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Manganese in manganism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Batten disease: A narrative review
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.217949
The collective evidence to date suggests that environmental exposure to excessive amounts of manganese (Mn) can cause a neurodegenerative condition known as manganism. It is now also relatively clear that Mn is involved in the pathogenesis of Alzheimer's disease and at least some prion diseases. The potential involvement of Mn in a panel of other neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Batten disease has been suggested and investigated, but the results to date are somewhat inconclusive. Herein, previously reported experimental studies investigating the involvement of Mn in the pathogenesis of these conditions are narratively reviewed. Keywords: Amyotrophic lateral sclerosis, Batten disease, environmental exposure, Huntington's disease, manganese, manganism, neuronal ceroid lipofuscinosis, Parkinson's disease, soy milk
Key Message: Manganese (Mn) is involved in the pathogenesis of Alzheimer's disease and at least some prion diseases, but its involvement in other neurodegenerative diseases has not been conclusively proven. Occupational exposure to excessive Mn via inhalation can cause a neurodegenerative condition known as manganism, which mimics some of the symptoms of Parkinson's disease. The number of cytosine-adenine-guanine (CAG) repeats present in the huntingtin (HTT) gene definitely influences the age of onset of Huntington's disease, but Mn may also play a role in some cases. Studies assessing the potential involvement of Mn in the pathogenesis of amyotropic lateral sclerosis have yielded equivocal results. While the underlying determinant of Batten disease More Details is genetic, Mn has been implicated in its onset. The potential involvement of manganese (Mn) in neurodegenerative disorders has attracted increased research interest in recent years. Collectively, the evidence amassed to date derived from animal models and human samples suggests that Mn is highly likely to be involved in the pathogenesis of Alzheimer's disease [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11] and at least some prion diseases,[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] but its involvement or otherwise in a panel of other neurodegenerative conditions remains to be determined. This narrative review begins with a section on the neurodegenerative disorder known as manganism. While evidence strongly suggests that the condition is caused by environmental Mn exposure,[23] due to a relative scarcity of cases, details such as the precise mechanism or mechanisms involved and the thresholds of exposure required to cause it in humans remain unclear. The collective results of a collation of relevant studies, case reports, and case series are reviewed below. The potential involvement of Mn in the pathogenesis of various other neurodegenerative conditions is then explored with reference to the literature to date. It has been postulated that Mn may be involved in Parkinson's disease, but the bulk of the evidence now available suggests that this may not be the case.[24] Evidence implying the involvement of Mn in the onset of Huntington's disease (HD) is more convincing, specifically that arising from a thorough study recently reported by Tidball et al.[25] The involvement of Mn in amyotrophic lateral sclerosis (ALS) has been suggested,[26] but recent studies [27],[28],[29],[30] have yielded mixed results, as discussed below. Lastly, reports potentially implicating Mn in the pathogenesis of the relatively rare condition known as Batten disease [31],[32] are discussed.
