Effect of Chelation Therapy on a Korean Patient With Brain Manganese Deposition Resulting From a Compound Heterozygous Mutation in the SLC39A14 Gene.

Importance: Hypermanganesemia with dystonia type 2 is a rare autosomal recessive neurodegenerative disorder characterized by the loss of previously acquired milestones, dystonia, parkinsonian features, a high serum manganese level, and characteristic neuroimaging findings such as bilateral and symmetrically increased T1 and decreased T2/fluid-attenuated inversion recovery signal intensity in the basal ganglia. This condition is secondary to a mutation in the SLC39A14 gene. Objective: To present a series of three cases of hypermanganesemia with dystonia type 2, which was genetically confirmed secondary to a mutation in the SLC39A14 gene, and to describe the treatment and clinical course in these cases. Design: A retrospective case series. Setting: University, Tertiary hospital. Participants: Three unrelated pediatric patients with hypermanganesemia with dystonia type 2, genetically confirmed to be secondary to a mutation in the SLC39A14 gene. Exposures: Chelation therapy using calcium disodium edetate. Main outcome(s) and measure(s): The response to chelation therapy based on clinical improvements in motor and cognition developments. Results: All three patients were started on chelation therapy using calcium disodium edetate, and two of them showed an improvement in their clinical course. The chelation therapy could alter the course of the disease and prevent deterioration in the clinical setting. Conclusions and Relevance: Early diagnosis and intervention with chelating agents, such as calcium disodium edetate, will help change the outcome in patients with hypermanganesemia with dystonia type 2. This finding highlights the importance of early diagnosis and treatment in improving the outcomes of patients with treatable neurodegenerative disorders.

Various factors can affect blood and tissue levels of trace elements in patients with end-stage renal disease. There are a few studies showing hyperintensity of basal ganglia associated with manganese deposition in hemodialysis (HD) patients. The present study aimed to investigate the intensity changes as markers of manganese deposition in the basal ganglia and to demonstrate their association with blood manganese levels using ICP/MS technique in HD, peritoneal dialysis (PD), and renal transplant patients. The study included 20 HD, 20 PD, 20 renal transplant patients, and 20 healthy controls. Blood manganese levels were obtained, and cranial magnetic resonance images were evaluated for basal ganglia hyperintensity. Blood manganese levels were similar across all study groups (p=0.308), whereas symmetric basal ganglia hyperintensity indicating manganese deposition was detected only in HD patients (p=<0.001). There was a significant relationship between manganese deposition and duration of dialysis (p=0.05). Imaging findings suggesting manganese deposition in the basal ganglia being present only in HD patients suggest that manganese deposition could be caused by the hemodialysis method itself rather than uremia and renal failure. Further studies are required in this regard, as previous studies have not clearly identified the mechanisms by which hemodialysis causes these changes.

Manganese is vital in human nutrition. When oral intake is precluded, the recommended parenteral supplementation is 0.15 to 0.8 mg/day. Manganese is excreted primarily in the bile; during cholestasis, serum manganese levels may rise, and manganese toxicity ensue. Neuropsychiatric symptoms are prominent. Phenothiazine-derivative drugs may potentiate manganese toxicity. Serum or whole blood manganese levels should guide manganese therapy in jaundiced patients.

Pregnant women in developing countries have been reported to consume diets with low density of minerals and essential trace elements. Therefore, this study aims to assess the serum levels of magnesium and manganese and its trimester correlates among pregnant women in Ika community of Delta state, Nigeria. An analytical cross-sectional study was conducted to assess the serum levels of magnesium and manganese among 64 apparently healthy pregnant and age matched 25 healthy non-pregnant women attending antenatal clinic at obstetrics and gynaecology unit of central hospital Agbor. The mean serum levels of manganese increased with increase in gestational age while hypomagnesaemia 12.24ug/dl was observed in 60 (93.8%) of the pregnant women with a larger preponderance in the second trimester There was significant difference between the serum level of manganese in pregnant women compared to non-pregnant women (p<0.001). There were no statistical significance between the serum levels of these trace elements and occupation, nature of dietary intake, age of participants and trimester of pregnancy. We observed an increase in the mean serum levels of manganese with trimester progression while a high prevalence rate (93.8%) of magnesium deficiency among pregnant women was noted in this study. Maximal awareness (advocacy) should therefore be given to pregnant women on the need for adequate dietary intake and supplementation to avoid the complications associated with deficiency of this nutrient. Keywords: Magnesium, Manganese, Pregnant, Women, Agbor, Nigeria

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.

