SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation

Am J Hum Genet. 2015 Dec 3;97(6):894-903. doi: 10.1016/j.ajhg.2015.11.003.


SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Carbohydrate Sequence
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics*
  • Cations, Divalent
  • Congenital Disorders of Glycosylation / blood
  • Congenital Disorders of Glycosylation / complications
  • Congenital Disorders of Glycosylation / diet therapy
  • Congenital Disorders of Glycosylation / genetics*
  • Dwarfism / blood
  • Dwarfism / complications
  • Dwarfism / diet therapy
  • Dwarfism / genetics*
  • Female
  • Galactose / therapeutic use
  • Gene Expression
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Ion Transport
  • Manganese / blood*
  • Manganese / deficiency
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Sequence Alignment
  • Spasms, Infantile / blood
  • Spasms, Infantile / complications
  • Spasms, Infantile / diet therapy
  • Spasms, Infantile / genetics*


  • Cation Transport Proteins
  • Cations, Divalent
  • SLC39A8 protein, human
  • Manganese
  • Galactose