Disorders of manganese transport

Manganese transport across cell membranes is highly regulated to prevent toxic accumulation or deficiency. In recent years, three autosomal recessive disorders of manganese transport have been reported. Patients with biallelic pathogenic variants in SLC30A10 manifest hypermanganesemia, dystonia, parkinsonism, liver dysfunction, and polycythemia (hypermanganesemia with dystonia 1, HMNDYT1), whereas patients with pathogenic variants in SLC39A14 have a similar neurological presentation but without liver disease or polycythemia (hypermanganesemia with dystonia 2, HMNDYT2). In both disorders, brain magnetic resonance imaging reveals T1 hyperintensities in the basal ganglia, pituitary, brainstem, and the dentate nucleus of the cerebellum consistent with manganese deposition. The treatment consists of chelation with disodium calcium edetate and oral iron supplementation to reduce the manganese load. In contrast, patients with biallelic pathogenic variants in SLC39A8 present with infantile or early childhood-onset manganese deficiency causing a congenital disorder of glycosylation (CDG2N). The clinical phenotype consists of a variety of neurodevelopmental features that include hypotonia, brain malformations, strabismus, growth retardation, and occasional seizures. Ongoing research aims to elucidate the regulatory mechanisms of manganese transport, its distribution at cellular and subcellular levels, and its role in neurotransmission, with the goal of developing new treatments.