Manganese is an essential trace metal for numerous metalloenzymes. Manganese homeostasis requires tight regulation in vivo and disruption of this balance can lead to manganese overload and subsequent accumulation of manganese in brain, liver, and blood. Mutations in SLC30A10, a cell surface-localized manganese efflux transporter, cause an autosomal recessive hypermanganesemia syndrome with two distinct phenotypes: childhood onset dystonia and adult onset Parkinsonism, associated with chronic liver disease, polycythemia and features of iron depletion. MRI brain appearances are characteristic of Mn deposition with hyperintense basal ganglia on T1-weighted images. Chelation therapy with disodium calcium edetate and iron supplementation effectively lower blood manganese levels, halt liver disease progression and improve neurological symptoms.The inherited form of hypermanganesemia can be distinguished from acquired causes of manganese overload including environmental overexposure and acquired hepatocerebral degeneration in cases of end stage liver disease.

<h3>Objective:</h3> NA <h3>Background:</h3> Hypermanganesemia with dystonia type 2 is an established, rare autosomal recessive partially reversible neurodegenerative condition characterised by mutations in the SLC39A14 gene. Manganese deposition in such cases has a special predilection for the basal ganglia structures leading to dystonia and parkinsonian features. We report such a case of hypermanganesemia in a 1 year old child presenting with extrapyramidal features. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 1 year old female child presented with regression of developmental milestones for the past 2 months, losing the ability to stand or even sit without support—skills that she had previously acquired at an appropriate time. This was associated with dystonic posturing of her neck and limbs for the last 1 month. Cognitive skills were normal as per her age without any history of convulsions or other systemic features. Her birth and family history were unremarkable. Her neurological examination was remarkable only for generalised dystonia of her limbs, neck and trunk. Magnetic resonance imaging was suggestive of paramagnetic substance deposition in bilateral basal ganglia and dentate nucleus. Normal routine blood parameters were followed by extensive investigations to rule out Wilson’s disease, NBIA and other autoimmune pathologies. Her blood manganese levels were significantly elevated and her genetic sequencing revealed compound heterozygous mutations of the SLC39A14 gene at exons 7 and 8. She was started on chelation therapy with Penicillamine and oral iron. Dystonia resolved significantly by the end of 6 months of therapy with marked improvement in her motor developmental milestones. <h3>Conclusions:</h3> Hypermanganesemia with dystonia type 2 (HMNDYT2) is a rare genetic disorder characterised by neuronal manganese deposition without other systemic features. This case highlights the importance of recognising this potentially rare treatable condition and with adequate chelation therapy at the right time, near total restoration of motor symptomatology is possible. <b>Disclosure:</b> Dr. Bhattacharya has nothing to disclose. Dr. Chintha has nothing to disclose. Dr. Biswas has nothing to disclose. Dr. Das has nothing to disclose. Dr. Chakraborty has nothing to disclose. Dr. Mukherjee has nothing to disclose.

