Aicardi–Goutières syndrome

Aicardi syndrome Goutières (AGS ) is an autosomal recessive genetic disease that was first described in 1984 by the French physicians Jean François Aicardi and Françoise Goutières. Must be distinguished Aicardi syndrome, which is a completely different hereditary brain development disorder.

Aicardi - Goutières syndrome is a genetically heterogeneous brain alteration ( encephalopathy ), which clinically has similarities to a utero acquired infection, but without proven pathogen. Rather is an underlying genetic cause, decreased in the nuclear enzymes are active, " clean up" the chromosomes of falsely built- RNA proteins. The reduced enzyme activity, DNA fragments accumulate in the cell, thereby perishes and mediated by the immune system triggers inflammation.

So far, less than a hundred cases have been described.

Symptoms

Affected children usually fall on by feeding difficulty, jerky eye movements, occasional slight attacks of fever, vomiting, and fidgeting. In approximately one third of patients experience at the age of six months to loss previously learned motor skills. The children show spasticity or dystonia, uncoordinated movements. The spasticity and movement disorders often lead to contractures of the arms and legs. Occasionally, seizures. There will be an increasing psychomotor retardation. Many patients die in early childhood.

In a study of eleven Italian children, the first symptoms at a mean of 3.3 months occurred, usually several symptoms at the same time: the five Irritabiliät and psychomotor developmental disorder, four times each fever and dysphagia, as well as four times Muskeltonusstörungen (hypo - and hypertension), in a child seizures, and enlargement of the liver and spleen.

In the examination of the cerebrospinal fluid ( CSF) shows an increase in white blood cells ( CSF lymphocytosis ) and alpha - interferon as an indication of an inflammatory cause. In the blood, there are a decrease in blood platelets ( thrombocytopenia) and an increase in liver enzymes (liver transaminases ). Often the liver and spleen are enlarged.

In a sectional view examination of the skull (computed tomography ) is a loss of brain parenchyma detectable ( atrophy), and a malformation of the cerebral white matter is ( leukodystrophy ). There are also numerous foci of calcification. Therefore, the disease is also known as the basal ganglia calcification encephalopathy with encephalopathy or intracranial calcification and chronic CSF lymphocytosis.

Since occasionally lesions, a Komplementfaktormangel and antinuclear antibodies were detected, a connection has been suggested with rheumatic diseases.

Because of the similarity with an intrauterine infection with Toxoplasma parasites ( toxoplasmosis ), the syndrome has been synonymously referred to as Pseudotoxoplasmose syndrome.

Localization of the gene mutation

Meanwhile, five loci have been localized ( TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 ) that can cause this syndrome. First, a mutation of the gene on chromosome 3p21 TREX1 has been described in five unrelated families.

Wherein the genes RNASEH2 -A,- B and -C is the loci of the three proteins, which together form the nucleus trimeric enzyme ribonuclease H2 (RNase H). This is responsible for the removal of wrongly in the integrated DNA, RNA molecules, which occurs physiologically regularly. The RNA molecules are much more sensitive to damage than the normal DNA molecules with increased genetic stability through to hydrolysis with disorder of genetic information. If the RNase H completely off, this results in the knockout mouse embryonic lethality at an early by interrupting the cell cycle already during gastrulation. For partially reduced enzyme activity, gene fragments accumulate in the cells and trigger a p53 -mediated disruption of the cell cycle or apoptosis, which then leads to an inflammatory response by the innate immune response that resembles an autoimmune reaction, as with systemic lupus erythematosus.