morris, 1998). As Arg is a precursor of NO, through the nitric oxide synthase (NOS) enzyme, these enzymes compete for the same substrate (Wu et al., 2010). There is a complex pathway of Arg degradation; therefore, its dietary supplementation is needed to ensure both the health of the animal and the function of the body in physiological or pathological conditions."
"We hypothesized that as some organic mineral sources have been reported as a more bioavailable and with higher efficacy compared to inorganic sources (Swiatkiewicz et al., 2014), more ornithine will be formed by the Arg breakdown through arginase, boosting the lymphocyte proliferation and supplementing with Arg enough substrate will be present to guarantee satisfactory NO production through NOS, modulating the immune system of broilers."
"No other study has assessed the immune modulation by the combination of Mn and Arg. The objective of this study was to evaluate the combined effects of amino acid-complexed Mn and Arg supplementation on macrophage phagocytic activity, cellular and humoral immunity, and weight of lymphocytes organ of broilers exposed to Salmonella Enteritidis as an immune stimulator."
"It is understood that during lymphocyte activation, there is a clonal expansion generating effector and specific memory lymphocytes. For immune stimulated birds, there was smaller T cytotoxic lymphocytes (CD8+) percentage when birds were fed MnAA diets, compared to birds fed IM; despite this, the dietary supplementation with MnAA associated with a higher level of Arg, resulted in a higher production of antibodies (IgM, Figure 3). This demonstrates that birds fed [organic] MnAA could express an adaptive cellular response to vaccine stimulus in this period in a shorter, but more efficiently than birds fed inorganic Mn."
"We hypothesized that as some organic mineral sources have been reported as a more bioavailable and with higher efficacy compared to inorganic sources (Swiatkiewicz et al., 2014), more ornithine will be formed by the Arg breakdown through arginase, boosting the lymphocyte proliferation and supplementing with Arg enough substrate will be present to guarantee satisfactory NO production through NOS, modulating the immune system of broilers."
"No other study has assessed the immune modulation by the combination of Mn and Arg. The objective of this study was to evaluate the combined effects of amino acid-complexed Mn and Arg supplementation on macrophage phagocytic activity, cellular and humoral immunity, and weight of lymphocytes organ of broilers exposed to Salmonella Enteritidis as an immune stimulator."
"It is understood that during lymphocyte activation, there is a clonal expansion generating effector and specific memory lymphocytes. For immune stimulated birds, there was smaller T cytotoxic lymphocytes (CD8+) percentage when birds were fed MnAA diets, compared to birds fed IM; despite this, the dietary supplementation with MnAA associated with a higher level of Arg, resulted in a higher production of antibodies (IgM, Figure 3). This demonstrates that birds fed [organic] MnAA could express an adaptive cellular response to vaccine stimulus in this period in a shorter, but more efficiently than birds fed inorganic Mn."
OP
Amazoniac
Member
- SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation
- SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy (follow-up)
- Galactose in human metabolism, glycosylation and congenital metabolic diseases: Time for a closer look
- Polymorphisms in Manganese Transporters SLC30A10 and SLC39A8 Are Associated With Children's Neurodevelopment by Influencing Manganese Homeostasis
"The solute carrier (SLC) gene superfamily comprises a group of nearly 400 putative transporter proteins.[1,2] Among them, the SLC39 family consists of 14 zinc- and iron-related proteins (ZIPs) functioning as divalent cation transporters.[2]"
"SLC39A8 (MIM: 608732) encodes an electroneutral Mn2+/(HCO3−)2 and Zn2+/(HCO3−)2 influx symporter, most commonly known as ZIP8. The transmembrane protein has 462 amino acids and a wide tissue distribution with highest expression in placenta, lung, and kidney.[1,3] ZIP8 plays a role in manganese reabsorption in the proximal tubule of the kidney[4] and in manganese uptake into the brain.[5] It localizes mainly to the cell-surface membrane, but also to lysosomal and mitochondrial membranes.[3,6] ZIP8 is able to transport a number of other divalent cations including zinc,[7] cadmium,[7] iron,[8] and cobalt.[8] Although zinc uptake is carried out by other members of the ZIP family as well,[6] manganese transport might be a principal endogenous function of ZIP8.[7]"
"Manganese is an essential trace element. In the first 6 months of life, manganese intake is very low because human milk contains only 15 μg/l.[9] Recommended daily intake for adults is 2 mg.[10] The trace element is taken up from the proximal small gut as Mn2+ via the divalent metal transporter-1 (DMT1; official name SLC11A2).[4] In the blood, Mn2+ is oxidized to Mn3+ by coeruloplasmin, binds to transferrin as the major manganese-binding protein,[11] and enters the cell via the transferrin receptor into endosomal vesicles where it is reduced to Mn2+ and exported via DMT1 and perhaps other transporters to the cytoplasm.[4] Elimination occurs primarily via the bile, and very little Mn2+ is found in urine.[9,12]"
"Manganese-deficient animals exhibit skeletal abnormalities with shortened limbs caused by diminished production of N-acetylgalactosamine containing chondroitin sulfate.[17] The Golgi-localized enzyme β-1,4-galactosyltransferase is manganese dependent.[18]"
"Due to the complex clinical phenotype [of our patient], selective metabolic screening included investigation of glycosylation of serum transferrin, the common biomarker used to screen for congenital disorders of glycosylation (CDG).[20,21,22]"
"Serum transferrin has two N-linked sugar side chains, each bearing two terminal, negatively charged sialic acid residues (tetrasialo-transferrin) (Figure 2A). Loss of a side chain leads to the loss of two sialic acid residues (type I pattern); truncation of the side chain results in uneven loss of sialic acid residues (type II pattern). Because loss of sialic acids results in an overall alteration in the charge of the transferrin molecule, N-glycosylation abnormalities can be visualized by IEF."
