Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières Syndrome and Beyond.

The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7). All of these genes encode proteins involved in nucleotide metabolism and/or sensing. Mutations in these genes result in the induction of type 1 interferon production and an upregulation of interferon stimulated genes. As more patients harboring mutations in these genes have been described, in particular facilitated by the advent of whole exome sequencing, a remarkably broad spectrum of associated neurologic phenotypes has been revealed, which we summarize here. We propose that the term AGS has continued clinical utility in the designation of a characteristic phenotype, which suggests relevant diagnostic investigations and can inform outcome predictions. However, we also suggest that the use of the term "type 1 interferonopathy" is appropriate for the wider spectrum of disease consequent upon dysfunction of these genes and proteins since it implies the possibility of a common "anti-interferon" approach to therapy as such treatments become available.

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.

Circulating interferon in man after administration of exogenous human leukocyte interferon.

Interferon was measured at different intervals after the iv, sc, and im application of exogenous human leukocyte interferon to patients with various virus diseases or neoplasms. Interferon injected iv into patients had a half-life of about 15 minutes in the 1st hour and of about 90 minutes in the next 3 hours. Six hours after iv injection of 30 million U, no serum interferon was detectable. With a continuous iv infusion, a relatively high serum interferon level was reached. By the im administration of 1 million U interferon, a peak level of serum interferon (mean value 107 U/ml serum) occurred after 2 hours and was fairly stable for about 6 hours. Twenty-four hours after im application, a low level of serum interferon was still detectable. Similar results were found after sc interferon injections. In a patient with subacute sclerosing panencephalitis, no interferon was found in the cerebrospinal fluid at the time of the highest serum interferon level and 24 hours after two im interferon injections. Only minimal side reactions resulted from sc and im interferon injections. In one patient, a shock reaction occurred after iv application. For therapeutic trials, about 1 million U exogenous human interferon should be injected twice daily im or sc.

Serum interferon in patients with psychosis.

High titers of interferon were found in serum from 20 (24.4%) of 82 patients with psychosis and from only two (3.1%) of 64 control subjects. Interferon-positive patients were more likely than interferon-negative patients to have had a recent onset or exacerbation of their illness and to be on low-dose or no medication. No interferon was detected in the CSF of 65 patients or 20 control subjects. These findings suggest that there may be immunological abnormalities or viral infections in some patients with psychosis.

CSF and serum interferon in multiple sclerosis: longitudinal study.

We studied interferon (IFN) in the serum and CSF of 31 patients with multiple sclerosis. The sensitive IFN bioassay required only small volumes and detected IFN levels as low as 0.5 international units/ml (CSF) or 4 international units/ml (serum) of IFN. Two hundred twenty-eight paired CSF/serum samples were tested, and no IFN was found.

Viral antibodies and interferon in acute psychiatric disorders.

In a prospective study of 54 patients with acute psychiatric disorders, interferon and antibodies in serum and CSF were measured to 19 microbes by the complement fixation (CF) test and to 7 viruses by enzyme immunoassay (EIA). The CF test revealed a fourfold or greater change (p less than .001) in serum antibody titers in 20 patients, and EIA showed a twofold or greater change in CSF titers in 7 patients. Pathological serum/CSF antibody ratio by EIA was observed in 8 patients. The results suggest that viral infections and inflammatory processes have significance in the etiopathogenesis of acute psychiatric disorders.

Central nervous system toxicity of interferons and other cytokines.

Prolonged administration of interferons, interleukins and tumor necrosis factor are accompanied by a range of toxic effects of which central nervous system toxicity may be an important dose-limiting factor. While symptoms are widely reported, practically nothing is known about mechanisms of action. This review attempts to distinguish between a direct effect of cytokines upon circumventricular organs and an indirect effect mediated by factors released by endothelial-glial cells of the blood-brain barrier normally impermeable to cytokines. In order to reduce the toxicity of biological response modifiers the definition of the minimum effective dose, the use of the lymphatic route and the observance of the chronobiological rules may help to improve the therapeutic index of these hormone-like compounds. It appears however, that the relationship between cytokine: dose: route: schedule: timing on one side and efficacy: toxicity on the other is complex, and so far no general rule has clearly emerged so that at the moment it appears necessary to find out the optimal therapeutic index for each particular disease.

Minimal interferon induction in dogs, using a modified polyriboinosinic-polyribocytidylic acid complex.

