Neuropediatrics 2010; 41 - V1265
DOI: 10.1055/s-0030-1265527

Lupus erythematosus and Aicardi-Goutières Syndrome: a continuum of immune mediated diseases

G Ramantani 1, J Kohlhase 2, T Bast 3, P Niggemann 4, K Ungerath 5, C Hertzberg 6, M Innes 7, H Walkenhorst 8, A Bevot 9, C von Stülpnagel 10, K Thomas 11, F Niemann 12, M Häusler 13, U Tacke 14, M Ae Lee-Kirsch 15
  • 1Epilepsy Center, University of Freiburg, Germany
  • 2Center of Human Genetics Freiburg, Freiburg, Germany
  • 3Klinik für Kinder und Jugendliche, Epilepsiezentrum Kork, Kehl-Kork, Germany
  • 4Privatpraxis für Kernspintomografie, Köln-Rodenkirchen, Germany
  • 5Altonaer Kinderkrankenhaus, Hamburg, Germany
  • 6Diagnose und Behandlungszentrum für Kinder und Jugendliche, Vivantes Klinikum Neukölln, Berlin, Germany
  • 7Department of Medical Genetics, Alberta Health Services, University of Calgary, Calgary, Alberta, Canada
  • 8Evangelisches Krankenhaus Bethanien, Iserlohn, Germany
  • 9Universitätsklinik für Kinder- und Jugendmedizin, Tübingen, Germany
  • 10Klinik für Kinder- und Jugendmedizin, Klinikum Harlaching, Munich, Germany
  • 11Children's Hospital of The King's Daughters and Eastern Virginia Medical School, Norfolk, Virginia, USA
  • 12Kinder- und Jugendklinik Gelsenkirchen, Gelsenkirchen, Germany
  • 13Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Aachen, Aachen, Germany
  • 14Division of Neuropediatrics and Muscular Disorders, Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Germany
  • 15Klinik und Poliklinik für Kinder- und Jugendmedizin, Technische Universität Dresden, Dresden, Germany

Introduction: Aicardi-Goutières syndrome (AGS) is an early-onset encephalopathy resembling congenital viral infection characterized by basal ganglia calcifications, loss of white matter, cerebrospinal fluid (CSF) lymphocytosis, and elevated interferon-α in CSF. AGS is an autosomal recessive disease caused by mutations in 5 genes encoding the DNA exonuclease (TREX1), the three subunits of the ribonuclease H2 (RNASEH2A-C), and the SAM domain and HD domain-containing protein 1 (SAMHD1), respectively, suggesting that defects in nucleic acid metabolism could trigger an innate immune response.

Methods: Clinical, imaging and lab data including follow-up over several years were collected from 27 patients with the clinical diagnosis of AGS. Genomic DNA was screened for mutations in all 5 AGS genes by direct sequencing and sera analyzed for auto-antibodies.

Results: The clinical picture was dominated by severe early onset of neurological disease with episodic deterioration reaching a plateau after infancy. A significant number of children in our cohort were small and light for dates, one third presented with neonatal infection, respiratory distress and newborn seizures. The vast majority presented with initial lethargy and feeding difficulties followed by overt startle reaction, crying fits and paroxysmal dystonia. Overall, most children showed severe developmental delay and a high prevalence of refractory epilepsy and dystonia evolving in quadriparesis. Additional features included hearing loss, cortical blindness, cardiomyopathy, renal malformation and intestinal atresia. An important finding was the high prevalence of clinical (rash, arthritis, oral ulcers) or laboratory (auto-antibodies to nuclear antigens, reduced complement, thrombopenia, leucopenia) findings commonly seen in patients with lupus erythematosus. Further features of autoimmune disease included celiac disease and insulin dependent diabetes mellitus. Imaging features corresponded to severity, with calcifications often missed on conventional MRIs.

Conclusion: In our cohort of AGS patients we further define the phenotypic spectrum of AGS by demonstrating a high prevalence of signs of autoimmunity in addition to neurological disease. Our findings suggest that serological parameters indicative of systemic autoimmunity such as anti-nuclear antibodies may represent valuable diagnostic markers for AGS. Early diagnosis may potentially have a significant impact on clinical management with immune modulating agents.