Neurologic and radiologic disorders have been reported in patients receiving long-term parenteral nutrition (PN). On the basis of elevated serum manganese levels, some of these abnormalities have been attributed to manganese intoxication. Alterations of the basal ganglia signal intensity on T1-weighted magnetic resonance images (MRIs) have been previously reported, but the precise nature of these alterations remains controversial although the deposition of manganese has been suggested in patients with chronic hepatic encephalopathy due to liver failure. We report the case of a patient who was receiving PN and exhibited a chronic cholestasis. Neurologic disorders appeared after several months of PN, when a hypersignal in the basal ganglia and white matter was found on T1-weighted MRIs of the brain in association with elevated serum and manganese levels. Elevated autopsic concentrations of manganese were found in the radiologic abnormal cerebral areas. Our observation is the first demonstration of a relationship between high intracerebral manganese levels, radiologic abnormalities, and neurologic disorders during long-term PN. Moreover, serum manganese levels are not a good indicator of cerebral levels. In fact, in our patient, serum manganese levels returned to normal, whereas those of cerebral manganese remained increased.

Background: β-Thalassemia major is considered to be one of the most common inherited hemolytic anemia. Enhanced years of survival of thalassemia have led to unmasking related complications related to alterations in certain trace elements like magnesium, calcium, phosphorus, copper, zinc etc.&#x0D; Objective: Present study was conducted to evaluate the effect of iron chelation therapy and blood transfusion on certain trace elements (Magnesium, Calcium, Phosphorus, Copper, Zinc) in β-thalassemic patients on chelation therapy more than one year.&#x0D; Materials and Methods: In the present cross sectional study, 100 β-thalassemic patients receiving chelation therapy for atleast 1year were recruited from Civil Hospital Ahmedabad, Gujarat during February, 2017 to December, 2018 and equal number (n=100) of healthy subjects were taken as a control group in the age range of 8 to 15 years of both sexes (male &amp; female). The levels of serum magnesium, calcium, phosphorus, zinc, and copper in serum were analyzed and results were correlated with normal healthy subjects.&#x0D; Results: A significant increase in serum copper (P≤ 0.01) and phosphorus (P≤ 0.001) were observed levels while a significant (P≤ 0.05) fall in magnesium, calcium and zinc levels recorded in β-thalassemic patients in comparison to healthy control subjects.&#x0D; Conclusion: Aforementioned observations suggested that fluctuations in the trace elements levels in β- thalassemic children receiving blood transfusion and iron chelation therapy could leads to different complications like hemolyzed red cells, infections &amp; hemochromatosis renal damage, hypoparathyroidism etc. if remains untreated. Hence routine assessment of these elements is recommended for better management.

Background The health implications of trace elements have become increasingly concerning, yet the connection between blood manganese levels and anemia remains insufficiently examined. This research endeavors to explore the potential linkage between blood manganese concentrations and anemia. Methods Utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018, this study examines the correlation between blood manganese levels and anemia among U.S. adults, offering a comprehensive national perspective. The study included 11,300 adults aged 20 and above, with both blood manganese and hemoglobin levels measured. Generalized Additive Model (GAM) was applied to delineate smooth curves, and threshold effect analysis was performed to identify the inflection points of these curves. Subsequently, unconditional logistic regression was employed to assess the risk. Results Our research involved a total of 11,300 individuals, among which 1,143 (10.1%) were identified with anemia. The curve fitting analysis indicated a U-shaped relationship between blood manganese levels and the risk of anemia. Specifically, when blood manganese levels were below 8.69 µg/L, increasing concentrations were linked to a decreased risk of anemia, with an adjusted OR of 0.838 (95% CI: 0.735–0.954), indicating a protective effect of this level of blood manganese against anemia. Conversely, when blood manganese levels were at or above 8.69 µg/L, further elevations were strongly associated with an increased risk of anemia, with the adjusted OR rising to 1.160 (95% CI: 1.124–1.196), suggesting that excessively high blood manganese levels significantly raised the risk of developing anemia. Conclusion This study provides novel insights into the association between blood manganese levels and anemia. Further extensive, population-based cohort studies are necessary to validate the causality and to uncover the intrinsic toxicological mechanisms.

Association of blood manganese levels with non-alcoholic fatty liver disease in NHANES 2017-2020: A retrospective cross-sectional study.

