ADAMTS13 dysfunction and a novel frameshift mutation in the TREX1 gene in a patient with Aicardi-Goutières syndrome

Aicardi-Goutières syndrome (AGS) is a genetic infantile encephalopathy with intracerebral calcifications, leukodystrophy, cerebral atrophy, lymphopleocytosis and raised interferon-α in cerebrospinal fluid (CSF) that shares phenotypical similarities with congenital viral infections and systemic lupus erythematodes (SLE). An 8 month old male patient presenting with acquired microcephaly, developmental retardation, abnormal muscle tone and irritability was diagnosed with AGS on grounds of typical findings in laboratory and neuroimaging studies.

The patient subsequently developed an epilepsy and extraneurological symptoms with hepatomegaly, elevated liver enzymes, hypothyroidism as well as cardiolipin and β2-glycoprotein IgG-antibodies. With 14 month of age skin lesion on the fingers were present that are described as chilblain-like in AGS.

Neuropathology investigations in AGS gave hints to cerebral thrombotic microangiopathy. FVIII activity (217%), VWF:Ag (179%) and VWF:RCo (241%) were elevated in terms of endothelial cell activation. We therefore investigated the von Willebrand factor cleaving metalloprotease ADAMTS13 that plays a role in thrombotic thrombocytopenic purpura (TTP) as well as in SLE. We found low levels of ADAMTS13 activity (14.0 resp. 38.5%, normal range 50–110) and antigen concentration (0.24 resp. 0.19µg/ml, normal range 0.60–1.60). As ADAMTS13 autoantibodies were not detected an acquired form of ADAMTS13 dysfunction is unlikely. Further investigations must explore a possible congenital disorder like Upshaw-Schulman syndrome (chr. 9q34).

In the AGS1 gene (TREX1, Chr. 3p21) a novel frameshift mutation (paternal) and a known missense mutation (maternal) were found. TREX1 encodes the single-stranded DNA-cleaving 3′-5′-exonuclease. It is assumed that intracellular accumulation of nucleic acids due to TREX1 malfunction triggers an α interferone-mediated innate immune response. TREX1 mutations are also found in a small number of SLE patients.

In summary our patient with AGS displayed clinical and laboratory features that also occur in SLE. We were able to show ADAMTS13 dysfunction supporting the theory of a thrombotic microangiopathy. This is in accordance with the assumed common autoimmune pathogenesis of AGS and SLE.