Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.

Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity.

Excessive levels of the essential metal manganese (Mn) may cause a syndrome similar to Parkinson's disease. The model organism Caenorhabditis elegans mimics some of Mn effects in mammals, including dopaminergic neurodegeneration, oxidative stress, and increased levels of AKT. The evolutionarily conserved insulin/insulin-like growth factor-1 signaling pathway (IIS) modulates worm longevity, metabolism, and antioxidant responses by antagonizing the transcription factors DAF-16/FOXO and SKN-1/Nrf-2. AKT-1, AKT-2, and SGK-1 act upstream of these transcription factors. To study the role of these proteins in C. elegans response to Mn intoxication, wild-type N2 and loss-of-function mutants were exposed to Mn (2.5 to 100 mM) for 1 h at the L1 larval stage. Strains with loss-of-function in akt-1, akt-2, and sgk-1 had higher resistance to Mn compared to N2 in the survival test. All strains tested accumulated Mn similarly, as shown by ICP-MS. DAF-16 nuclear translocation was observed by fluorescence microscopy in WT and loss-of-function strains exposed to Mn. qRT-PCR data indicate increased expression of γ-glutamyl cysteine synthetase (GCS-1) antioxidant enzyme in akt-1 mutants. The expression of sod-3 (superoxide dismutase homologue) was increased in the akt-1 mutant worms, independent of Mn treatment. However, dopaminergic neurons degenerated even in the more resistant strains. Dopaminergic function was evaluated with the basal slowing response behavioral test and dopaminergic neuron integrity was evaluated using worms expressing green fluorescent protein (GFP) under the dopamine transporter (DAT-1) promoter. These results suggest that AKT-1/2 and SGK-1 play a role in C. elegans response to Mn intoxication. However, tissue-specific responses may occur in dopaminergic neurons, contributing to degeneration.

Screening for early detection of parkinsonism using a self-administered questionnaire: a cross-sectional epidemiologic study.

BACKGROUND: Manganese (Mn) is a common component of welding fume. Exposure to Mn fume has been associated with parkinsonism. A simple and reliable screening tool to evaluate Mn exposed workers for neurotoxic injury would have broad occupational health application. METHODS: This study investigated 490 occupational welders recruited from a trade union list. Subjects were examined by a movement disorders specialist using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Parkinsonism, intermediate, and normal groups were defined as UPDRS3 score ≥ 15, 6-15, and <6, respectively. Workers completed a health status questionnaire (PDQ39) and a Parkinson disease (PD) Symptoms Questionnaire. Areas under receiver operator curve (AUC) were analyzed based on these scores, adjusted for age, smoking, race, gender, and neurologist, using normal as the reference. RESULTS: The AUC was 0.79 (95% confidence interval [CI]=0.73-0.84) for PDQ39 and 0.78 (95% CI=0.72-0.85) for PD Symptoms Questionnaire score. At 70% sensitivity, the specificity for PDQ39 score and PD Symptoms Questionnaire score for the prediction of parkinsonism was 73.1% and 80.1%, respectively. CONCLUSIONS: These results suggest the questionnaires have reasonably good sensitivity and specificity to predict parkinsonism in Mn exposed workers. These questionnaires could be a valuable first step in a tiered screening approach for Mn exposed workers.

Manganese toxicity in a child with iron deficiency and polycythemia.

A previously healthy 5-year-old girl presented with pica, emotional lability, and marked gait abnormalities. She had concurrent severe iron deficiency and polycythemia. Her magnetic resonance imaging (MRI) scan showed increased signal in the basal ganglia on T1-weighted images consistent with manganese neurotoxicity. Manganism was subsequently confirmed as her blood manganese levels were extremely elevated. Chelation therapy resulted in improvement in her mobility but she continues to have significant gait impairment. An epidemiological investigation identified well water as the potential source of manganese exposure for our patient, but to date, we have been unable to identify the nature of her neurotoxic susceptibility.

From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure.