"All of [our subjects] had abnormal transferrin glycosylation patterns with decreased tetrasialo-transferrin (81.94%–83.67% [reference range 85.7%–94.0%]), increased trisialo-transferrin (11.88%–12.85% [reference range 1.16%–6.36%]), and increased monosialo-transferrin (0.31%–0.46% [reference range 0%])(Figures 4A and 4B)."
"Given the severe clinical presentation of individual A, we attempted to improve the impaired galactosylation during N-glycan formation by increasing her dietary galactose intake. Daily galactose intake was raised from 1 g to 2 g/kg body weight within 2 weeks, given in 5 daily doses. After 4 weeks, galactose was discontinued for 2 weeks. Galactose therapy was reinitiated and increased to a daily dose of 3.75 g/kg body weight given over 22 hr via gastrointestinal pump feeding. Uridine (150 mg/kg bodyweight) was added to ensure that sufficient uridine was available for UDP-galactose formation.[32] Excrement sampling for reducing substances was negative––indicating complete galactose uptake."
"Galactose supplementation resulted in dramatic improvements in glycosylation. The amount of normally glycosylated tetrasialo-transferrin before treatment was severely decreased to 10.16% (HPLC reference range 85.7%–94.0%) with strong elevations of hypogalactosylated transferrin isoforms. After galactose therapy, glycosylation became completely normalized with a tetrasialo-transferrin of 87.74% (Figure 3A). Only trisialo-transferrin was still slightly increased after 4 months of treatment (7.7% [HPLC reference range 1.16%–6.36%]). Improvement of galactosylation was instantaneous, apparently dependent only on transferrin biosynthesis, which has a biological half life of 7–10 days.[33] ESI-TOF mass spectrometry of transferrin confirmed the complete normalization of previously severely hypoglycosylated transferrin (Figure 3B, day 120)."
"The underlying pathomechanism of SLC39A8 deficiency links a trace element deficiency to an inherited glycosylation disorder. Glycosylation is an essential co- and post-translational modification that occurs in about half the proteins synthesized in the cell. N-glycosylation takes place on asparagine residues that acquire a preassembled oligosaccharide side chain in the endoplasmic reticulum, which is subsequently modified extensively in the Golgi apparatus. Ultimately, the proteins obtain branched oligosaccharide side chains with terminal galactose and sialic-acid residues."
"SLC39A8 deficiency in its severe form has a striking similarity to UDP-galactose transporter deficiency. In fact, clinical presentation and transferrin hypogalactosylation led to the initial suspicion of SLC35A2-CDG in individual A described herein."
"Galactose transfer to a vast number of acceptor proteins is carried out by the so-called galactosyltransferases (GalT), a group of enzymes located in the Golgi apparatus.[38] Galactosylation is carried out mainly by the enzymes UDP-Gal:N-acetylglucosamine β-1,4-galactosyltransferase I (B4GALT1; EC 2.4.1.22) and UDP-Gal:N-acetylglucosamine β-1,4-galactosyltransferase II (B4GALT2; EC 2.4.1.22).[39]"
"Several experimental studies have investigated the importance of divalent cations for galactosyltransferases. GalT activation is absolutely metal-ion dependent, with divalent manganese being the most potent and natural activator.[40,41] Manganese attaches to two different binding sites. The high-affinity site I binds manganese with a Km value of 0.4 μM in intact Golgi vesicles; complete absence of manganese leads to no residual enzyme activity.[41] The low-affinity activator site II binds manganese with a Km value of 440 μM.[41] Site I will accept zinc instead of manganese, resulting in enzyme activity that is decreased by more than 60%; it does not bind magnesium or calcium.[40,41] In the absence of manganese, calcium can substitute at site II, resulting in 25-fold poorer affinity for UDP-galactose.[40]"
"There were no detectable serum or urinary manganese levels in individual A. Due to the manganese dependence of β-1,4-galactosyltransferase involved in N-glycosylation, severe transferrin hypogalactosylation occurred. The enzyme activity curve at low manganese concentrations has a hyperbolic shape, so that small changes in manganese concentration will have strong effects on the galactosylation activity.[41] Accordingly, the case subjects described by Boycott et al. with diminished (but measurable) manganese concentrations had impaired, but less severe, hypoglycosylation defects."
