Summary
Manganese is an essential trace metal that is a constituent of metalloenzymes and is required as an enzyme activator. Blood manganese levels are under tight homeostatic control by the liver as both manganese overload and deficiency impair neuronal function and integrity.
To date, three inherited manganese transporter defects have been identified that lead to abnormal blood manganese levels: mutations in SLC30A10 (hypermanganesaemia with dystonia 1, HMNDYT1) and SLC39A14 (hypermanganesaemia with dystonia 2, HMNDYT2) cause manganese overload, while mutations in SLC39A8 (Congenital Disorder of Glycosylation, Type IIn; CDG2N) cause manganese deficiency. SLC39A14 and SLC30A10 are required for hepatic uptake and adequate biliary excretion of manganese, respectively. Both these transporter defects are characterised by childhood-onset, progressive Parkinsonism-dystonia due to the accumulation of manganese in the basal ganglia, particularly the globus pallidus, with pathognomonic MRI brain appearances of hyperintensity on T1-weighted images. Whole blood manganese levels are highly raised. In addition to the movement disorder, SLC30A10 loss-of-function causes liver disease, polycythaemia and depletion of iron stores. Intravenous chelation with disodium calcium edetate and iron supplementation effectively lowers the manganese load and can lead to significant improvement in neurological symptoms and halt the progress of liver disease.
SLC39A8 is required for manganese uptake into the organism. Loss-of-function leads to a manganese deficiency syndrome characterised by neurodevelopmental delay, seizures, dystonia and short stature. Biochemically, SLC39A8 deficiency causes hypomanganesaemia and a characteristic dysglycosylation pattern corresponding to a type II congenital disorder of glycosylation because manganese acts as a cofactor for the β-1,4-galactosyltransferase. In addition, manganese deficiency leads to respiratory chain abnormalities and Leigh-like mitochondrial disease. Manganese supplementation can improve clinical symptoms and normalise biochemical findings.
Manganese dyshomeostasis has also been observed in a juvenile type of Parkinson’s disease associated with supranuclear gaze palsy, spasticity and dementia due to mutations in ATP13A2 (PARK9), also known as Kufor-Rakeb Syndrome. ATP13A2 has been shown to transport manganese from the cytosol to the lysosome. In addition, the phenotype can vary from neuronal ceroid lipofuscinosis type 12 (CLN12) to complicated hereditary spastic paraplegia (HSP).
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Tuschl, K., Mills, P.B., Clayton, P.T. (2022). Disorders of Manganese Metabolism. In: Blau, N., Dionisi Vici, C., Ferreira, C.R., Vianey-Saban, C., van Karnebeek, C.D.M. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-67727-5_38
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