Purpose. The purpose of this study was to explore anecdotal evidence for an increase in the prevalence of autoimmune diseases in family members of patients with Aicardi-Goutières syndrome (AGS). Methods. Pedigrees of patients and controls were analyzed using chi-square and logistic regression to assess differences in reports of autoimmune disease among family members of cases and controls. Data was collected at Children's National Medical Center in Washington, DC, USA and at the International Aicardi-Goutières Syndrome Association Scientific Headquarters, C. Mondino National Institute of Neurology in Pavia, Italy. Results. The number of individuals with reported autoimmune disease is significantly related to having a family member with AGS ( , ); 10% (35/320) of relatives of patients with AGS had a reported autoimmune disease diagnosis compared to 5% (18/344) of relatives of controls. There was a greater percent of maternal relatives of patients with AGS reporting autoimmune disease (14.6%), compared to controls (6.8%), with the association being statistically significant. The association was not significant for paternal relatives. Conclusion. The prevalence of autoimmune disease in relatives of children with AGS is significantly increased compared to controls. More research is needed to better understand this association. 1. Introduction Aicardi-Goutières syndrome (AGS) is a heritable neurologic disorder with an immune basis. Patients most typically present early in life with increased cerebrospinal fluid (CSF) interferon alpha and markers of inflammation, elevated liver enzymes, thrombocytopenia, intracranial calcifications and leukoencephalopathy. Patients with AGS usually demonstrate severe neurologic dysfunction and life-long disability. The immune basis of AGS was originally suspected by Aicardi and Goutières, as a persistent CSF pleocytosis was seen in affected infants. Infants presented with what appeared to be a congenital infection [1], and reports of elevations of CSF IFNα [2] and neopterin [3, 4] further suggested that an immune process was at play. However, it was not until the identification of AGS related mutations in nucleases, including TREX1 and the three constituent subunits of RNase H2, as well as a nonnuclease, SAMHD1, that the relationship between innate cellular immunity and AGS began to be more fully understood. Discovery of the genes associated with AGS allowed for further definition of the phenotype. Most patients with AGS were found to have homozygous or compound heterozygous changes in these genes. AGS was also found to be
References
[1]
Y. J. Crow and J. H. Livingston, “Aicardi-Goutières syndrome: an important Mendelian mimic of congenital infection,” Developmental Medicine and Child Neurology, vol. 50, no. 6, pp. 410–416, 2008.
[2]
P. Lebon, J. Badoual, G. Ponsot, F. Goutieres, F. Hemeury-Cukier, and J. Aicardi, “Intrathecal synthesis of interferon-α in infants with progressive familial encephalopathy,” Journal of the Neurological Sciences, vol. 84, no. 2-3, pp. 201–208, 1988.
[3]
N. Blau, L. Bonafé, I. Kr？geloh-Mann et al., “Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome: a new phenotype,” Neurology, vol. 61, no. 5, pp. 642–647, 2003.
[4]
E. Wassmer, J. Singh, S. Agrawal, S. Santra, and Y. J. Crow, “Elevated pterins in cerebral spinal fluid—biochemical marker of Aicardi-Goutières syndrome,” Developmental Medicine and Child Neurology, vol. 51, no. 10, pp. 841–842, 2009.
[5]
J. Aicardi and F. Goutieres, “Systemic lupus erythematosus or Aicardi-Goutières syndrome?” Neuropediatrics, vol. 31, no. 3, article 113, 2000.
[6]
Y. J. Crow, D. N. Black, M. Ali et al., “Cree encephalitis is allelic with aicardi-goutières syndrome: implications for the pathogenesis of disorders of interferon α metabolism,” Journal of Medical Genetics, vol. 40, no. 3, pp. 183–187, 2003.
[7]
C. de Laet, P. Goyens, C. Christophe, A. Ferster, F. Mascart, and B. Dan, “Phenotypic overlap between infantile systemic lupus erythematosus and Aicardi-Goutières syndrome,” Neuropediatrics, vol. 36, no. 6, pp. 399–402, 2005.
[8]
R. C. Dale, S. Ping Tang, J. Z. Heckmatt, and F. M. Tatnall, “Familial systemic lupus erythematosus and congenital infection-like syndrome,” Neuropediatrics, vol. 31, no. 3, pp. 155–158, 2000.
[9]
M. A. Lee-Kirsch, M. Gong, D. Chowdhury et al., “Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus,” Nature Genetics, vol. 39, no. 9, pp. 1065–1067, 2007.
[10]
B. Namjou, P. H. Kothari, J. A. Kelly et al., “Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort,” Genes and Immunity, vol. 12, no. 4, pp. 270–279, 2011.
[11]
C. Günther, M. Meurer, A. Stein, A. Viehweg, and M. A. Lee-Kirsch, “Familial chilblain lupus—a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1,” Dermatology, vol. 219, no. 2, pp. 162–166, 2009.
[12]
G. Rice, W. G. Newman, J. Dean et al., “Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutières syndrome,” American Journal of Human Genetics, vol. 80, no. 4, pp. 811–815, 2007.
[13]
J. C. Ravenscroft, M. Suri, G. I. Rice, M. Szynkiewicz, and Y. J. Crow, “Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus,” American Journal of Medical Genetics A, vol. 155, no. 1, pp. 235–237, 2011.
[14]
A. Richards, A. M. J. M. van den Maagdenberg, J. C. Jen et al., “C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy,” Nature Genetics, vol. 39, no. 9, pp. 1068–1070, 2007.
[15]
D. C. Goldstone, V. Ennis-Adeniran, J. J. Hedden, et al., “HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase,” Nature, vol. 480, no. 7377, pp. 379–382, 2011.
[16]
G. I. Rice, J. Bond, A. Asipu, et al., “Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response,” Nature Genetics, vol. 41, no. 7, pp. 829–832, 2009.
[17]
D. B. Stetson, J. S. Ko, T. Heidmann, and R. Medzhitov, “Trex1 prevents cell-intrinsic initiation of autoimmunity,” Cell, vol. 134, no. 4, pp. 587–598, 2008.
[18]
D. L. Jacobson, S. J. Gangea, N. R. Roseb, and N. M.H. Graham, “Epidemiology and estimated population burden of selected autoimmune diseases in the United States,” Clinical Immunology and Immunopathology, vol. 84, no. 3, pp. 223–243, 1997.
[19]
J. C. Prinz, “The role of T cells in psoriasis,” Journal of the European Academy of Dermatology and Venereology, vol. 17, no. 3, pp. 257–270, 2003.
[20]
J. C. Diniz, R. T. Almeida, N. E. Aikawa, A. Sallum, P. T. Sakane, and C. A. Silva, “Kawasaki disease and juvenile systemic lupus erythematosus,” Lupus, vol. 21, no. 1, pp. 89–92, 2012.
[21]
Y. J. Crow, “Type I interferonopathies: a novel set of inborn errors of immunity,” Annals of the New York Academy of Sciences, vol. 1238, no. 1, pp. 91–98, 2011.
[22]
T. B. Niewold, J. Hua, T. J. A. Lehman, J. B. Harley, and M. K. Crow, “High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus,” Genes and Immunity, vol. 8, no. 6, pp. 492–502, 2007.
[23]
T. B. Niewold, S. C. Wu, M. Smith, G. A. Morgan, and L. M. Pachman, “Familial aggregation of autoimmune disease in juvenile dermatomyositis,” Pediatrics, vol. 127, no. 5, pp. e1239–e1246, 2011.