"Dietary supplementation of galactose alone, or galactose in combination with uridine, improves galactosylation by increasing the intracellular UDP-galactose pool.[42] In SLC39A8 deficiency, low manganese concentrations probably will decrease the affinity of galactosyltransferase for UDP-galactose. Increasing the UDP-galactose pool by galactose and uridine supplementation completely restores galactosylation. The similarities of SLC39A8 and SLC35A2 deficiencies suggest that the secondary glycosylation abnormality has a major role in pathogenesis of this disease, which might become normalized by simple dietary changes."
"Dietary manganese deficiency leads to bone and connective tissue disease in animals.[43] Although skeletal abnormalities were present in individual A, N-acetylgalactosamine containing chondroitin sulfate was found in normal concentrations in the urine. There were no biochemical indications of impairment of other manganese-dependent metalloenzymes, e.g., arginase,[44] glutamine synthase,[15,16] or pyruvate carboxylase.[45] However, elevated xanthine excretion in the urine indicated decreased activity of manganese-dependent xanthine oxidase [?].[46(⇈)]"
"Defective glycosylation of serum transferrin is a shared laboratory parameter and should be tested for in any case of developmental delay and dysmorphic features of unknown origin."
"In summary, our data show that disruption at highly conserved sites of the ZIP8 symporter alters function of the protein, resulting in low serum manganese levels, probably through insufficient renal reabsorption, intestinal manganese resorption, or both. ZIP8 appears to be more important for manganese than zinc homeostasis. Decreased serum manganese concentrations impair the function of galactosyltransferases, linking for the first time a trace element deficiency with inherited glycosylation disorders. Correcting hypogalactosylation by dietary galactose supplementation might well be the single most important therapeutic step for individuals with SCL39A8 deficiency. Because transferrin is the major manganese-binding protein in vascular circulation, correction of transferrin glycosylation, prior to attempting manganese supplementation, might also be reasonable,[11] especially because manganese uptake across the blood-brain-barrier is known to be transferrin dependent.[4] Additional benefits might occur with manganese supplementation. Manganese sulfate is the most soluble salt and the one normally used in nutritional supplements.[47] Given the long-term consequences of the severe presentations of SLC39A8 deficiency such as seizures on the developing brain, early galactose and manganese supplementation should be considered. The promising effects observed from dietary galactose supplementation on glycosylation by serum transferrin analysis will require further evaluation, particularly with regard to the clinical course."
"SLC39A8 (MIM: 608732) encodes an electroneutral Mn2+/(HCO3−)2 and Zn2+/(HCO3−)2 influx symporter, most commonly known as ZIP8. The transmembrane protein has 462 amino acids and a wide tissue distribution with highest expression in placenta, lung, and kidney.[1,3] ZIP8 plays a role in manganese reabsorption in the proximal tubule of the kidney[4] and in manganese uptake into the brain.[5] It localizes mainly to the cell-surface membrane, but also to lysosomal and mitochondrial membranes.[3,6] ZIP8 is able to transport a number of other divalent cations including zinc,[7] cadmium,[7] iron,[8] and cobalt.[8] Although zinc uptake is carried out by other members of the ZIP family as well,[6] manganese transport might be a principal endogenous function of ZIP8.[7]"
"Manganese is an essential trace element. In the first 6 months of life, manganese intake is very low because human milk contains only 15 μg/l.[9] Recommended daily intake for adults is 2 mg.[10] The trace element is taken up from the proximal small gut as Mn2+ via the divalent metal transporter-1 (DMT1; official name SLC11A2).[4] In the blood, Mn2+ is oxidized to Mn3+ by coeruloplasmin, binds to transferrin as the major manganese-binding protein,[11] and enters the cell via the transferrin receptor into endosomal vesicles where it is reduced to Mn2+ and exported via DMT1 and perhaps other transporters to the cytoplasm.[4] Elimination occurs primarily via the bile, and very little Mn2+ is found in urine.[9,12]"
"Manganese-deficient animals exhibit skeletal abnormalities with shortened limbs caused by diminished production of N-acetylgalactosamine containing chondroitin sulfate.[17] The Golgi-localized enzyme β-1,4-galactosyltransferase is manganese dependent.[18]"
"Due to the complex clinical phenotype [of our patient], selective metabolic screening included investigation of glycosylation of serum transferrin, the common biomarker used to screen for congenital disorders of glycosylation (CDG).[20,21,22]"
"Serum transferrin has two N-linked sugar side chains, each bearing two terminal, negatively charged sialic acid residues (tetrasialo-transferrin) (Figure 2A). Loss of a side chain leads to the loss of two sialic acid residues (type I pattern); truncation of the side chain results in uneven loss of sialic acid residues (type II pattern). Because loss of sialic acids results in an overall alteration in the charge of the transferrin molecule, N-glycosylation abnormalities can be visualized by IEF."
