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Aicardi Goutieres SyndromeEdit

Aicardi Goutières syndrome (AGS) is a rare, genetically caused neuroinflammatory disorder that presents early in life with signs of encephalopathy and distinctive brain imaging. Described in the 1980s by French physicians Jean Aicardi and Jean Goutières, AGS has since been understood as part of a broader group of disorders known as interferonopathys—conditions driven by chronic activation of type I interferon signaling. The condition is typically severe and lifelong, and there is no cure. Care is focused on managing symptoms and supporting development, with ongoing research aimed at tempering the underlying immune activation.

AGS is characterized by a combination of neurological abnormalities that begin in infancy, often within the first few months of life. Typical features include microcephaly (an unusually small head for age), irritability or poor sleep, seizures, hypotonia or spasticity, and a progressive decline in motor and cognitive function. Some affected children also develop skin lesions resembling chilblains, particularly after cold exposure. Across cases, neuroimaging frequently reveals cerebral calcifications, especially in the basal ganglia and deep white matter, along with calcified basal ganglia, leukodystrophy, and brain atrophy. Elevated levels of interferon alpha in the cerebrospinal fluid (CSF) and a persistent interferon-stimulated gene signature in blood are common laboratory hallmarks, reflecting the pathophysiology of AGS as a chronic interferonopathy. For many patients, the combination of clinical, radiologic, and laboratory features prompts genetic testing to confirm the diagnosis. interferonopathy; IFIH1; TREX1; RNASEH2A; RNASEH2B; RNASEH2C; SAMHD1.

Presentation

  • Onset: Usually in the neonatal period or early infancy, but some cases are identified later.
  • Neurological signs: Developmental delay, abnormal tone (hypotonia early, later spasticity), movement disorders, seizures, irritability, difficulties with feeding.
  • Growth and sensory findings: Microcephaly is common; vision and hearing can be affected in some cases.
  • Skin and other features: Chilblain-like lesions may appear after cold exposure; occasional liver or other organ involvement is reported in certain genetic forms.
  • Imaging: MRI and CT commonly show intracranial calcifications, extensive white matter abnormalities, and brain atrophy over time.

Genetics and pathophysiology

AGS is associated with mutations in several genes that affect nucleic acid metabolism or innate immune sensing. Most forms are inherited in an autosomal recessive pattern, reflecting the need for mutations in both copies of a gene. However, certain mutations in IFIH1 (which encodes the RNA sensor MDA5) can cause autosomal dominant inheritance with a gain-of-function mechanism, illustrating the genetic heterogeneity of the syndrome. The genes most commonly linked to AGS include:

  • TREX1
  • RNASEH2A, RNASEH2B, RNASEH2C
  • SAMHD1
  • IFIH1 (MDA5)
  • LSM11
  • ZNFX1
  • ADAR1 (also associated with AGS-like inflammatory phenotypes)

These genetic lesions lead to accumulation of self-derived nucleic acids or heightened sensing of nucleic acids by innate immune pathways. The result is chronic activation of type I interferon signaling, which in turn drives the inflammatory brain injury seen in AGS. The distinctive “interferon signature” helps distinguish AGS from other early-onset encephalopathies and underscores the disease mechanism. TREX1; RNASEH2A; RNASEH2B; RNASEH2C; SAMHD1; IFIH1; LSM11; ZNFX1; ADAR1; interferonopathy.

Diagnosis

Diagnosis rests on a combination of clinical features, neuroimaging findings, laboratory markers, and confirmatory genetic testing. Key diagnostic elements include:

  • Early-onset neurodevelopmental disease with brain imaging showing calcifications and white matter abnormalities.
  • Evidence of chronic type I interferon activation: elevated CSF interferon alpha and/or an interferon-stimulated gene signature in blood.
  • Molecular confirmation of biallelic pathogenic variants in one of the AGS-associated genes (or a pathogenic IFIH1 variant with a dominant pattern).

Because AGS can resemble congenital infections (TORCH infections) in infancy, differential diagnosis often includes infectious etiologies, congenital leukoencephalopathies, and other inflammatory brain diseases. TORCH infections; interferonopathy; Aicardi–Goutières syndrome (the article itself is this topic).

Management and prognosis

There is no cure for AGS, and treatment is multidisciplinary and supportive. Management priorities typically include:

  • Seizure control with antiepileptic medications as needed.
  • Physical, occupational, and speech therapies to support motor and communication development.
  • Management of spasticity and motor symptoms (e.g., physical therapy, baclofen, botulinum toxin in some cases).
  • Regular ophthalmologic, audiologic, and nutritional assessments to monitor and address sensory and feeding issues.
  • Monitoring and supportive management of infections or other organ involvement where present.

Given the central role of interferon signaling in AGS, researchers have explored immunomodulatory approaches to slow disease progression. Agents that inhibit type I interferon signaling, such as JAK inhibitors (for example baricitinib or ruxolitinib), have been studied in small case reports and series with variable results. While some patients show stabilization or modest improvement in symptoms or inflammatory markers, the long-term safety and efficacy of these therapies remain uncertain, and access is limited by cost and the need for careful monitoring. Clinicians weigh potential benefits against risks on a case-by-case basis. The ethics and logistics of early intervention, including debates about pre-symptomatic treatment in infants with known mutations, are ongoing topics of discussion in the field. Some discussions also address the broader question of when to pursue aggressive newborn screening or early genetic testing for rare interferonopathies. baricitinib; ruxolitinib; interferonopathy.

Prognosis varies widely and generally reflects the extent of early brain injury and the underlying genotype. Many individuals experience significant neurodevelopmental impairment, and motor and cognitive milestones may be markedly delayed or not achieved. Life expectancy is reduced relative to the general population, though outcomes differ by genetic subtype and the degree of early brain involvement. Ongoing care from a coordinated team remains essential to optimize quality of life and symptom management. interferonopathy; Aicardi–Goutières syndrome.

Research and historical context

The understanding of AGS has evolved from a suspicion of congenital infection to a recognition of inherited defects in nucleic acid metabolism and innate immune sensing. The research program continues to map additional AGS-related genes, refine genotype–phenotype correlations, and develop therapies aimed at dampening pathological interferon signaling. Animal models and patient-derived cellular models are central to evaluating candidate treatments and understanding why certain tissues, such as the brain, show particular vulnerability. These investigations connect AGS to the broader study of neuroinflammation and the biology of type I interferons. IFIH1; TREX1; RNASEH2A; RNASEH2B; RNASEH2C; SAMHD1.

See also