Novel founder intronic variant in SLC39A14 in two families causing Manganism and potential treatment strategies

Abstract

Congenital disorders of manganese metabolism are rare occurrences in children, and medical management of these disorders is complex and challenging. Homozygous exonic mutations in the manganese transporter SLC39A14 have recently been associated with a pediatric-onset neurodegenerative disorder characterized by brain manganese accumulation and clinical signs of manganese neurotoxicity, including parkinsonism-dystonia. We performed whole exome sequencing on DNA samples from two unrelated female children from the United Arab Emirates with progressive movement disorder and brain mineralization, identified a novel homozygous intronic mutation in SLC39A14 in both children, and demonstrated that the mutation leads to aberrant splicing. Both children had consistently elevated serum manganese levels and were diagnosed with SLC39A14-associated manganism. Over a four-year period, we utilized a multidisciplinary management approach for Patient 1 combining decreased manganese dietary intake and chelation with symptomatic management of dystonia. Our treatment strategy appeared to slow disease progression, but did not lead to a cure or reversal of already established deficits. Clinicians should consider testing for noncoding mutations in the diagnosis of congenital disorders of manganese metabolism and utilizing multidisciplinary approaches in the management of these disorders.

Intestine-specific deletion of metal transporterZip14 (Slc39a14)causes brain manganese overload and locomotor defects of manganism

“…Mutations in the SLC39A14 gene encoding the ZIP14 transporter were found in patients with childhood-onset parkinsonism and dystonia with systemic and brain Mn accumulation (35). Since that discovery, there have been a number of case reports of similar symptoms in humans with ZIP14 mutations (17, 23, 31, 38). Whole-body Zip14 KO mice display phenotypes similar to those of human carriers of ZIP14 mutations, including spontaneous systemic and brain Mn overload, specifically in the globus pallidus, and motor dysfunction (3).…”

Movement Disorders in Treatable Inborn Errors of Metabolism

“…Even more recently, a syndrome of infantile‐ or childhood‐onset dystonia with hypermanganesemia (OMIM #617013) has been linked to biallelic mutations in yet another divalent cation transporter gene, SLC39A14 , responsible for manganese elimination . This disorder presents in infancy or early childhood with developmental delay, dystonia, and bulbar dysfunction . The course is progressive, and most children develop generalized dystonia, spasticity, contractures, and severe scoliosis within the first 10 years of life .…”

“…Excessive manganese levels are neurotoxic as has been well described in “manganism” secondary to environmental manganese exposure . Chelation therapy with disodium calcium ethylenediaminetetraacetic acid (EDTA) combined with iron supplementation can lower blood manganese levels in both SLC3A10 ‐ and SLC39A14 ‐related hypermanganesemia, halt disease progression, and improve the movement disorder . Penicillamine and dimercaptosuccinic acid have been suggested as alternative chelating agents (Table ) …”

“…47,[93][94][95] This disorder presents in infancy or early childhood with developmental delay, dystonia, and bulbar dysfunction. 47,96 The course is progressive, and most children develop generalized dystonia, spasticity, contractures, and severe scoliosis within the first 10 years of life. 47 Akinetic-rigid parkinsonism may develop.…”

“…97,98 Chelation therapy with disodium calcium ethylenediaminetetraacetic acid (EDTA) combined with iron supplementation can lower blood manganese levels in both SLC3A10-and SLC39A14-related hypermanganesemia, halt disease progression, and improve the movement disorder. 46,47,87,90,96,[99][100][101][102] Penicillamine and dimercaptosuccinic acid have been suggested as alternative chelating agents (Table 1). 92,103…”