"All of [our subjects] had abnormal transferrin glycosylation patterns with decreased tetrasialo-transferrin (81.94%–83.67% [reference range 85.7%–94.0%]), increased trisialo-transferrin (11.88%–12.85% [reference range 1.16%–6.36%]), and increased monosialo-transferrin (0.31%–0.46% [reference range 0%])
"Given the severe clinical presentation of individual A, we attempted to improve the impaired galactosylation during N-glycan formation by increasing her dietary galactose intake. Daily galactose intake was raised from 1 g to 2 g/kg body weight within 2 weeks, given in 5 daily doses. After 4 weeks, galactose was discontinued for 2 weeks. Galactose therapy was reinitiated and increased to a daily dose of 3.75 g/kg body weight given over 22 hr via gastrointestinal pump feeding. Uridine (150 mg/kg bodyweight) was added to ensure that sufficient uridine was available for UDP-galactose formation.[32] Excrement sampling for reducing substances was negative––indicating complete galactose uptake."
"Galactose supplementation resulted in dramatic improvements in glycosylation. The amount of normally glycosylated tetrasialo-transferrin before treatment was severely decreased to 10.16% (HPLC reference range 85.7%–94.0%) with strong elevations of hypogalactosylated transferrin isoforms. After galactose therapy, glycosylation became completely normalized with a tetrasialo-transferrin of 87.74% (Figure 3A). Only trisialo-transferrin was still slightly increased after 4 months of treatment (7.7% [HPLC reference range 1.16%–6.36%]). Improvement of galactosylation was instantaneous, apparently dependent only on transferrin biosynthesis, which has a biological half life of 7–10 days.[33] ESI-TOF mass spectrometry of transferrin confirmed the complete normalization of previously severely hypoglycosylated transferrin (Figure 3B, day 120)."
"The underlying pathomechanism of SLC39A8 deficiency links a trace element deficiency to an inherited glycosylation disorder. Glycosylation is an essential co- and post-translational modification that occurs in about half the proteins synthesized in the cell. N-glycosylation takes place on asparagine residues that acquire a preassembled oligosaccharide side chain in the endoplasmic reticulum, which is subsequently modified extensively in the Golgi apparatus. Ultimately, the proteins obtain branched oligosaccharide side chains with terminal galactose and sialic-acid residues."
"SLC39A8 deficiency in its severe form has a striking similarity to UDP-galactose transporter deficiency. In fact, clinical presentation and transferrin hypogalactosylation led to the initial suspicion of SLC35A2-CDG in individual A described herein."
"Galactose transfer to a vast number of acceptor proteins is carried out by the so-called galactosyltransferases (GalT), a group of enzymes located in the Golgi apparatus.[38] Galactosylation is carried out mainly by the enzymes UDP-Gal:N-acetylglucosamine β-1,4-galactosyltransferase I (B4GALT1; EC 2.4.1.22) and UDP-Gal:N-acetylglucosamine β-1,4-galactosyltransferase II (B4GALT2; EC 2.4.1.22).[39]"
"Several experimental studies have investigated the importance of divalent cations for galactosyltransferases. GalT activation is absolutely metal-ion dependent, with divalent manganese being the most potent and natural activator.[40,41] Manganese attaches to two different binding sites. The high-affinity site I binds manganese with a Km value of 0.4 μM in intact Golgi vesicles; complete absence of manganese leads to no residual enzyme activity.[41] The low-affinity activator site II binds manganese with a Km value of 440 μM.[41] Site I will accept zinc instead of manganese, resulting in enzyme activity that is decreased by more than 60%; it does not bind magnesium or calcium.[40,41] In the absence of manganese, calcium can substitute at site II, resulting in 25-fold poorer affinity for UDP-galactose.[40]"
"There were no detectable serum or urinary manganese levels in individual A. Due to the manganese dependence of β-1,4-galactosyltransferase involved in N-glycosylation, severe transferrin hypogalactosylation occurred. The enzyme activity curve at low manganese concentrations has a hyperbolic shape, so that small changes in manganese concentration will have strong effects on the galactosylation activity.[41] Accordingly, the case subjects described by Boycott et al. with diminished (but measurable) manganese concentrations had impaired, but less severe, hypoglycosylation defects."
"Dietary supplementation of galactose alone, or galactose in combination with uridine, improves galactosylation by increasing the intracellular UDP-galactose pool.[42] In SLC39A8 deficiency, low manganese concentrations probably will decrease the affinity of galactosyltransferase for UDP-galactose. Increasing the UDP-galactose pool by galactose and uridine supplementation completely restores galactosylation. The similarities of SLC39A8 and SLC35A2 deficiencies suggest that the secondary glycosylation abnormality has a major role in pathogenesis of this disease, which might become normalized by simple dietary changes."
"Dietary manganese deficiency leads to bone and connective tissue disease in animals.[43] Although skeletal abnormalities were present in individual A, N-acetylgalactosamine containing chondroitin sulfate was found in normal concentrations in the urine. There were no biochemical indications of impairment of other manganese-dependent metalloenzymes, e.g., arginase,[44] glutamine synthase,[15,16] or pyruvate carboxylase.[45] However, elevated xanthine excretion in the urine indicated decreased activity of manganese-dependent xanthine oxidase [?].[46(⇈)]"
"Defective glycosylation of serum transferrin is a shared laboratory parameter and should be tested for in any case of developmental delay and dysmorphic features of unknown origin."
