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Mastering Manganese

‘A well-known professional basketball player was a devout vegetarian.

He felt he performed better if he kept to a strict vegetarian diet. However, while his shooting and concentration seemed improved, he kept breaking bones, which then healed very, very, slowly. His joints also became increasingly unstable.
His basketball career seemed to be at a halt’.

‘Eventually, his physicians discovered he had no detectable manganese in his system. They immediately
prescribed manganese supplements. Over a period of several months his bones began to mend, making
him strong enough to return to the NBA court’. 1

What does manganese do?

Manganese (Mn) is the twelfth most abundant element on earth. It is a trace mineral, vital to human
and animal life. In humans it appears to be required for the regulation of blood sugar levels and the
growth and repair of connective tissues and cartilage. It is important for energy production, the
breakdown of fats and the healthy function of the thyroid and adrenals. It is distributed throughout the
human body’s tissue with most being found in the bone, kidneys, liver, pituitary, pancreas and brain. 2
Importantly, Mn activates enzymes associated with fatty acid metabolism and protein synthesis. 1
Mn is essential in bone metabolism along with cofactors, calcium, copper and zinc. Studies of postmenopausal
women have demonstrated the effectiveness of supplementation with calcium, copper, Mn
and zinc for bone mineral density. 3 A deficiency of Mn results in abnormal skeletal development
because it is a preferred cofactor of enzymes called glycosyltransferases. These enzymes are required
for the synthesis of proteoglycans needed for the formation of healthy cartilage and bone. 4
Mn functions as a cofactor for a variety of enzymes, including arginase, glutamine synthetase (GS),
pyruvate carboxylase and manganese superoxide dismutase (MnSOD). Through these, Mn plays critically
important roles in development, digestion, reproduction, antioxidant defense, energy production,
immune response and regulation of neuronal activities. 5
 The Mn metalloezyme arginase has the homeostatic purpose of ridding the body of ammonia
through urea synthesis, and to produce ornithine, the precursor for polyamines and prolines.
Polyamines produced through ornithine decarboxylase are necessary for cell proliferation and
regulation of several ion channels. 7
 Glutamine synthetase is an enzyme responsible for catalyzing the reaction that synthesizes
glutamine from glutamate which is neurotoxic and ammonia which is toxic. 7
 Pyruvate carboxylase is a protein important in the conversion of carbon dioxide and pyruvate to
oxaloacetate. It is involved in gluconeogenesis, lipogenesis and the krebs cycle. 13
 MnSOD is one of a family of enzymes that catalyses the disproportionation (the transformation of
a substance into two or more dissimilar substances usually by simultaneous oxidation and
reduction) of superoxide anion. This protects cells against oxidative damage. Aerobic life without
MnSOD is not sustainable. It is a ubiquitous metalloenzyme essential for the survival of all aerobic
organisms from bacteria, to humans. 6


Genetic Variations Affecting Homeostasis

Several genes affect Mn homeostasis. SLC39A8 deficiency (SLC39A8 – CDG) is an inborn error of
metabolism affecting Mn transport via ZIP8. This results in Mn deficiency and neurological and motor
dysfunction. Congenital glycosylation is another feature of this phenotype. In a small cohort, high doses
of Mn sulfate (15-20 mg per kg) have been noted to resolve the enzyme dysfunction.8
The C allele of the SLC30A10 causes deficiency due to increased Mn efflux, which results in lower blood
Mn. Conversely, the A allele of the same gene limits Mn efflux from cells and its transport to bile for
excretion. This results in significantly higher blood levels and is associated with neurodevelopmental
issues in children.9


Dietary Intake

In the diet Mn is mostly obtained from legumes, whole grains, nuts and rice. Studies have found that Mn
intake has declined throughout the western world. At the turn of the century diets were based on
wholegrains, cereals and other traditional foods. This meant that Mn intakes were much greater than
the average intake today. As society has developed diets have become high in processed foods, fat and
sugar. These foods contain almost no Mn due to the removal of the bran and germ of grains during
processing. 10
The amount of Mn absorbed orally from food in humans ranges from 1% to 5% and is dependent on the
amount and form of Mn and other dietary components such as fibre and phytates which can have a
dramatic effect on absorption.
Mn is absorbed by the intestinal cells as Mn+3 by binding to transferrin. Through endocytosis it is
brought into the cell and dissociated into Mn+3 and Mn+2. Mn+2 is then transported into the cytosol. The
protein ferroportin, exports iron from the cell and has been implicated in Mn efflux. Mn is then released
into the circulation where it is bound to albumin and β-albumin for transport to the peripheral tissues.
Due to the shared use of the transporter transferrin, Mn absorption can be adversely affected by the
presence of iron in the diet. Other minerals that may compete for Mn absorption are calcium, zinc and
cadmium. 10
A deficiency in trace elements that are synergistic can also lead to poor Mn status. Nutrients considered
synergistic to Mn include the minerals iron, magnesium, phosphorus, potassium and zinc; and vitamins
A, B1, B3, B5, B6 and E. 1