Manganism is a distinct medical condition from Parkinson's disease. Manganese exposure scenarios in the last century generally have changed from the acute, high-level exposure conditions responsible for the occurrence of manganism to chronic exposure to much lower levels. Such chronic exposures may progressively extend the site of manganese deposition and toxicity from the globus pallidus to the entire area of the basal ganglia, including the substantia nigra pars compacta involved in Parkinson's disease. The mechanisms of manganese neurotoxicity from chronic exposure to very low levels are not well understood, but promising information is based on the concept of susceptibility that may place individuals exposed to manganese at a higher risk for developing Parkinsonian disturbances. These conditions include mutations of genes which play important pathogenetic roles in both Parkinsonism and in the regulation of manganese transport and metabolism. Liver function is also important in manganese-related neurotoxicity and sub-clinical impairment may increase the risk of Parkinsonism. The purpose and scope of this report are to explore the literature concerning manganese exposure and potential subclinical effects and biological pathways, impairment, and development of diseases such as Parkinsonism and manganism. Inhalation and ingestion of manganese will be the focus of this report.

Are there common biochemical and molecular mechanisms controlling manganism and parkisonism.

Over the past several decades there has been considerable progress in our basic knowledge as to the mechanisms and factors regulating Mn toxicity. The disorder known as manganism is associated with the preferential accumulation of Mn in the globus pallidus of the basal ganglia which is generally considered to be the major and initial site of injury. Because the area of the CNS comprising the basal ganglia is very complex and dependent on the precise function and balance of several neurotransmitters, it is not surprising that symptoms of manganism often overlap with that of Parkinson's disease. The fact that neurological symptoms and onset of Mn toxicity are quite broad and can vary unpredictably probably reflects specific genetic variance of the physiological and biochemical makeup within the basal ganglia in any individual. Differences in response to Mn overexposure are, thus, likely due to underlying genetic variability which ultimately presents in deviations in both susceptibility as well as the characteristics of the neurological lesions and symptoms expressed. Although chronic exposure to Mn is not the initial causative agent provoking Parkinsonism, there is evidence suggesting that persistent exposure can predispose an individual to acquire dystonic movements associated with Parkinson's disease. As noted in this review, there appears to be common threads between the two disorders, as mutations in the genes, parkin and ATP13A2, associated with early onset of Parkinsonism, may also predispose an individual to develop Mn toxicity. Mutations in both genes appear to effect transport of Mn into the cell. These genetic difference coupled with additional environmental or nutritional factors must also be considered as contributing to the severity and onset of manganism.

Performance alterations associated with occupational exposure to manganese--a meta-analysis.

The review aimed at quantifying the evidence of performance effects resulting from occupational exposure to manganese. Epidemiological studies published between 1987 and 2008 were analyzed. The approach was based on the meta-analytical method of effect size estimates and sought to contribute to the following issues: (1) identification of the affected functions; (2) identification of sensitive neuropsychological tests; (3) analyses of exposure-effect relationships. Thirteen studies examining 958 exposed and 815 unexposed workers were included in the meta-analysis. Mean concentrations of inhalable manganese ranged from 0.05 to 1.59 mg/m(3), mean concentrations of manganese in whole blood ranged from 8.1 to 48.4 microg/L. Nineteen neuropsychological performance variables were analyzed as they were included in at least three of the identified studies. Apart from two outcomes, the overall effects displayed a negative impact of manganese on performance. Significant overall effects were obtained for six test variables; their size ranged from d=-0.23 to -0.36. Four of the variables measured motor speed and two of them speed of information processing. The analysis of exposure-effect relationships showed that larger effect sizes were more consistently associated with higher concentrations of inhalable manganese than with manganese in blood. The evidence of cognitive and motor performance effects is in accordance with the knowledge about accumulation of manganese in the basal ganglia and the effect of manganese on the neurotransmitter dopamine. Inconsistencies in the relationship between effect sizes and the biomarker manganese in blood were discussed in the context of results indicating that the biomarker might not be sufficiently meaningful for the neurobehavioral alterations. Simple motor performance tests with a distinct speed component seem to be highly recommendable for further studies, because they seem to be appropriate for measuring manganese-related changes, seem to provide homogenous results and their outcomes show consistent relations to exposure. The rigorous quantitative approach was especially appropriate for revealing exposure-effect relationships, but information about individual cumulative exposure would enhance the potential for risk assessment of manganese.

