Article thumbnail

Cerebral Arterial Stenoses and Stroke: Novel Features of Aicardi-Goutières Syndrome Caused by the Arg164X Mutation in SAMHD1 Are Associated with Altered Cytokine Expression

By Holger Thiele, Marcel du Moulin, Katarzyna Barczyk, Christel George, Wolfram Schwindt, Gudrun Nürnberg, Michael Frosch, Gerhard Kurlemann, Johannes Roth, Peter Nürnberg and Frank Rutsch


Aicardi-Goutières syndrome (AGS) is a rare inborn multisystemic disease, resembling intrauterine viral infection and resulting in psychomotor retardation, spasticity and chilblain-like skin lesions. Diagnostic criteria include intracerebral calcifications and elevated interferon-alpha and pterin levels in cerebrospinal fluid (CSF). We report on four adult siblings with unknown neurodegenerative disease presenting with cerebrovascular stenoses, stroke and glaucoma in childhood, two of whom died at the age of 40 and 29 years. Genome-wide homozygosity mapping identified 170 candidate genes embedded in a common haplotype of 8Mb on chromosome 20q11-13. Next generation sequencing of the entire region identified the c.490C>T (p.Arg164X) mutation in SAMHD1, a gene most recently described in AGS, on both alleles in all affected siblings. Clinical diagnosis of AGS was then confirmed by demonstrating intracerebral calcifications on cranial computed tomography in all siblings and elevated pterin levels in CSF in three of them. In patient fibroblasts, lack of SAMHD1 protein expression was associated with increased basal expression of IL8, while stimulated expression of IFNB1 was reduced. We conclude that cerebrovascular stenoses and stroke associated with the Arg164X mutation in SAMHD1 extend the phenotypic spectrum of AGS. The observed vascular changes most likely reflect a vasculitis caused by dysregulated inflammatory stress response. © 2010 Wiley-Liss, Inc

Topics: Mutation in Brief
Publisher: Wiley Subscription Services, Inc., A Wiley Company
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (1984). A progressive familial encephalopathy in infancy, with calcifications of the basal ganglia, and chronic cerebrospinal fluid lymphocytosis.
  2. (2005). Aicardi-Goutières snydrome.
  3. (2009). Aicardi-Goutières syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity.
  4. (1998). Aicardi-Goutières Syndrome: An Update and Results of Interferon-α Studies.
  5. (2000). Allegro, a new computer program for multipoint linkage analysis.
  6. (2005). ALOHOMORA: a tool for linkage analysis using 10K SNP array data.
  7. (2003). Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome – A new phenotype.
  8. (2007). Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome.
  9. (2004). Congenital glaucoma and brain stem atrophy as features of AicardiGoutieres syndrome.
  10. (2008). Dendritic cell-derived interferon-γ-induced protein mediates tumor necrosis factor-α stimulation of human lung fibroblasts.
  11. (2009). Elevated pterins in cerebral spinal fluid – biochemical marker of Aicardi-Goutières syndrome.
  12. (2010). Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome.
  13. (2010). Familial Aicardi-Goutières syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures.
  14. gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.
  15. (2007). Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes.
  16. (2005). HaploPainter: a tool for drawing pedigrees with complex haplotypes.
  17. (2000). Identification of human homologue of mouse IFN-γ induced protein from human dendritic cells.
  18. (2003). Inflammatroy cytokines and cardiovascular disease. Curr Drug Targets Inflamm Allergy 3:257-265.
  19. (2008). Inhibition of G1P3 expression found in the differential display study on respiratory syncytial virus infection.
  20. (1992). Interleukin-8, a chemotactic and inflammatory cytokine.
  21. (1988). Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy.
  22. (2008). Linking Retroelements to Autoimmunity.
  23. (2006). Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection.
  24. (2009). Mutations involved in Aicardi-Goutières syndrome implicate SAMDH1 as regulator of innate immune response.
  25. (2008). New roles for the major human 3’-5’ exonuclease TREX1 in human disease.
  26. (2006). Nucleic acid by-products and chronic inflammation.
  27. (2005). SLE: challenges and candidates in human disease.
  28. (2006). Takayasu’s arteritis: An update on physiopathology.
  29. (2002). The neuropathology of Aicari-Goutières syndrome.
  30. (2007). TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity.
  31. (2005). Type I interferons (α/ß) in immunity and autoimmunity.
  32. (2005). Virus Infection Switches TLR-3-Positive Human Neurons To Become Strong Producers of Beta Interferon.