Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia - A new metabolic disorder

University College London Institute of Child Health with Great Ormond Street Hospital for Children NHS Trust, London, UK.
Journal of Inherited Metabolic Disease (Impact Factor: 3.37). 04/2008; 31(2):151-63. DOI: 10.1007/s10545-008-0813-1
Source: PubMed


We report a new constellation of clinical features consisting of hypermanganesaemia, liver cirrhosis, an extrapyramidal motor disorder and polycythaemia in a 12 year-old girl born to consanguineous parents. Blood manganese levels were >3000 nmol/L (normal range <320 nmol/L) and MRI revealed signal abnormalities of the basal ganglia consistent with manganese deposition. An older brother with the same phenotype died at 18 years, suggesting a potentially lethal, autosomal recessive disease. This disorder is probably caused by a defect of manganese metabolism with the accumulation of manganese in the liver and the basal ganglia similar to the copper accumulation in Wilson disease. In order to assess the genetic basis of this syndrome we investigated two candidate genes: ATP2C2 and ATP2A3 encoding the manganese-transporting calcium-ATPases, SPCA2 and SERCA3, respectively. Genotyping of the patient and the family for microsatellite markers surrounding ATP2C2 and ATP2A3 excluded these genes. The patient was found to be heterozygous for both gene loci. Despite the unknown pathophysiology, we were able to develop a successful treatment regime. Chelation therapy with disodium calcium edetate combined with iron supplementation is the treatment of choice, lowering blood manganese levels significantly and improving clinical symptoms.

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    • "If not resolved, manganism may evolve into established movement disorders including bradykinesia , dystonic postures, cock-walk gait, cogwheel rigidity, poor motor coordination and, sometimes, permanent and complete disability . A syndrome of inherited manganism (IM) leading to liver cirrhosis and polycythemia has been originally described in two siblings born from healthy, consanguineous parents of Arabic origin (OMIM 613280) [1]. After comprehensive investigation of 15 individuals from eight families with similar symptoms, mutations in the Mn transporter gene SLC30A10 have been recently identified as the cause of IM [2]. "
    Clinical neurology and neurosurgery 01/2013; 115(8). DOI:10.1016/j.clineuro.2012.12.032 · 1.13 Impact Factor
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    • "Normally it is found in human blood with concentration <320 nmol L-1 and functions as a cofactor for some enzymes. Exposure of man to high levels of manganese leads to hyper manganese anemia (high Mn levels in blood) and defect in its metabolism with its accumulation in the liver and the basal ganglia is lethal (Tuschl et al., 2008). Also, manganese intoxication has been described in children on long term parenteral nutrition presenting with liver and nervous system disorders (Kafritsa et al., 1998). "
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    ABSTRACT: Manganese ore is widely used in many industries. Such as ore contain natural radioactive nuclides at various concentrations. If this ore contain high concentrations of natural radioactive nuclides, workers handling them might be exposed to significant levels of radiation. Therefore it is important to determine the radioactive nuclides in this ore. Also the regulation of radon concentration at workplaces has gained an accentuated importance in all countries. Nevertheless, at this time there is no globally accepted workplace protocol that sets out safe radon concentration values. In this study the radon concentration measured by using an Alpha Guard radon monitor, the equilibrium factor which was greater than the value given in literature, effective radiation dose, which are necessary for the exact estimation of the radiation dose originating from radon. The regulation of radon concentration at workplaces has gained an accentuated importance in all countries. Approach: The natural radionuclides (238 U, 232 Th and 40 K) contents of manganese ore samples collected from Umm Bogma, southwest Sinai and from the mountain access Hamid South Eastern Desert, Egypt have been determined by low background spectroscopy using hyper-pure germanium (HPGe) detector. Results: The mean activities due to the three radionuclides (238 U, 232 Th and 40 K) were found to be 1500±65, 490±65 and 364±45 Bqkg -1 , respectively. The absorbed dose rate due to the natural radioactivity in samples under investigation ranged from 1522±45 → 1796±43 nGyh -1 . The radium equivalent activity varied from 3807±114→ 4446±133 Bqkg -1 .The representative external hazard index values for the corresponding samples are also estimated. Conclusion: The results of this assessment obtained by the gamma-ray spectroscopic analysis, have indicated that the levels of natural radioactivity were lower than the international recommended limits.
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    • "Although alimentary exposure to high manganese is usually not the problem, parenteral uptake of this element represents the main route for manganese intoxication. Indeed, chronic Mn 2+ inhalation by occupational or environmental exposition (Nelson et al. 1993; Sierra et al. 1995) or increase of Mn 2+ concentration by long-lasting total parenteral nutrition (Ono et al. 1995) or in cirrhotic patients (Krieger et al. 1995; Tuschl et al. 2008) results in Mn 2+ deposition in brain, that can be detected as increased signal on T 1 -weighted magnetic resonance imaging mainly in the globus pallidus (Silva et al. 2004; Massaad and Pautler 2011). In view of its abundance in the environment and since Mn 2+ can passively enter the cells in an unspecific way via a multitude of other bivalent ion channels and carriers, cells seldom experience a shortage of Mn 2+ . "
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    ABSTRACT: Excess Mn(2+) in humans causes a neurological disorder known as manganism, which shares symptoms with Parkinson's disease. However, the cellular mechanisms underlying Mn(2+) -neurotoxicity and the involvement of Mn(2+) -transporters in cellular homeostasis and repair are poorly understood and require further investigation. In this work, we have analyzed the effect of Mn(2+) on neurons and glia from mice in primary cultures. Mn(2+) overload compromised survival of both cell types, specifically affecting cellular integrity and Golgi organization, where the secretory pathway Ca(2+) /Mn(2+) -ATPase is localized. This ATP-driven Mn(2+) transporter might take part in Mn(2+) accumulation/detoxification at low loads of Mn(2+) , but its ATPase activity is inhibited at high concentration of Mn(2+) . Glial cells appear to be significantly more resistant to this toxicity than neurons and their presence in cocultures provided some protection to neurons against degeneration induced by Mn(2+) . Interestingly, the Mn(2+) toxicity was partially reversed upon Mn(2+) removal by wash out or by the addition of EDTA as a chelating agent, in particular in glial cells. These studies provide data on Mn(2+) neurotoxicity and may contribute to explore new therapeutic approaches for reducing Mn(2+) poisoning.
    Journal of Neurochemistry 07/2012; 123(5). DOI:10.1111/j.1471-4159.2012.07888.x · 4.28 Impact Factor
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