"In summary, our data show that disruption at highly conserved sites of the ZIP8 symporter alters function of the protein, resulting in low serum manganese levels, probably through insufficient renal reabsorption, intestinal manganese resorption, or both. ZIP8 appears to be more important for manganese than zinc homeostasis. Decreased serum manganese concentrations impair the function of galactosyltransferases, linking for the first time a trace element deficiency with inherited glycosylation disorders. Correcting hypogalactosylation by dietary galactose supplementation might well be the single most important therapeutic step for individuals with SCL39A8 deficiency. Because transferrin is the major manganese-binding protein in vascular circulation, correction of transferrin glycosylation, prior to attempting manganese supplementation, might also be reasonable,[11] especially because manganese uptake across the blood-brain-barrier is known to be transferrin dependent.[4] Additional benefits might occur with manganese supplementation. Manganese sulfate is the most soluble salt and the one normally used in nutritional supplements.[47] Given the long-term consequences of the severe presentations of SLC39A8 deficiency such as seizures on the developing brain, early galactose and manganese supplementation should be considered. The promising effects observed from dietary galactose supplementation on glycosylation by serum transferrin analysis will require further evaluation, particularly with regard to the clinical course."
- SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy (follow-up)
"Major clinical symptoms are cranial synostoses with lacunar skull, cerebral and cerebellar atrophy, severe psychomotor disability, seizures, and vision and hearing impairment."
"The exact pathomechanism underlying these symptoms is poorly understood. While some can be explained by manganese dependence of additional metalloenzymes such as superoxide dismutase 2 (EC 1.15.1.1), pyruvate carboxylase (EC 6.4.1.1), and glutamine synthase (EC 6.3.1.2),[5] others might be secondary effects of hypoglycosylation."
"Galactose supplementation had a favorable effect on both glycosylation and clinical presentation in a severely affected child with SLC39A8 deficiency.[1(↑)] Of course, this therapeutic approach can only treat those symptoms attributable to hypogalactosylation. Galactose supplementation corrects the malfunction of β-1,4-galactosyltransferase but not of the other manganese-dependent metalloenzymes. We therefore introduced high amounts of manganese(II)-sulfate monohydrate to the patients’ diet to reach sufficient manganese levels to correct all biochemical abnormalities, thereby establishing a causative therapy for SLC39A8 deficiency. We report on biochemical as well as clinical effects following more than 1 year of manganese(II)-sulfate monohydrate supplementation in two patients."
"Manganese doses were gradually raised over the course of 414 and 449 days [..] until normal levels of transferrin glycosylation were reached. Using this approach, we determined the definitive MnSO4 dose for both patients."
"Manganese(II)-sulfate monohydrate (Carl Roth, Karlsruhe, Germany) was chosen due to its high solubility as well as the favorable oxidation state of manganese.[10]"
"We have demonstrated that oral manganese substitution is a causative treatment for SLC39A8 deficiency. A dose of 200 mg of MnSO4 · H2O was able to correct glycosylation and lead to clinical improvement in an individual with a severe form of SLC39A8 deficiency. In a second individual, 600 mg of MnSO4· H2O were needed to maintain physiological Mn blood levels and to normalize glycosylation. These doses correspond to 20 and 15 mg/kg bodyweight respectively, indicating the therapeutic range of manganese substitution in SLC39A8 deficiency."
"SLC39A8 deficiency differs from [other] CDG subtypes since it is primarily a disorder of manganese metabolism that results in secondary hypoglycosylation and the first glycosylation disorder caused by abnormalities in trace element metabolism. While galactose supplementation was effective in restoring glycosylation, it did not affect other aspects of the disorder caused by lack of manganese in a variety of manganese-dependent enzymes. Manganese supplementation represents a better therapeutic approach than galactose therapy since it is able to correct all biochemical abnormalities that have been detected so far."
"MnSO4 · H2O supplementation was indeed able to correct defective glycosylation in SLC39A8 deficiency without additional galactose supplementation in both subjects. The daily dose needed for complete and persistent correction of glycosylation was 200 mg at a bodyweight of 9.24 kg, corresponding to approximately 21.6 mg/kg bodyweight and 600 mg at a bodyweight of 40 kg (15 mg/kg bodyweight) respectively. At these doses, blood concentrations of manganese stabilized at physiological levels in both subjects."
"Subject A’s manganese levels in CSF were comparable to those measured in healthy age-matched controls. This indicates that the administered quantity of MnSO4 · H2O is sufficient to assure physiological manganese levels in the CSF."
"In both subjects, the most sensitive parameter for sufficient manganese uptake seemed to be (dys-)glycosylation, which was used as an indicator to establish the necessary amount of daily MnSO4 · H2O intake. Other diagnostic parameters such as elevated urinary hypoxanthine excretion and elevated alkaline phosphatase in subject A normalized rapidly at low doses of manganese sulfate, when glycosylation was still insufficient. The search for better biomarkers to monitor manganese uptake remains an important goal of future research."