We report the findings on cranial computed tomography (CT) and magnetic resonance imaging (MRI) and their correlation with the clinical manifestations, disease severity and biochemical abnormalities in eight patients with cerebrotendinous xanthomatosis. CT revealed cerebral atrophy in seven cases, cerebellar atrophy in four and focal low density lesions in the cerebral white matter in two. T2-weighted MRI showed high signal lesions in the cerebral white matter, focal in four cases and diffuse in one, and in the globus pallidus in three patients, two of whom also had lesions in the cerebellar white matter. While severely affected patients showed variable CT and MRI abnormalities, our cases did not show the dramatic findings expected from the neurological manifestations. Diffuse lesions in the cerebral and cerebellar white matter have been emphasized in previous reports, but in our study the focal lesions in the cerebral white matter were also present; the globus pallidus was frequently involved.

Patients undergoing parenteral nutrition and those with portosystemic encephalopathy secondary to chronic liver disease and acquired and congenital portosystemic venous shunts frequently present manganese deposition in the basal ganglia, detected by MR imaging as hyperintense areas on T1-weighted sequences. We also observed similar abnormalities in the basal ganglia of patients with chronic renal failure undergoing maintenance hemodialysis. Our aim was to evaluate the pallidal signal intensity on T1-weighted images in a series of patients undergoing hemodialysis, with further evaluation of serum manganese levels and neurologic correlation, comparing them with patients with chronic renal failure without dialytic treatment. We performed MR imaging examinations in 9 patients with chronic renal failure, 5 of whom were undergoing hemodialysis. An experienced neuroradiologist scrutinized the presence of symmetric hyperintensities in the basal ganglia on T1-weighted sequences. We also determined the serum manganese levels and performed the neurologic evaluations in all patients. All patients undergoing hemodialysis presented elevated serum manganese levels and symmetric hyperintensities within the globus pallidus. In this group, 4 patients presented with parkinsonian symptoms, myoclonus, and syndromes with vestibular and vestibular-auditory symptoms. The patients without dialytic treatment presented with neither bilaterally increased T1 MR imaging signal intensity within the globus pallidus nor symptoms of manganism. Our preliminary results demonstrated the occurrence of bilateral pallidal hyperintensity on T1-weighted images in all patients undergoing hemodialysis associated with high serum manganese levels, revealing a new association.

BackgroundManganese is a critical trace element that not only has antioxidant properties, but also is essential for various metabolic pathways and neurotransmitters production. However, it can be toxic at high levels, particularly in the central nervous system. Manganese intoxication can be acquired, but an inherited form due to autosomal-recessive mutations in the SLC30A10 gene encoding a Mn transporter protein has also been reported recently. These mutations are associated with significant failure of manganese excretion and its storage in the liver, brain (especially basal ganglia), and other peripheral tissues, resulting in toxicity.Case presentationA 10-year-old boy from consanguineous parents presented with a history of progressive truncal instability, gait difficulty, and frequent falls for 2 months. He had dystonia, rigidity, ataxia, dysarthria, bradykinesia and a plethoric skin. Investigations showed polycythemia, low serum iron and ferritin levels, and increased total iron binding capacity. A brain MRI revealed symmetric hyperintensities in the basal ganglia and dentate nucleuses on TI images that were suggestive of brain metal deposition together with clinical manifestations. Serum calcium and copper levels were normal, while the manganese level was significantly higher than normal values. There was no history of environmental overexposure to manganese. Genetic testing showed a homozygous missense mutation in SLC30A10 (c.C1006T, p.His336Tyr) and Sanger sequencing confirmed a homozygous state in the proband and a heterozygous state in the parents. Regular treatment with monthly infusions of disodium calcium edetate and oral iron compounds resulted in decreased serum manganese and hemoglobin levels to normal values, significant resolution of MRI lesions, and partial improvement of neurological symptoms during 6 months of follow-up.ConclusionThe syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by SLC30A10 mutation is a treatable inherited metal deposition syndrome. The patient may only have pure neurological without hepatic manifestations. Although this is a rare and potentially fatal inborn error of metabolism, early diagnosis and continuous chelation therapy might improve the symptoms and prevent disease progression.

Chapter 48 - Disorders of manganese transport