VAC14 syndrome in two siblings with retinitis pigmentosa and neurodegeneration with brain iron accumulation

Cold Spring Harb Mol Case Stud. 2019 Dec 13;5(6):a003715. doi: 10.1101/mcs.a003715. Print 2019 Dec.


Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in VAC14, and the clinical phenotype is consistent with the recently described VAC14-related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). However, the phenotype includes a distinct clinical presentation of retinitis pigmentosa (RP), which has not previously been reported in association with VAC14 mutations. Brain magnetic resonance imaging (MRI) revealed abnormal magnetic susceptibility in the globus pallidus, which can be seen in neurodegeneration with brain iron accumulation (NBIA). RP is a group of inherited retinal diseases with phenotypic/genetic heterogeneity, and the pathophysiologic basis of RP is not completely understood but is thought to be due to a primary retinal photoreceptor cell degenerative process. Most cases of RP are seen in isolation (nonsyndromic); this is a report of RP in two siblings with VAC14-associated syndrome, and it is suggested that a connection between RP and VAC14-associated syndrome should be explored in future studies.

Keywords: moderate global developmental delay; retinitis pigmentosa inversa.

Publication types

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

MeSH terms

  • Adolescent
  • Brain / pathology
  • Exome / genetics
  • Exome Sequencing / methods
  • Family
  • Female
  • Homozygote
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mutation / genetics
  • Paraparesis, Spastic / genetics
  • Pedigree
  • Phenotype
  • Retina / pathology
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / metabolism
  • Siblings
  • Syndrome
  • Young Adult


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • VAC14 protein, human