Yanick Crow

Disorders with intracranial calcification

Aicardi-Goutières syndrome

Over the last eight years we have studied the genetic disease Aicardi-Goutières syndrome (AGS: [MIM 225750]), a rare childhood encephalopathy showing remarkable phenotypic overlap with systemic lupus erythematosus (SLE). Aicardi-Goutieres neuroimaging We have demonstrated that AGS results from recessive mutations in genes encoding the 3'-exonuclease TREX1 (AGS1) and the three non-allelic components of the RNASEH2 endonuclease protein complex (AGS2, 3 and 4). We have also described heterozygous TREX1 mutations as the cause of dominant AGS and the dominant autoimmune disorder familial chilblain lupus (CHBL: [MIM 610448]).

In 2003, we predicted that elucidation of the pathogenesis of AGS would inform our understanding of autoimmune diseases associated with raised levels of interferon alpha. Our description of heterozygous TREX1 mutations as the cause of CHBL, and the identification of heterozygous TREX1 mutations in a cohort of lupus patients, confirms this prediction and implicates TREX1, and the RNASEH2 complex, in the pathogenesis of SLE.

Building on these successes, our current efforts are aimed at the systematic clinical and immunological characterisation of AGS/FCL and an understanding of the cellular mechanisms by which TREX1 and RNaseH2 complex dysfunction cause AGS and allied phenotypes. Eventually, we hope that these studies will lead to useful therapies.

Related phenotypes

Although intracranial calcification is a relatively non-specific endpoint resulting from multiple pathologies, the identification of calcium deposits on brain imaging often provides a useful clinical starting point for the physician in the diagnostic assessment of a patient.

Through our work on AGS, we have collected information and samples from patients with a number of non-AGS phenotypes including Coats plus/CRMCC (cerebroretinal microangiopathy with calcification and cysts; see skull X-ray) and SPENCD (spondylo-enchondrodysplasia with spasticity, cerebral calcifications and immune dysregulation). Consequently, we are involved in gene identification in these diseases and the definition of a clinically useful diagnostic algorithm relating to intracranial calcification.