"During manganese supplementation, we did not observe any symptoms of manganese toxicity in either subject and two cranial MRI examinations of subject A during the observed period of therapy did not reveal any changes suspicious of manganese overexposure. In addition, manganese levels in whole-blood samples were analyzed regularly and remained within the lower normal reference range (reference: 7–11 ng/ml). However, manganese in whole-blood samples is an imperfect biomarker at best since a reliable marker for continuous manganese uptake has not been established.[3,5] Urinary manganese levels were even less consistent and ranged mostly above reference levels, although manganese excretion via urine is physiologically low.[36] This can in part be explained by the fact that ZIP8 is primarily expressed in the proximal tubule (S3 segment) of the kidney[37,38] and is believed to play a major role in tubular manganese reuptake.[38] Our findings support this notion since we observed elevated manganese excretion at physiological blood levels in patients with SLC39A8 deficiency."
"In summary, manganese supplementation in SLC39A8 deficiency corrects all biochemical abnormalities and leads to major clinical improvement. Compared to the normal daily intake of 1–2 mg manganese in adults, the required therapeutic dose is much higher. Manganese therapy should be monitored closely to prevent manganism. Individual dose finding is needed to ensure optimal treatment."
"The exact pathomechanism underlying these symptoms is poorly understood. While some can be explained by manganese dependence of additional metalloenzymes such as superoxide dismutase 2 (EC 1.15.1.1), pyruvate carboxylase (EC 6.4.1.1), and glutamine synthase (EC 6.3.1.2),[5] others might be secondary effects of hypoglycosylation."
"Galactose supplementation had a favorable effect on both glycosylation and clinical presentation in a severely affected child with SLC39A8 deficiency.[1(↑)] Of course, this therapeutic approach can only treat those symptoms attributable to hypogalactosylation. Galactose supplementation corrects the malfunction of β-1,4-galactosyltransferase but not of the other manganese-dependent metalloenzymes. We therefore introduced high amounts of manganese(II)-sulfate monohydrate to the patients’ diet to reach sufficient manganese levels to correct all biochemical abnormalities, thereby establishing a causative therapy for SLC39A8 deficiency. We report on biochemical as well as clinical effects following more than 1 year of manganese(II)-sulfate monohydrate supplementation in two patients."
"Manganese doses were gradually raised over the course of 414 and 449 days [..] until normal levels of transferrin glycosylation were reached. Using this approach, we determined the definitive MnSO4 dose for both patients."
"Manganese(II)-sulfate monohydrate (Carl Roth, Karlsruhe, Germany) was chosen due to its high solubility as well as the favorable oxidation state of manganese.[10]"
"Subject A was given an initial dose of 10 mg MnSO4 · H2O/day dissolved in water, which was added to her usual diet and was gradually increased. Initially, she was fed via a J-tube over the course of 22 hours. At the same time, the subject’s galactose substitution (dosage: 3.75 g/kg bodyweight) was tapered and eventually stopped altogether. The manganese dosage was increased when galactose tapering led to impaired glycosylation, as depicted in Figure 1, thus determining the minimal manganese dose necessary for complete biochemical correction in the absence of galactose. Due to major improvements of swallowing and her general condition, J-tube feeding was discontinued during the course of the treatment. Afterwards, the daily quantity of MnSO4 · H2O was given orally in five equal portions over the course of 24 hours."
"The final dose was 200 mg MnSO4 · H2O per day, given in five portions in an aqueous solution. This corresponds to 65 mg manganese. Glycosylation improved during manganese substitution. While tetrasialo-transferrin remained within reference ranges for most of the duration of manganese substitution, trisialo-transferrin increased rapidly under insufficient doses of MnSO4 · H2O. Doses were adapted in response to increases in trisialo-transferrin."
"Increasing doses of manganese sulfate led to preserved physiological glycosylation of serum transferrin despite tapering and ultimately cessation of galactose substitution in subject A (Figure 1). Generally, a reduction of the daily galactose dose resulted in an increase of hypogalactosylated trisialo-transferrin above its upper reference value of 6.5 area%. Other transferrin isoforms remained within their respective reference ranges for most of the time. Once an increase in trisialo-transferrin was observed, the daily MnSO4 · H2O dose was increased. After discontinuation of oral galactose supplementation, 200 mg of MnSO4 · H2O per day, which equals 65 mg manganese, was needed to maintain physiological levels of transferrin glycosylation (Figure 1)."
"No manganese was detectable in blood or in urine samples of subject A prior to oral supplementation.[1] Physiological blood levels of manganese were observed intermittently at different doses of MnSO4 · H2O, while only a dose of 200 mg/d resulted in stable physiological levels of blood manganese ranging from 7 to 7.9 ng/ml (normal range: 7–11 ng/ml)(Figure 2)."
"Elevated hypoxanthine levels in subject A decreased to normal levels after 31 days of MnSO4 · H2O supplementation and remained within reference ranges [<50 mmol/mol creatinine] throughout the observed period."
