@article{53e2f0320f1a470780257236dde87ed0,
title = "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.",
keywords = "Congenital manganism, Manganese toxicity, SLC39A14",
author = "Rodan, {Lance H.} and Marissa Hauptman and D'Gama, {Alissa M.} and Qualls, {Anita E.} and Siqi Cao and Karin Tuschl and Fatma Al-Jasmi and Jozef Hertecant and Hayflick, {Susan J.} and Marianne Wessling-Resnick and Yang, {Edward T.} and Berry, {Gerard T.} and Andrea Gropman and Woolf, {Alan D.} and Agrawal, {Pankaj B.}",
note = "Funding Information: This work was supported by the American Academy of Pediatrics (AAP) and funded (in part) by the Agency for Toxic Substances and Disease Registry (ATSDR) (cooperative agreement FAIN: 1U61TS000237-02 ). The U.S. Environmental Protection Agency (EPA) supports the PEHSU by providing partial funding to the ATSDR (Inter-Agency Agreement number DW-75-95877701 ). Neither EPA nor ATSDR endorse the purchase of any commercial products or services mentioned in PEHSU publications. AMD was supported by the NIGMS (grant number T32GM007753 ). PBA was supported by the NIH / NIAMS (grant number 1R01AR068429-01 ) and the NICHD / NHGRI / NIH (grant number U19HD077671 ). M.W.-R. was supported by NIH / NIEHS (grant number 1R01ES014638 ) and metal analysis was supported by NIH / NIEHS (grant number P01 ES000002 ). We thank Jose Carlo Sosa for technical help with ICP-MS experiments. The funding sources did not play any role in the design of this study; the collection, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication. The first draft of the manuscript was written by LHR; no honorarium, grant, or other form of payment was given to anyone to produce the manuscript. The authors have no potential, perceived, or real conflicts of interest to disclose. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. The authors would like to acknowledge the outstanding health care providers caring for these patients and families, specifically, Dr. Elizabeth Barkoudah, Dr. Christine Lee, Dr. David Fogelman, Dr. Leslie Martell as well as these patients and families for their continued partnership. Funding Information: This work was supported by the American Academy of Pediatrics (AAP) and funded (in part) by the Agency for Toxic Substances and Disease Registry (ATSDR) (cooperative agreement FAIN: 1U61TS000237-02). The U.S. Environmental Protection Agency (EPA) supports the PEHSU by providing partial funding to the ATSDR (Inter-Agency Agreement number DW-75-95877701). Neither EPA nor ATSDR endorse the purchase of any commercial products or services mentioned in PEHSU publications. AMD was supported by the NIGMS (grant number T32GM007753). PBA was supported by the NIH/NIAMS (grant number 1R01AR068429-01) and the NICHD/NHGRI/NIH (grant number U19HD077671). M.W.-R. was supported by NIH/NIEHS (grant number 1R01ES014638) and metal analysis was supported by NIH/NIEHS (grant number P01 ES000002). We thank Jose Carlo Sosa for technical help with ICP-MS experiments. The funding sources did not play any role in the design of this study; the collection, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication. The first draft of the manuscript was written by LHR; no honorarium, grant, or other form of payment was given to anyone to produce the manuscript. The authors have no potential, perceived, or real conflicts of interest to disclose. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. The authors would like to acknowledge the outstanding health care providers caring for these patients and families, specifically, Dr. Elizabeth Barkoudah, Dr. Christine Lee, Dr. David Fogelman, Dr. Leslie Martell as well as these patients and families for their continued partnership. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jun,
doi = "10.1016/j.ymgme.2018.04.002",
language = "English",
volume = "124",
pages = "161--167",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "2",
}