Normal brain development and function rely on the ingestion of a small amount of dietary Mn. Mn deficiency is rare in infants because breast milk, cow's milk, and infant formulae all contain sufficient amounts of Mn.[33] It is similarly rare in older children and adults because a normal diet also reportedly contains sufficient Mn.[34] However, the accumulation of excess Mn in the brain has been conclusively associated with a neurodegenerative condition known as manganism.[23] While food is unlikely to be a source of excessive neural Mn accumulation because the levels ingested via this route are ordinarily well within the limits of human homeostatic control, there are some reports suggesting that drinking-water contaminated with high levels of Mn may be associated with neurological symptoms.[35],[36] Notably however, these reports generally do not contain the type of rigorously acquired, controlled, and analyzed data required to draw firm conclusions. Of a sample of 25 Japanese subjects whose drinking-water contained an estimated 28 mg/L of Mn due to contamination from discarded batteries, 15 exhibited symptoms of poisoning including lethargy, tremors, and mental disturbances.[35] The severity of symptoms was correlated with age, suggesting a cumulative effect over time, but the individuals were also exposed to other potentially toxic chemicals; thus negating firm conclusions with regard to Mn. In a more recent study,[36] 188 elderly subjects from areas of Greece with approximately 4–15, 82–253, and 1800–2300 μg/L of Mn in their drinking-water were assessed for chronic manganism symptoms and hair Mn concentrations. In that study, both mean neurological scores and mean hair Mn concentrations increased significantly with drinking-water Mn concentration. Importantly however, other studies on populations subjected to long-term exposure to drinking-water with high Mn concentrations have not detected adverse effects.[37],[38] With the possible exception of infants given large amounts of soy milk or formula,[33],[39],[40] excessive environmental exposure to Mn is usually occupational and occurs via inhalation. Confined-space welding has now been conclusively associated with manganism symptoms [41] and the deposition of Mn in numerous areas of the brain.[42] Previous reports also suggest that miners, smelter workers, millers, battery workers, and those unduly exposed to the anti-knocking agent methylcyclopentadienyl manganese tricarbonyl (MTM) may also be at risk.[43] With regard to the amounts and locations of Mn accumulation in the brain, the results of a recent study strongly suggest that these are not solely dictated by the amount of Mn inhaled—the size of Mn particles inhaled, and whether they are inhaled in the form of a dust or a fume are evidently also of paramount importance.[42] The early symptoms of manganism are largely behavioral and include anorexia, mood swings, and irritability, as well as attention disturbances and reduced response times. As the condition progresses, the patient begins to exhibit many of the symptoms of idiopathic Parkinson's disease (PD) including hypomimia, disturbed speech, bradykinesia, rigidity, and walking difficulty.[39] In its later stages, patients with severe manganism tend to exhibit a characteristic abnormal gait associated with rigidity and postural instability.[23] There are well established differences between manganism and PD however.[44] Resting tremor is often absent even in late-stage manganism, but it is typical of advanced PD.[45] Pathologically, “Lewy bodies” are absent in manganism [46] but they are a characteristic feature of PD. With regard to treatment, manganism is usually unresponsive or only transiently responsive to levodopa,[47] while in PD the response is often marked and long-lasting.[48] The primary site of Mn accumulation in manganism is the globus pallidus of the basal ganglia.[49] Normal basal ganglia function involves numerous different neurotransmitters, and is thus influenced by genetic variation in the physiological and biochemical makeup of each individual. Evidently this genetic variation may contribute to the observed differences in the onset of manganism and the severity of its symptoms in different individuals with similar levels of exposure.[50],[51] Cases of the successful treatment of Mn poisoning incorporating ethylenediaminetetraacetic acid (EDTA)-based chelating agents have been intermittently reported since the 1950s, but these have generally consisted of case studies, or case series involving very small cohorts.[52],[53],[54],[55],[56] Drawing firm conclusions on the efficacy of such therapy from these reports is problematic, because in most cases the chelation therapy was initiated at the same time that the patient was removed from the source of chronic Mn exposure, or soon thereafter; thus the relative contribution of the therapy to the reported improvements is unclear. Given the substantial improvements in the capacity for accurate monitoring of occupational Mn exposure that have been developed in the last two decades (and to varying extents utilized in the relevant industries worldwide), it is hoped that the efficacy or otherwise of treatment options for chronic occupational exposure will become an outdated concept. As suggested by Herrero Hernandez et al.,[56] the relevant industries should regard routine occupational exposure to potentially deleterious levels of inhaled Mn as something that is entirely avoidable, rather than something that is potentially treatable.
Long-term exposure to inhaled Mn has been positively associated with PD in 3 patients in one case control study [57] and 2 individual cases in another report.[58] In the vast majority of case control studies however, occupational Mn inhalation has not been associated with PD.[58],[59],[60],[61] The authors of a systematic review of a series of pathology-based studies in manganism patients and experimentally Mn-exposed primates also concluded that manganism and PD are pathologically distinct conditions.[62] Thus, it is now relatively clear that while Mn inhalation is associated with the “Parkinsonian” disorder known as manganism, it is most likely not causatively associated with PD.