Adult Beagles failed to respond to high concentrations of interferon (IF) when they were injected with a nuclease-resistant complex poly I:C with poly-L-lysine and carboxymethylcellulose (PICLC), by the IV or intrathecal route. An IV dose of 1 mg of PICLC/kg of body weight was lethal to 1 of 3 adult dogs, but induced IF in only 2 dogs. Smaller doses were less toxic, but also were less effective. The injection of a high dose of a known IF inducer (3 X 10(8) egg LD50 of Newcastle disease virus) also failed to induce IF in Beagles. Interferon could not be induced in vitro when primary cultures of neonatal dog lung or kidney were treated with cultures of neonatal dog lung or kidney were treated with PICLC. When these primary cell cultures were compared with the cell line Madin-Darby canine kidney in an IF assay, no difference in sensitivity to IF-induced protection from infection with vesicular stomatitis virus could be shown. This indicated that the sensitivity of the Madin-Darby cell line was not the only factor in determining the lack of IF response in dogs and indicates that the dogs are poor responders to IF induction.

Interferon crosses blood-cerebrospinal fluid barrier in monkeys.

Interferon was detected in the cerebrospinal fluid (CSF) of monkeys injected iv or im with 30 million units of human leukocyte interferon. The im injection maintained a long-lasting plateau at about 1/30th of the corresponding level of interferon in the serum. Interferon injected into the serum. Interferon injected into the cerebrospinal canal was cleared from CSF at a similar rate as it disappeared from blood after iv administration of a high dose. A relatively stable serum level was maintained for 12-24 hr after the injection of interferon into the CSF space.

Bacteria and viruses induce production of interferon in the cerebrospinal fluid of children with acute meningitis: a study of 57 cases and review.

The CSF of 57 infants and children with bacterial or enterovirus meningitis was analyzed for the presence of interferon (IFN). CSF was collected when the diagnosis of meningitis was made; a bacterium or enterovirus was isolated in all cases. IFN was detectable in CSF in 24% of cases of bacterial meningitis and in 75% of cases of viral meningitis. Titers of IFN were generally lower in cases of bacterial meningitis. Neither the presence of IFN nor the level of IFN titers correlated with the patient's age or number of white blood cells or mononuclear cells in the CSF. Coxsackievirus induced production of IFN more consistently and in higher titers than did echovirus. None of 35 control patients had detectable IFN in CSF. A literature review and our data indicate that the presence of IFN in CSF suggests infection of the CNS but does not differentiate bacterial from viral infection. The finding of IFN in the CSF of children with bacterial meningitis supports evidence that bacteria and other nonviral microorganisms induce IFN production. The protective role of IFN in nonviral infections deserves further investigation.

[Presence of interferon in cerebrospinal fluid in nontumoral opsomyoclonic ataxia]. / Présence d'interféron dans le LCR au cours d'une ataxie opsomyoclonique d'origine non tumorale.

A case of opsoclonus myoclonus ataxia shown not to be due to neuroblastoma was biologically and virologically studied. The presence of interferon was found in the patient's CSF. Its implication in the etiology of cerebellar ataxia is discussed.

Human leukocyte interferon administration to patients with symptomatic and suspected rabies.

Body fluids and brain tissue from rabid human patients have demonstrated only low titers of interferon. Therefore, pharmacokinetic studies of systemically administered and locally injected leukocyte interferon were performed in 2 North American patients with suspected rabies who showed no clinically important side effects of this therapy. Similar therapy was given to 5 patients with symptomatic rabies in Europe and America. Although no prolongation of the clinical course was seen in 3 patients given high-dose intraventricular and systemic therapy, treatment was not initiated until between 8 and 14 days after symptoms were seen. The intraventricular dosage regimen produced cerebrospinal fluid levels that appeared to fall progressively over the 24 hours after injection and demonstrated good but somewhat delayed distribution into the lumbar sac. Titers produced by this therapy were 30- to 10,000-fold higher than those normally observed in this infection, however. In the patients treated at the highest dosage, a diminished and delayed antirabies neutralizing antibody titer was observed, probably a result of the administration of the exogenous interferon.

Intrathecal interferon in subacute sclerosing panencephalitis.

Five patients with clinically advanced subacute sclerosing panencephalitis (SSPE) were given human leukocyte interferon (IFN) by the lumbar route, 1 million IU every other day for a total of 30 days. Intrathecal IFN produced a meningeal inflammatory reaction in all patients and was associated with transient hemiparesis in 1. It persisted in the cerebrospinal fluid at measurable levels for 48 hours after a single injection. Although improvement was temporally related to intrathecal IFN in 1 patient, it is not clear whether this was induced by IFN or a spontaneous remission. A randomized controlled trial would be necessary to evaluate IFN critically as a therapy for SSPE.