"Subject A also initially presented with elevated alkaline phosphatase, a finding that has previously been reported in cases of manganese deficiency.[13] The highest recorded level of 749 U/l (reference: 124–341 U/l) was measured shortly before introduction of manganese supplementation. On the 87th day of manganese substitution, at a daily dose of 30 mg MnSO4· H2O, alkaline phosphatase levels were within normal ranges and no further elevation was measured."
"The clinical presentation improved drastically under MnSO4 · H2O therapy. The initially observed juvenile seizures with hypsarrhythmia decreased in frequency and in severity. In a control electroencephalogram at day 206 of MnSO4 · H2O therapy, no susceptibility to seizures was detectable(Figure 3)."
"The improved vision is indicated by the subject’s ability to fixate objects as well as persons. She smiles responsively and spontaneously, and shows head control. Her swallowing has improved so that complete oral feeding is now possible."
"The subject’s hearing improved over the course of manganese supplementation."
"Subject B did not receive oral galactose substitution but was given oral manganese supplementation from the beginning. The initial dose of 10 mg MnSO4 · H2O/day was given in five equal portions."
"Initially, no manganese was detectable in this subject’s blood or urine samples.[1] During the course of the treatment, blood manganese levels rose and reached physiological values when 600 mg of MnSO4 · H2O (corresponding to approximately 195 mg of manganese or 15 mg MnSO4 · H2O/kg bodyweight) was given every day. The measured levels of manganese in urine varied considerably, the highest measured value of 5 ng/ml having been measured at a MnSO4 · H2O dose of 150 mg/d."
"In subject B, increased MnSO4 · H2O doses also led to improved glycosylation of serum transferrin."
"In subject B, improved motor abilities were observed. Previously observed repetitive movements of the head were observed less frequently and she became able to perform the finger-to-nose test indicating reduced ataxia. Muscle strength improved and she is now able to sit without support."
"The final dose was 200 mg MnSO4 · H2O per day, given in five portions in an aqueous solution. This corresponds to 65 mg manganese. Glycosylation improved during manganese substitution. While tetrasialo-transferrin remained within reference ranges for most of the duration of manganese substitution, trisialo-transferrin increased rapidly under insufficient doses of MnSO4 · H2O. Doses were adapted in response to increases in trisialo-transferrin."
"Increasing doses of manganese sulfate led to preserved physiological glycosylation of serum transferrin despite tapering and ultimately cessation of galactose substitution in subject A (Figure 1). Generally, a reduction of the daily galactose dose resulted in an increase of hypogalactosylated trisialo-transferrin above its upper reference value of 6.5 area%. Other transferrin isoforms remained within their respective reference ranges for most of the time. Once an increase in trisialo-transferrin was observed, the daily MnSO4 · H2O dose was increased. After discontinuation of oral galactose supplementation, 200 mg of MnSO4 · H2O per day, which equals 65 mg manganese, was needed to maintain physiological levels of transferrin glycosylation (Figure 1)."
"No manganese was detectable in blood or in urine samples of subject A prior to oral supplementation.[1] Physiological blood levels of manganese were observed intermittently at different doses of MnSO4 · H2O, while only a dose of 200 mg/d resulted in stable physiological levels of blood manganese ranging from 7 to 7.9 ng/ml (normal range: 7–11 ng/ml)
"Elevated hypoxanthine levels in subject A decreased to normal levels after 31 days of MnSO4 · H2O supplementation and remained within reference ranges [<50 mmol/mol creatinine] throughout the observed period."
"Subject A also initially presented with elevated alkaline phosphatase, a finding that has previously been reported in cases of manganese deficiency.[13] The highest recorded level of 749 U/l (reference: 124–341 U/l) was measured shortly before introduction of manganese supplementation. On the 87th day of manganese substitution, at a daily dose of 30 mg MnSO4· H2O, alkaline phosphatase levels were within normal ranges and no further elevation was measured."
"The clinical presentation improved drastically under MnSO4 · H2O therapy. The initially observed juvenile seizures with hypsarrhythmia decreased in frequency and in severity. In a control electroencephalogram at day 206 of MnSO4 · H2O therapy, no susceptibility to seizures was detectable
"The improved vision is indicated by the subject’s ability to fixate objects as well as persons. She smiles responsively and spontaneously, and shows head control. Her swallowing has improved so that complete oral feeding is now possible."
"The subject’s hearing improved over the course of manganese supplementation."
"Subject B did not receive oral galactose substitution but was given oral manganese supplementation from the beginning. The initial dose of 10 mg MnSO4 · H2O/day was given in five equal portions."
"Initially, no manganese was detectable in this subject’s blood or urine samples.[1] During the course of the treatment, blood manganese levels rose and reached physiological values when 600 mg of MnSO4 · H2O (corresponding to approximately 195 mg of manganese or 15 mg MnSO4 · H2O/kg bodyweight) was given every day. The measured levels of manganese in urine varied considerably, the highest measured value of 5 ng/ml having been measured at a MnSO4 · H2O dose of 150 mg/d."
