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

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


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cation Transport Proteins / genetics*
  • Chelating Agents / therapeutic use
  • Child
  • Child, Preschool
  • Dystonic Disorders / drug therapy
  • Dystonic Disorders / genetics*
  • Dystonic Disorders / pathology
  • Female
  • Humans
  • Male
  • Manganese / metabolism*
  • Metal Metabolism, Inborn Errors / drug therapy
  • Metal Metabolism, Inborn Errors / genetics*
  • Metal Metabolism, Inborn Errors / pathology
  • Mutation*
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / pathology
  • Pedigree


  • Cation Transport Proteins
  • Chelating Agents
  • SLC39A14 protein, human
  • Manganese