Wednesday, December 23, 2015

Aicardi-Goutieres syndrome

La Piana R, Uggetti C, Roncarolo F, Vanderver A, Olivieri I, Tonduti D, Helman
G, Balottin U, Fazzi E, Crow YJ, Livingston J, Orcesi S. Neuroradiologic patterns
and novel imaging findings in Aicardi-Goutières syndrome. Neurology. 2015 Nov 18.
pii: 10.1212/WNL.0000000000002228. [Epub ahead of print]

Objective: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutières syndrome (AGS).
Methods: The neuroradiologic data of 121 subjects with AGS were collected. The CT and MRI data were analyzed with a systematic approach. Moreover, we evaluated if an association exists between the neuroradiologic findings, clinical features, and genotype.
Results: Brain calcifications were present in 110 subjects (90.9%). Severe calcification was associated with TREX1 mutations and early age at onset. Cerebral atrophy was documented in 111 subjects (91.8%). Leukoencephalopathy was present in 120 children (99.2%), with 3 main patterns: frontotemporal, diffuse, and periventricular. White matter rarefaction was found in 54 subjects (50.0%), strongly associated with mutations in TREX1 and an early age at onset. Other novel radiologic features were identified: deep white matter cysts, associated with TREX1 muta­tions, and delayed myelination, associated with RNASEH2B mutations and early age at onset.
Conclusions: We demonstrate that the AGS neuroradiologic phenotype is expanding by adding new patterns and findings to the classic criteria. The heterogeneity of neuroradiologic patterns is partly explained by the timing of the disease onset and reflects the complexity of the patho­genic mechanisms.
Uzgil B, Sherr EH. Neuroimaging in Aicardi-Goutières syndrome: Biomarkers for
a progressive encephalopathy. Neurology. 2015 Nov 18. pii:
10.1212/WNL.0000000000002227. [Epub ahead of print]
In 1984, 2 pediatric neurologists, Jean Aicardi and Françoise Goutières, published their seminal case report of 8 patients (from 5 families) with a devastating neonatal encephalopathy characterized by striking cerebral calcifications, white matter hypodensities, visualized on CT, accompanied by a persistent CSF lymphocytosis.  Notably, the neuroradiologic findings suggested a perinatal toxoplasmosis, other (syphilis, varicella-zoster, parvovirus b19), rubella, cytomegalovirus, and herpes (TORCH) infection, and these patients often have an elevation of interferon-a in the CSF.  Three decades of highly productive clinical and scientific investigation of Aicardi-Goutières syndrome (AGS) has led to the discovery of 7 causative genes and the realization that mutation in any of these leads to a genetically mediated autoimmune response to nucleic acid metabolism, analogous to systemic lupus erythematosus, in the developing brain
For example, brain calcifications were present in 110/121 patients, with severe calcifications (defined as involving multiple locations beyond lentiform nuclei, deep white matter, and thalami, and having multiple and variable patterns) being much more prevalent in patients with TREX1 mutations.  In contrast, the presence of RNASEH2B mutations was inversely associated with severe calcifications.  Another notable finding was that a frontotemporal pattern of leukoencephalopathy had a significant association with clinical severity. These findings help the clinician if a mutation in TREX1 or RNASEH2B is identified, but with 7 genes implicated in AGS, including RNASEH2A, RNASEH2C, SAMHD1, ADAR, and IFIH1, these findings only point to the need for expanding the available cohort…
We are reminded again that imaging findings in AGS clearly mimic those of TORCH infections, and in all cases where a TORCH infection is considered, testing for AGS should commence promptly if no clear sign of infection is identified. Because most cases of AGS are mediated by autosomal recessive genetics, rapid identification of the etiology can immediately help with family planning. However, as the genetic community is discovering, there are also examples where de novo mutations function in a dominant fashion to cause disease. For example, autosomal recessive mutations in the gene KIF1A can lead to peripheral neuropathy, while dominant de novo mutations can lead to a severe and progressive encephalopathy with a level of clinical impairment analogous to AGS. By comparison, there are dominant heterozygous mutations in both IFIH1 and TREX1 that lead to AGS; others are likely to be identified…
Thus, not only can autosomal dominant mutations in TREX1 lead to AGS, but these mutations can also lead to familial chilblain lupus, further strengthening this linkage to a progressive autoimmune disorder that could potentially be treated prior to symptoms.

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