It is a type of leukodystrophy , a group of conditions that affect the white matter of the brain. These diseases damage the myelin sheath, which surrounds and protects the nerve cells in the brain and spinal cord and speeds transmission of messages between cells. It is the loss of myelin that is responsible for the symptoms of AGS. Most children with AGS end up with mild to severe intellectual or physical impairments. The mutation leads to a buildup of small pieces of DNA in the brain, which is thought to trigger the immune response that leads to the symptoms of AGS.
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Rice et al  5. This finding raises the possibility, unproven, that the heterozygous parents of children with AGS caused by TREX1 pathogenic variants, at least those with variants in the C terminus of the gene , may be at risk of developing RVCL. This finding raises the possibility that individuals with AGS caused by mutation of TREX1 as well as their heterozygous parents may be at risk of developing signs and symptoms similar to SLE.
Rice et al [a] described a heterozygous TREX1 pathogenic variant in affected members of a family with chilblain lupus; a second distinct pathogenic variant was subsequently described by Lee-Kirsch et al [a]. Additional pathogenic variants have been described. Differential Diagnosis Calcification of the basal ganglia is a nonspecific finding seen in many diseases. However, in the context of an early-onset encephalopathy, conditions to consider include the following: TORCH congenital infections are the most common conditions in the differential and the most important to rule out because misdiagnosis would result in erroneous counseling as to risk of recurrence.
Note: Other congenital infections, such as those associated with Zika and HIV, should also be considered in the differential diagnosis. The microcephaly-intracranial calcification syndrome MICS. However, a number of other phenotypes are associated with neonatal intracranial calcification [ Knoblauch et al , Gardner et al ]; thus, this phenotype undoubtedly represents a heterogeneous group of diseases see Nomenclature.
The degree of white matter hypomyelination at an early age has also prompted consideration of Pelizeaus-Merzbacher disease in some individuals. In general terms, AGS should be considered in the differential diagnosis of an unexplained leukoencephalopathy.
This clinical point is of particular importance because intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most medical facilities. Classic Cockayne syndrome CS type 1 , a leukodystrophy with striocerebellar calcifications, is variably characterized by its distinctive facial features, dwarfism, nerve deafness, cataracts, retinal dystrophy, and skin photosensitivity.
Inheritance is autosomal recessive. Neonatal lupus erythematosus. Prendiville et al  described basal ganglia calcifications and patchy white matter attenuation in infants with neonatal lupus erythematosus reminiscent of the imaging findings seen in AGS.
These children demonstrated extensive erythematous skin lesions distinct from the chilblain lesions seen in AGS. The authors reported normal neurologic outcome in these cases. Hoyeraal Hreidarsson syndrome presents in the first months of life with microcephaly, cerebellar hypoplasia, and intracerebral calcifications. Affected males develop a pancytopenia that persists in contrast to the thrombocytopenia seen in some individuals with AGS, which usually resolves in the first few weeks of life.
Mitochondrial cytopathies, including Leigh syndrome and the familial mitochondrial encephalopathy with intracerebral calcifications described by Samson et al .
See also Mitochondrial Disorders Overview. Chitayat et al  described monozygotic male twins, born to nonconsanguineous parents, who had dysmorphic facial features, microcephaly, migrational brain disorder, and congenital intracerebral calcification. Blau et al  described three individuals with microcephaly, severe intellectual disability and motor retardation, dyskinesia, spasticity, and occasional seizures with extremely high CSF concentrations of neopterin and biopterin and low CSF concentration of 5-methyltetrahydrofolate.
Thus, these individuals may have an undefined syndrome within the group of infants with encephalopathy and intracranial calcifications. However, it is now known that a similar pterin profile can be observed in individuals with molecularly confirmed AGS [ Rice et al b ]. Search ClinicalTrials. Other Corticosteroids can lower the CSF concentration of interferon [PG Barth , personal communication]; the clinical benefit of such treatment is unproven.
Note: The description of intracranial large-vessel disease in association with biallelic pathogenic variants in SAMHD1 raises important questions about the management of such individuals. The occlusive and aneurysmal arteriopathies described could be amenable to treatment revascularization for the former and coiling or clipping for the latter.
Moreover, the likely inflammatory basis of the arteriopathy suggests that immunosuppression may play a role in management. A key question is whether inflammatory disease is active at the time of clinical presentation, or whether the arterial abnormalities observed represent the end result of a now-quiescent inflammatory process.
Given the lack of evidence, no definitive statement about these issues can be made at present. However, the potential for intervention exists, and it could be argued that some individuals e. Chilblains were present in all the affected individuals described by Ramesh et al  , and it may be that their presence predicts an increased risk for intracranial vasculopathy. Genetic Counseling Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.
The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members.
This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. Autosomal Recessive Inheritance.
Rice et al  5. This finding raises the possibility, unproven, that the heterozygous parents of children with AGS caused by TREX1 pathogenic variants, at least those with variants in the C terminus of the gene , may be at risk of developing RVCL. This finding raises the possibility that individuals with AGS caused by mutation of TREX1 as well as their heterozygous parents may be at risk of developing signs and symptoms similar to SLE. Rice et al [a] described a heterozygous TREX1 pathogenic variant in affected members of a family with chilblain lupus; a second distinct pathogenic variant was subsequently described by Lee-Kirsch et al [a].
Aicardi-Goutieres Syndrome Information Page
An increase in the number of white cells particularly lymphocytes in the CSF,  and high levels of interferon-alpha activity and neopterin in the CSF    are important clues - however, these features are not always present. Thus, this interferon signature appears to be a very good marker of disease. Neuroradiology: The spectrum of neuroradiological features associated with AGS is broad,   but is most typically characterised by the following: Cerebral calcifications: Calcifications on CT computed tomography are seen as areas of abnormal signal, typically bilateral and located in the basal ganglia, but sometimes also extending into the white matter. Calcifications are usually better detected using CT scans and can be missed completely on MRI without gradient echo sequences magnetic resonance imaging. Signal changes can be particularly prominent in frontal and temporal regions. White matter abnormalities sometimes include cystic degeneration. Cerebral atrophy: is seen frequently.
Symptoms of Aicardi-Goutieres Syndrome usually appear within the first six months of life. Aicardi-Goutieres Syndrome is generally either fatal, or else it results in a persistent vegetative state in early childhood. Generally, the first symptoms observed are vomiting, feeding difficulties, and lack of progress in motor and social skills. A subset of patients has a later onset of disease, which usually occurs between six-twelve months of age, and is marked by loss of previously acquired motor skills and spasticity. However, in some cases, there can be less impairment, and some retention of contact with surroundings and social interactions. Below is a list of symptoms that may be present for Aicardi-Goutieres syndrome, along with definitions as necessary. Please note that all of these symptoms are not present in all cases.