Deficiency and Excess

A deficiency of Mn has been associated with numerous diseases and poor health outcomes and is due
mostly to inadequate intake or interaction with competing minerals. Mn deficiency symptoms can be
non-specific ranging from poor bone growth, skeletal defects and impaired growth, to poor glucose
tolerance and abnormal metabolism of carbohydrates and fats.
It has been suggested that Mn intake could serve as a protective antioxidant against chronic diseases
associated with low Mn levels such as diabetes, metabolic syndrome, asthma, osteoporosis and
dyslipidemia. 10
On the other hand Mn excess symptoms tend to target those organs that are primary storage sites,
especially the brain. Symptoms can include irritability, aggressiveness, cognitive and behavioural deficits
and reduction in motor function. A susceptibility to manganese toxicity can be caused by chronic liver
disease and iron deficiency. 4

How to determine Manganese status

In the United States, Hair Tissue Mineral Analysis (HTMA) results appear to show Mn deficiency to be as
prevalent as iron deficiency. 1 Since many of the symptoms of Mn deficiency are non-specific and
permanent, finding a quick, non-invasive way to screen for deficiency is imperative. A study has shown
that ‘mineral balance and excretion data are not useful biomarkers of manganese exposure’, therefore it
is essential to find another way to obtain Mn status. 11
Hair Tissue Mineral Analysis (HTMA) has a long history. For many years researchers have used it to study
minerals excesses and deficiencies in human nutrition. HTMA is not a diagnostic tool but provided the
sample is properly obtained; it can reveal nutritional and toxic element levels. With a proper
understanding of nutrition, and the complex interrelationships between minerals, an individual
metabolic profile of the body can be understood. (See for a list of studies
using HTMA). From the results of an HTMA, a practitioner can then choose other focused testing to
confirm the best treatment.

InterClinical Comment

Manganese is essential for life, but because of the decline in the quality of the average diet, dietary
intake has decreased. Conducting a test for nutrient levels can establish if a deficiency is present.
However, obtaining mineral content from blood samples is complex. HTMA can measure essential trace
elements with appropriate specificity, sensitivity, speed, simplicity and cost. 12 With careful
supplementation and a healthy eating plan deficiency can be addressed.



1 Watts, D. Trace elements and other essential nutrients, 1995 Ch. 10, p 117-123
2 Frontiers in Bioscience, Landmark 23 (2018) pp. 1655-1679
3 Saltman PD, Strause LG. The role of trace minerals in osteoporosis. J Am Coll Nutr. 1993 Aug; 12(4):384-9
4 Linus Pauling Institute: Manganese
5 Chen.P, Bornhorst.J, Maschner.J. Manganese metabolism in humans. Front Biosci (Landmark Ed.). 2018
6 Miriyala. S, et al Manganese superoxide dismutase, MnSOD and its mimics. Biochimica et Biophysica Acta 1822
(2012) 794-814
7 Caldwell, R.B, Toque, H.A, Narayanan, S.P, Caldwell R.W. Arginase: an old enzyme with new tricks. Trends
Pharmacol Sci, 2015 Jun; 36(6): 395-405
8 Park, J.H et al, SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese
therapy. Genetics in Medicine. Feb 2018, vol. 20, No. 2.
9 Whalberg K.E et al. Polymorphisms in Manganese Transporters SLC30A10 and SLC39A8 are associated with
children’s neurodevelopment by influencing manganese homeostasis. Frontiers in Genetics, Dec. 2018 Vol 9,
Article 664
10 Freeland-Graves JH, Mousa TY, Kim S. International variability in diet and requirements of manganese: causes
and consequences. Journal of Trace Elements in Medicine and Biology 2016;38(supplement C):24-32
11 Greger JL. Nutrition versus toxicology of manganese in humans: evaluation of potential biomarkers.
Neurotoxicology. 1999 Apr-Jun;20(2-3):205-12
12 Park, SB, Choi SW, Nam AY. Hair Tissue Mineral Analysis and Metabolic Syndrome. Biol Tace Elem Res 2009
13 Smith LD, Garg U. Biomarkers in Inborn Errors of Metabolism. 2017 1st Ed. Elsevier Ch 5.







Susan Szczesny
Additional Tags
Hair Tissue Mineral Analysis

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InterClinical Labs
InterClinical Laboratories is one of Australasia's leading companies in complementary medicines, practitioner nutritional products and health screening services.

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