Aicardi-Goutières syndrome
| Classification according to ICD-10 | |
|---|---|
| G93.4 | Encephalopathy unspecified |
| ICD-10 online (WHO version 2019) | |
Aicardi syndrome Goutières ( AGS ) is an autosomal - recessive genetic disease , for the first time in 1984 by the French described doctors Jean François Aicardi and Françoise Goutières. Aicardi syndrome , which is a completely different hereditary brain development disorder , must be distinguished .
The Aicardi-Goutières syndrome is a genetically heterogeneous brain change ( encephalopathy ) that is clinically similar to an infection acquired intrauterine , but without evidence of pathogens. Rather, it is based on a genetic cause in which the activity of the nucleus enzymes is reduced and they “clean” the chromosomes of incorrectly incorporated RNA proteins. Due to the reduced enzyme activity , DNA segments accumulate in the cell, which then perishes and triggers an inflammation mediated by the immune system .
The syndrome can also be classified as one of the leukodystrophies, which are associated with a disorder of myelination .
Hardly a hundred cases have been described so far.
Symptoms
The affected children are mostly noticeable by difficulty in feeding, jerky eye movements , occasional slight bouts of fever , vomiting and fidgety . Approximately one third of patients lose previously learned motor skills by the age of six months . The children show spastic paralysis or dystonic , uncoordinated movements. The spasticity and movement disorders often lead to contractures in the arms and legs. Occasionally, seizures occur. There is an increasing psychomotor retardation. Many patients die in early childhood.
In a study on eleven Italian children, the first symptoms appeared on average after 3.3 months, usually several symptoms at the same time: five times irritability and psychomotor development disorder, four times fever attacks and four times swallowing disorders and four times muscle tone disorders (hypo- and hypertension) in one child Seizures and an enlarged liver and spleen.
The examination of the cerebrospinal fluid ( liquor cerebrospinalis ) shows an increase in the white blood cells (CSF lymphocytosis ) and alpha interferon as an indication of an inflammatory cause. In the blood there is a decrease in the number of platelets ( thrombocytopenia ) and an increase in the liver enzyme values (liver transaminases). Often the liver and spleen are enlarged.
A cross-sectional examination of the head ( computed tomography , magnetic resonance tomography ) reveals a loss of brain matter ( atrophy ) as well as a malformation of the white brain matter ( leukodystrophy ). There are also numerous foci of calcification. Therefore, the disease is also known as basal ganglia encephalopathy or calcifying encephalopathy with intracranial calcification and chronic CSF lymphocytosis .
Since skin changes, a complement factor deficiency and antinuclear antibodies were occasionally detected, a connection with rheumatic diseases was suspected.
Because of the similarity with an intrauterine infection with Toxoplasma parasites ( toxoplasmosis ), the syndrome has also been referred to synonymously as pseudotoxoplasmosis syndrome .
Location of the gene mutation
Meanwhile, five loci located (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 ) that can cause this syndrome. First, a mutation in the TREX1 gene on chromosome 3p21 was described in five unrelated families .
The genes RNASEH2-A, -B and -C are the gene loci for the three proteins that together form the trimeric cell nucleus enzyme ribonuclease H2 ( RNase H ). This is responsible for removing RNA molecules incorrectly built into the DNA, which physiologically occurs regularly. The RNA molecules are much more susceptible to damage than the normal DNA molecules with increased genetic instability up to hydrolysis with disruption of the genetic information. If the RNase H is completely switched off, this leads to early embryonic lethality in the knockout mouse by interrupting the cell cycle already during gastrulation . With partially reduced enzyme activity, gene fragments accumulate in the cells and trigger a p53 -mediated interruption of the cell cycle or apoptosis , which then leads to an inflammatory reaction through the innate immune response , which is similar to an autoimmune reaction as in systemic lupus erythematosus .
Web links
Individual evidence
- ↑ G. Lanzi et al. a .: Neurology. Volume 64, 2005, pp. 1621-1624 (first symptoms in eleven Italian children).
- ^ Aicardi-Goutières syndrome. In: Online Mendelian Inheritance in Man . (English)
- ↑ YJ Crow et al. a .: Mutations in the gene encoding the 3'-5 'DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. In: Nature Genet . Volume 38, 2006, pp. 917-920, PMID 16845398 (first description of the TREX1 mutation).
- ↑ G. Ramantani, J. Kohlhase et al. a .: Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. In: Arthritis and Rheumatism. Volume 62, number 5, May 2010, pp. 1469–1477, doi: 10.1002 / art.27367 .
- ↑ Martin AM Reijns u. a .: Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development . In: Cell . tape 149 , May 25, 2012, p. 1008-1022 , doi : 10.1016 / j.cell.2012.04.011 .