Liver transplantion in a patient with rapid onset parkinsonism-dementia complex induced by manganism secondary to liver failure

Bilateral and symmetric globus-pallidus hyperintensities are observed on T1-weighted MRI in most of the patients with chronic liver failure, due to manganese accumulation. We report a 53-year-old man, with rapid onset parkinsonism-dementia complex associated with accumulation of manganese in the brain, secondary to liver failure. A brain MRI was performed and a high signal on T1-weighted images was seen on globus-pallidus, as well as on T2-weighted images on the hemispheric white-matter. He was referred to a liver-transplantation. The patient passed away on the seventh postoperative day. Our findings support the concept of the toxic effects of manganese on the globus-pallidus. The treatment of this form of parkinsonism is controversial and liver-transplantation should not be considered as first line treatment but as an alternative one.

Hiperintesidades simétricas e bilaterais dos gânglios da base são observadas em imagens de ressonância magnética encefálica (RM) ponderadas em T1 na maioria dos pacientes com insuficiência hepática crônica devidas ao acúmulo de manganês. Nós relatamos o caso de um homem, com 53 anos de idade, com um complexo parkinsonismo-demência rapidamente progressivo associado com o acúmulo de manganês no cérebro, secundariamente a insuficiência hepática. Uma RM encefálica foi realizada e foram observadas imagens hiperintensas/hipersinal nas imagens ponderadas em T1 no globo pálido e, também, na substância branca dos hemisférios cerebrais ponderadas em T2. Devido à falta de resposta ao tratamento clinico optamos pelo transplante hepático. O paciente faleceu no 7° dia de PO. Nossos achados corroboram o conceito dos efeitos tóxicos do manganês nos gânglios da base/globo pálido. O tratamento desta forma de parkinsonismo é controverso e o transplante hepático não deverá ser considerada uma opção terapêutica de primeira linha, porém como um tratamento alternativo considerando-se os riscos-benefícios dessa escolha.

Economic implications of manganese neurotoxicity.

Manganese neurotoxicity is linked primarily to inhalation exposure, and its clinical features are almost totally based on high doses, such as those experienced by miners. Manifestations of lower level exposures can take two forms. One is the appearance of neurobehavioral deficits. A second, equally subtle, form is as a promoter, borrowing the term used in carcinogenesis, of neurodegenerative disease. Such low-level environmental exposures may be more potent than expected if they occur as ultrafine particles able to penetrate directly into the brain. The neurological disorder linked most closely to manganese is Parkinson's disease (PD). Although most observers recognize that the features of manganese-induced parkinsonism differ from those of idiopathic PD, they overlap considerably. The overlaps should be expected because the underlying lesions, although distinguishable, are closely linked because they belong to structures with complex interdependent circuitry. Such interdependence makes it feasible to undertake an analysis of how manganese neurotoxicity might elevate the risks of PD. A relatively small increment in risk, expressed as a leftward shift in the age prevalence of PD, incurs significant economic costs.

Lethal manganese-cadmium intoxication. A case report.

A case of a lethal manganese-cadmium (Mn-Cd) intoxication is reported. The postmortem examination revealed a noticeable reddish-violet discolouration of the serous cutes of all body cavities, but there was no indication of any corrosive burns of the mucous membranes of the gastrointestinal tract. An Mn concentration of 899 micro g/l blood and a Cd concentration of 238 micro g/l blood were found in the deceased woman. These concentrations are higher than normal levels by a factor of about 100. A subacute or chronic manganese-cadmium absorption must be assumed.

Manganese deposits in patients with biliary atresia after hepatic porto-enterostomy.

PURPOSE: The aim of this study was to determine if there is latent manganese toxicity in patients with biliary atresia. METHODS: Fifteen children with biliary atresia were examined postoperatively with regard to whole-blood manganese levels using brain magnetic resonance imaging (MRI) and I-123 iodoamphetamine (IMP) per rectal portal scintigraphy. RESULTS: Nine (60%) of the 15 had high whole-blood manganese levels (mean, 4.1 microg/dL; range, 1.2 to 9.6; normal, 0.5 to 2.5), and these 9 had hyperintense globus pallidus on T1-weighted images, with no corresponding signal change in T2 sequences. I-123 IMP per rectal portal scintigraphy was done for 13 patients to evaluate portosystemic shunt flow. 12 (92%) of these patients had an increased flow. Mean shunt ratio was estimated to be 41% (range, 0.6 to 98; normal, <5%). Encephalopathy was evident in only 1 patient. CONCLUSIONS: Some patients with biliary atresia in the postoperative period have manganese deposits in globus pallidus on T1-weighted images and high whole-blood manganese levels, possibly caused by increased portsystemic shunt, and a latent or subclinical encephalopathy is also present.