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Mol Genet Metab. 2018 Jun;124(2):161-167. doi: 10.1016/j.ymgme.2018.04.002. Epub 2018 Apr 6.

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

Author information

1
Department of Neurology, Boston Children's Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States. Electronic address: lance.rodan@childrens.harvard.edu.
2
Harvard Medical School, Boston, MA, United States; Pediatric Environmental Health Center, Division of General Pediatrics, Boston Children's Hospital, Boston, MA, United States; Region 1 New, England, Pediatric Environmental Health Specialty Unit (PEHSU), Boston, MA, United States.
3
Harvard Medical School, Boston, MA, United States; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States.
4
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, United States; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, United States.
5
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, United States; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, United States.
6
Department of Cell and Developmental Biology, University College London Great Ormond Street Institute of Child Health, London, UK.
7
Department of Pediatrics, United Arab Emirates University, Al Ain, United Arab Emirates.
8
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, United States; Department of Pathology, Oregon Health & Science University, Portland, OR, United States.
9
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
10
Department of Radiology, Boston Children's Hospital, Boston, MA, United States.
11
Division of Neurodevelopmental Disabilities and Neurogenetics, Children's National Health System, Washington, DC, United States.

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

PMID:
29685658
PMCID:
PMC5976541
DOI:
10.1016/j.ymgme.2018.04.002
[Indexed for MEDLINE]
Free PMC Article

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