HD is a lethal autosomal dominant neurodegenerative disease. Patients may initially only exhibit cognitive and emotional disturbances,[63] but this is invariably followed by the gradual but ultimately completely debilitating deterioration of motor skills.[64] The primary site involved is the corpus striatum, the medium spiny neurons of which are lost as the disease progresses.[65] Age at the onset of symptoms is inversely correlated with the extent of expansion of the glutamine-encoding triplet repeat (CAG) of the “huntingtin” (HTT) gene.[66] It has been demonstrated that the HTT protein participates in Mn transport,[67] and in a study comparing Mn accumulation in a mutant cell line model of HD (STHdh) and corresponding wild-type cells there was reportedly significantly less Mn accumulation in the HD line.[68] In that same study the authors identified lower striatal Mn levels in a murine HD model (strain YAC128Q) than in control mice, after three subcutaneous injections with manganese chloride tetrahydrate over the course of 1 week. It was subsequently determined via western blotting of cell lysates that the diminished Mn accumulation in STHdh cells was not due to reduced divalent metal transporter 1 (DMT1) activity, which was a theoretical possibility given that DMT1 can transport both Mn and iron. Conversely, transferrin receptor (TfR) levels were reduced in STHdh cells.[69] These results suggested the potential involvement of Mn and associated transport pathways in the pathology of HD, and there have been further recent developments in this area. Kumar et al.,[70] hypothesized that the reduced Mn transport reported in cellular and murine HD models may represent compensatory metabolic responses to HD pathology. After subjecting an immortalized murine HD striatal cell line and control cells to exogenous Mn, they detected lower metabolite levels of pantothenic acid and glutathione in the HD line, and Mn dose-dependent reduction in isobutyryl carnitine induction. At the highest Mn concentration tested, they also observed concurrent induction of metabolites in the pentose shunt pathway.[70] While these observations will contribute to the elucidation of the causal (or otherwise) involvement of Mn and associated pathways in the pathogenesis of HD in the future, they do not of themselves suggest obvious possibilities. In the most compelling study of its kind to date, Tidball et al.,[25] recently provided strong evidence that ataxia telangiectasia mutated (ATM)-p53 signaling is involved in the abnormal transport of Mn observed in cellular HD models. They reported that a Mn-dependent ATM-p53 signaling pathway was selectively impaired in both human HD patient-derived neuroprogenitor cells and immortalized murine striatal cell models of HD. In both models the associated Mn-induced phosphorylation of p53 was Mn dose-dependent, implying causality. The murine control neuroprogenitors exhibited a significant Mn-dependent increase in mRNA expression of the p53 transcriptional target p21 while the HD mutant cells did not, prompting the authors to suggest that elevated expression of this p53 transcriptional target is highly consistent with Mn exposure increasing p53 transcriptional activity. They went on to demonstrate that the HD-dependent deficit in ATM activation was Mn-specific, and resulted in reductions in cellular Mn accumulation in both the human and murine models. The Tidball et al.,[25] study constitutes highly convincing evidence for the potential involvement of Mn in HD pathogenesis because the investigations conducted by the authors were extensive, and they were performed and reported rigorously.
