Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

White matter alterations associated with chromosomal disorders.

White matter alterations in chromosomal disorders have been reported mainly in 18q-syndrome. Our aim was to evaluate white matter alterations in patients with chromosomal abnormalities detected through conventional cytogenetic techniques. Forty-four patients with chromosomal abnormalities, excluding trisomy 21, were diagnosed in our hospital between May 1999 and December 2002 (24 males, 20 females; mean age 6 years 4 months [SD 3 years 2 months], range 0 to 18 years). Of the 44 patients, 14 had brain magnetic resonance imaging (12 males, 2 females; mean age 4 years 2 months [SD 4 years 4 months]; five with sex chromosomal disorders [SCD] and nine with autosomal chromosomal disorders [ACD]). Of these 14 patients, eight (four with SCD and four with ACD) had abnormal white matter findings of similar patterns. These patients had pseudonodular, subcortical, and periventricular white matter high signal intensity images in T2, and fluid-attenuated inversion recovery sequences that were isolated or confluent. The images did not correlate with the neurological clinical state. Given that eight of the 14 patients showed these lesions, their prevalence in different chromosomal abnormalities appears to be high, even though they have not been well reported in the literature. To our knowledge, these alterations have never been described in SCD. We concluded that unknown factors related to the myelination processes may be localized in different chromosomes.