Genetic Disorders of Manganese Metabolism

Abstract

Purpose of Review This article provides an overview of the pathogenesis, clinical presentation and treatment of inherited manganese transporter defects. Recent Findings Identification of a new group of manganese transportopathies has greatly advanced our understanding of how manganese homeostasis is regulated in vivo . While the manganese efflux transporter SLC30A10 and the uptake transporter SLC39A14 work synergistically to reduce the manganese load, SLC39A8 has an opposing function facilitating manganese uptake into the organism. Bi-allelic mutations in any of these transporter proteins disrupt the manganese equilibrium and lead to neurological disease: Hypermanganesaemia with dystonia 1 (SLC30A10 deficiency) and hypermanganesaemia with dystonia 2 (SLC39A14 deficiency) are characterised by manganese neurotoxicity while SLC39A8 mutations cause a congenital disorder of glycosylation type IIn due to Mn deficiency. Summary Inherited manganese transporter defects are an important differential diagnosis of paediatric movement disorders. Manganese blood levels and MRI brain are diagnostic and allow early diagnosis to avoid treatment delay.

Bile acid composition regulates the manganese transporter Slc30a10 in intestine

“…Most cases of Mn toxicity are due to occupational and environmental exposures (31,62). Mn toxicity has also been reported in cases of severe liver diseases, in patients receiving total parenteral nutrition, and in rare genetic loss-offunction mutations (34,35,44,(64)(65)(66)(67). Current treatment for Mn toxicity is with chelation therapy, which increases urinary Mn excretion (44), but is nonspecific.…”

“…Mn toxicity has also been reported in cases of severe liver diseases, in patients receiving total parenteral nutrition, and in rare genetic loss-offunction mutations (34,35,44,(64)(65)(66)(67). Current treatment for Mn toxicity is with chelation therapy, which increases urinary Mn excretion (44), but is nonspecific. Since the identification of diseasecausing mutations of SLC30A10, there has been considerable progress in understanding how the transporter works and where it is localized in cells (36,68).…”

“…Some researchers have reported that patients with type-2 diabetes have plasma or serum Mn at levels higher than controls, while others have reported the opposite (73)(74)(75)(76). Because Mn levels must be maintained within a small range (31,44), it makes sense that both deficiency and excess of Mn would lead to negative consequences. Accordingly, a recent report showed a U-shaped relationship between plasma Mn and the odds ratio for type-2 diabetes (77).…”

GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms

“…Importantly, of the Mendelian syndromes of genes encoding manganese transporters, only SLC30A10 (causing HMNDYT1) involves hepatic symptoms 59,72 . Hepatotoxicity in HMNDYT1 is thought to be due to cytotoxic manganese overload within hepatocytes; polycythemia is thought to be caused by upregulation of erythropoietin by manganese; and iron anemia through systemic dysregulation of iron homeostasis by excess manganese 72,73 . Our results indicate that polymorphism in SLC30A10 is a risk factor for manganese-induced hepatocellular damage, polycythemia, and iron anemia in a much broader population beyond the rare recessive syndrome HMNDYT1.…”

Genetic Disorders Associated with Metal Metabolism

“…Homozygous mutations in the SLC39A8 gene (OMIM 608732) located on chromosome 4q24 have been associated with congenital disorder of glycosylation type IIn (OMIM 616721). Clinical features associated with the disorder include short stature, eye deformity (strabismus, astigmatism, nystagmus), osteopenia, hypotonia, an inability to walk, and laboratory results suggested decreased plasma zinc and manganese levels and increased urinary zinc and manganese levels [104,105].…”