ALS is a rapidly progressive neurodegenerative disease involving the death of motor neurons. It is relatively rare, with a reported prevalence of approximately 1/20,000 in the US in 2012,[71] and it is invariably fatal. In the vast majority of cases there is no readily identifiable “risk factor,” though in a small minority of cases familial analysis strongly suggests that the cause is genetic.[72] The first report indicating the possible involvement of Mn in the pathogenesis of ALS was a small study in which Mn distributions were assessed in cross-sections of the cervical, thoracic, and lumbar portions of the spinal cords of 7 ALS and 6 control cadavers.[26] In that study, a significantly higher mean Mn concentration was detected in the anterior horns of the cervical cords of ALS patients than in those of the controls. The authors concluded that the neurological degenerative changes seen in ALS patients may result from localized Mn metabolism disturbances in the spinal cord, given that Mn inhibits neuronal transmission. More recent larger-scale studies investigating the potential involvement of Mn in the pathogenesis of ALS have yielded mixed results. Royce-Nagel et al.,[27] found no significant difference in the magnesium or Mn levels in hair samples from 100 ALS patients and 100 healthy age-matched controls, and also reported that in the ALS group there was no association between metal levels and age at onset of symptoms. Notably however, ALS patients were significantly more likely to report a history of occupational gasoline exposure. Roos et al.,[28] tested Mn levels in the plasma and cerebrospinal fluid (CSF) of 17 ALS patients and 10 healthy controls via high-resolution inductively coupled plasma mass spectrometry. They reported that the ALS group exhibited significantly higher Mn concentrations in CSF, but not in plasma. Perhaps unsurprisingly given that result, in the ALS patients they also detected significantly higher Mn levels in CSF than in plasma; suggesting the possible transport of Mn into the CSF in ALS patients. In a study utilizing atomic absorption spectroscopy, Garzillo et al.,[30] also reported a lack of significantly elevated Mn in the serum of 34 ALS patients compared to 25 controls. If the elevation of Mn in ALS is specific to the CSF, this would explain why Royce-Nagel et al.,[27] found no elevation of Mn in hair samples from ALS patients. With regard to familial ALS, in a recent study in transgenic mice expressing a mutant disease-causing form of the human TAR DNA binding protein-43 (TDP-43) gene, significant Mn accumulation in the CSF of mutant mice as compared to wild-type litter-mates was detected.[29] However, significantly elevated Mn levels were not detected in the brain. While the relevance of this finding to nonfamilial (“spontaneous”) ALS remains to be determined, it constitutes another indication that future studies investigating the potential role of Mn in the pathogenesis of ALS should—where possible—include the assessment of CSF, rather than focusing solely on serum levels and/or levels in specific areas of the brain.
The root cause of Batten disease is clearly genetic, but some animal studies suggest that abnormal Mn processing may be involved in its onset and progression.[31],[32] While the term “Batten disease” has historically been used relatively exclusively to refer specifically to the juvenile form of neuronal ceroid lipofuscinosis (NCL), the most prevalent form, it is now widely used to refer to NCLs more generally.[73],[74],[75],[76] Juvenile NCL is an invariably fatal condition resulting from one of various known autosomal recessive genetic mutations (see Sleat et al.,[77] for the most comprehensive genetic analysis available to date), presenting between the ages of 5 and 8 years. Patients exhibit progressive loss of sight and ultimately seizures, and numerous disturbances to other neuronally influenced functions including learning, personality, behavior, speech, and motor-skills to varying degrees. Studies in both murine [31] and ovine [32] models of juvenile NCL imply that Mn processing may be involved in its progression in humans. Notably however, Palmer et al.,[78] suggest that firm conclusions on this cannot be drawn from the scant evidence published to date. In a murine model of juvenile NCL, Benedict et al.,[31] detected an increase in the amount of the antioxidant enzyme Mn superoxide dismutase in the thalamus, and surmised that it may represent a response to increased deleterious superoxide radicals. The focus of that study was oxidative damage however, and actual Mn concentrations in tissues were not assessed. In a more recent study, Mn concentrations in various central nervous system (CNS) tissues were investigated in three murine NCL models, CLN1, CLN3, and CLN5.[79] In that study, progressive elevations in Mn concentrations were detected in the CLN1 and CLN5 models, but not the CLN3 model. In the ovine “CLN6 merino” Batten disease model, Kanninen et al.,[32] detected significantly elevated Mn in numerous brain tissues of affected sheep including the frontal, occipital, and parietal lobes, as well as the thalamus and brainstem (but not the cerebellum) in conjunction with neurodegeneration. They also reported alterations in various synaptic proteins, the metal-binding protein metallothionein, and the Akt/GSK3 and ERK/MAPK cellular signaling pathways, but the relevance of these observations to the increases in Mn detected in the brain tissues of affected sheep remains to be elucidated. Mn concentrations in numerous tissues of preclinical sheep were also compared with those of controls in that study, and there were no significant alterations in any of the neural tissues examined. Interestingly, at 3 months of age the preclinical CLN6 sheep exhibited significantly lower Mn concentrations in the liver than the control sheep.[32] By the age of 7 months there was no longer a significant difference however, suggesting that the reduced hepatic Mn observed at 3 months of age in the experimental sheep may have been an artifact, rather than a phenomenon inherently related to the pathogenesis of disease in this ovine model.
