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

Details

• Alternative Title:
  Mol Genet Metab
• Personal Author:
  Rodan, Lance H. ; Hauptman, Marissa ; D’Gama, Alissa M. ; Qualls, Anita E. ; Cao, Siqi ; Tuschl, Karin ; Al-Jasmi, Fatma ; Hertecant, Jozef ; Hayflick, Susan J. ; Wessling-Resnick, Marianne ; Yang, Edward T. ; Berry, Gerard T. ; Gropman, Andrea ; Woolf, Alan D. ; Agrawal, Pankaj B.
• Description:
  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.
• Subjects:
  Article Cation Transport Proteins Chelating Agents Child Child, Preschool Congenital Manganism Dystonic Disorders Female Humans Male Manganese Manganese Toxicity Metal Metabolism, Inborn Errors Mutation Parkinsonian Disorders Pedigree SLC39A14

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• Source:
  Mol Genet Metab. 124(2):161-167
• Pubmed ID:
  29685658
• Pubmed Central ID:
  PMC5976541
• Document Type:
  Journal Article
• Funding:
  R01 ES014638/ES/NIEHS NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; U61 TS000237/TS/ATSDR CDC HHS/United States ; T32 GM007753/GM/NIGMS NIH HHS/United States ; U19 HD077671/HD/NICHD NIH HHS/United States ; R01 AR068429/AR/NIAMS NIH HHS/United States
• Volume:
  124
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:f04ee448a2a46cbc6db9815f7b5cc2b86a700ff4f04e21cfb49c204e985e7059
• Download URL:
  https://stacks.cdc.gov/view/cdc/55383/cdc_55383_DS1.pdf
• File Type:
  [PDF - 580.95 KB ]