|Classification and external resources|
Aicardi–Goutières syndrome (AGS) is a congenital immune-mediated neurodevelopmental disorder caused by mutations in the SAMHD1, TREX1, or Ribonuclease H2 (RNASEH2A, RNASEH2B, RNASEH2C) genes. This neurological disease usually presents at the age of four months and is characterized by the neurological symptoms of cerebral calcification (accumulation of calcium), white matter abnormalities, and cerebral atrophy. It is a type of autosomal recessive leukodystrophy, usually presenting within the first few weeks of life, and it is generally fatal within the first few years. If the patient does survive, treatment focuses on symptoms because no specific treatment has been developed to target the cause. It is also known as Cree encephalitis and pseudo-TORCH syndrome, both of which were once considered separate disorders.
In 1984, Jean Aicardi and Francoise Goutieres described eight children from five families presenting with severe early onset encephalopathy. This encepholapathy was characterized by calcification of basal ganglia, abnormalities in white matter and chronic cerebrospinal fluid lymphocytosis. The parents of the children were genetically related to each other and the children were both male and female. This suggested that the disease was autosomal recessive. In 1988, Pierre Lebon identified the additional feature of raised levels of interferon-alpha in the cerebral spinal fluid without the presence of infection in the central nervous system. The disease was first described as ‘Aicardi-Goutieres syndrome’ (AGS) in 1992. The first International Meeting on AGS was held in 2001 in Pavia, Italy. Over 100 cases have been reported around the world, as of 2009, including Europe, North Africa, North and South America, and Japan.
Signs and Symptoms
Aicardi-Goutieres Syndrome usually does not appear until about four months of age, although, in a fifth of the cases, it can present in the neonatal period. These babies are characterized by microcephaly, cerebral calcifications, neonatal seizures, poor feeding, and jitteriness. The cerebral calcifications indicate that the AGS started to manifest before birth. These infants often have hepatosplenomegaly which eventually leads to anemia.
The pregnancy and delivery appear to be normal. Babies present AGS symptoms at approximately four months of age. This is characterized by the baby becoming irritable, starting to develop problems feeding, developing a persistent medium-grade fever and acquiring a disturbed sleep wake cycle. In addition to these physical symptoms, which tend to disappear after a couple of months, the child develops neurological symptoms. As a result, patients often have severe cognitive and motor defects. These neurological conditions include poor head control, tetraplegia and abnormal eye movement. Good auditory functioning and the lack of retinal abnormalities can be used in differential diagnosis. The babies also present startling in response to stimuli, known as the “startle reaction.” The skin often shows lesions around fingers, toes, ears, and pressure points, which can be scaly or necrotic. Congenital glaucoma can also be present.
The majority of patients are severely impaired intellectually and physically, but a few patients with RNASEH2B mutations have considerably preserved intellectual function, good comprehension, and some communication. There is at least one known AGS patient, presenting with spastic cerebral palsy and associated intracranial calcification, that is of normal intelligence at age 19.
This disease is diagnosed differently according to the stage of the disease. There are different characteristics or signs of the disease throughout these different stages. During the beginning of the disease, doctors can diagnose the patient according to the presence of cerebral spinal fluid lymphocytosis. CT scans or MRIs can be performed in order to find calcifications in the brain, problems with the white matter, and/or cerebral atrophy. There are other different diagnostic criteria, such as lesions and infections, that can be helpful depending on what stage of the disease the patient is in. In addition, there are specific genes that have been shown to be mutated. Thus, analysis of a patient's genome can also help to determine if the patient does in fact have the disease. If these genes are mutated, they will cause the signs and symptoms of the disease. Research has not yet proven how or when the signs and symptoms of the disease begin.
AGS is difficult to diagnose because diagnosis is based on symptoms, which can resemble other diseases and brain scans. The medium grade fever that appears at the fourth month of life can lead to the misdiagnosis of meningitis or encephalitis. Infants with AGS appear to have contracted a virus infection in utero. If no virus is detected, AGS should be considered. A spinal tap showing a high number of lymphocytes without evidence otherwise of an infection and high levels of interferon gamma can be a good indicator of AGS. Brain imaging of one with AGS would show cerebral calcifications, white matter abnormalities, and cerebral atrophy. Currently, AGS is thought of as a possible autoimmune disease.
AGS is characterized radiologically by three, universally reported, features: cerebral calcifications, white matter abnormalities, and cerebral atrophy. The calcifications are typically bilateral and located in the basal ganglia, but in 50-70% of cases the calcifications also extend into the white matter. White matter abnormalities are found in 75-100% of cases. They are detected by CT scans as hypodense areas. Because calcifications can be better detected by the CT scan, CT scans are the preferred method for investigation rather than MRI. White matter abnormalities are most prevalent in the periventricular white matter and are particularly prominent in frontal and temporal regions. White matter abnormalities sometimes include cystic degeneration. Cerebral atrophy of AGS is typically in the periventricular region and in an enlargement of the cerebral sulci. Cerebral atrophy is found in 94%  of cases and tends to remain stable or progress.
Aicardi-Goutieres syndrome is believed to be related to mutations occurring in the TREX1 on chromosome 3 (known as ASG1), RNASEH2A on chromosome 19 (known as AGS4), RNASEH2B on chromosome 13 (known as AGS2), RNASEH2C on chromosome 11 (known as AGS3), and SAMHD1 genes on chromosome 20. Of these, mutations in RNASEH2B are the most prevalent. Other currently unknown genes may be involved as well. In most cases these mutations are the result of an autosomal recessive inheritance pattern. Rarely, this condition may be the result of de novo mutations, or an autosomal dominant inheritance pattern. The latter is highly unlikely because of the general early onset of this disorder. Sometimes Aicardi-Goutieres syndrome has a delayed onset, in which case the individual may pass on the mutation.
Other genetic diseases related to Aicardi-Goutieres Syndrome include chilblain Lupus, cerebitis, hepatitis, microcephaly, cerebral atrophy, and thrombocytopenia. While many other related disease may exist genetic and otherwise, these diseases are important because mutations found in the TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 genes can cause AGS as well as these diseases.
Treatment depends on the severity of the disease and the age of the person with the disease. Many of the treatments help to ensure the proper diet and eating patterns for patients suffering with Aicardi-Goutieres Syndrome. Patients are regularly screened for treatable symptoms, such as glaucoma and endocrine problems. Other treatments can help with the specific symptoms of the disease. Drugs are administered to help with epilepsy, to prevent infections, to prevent complications due to abnormalities with the patients’ posture, and to help more of the other symptoms that are associated with this deadly disease. Currently, no specific treatment is available to help the disease itself. There are several working hypotheses concerning different drugs that may help the disease, but none to date have been scientifically proven.
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