Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation

Cristina Dias, Allison McDonald, Murat Sincan, Rosemarie Rupps, Thomas Markello, Ramona Salvarinova, Rui F. Santos, Kamal Menghrajani, Chidi Ahaghotu, Darren P. Sutherland, Edgardo S. Fortuno, Tobias R. Kollmann, Michelle Demos, Jan M. Friedman, David P. Speert, William A. Gahl, Cornelius F. Boerkoel

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a symmetric signal abnormality of the cerebellar and peritrigonal white matter. Following a progressive course of partial remissions and relapses, she died at 5 years of age. Her older sister had a similar course following varicella infection, she died within 13 months. Both sisters had unremarkable routine laboratory testing, with exception of a transient mild cytopenia in the proband 19 months after presentation. Exome sequencing identified a biallelic perforin1 mutation (PRF1; p.R225W) previously associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient interleukin-1 beta (IL-1β) production. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection and possibly due to primary immunodeficiency.

Original languageEnglish (US)
Pages (from-to)1232-1239
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number11
StatePublished - Nov 2013
Externally publishedYes


  • cerebellar white matter
  • exome sequencing
  • familial hemophagocytic lymphohistiocytosis
  • interleukin-1 beta
  • neurodegeneration

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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