"In subject B, increased MnSO4 · H2O doses also led to improved glycosylation of serum transferrin."
"In subject B, improved motor abilities were observed. Previously observed repetitive movements of the head were observed less frequently and she became able to perform the finger-to-nose test indicating reduced ataxia. Muscle strength improved and she is now able to sit without support."
"We have demonstrated that oral manganese substitution is a causative treatment for SLC39A8 deficiency. A dose of 200 mg of MnSO4 · H2O was able to correct glycosylation and lead to clinical improvement in an individual with a severe form of SLC39A8 deficiency. In a second individual, 600 mg of MnSO4· H2O were needed to maintain physiological Mn blood levels and to normalize glycosylation. These doses correspond to 20 and 15 mg/kg bodyweight respectively, indicating the therapeutic range of manganese substitution in SLC39A8 deficiency."
"SLC39A8 deficiency differs from [other] CDG subtypes since it is primarily a disorder of manganese metabolism that results in secondary hypoglycosylation and the first glycosylation disorder caused by abnormalities in trace element metabolism. While galactose supplementation was effective in restoring glycosylation, it did not affect other aspects of the disorder caused by lack of manganese in a variety of manganese-dependent enzymes. Manganese supplementation represents a better therapeutic approach than galactose therapy since it is able to correct all biochemical abnormalities that have been detected so far."
"MnSO4 · H2O supplementation was indeed able to correct defective glycosylation in SLC39A8 deficiency without additional galactose supplementation in both subjects. The daily dose needed for complete and persistent correction of glycosylation was 200 mg at a bodyweight of 9.24 kg, corresponding to approximately 21.6 mg/kg bodyweight and 600 mg at a bodyweight of 40 kg (15 mg/kg bodyweight) respectively. At these doses, blood concentrations of manganese stabilized at physiological levels in both subjects."
"Subject A’s manganese levels in CSF were comparable to those measured in healthy age-matched controls. This indicates that the administered quantity of MnSO4 · H2O is sufficient to assure physiological manganese levels in the CSF."
"In both subjects, the most sensitive parameter for sufficient manganese uptake seemed to be (dys-)glycosylation, which was used as an indicator to establish the necessary amount of daily MnSO4 · H2O intake. Other diagnostic parameters such as elevated urinary hypoxanthine excretion and elevated alkaline phosphatase in subject A normalized rapidly at low doses of manganese sulfate, when glycosylation was still insufficient. The search for better biomarkers to monitor manganese uptake remains an important goal of future research."
"During manganese supplementation, we did not observe any symptoms of manganese toxicity in either subject and two cranial MRI examinations of subject A during the observed period of therapy did not reveal any changes suspicious of manganese overexposure. In addition, manganese levels in whole-blood samples were analyzed regularly and remained within the lower normal reference range (reference: 7–11 ng/ml). However, manganese in whole-blood samples is an imperfect biomarker at best since a reliable marker for continuous manganese uptake has not been established.[3,5] Urinary manganese levels were even less consistent and ranged mostly above reference levels, although manganese excretion via urine is physiologically low.[36] This can in part be explained by the fact that ZIP8 is primarily expressed in the proximal tubule (S3 segment) of the kidney[37,38] and is believed to play a major role in tubular manganese reuptake.[38] Our findings support this notion since we observed elevated manganese excretion at physiological blood levels in patients with SLC39A8 deficiency."
"In summary, manganese supplementation in SLC39A8 deficiency corrects all biochemical abnormalities and leads to major clinical improvement. Compared to the normal daily intake of 1–2 mg manganese in adults, the required therapeutic dose is much higher. Manganese therapy should be monitored closely to prevent manganism. Individual dose finding is needed to ensure optimal treatment."
- Galactose in human metabolism, glycosylation and congenital metabolic diseases: Time for a closer look
- Polymorphisms in Manganese Transporters SLC30A10 and SLC39A8 Are Associated With Children's Neurodevelopment by Influencing Manganese Homeostasis
Mito
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Am I glad to see this thread! I have been eating an entire pineapple a day for quiet some time which I believe is 8.6 mgs - my androgens do feel high doing but I am not sure if I am doing damage
Is there any key signs to look out for ? I am not sure if I am eating too much - most of the symptoms I have not experienced like for example I don't have any anxiety or asthma - but my sense of smell is strong and occasionally my fingernails bleed a little bit after eating pineapple - it's very slight but I suspected it was because pineapple was inflammatory
Does the sense of smell become sensitive when this occurs ? I notice I can smell just about anything from about 10 feet away @Amazoniac @aliml
Is there any key signs to look out for ? I am not sure if I am eating too much - most of the symptoms I have not experienced like for example I don't have any anxiety or asthma - but my sense of smell is strong and occasionally my fingernails bleed a little bit after eating pineapple - it's very slight but I suspected it was because pineapple was inflammatory
Does the sense of smell become sensitive when this occurs ? I notice I can smell just about anything from about 10 feet away @Amazoniac @aliml
EMF Mitigation - Flush Niacin - Big 5 Minerals