It now seems clear that Mn is involved in the pathogenesis of Alzheimer's disease [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11] and at least some prion diseases,[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] but its involvement in a panel of other neurodegenerative diseases is not clear. The collective evidence to date suggests that Mn is not causally involved in the pathogenesis of PD,[24] but cohort studies suggest that occupational exposure to excessive Mn via inhalation can cause a neurodegenerative condition known as manganism, which mimics some of its symptoms. Whether the ingestion of “excessive” dietary Mn has deleterious neurological effects, and if so, what constitutes an excessive amount in this context have not been conclusively determined in humans. Thus far, the only incontrovertible evidence that excessive dietary Mn can cause neurological symptoms is derived from animal studies. The case for Mn involvement in the age of onset of HD has been substantially strengthened by studies conducted in recent years.[25],[68],[70] That said, the presence or absence of the disease is known to be determined by the number of CAG repeats present in the HTT gene, and this number is also known to account for approximately 50% of the variation in the age of onset.[80] Therefore, even if it is possible to delay the age of onset of HD by limiting dietary Mn, it is reasonable to expect that such delays may not be substantial, particularly in patients with a relatively high number of CAG repeats. The results of the few studies conducted to date investigating the potential involvement of Mn in the pathogenesis of ALS are mixed. Collectively they suggest that investigations should focus on the brain and wider CNS (including CSF), rather than samples that can be readily obtained from living patients such as blood and hair, which have tended to yield negative results. This presents a problem however, as ALS patients are relatively rare, with a prevalence rate of approximately 1/20,000 in the US.[71] Obtaining a number of brain samples post-mortem large enough to facilitate the generation of statistically significant results would be an arduous and long-term endeavor, and even obtaining a substantial number of CSF samples from living patients would be problematic due to the relatively complex and invasive nature of the collection procedure. As with HD, while the underlying determinant of the presence of Batten disease is genetic,[77] Mn has been implicated in its onset.[31],[32] Notably however, this has largely been on the basis of murine and ovine models. While no incontrovertible evidence for the involvement of Mn in the actual pathogenesis of Batten disease in humans has been reported to date, this may be due to a lack of relevant studies rather than a lack of Mn involvement. The same considerations that apply to ALS with regard to rarity also apply to Batten disease. While prevalence rates in different geographical regions evidently vary substantially, all reported rates are less than 1/10,000 and in some European countries they are much lower than that.[77] Determining the involvement or otherwise of Mn in neurological conditions in humans is rendered problematic by several factors. With regard to environmental exposure (inhalation or dietary), controlled human experiments are not possible so evidence is essentially limited to a relatively small number of cohort studies and animal studies. Another hindrance is the fact that the primary site of interest, the brain, is not amenable to biopsies or similarly invasive exploratory techniques in living humans; thus, relevant investigations are largely limited to brain imaging, CSF sample analysis, and cadaveric studies. The fact that Mn is present in the brain in much lower concentrations than other potentially pathogenic metals such as copper and zinc may also render it difficult to verify significant increases in Mn levels in any given part of the brain, even via the most sensitive of the analytical techniques currently available. This may in turn render the results of cadaveric investigations inconclusive with regard to Mn. Lastly, for relatively rare conditions such as ALS and Batten disease, the low number of post-mortem samples made available for analysis represents a practical research limitation. Yet to be developed techniques that enable noninvasive, highly sensitive assessment of Mn levels in very specific locations of the brain in living patients may be required before it can be conclusively determined whether or not Mn is involved in the pathogenesis of some of the rarer neurodegenerative disorders. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
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