Aicardi-Goutières Syndrome

Aicardi-Goutières syndrome (AGS) is a genetic type I interferonopathy, caused by variants in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH1, LSM11 or RNU7-1. It causes an early onset encephalopathy with microcephaly, basal ganglia calcification, leukodystrophy, chronic cerebrospinal fluid lymphocytosis and an interferon signature, and mimics congenital infection.

Pathophysiology. The AGS genes encode proteins that remove or sense endogenous nucleic acids. Failure of clearance of DNA and RNA-DNA hybrids, or abnormal sensing of RNA, triggers a continuous type I interferon response and tissue inflammation.

Inheritance is mostly autosomal recessive, with dominant forms in TREX1 and IFIH1.

Severity relates to the gene: TREX1 and RNASEH2B tend to differ in neonatal and later onset.

• Early onset form (first weeks): feeding difficulty, irritability, jitteriness, fever without infection, seizures, hepatosplenomegaly, thrombocytopenia and raised liver enzymes.
• Later onset form (after the first months): subacute encephalopathy with loss of skills, irritability and sleep disturbance.
• Microcephaly, spasticity, dystonia and severe developmental delay
• Chilblain like lesions on the fingers, toes and ears in cold weather
• Glaucoma, and cortical visual impairment
• Hypothyroidism and other endocrine problems
• Autoimmune features: lupus like disease, vasculopathy and arthritis
• Stroke and moyamoya in SAMHD1 disease
• Milder presentations: spastic paraparesis or isolated chilblains

• CSF: lymphocytosis (over 5 cells/microlitre) in early life, raised interferon alpha and neopterin.
• Interferon signature in whole blood (interferon stimulated gene expression).
• Brain imaging: calcification of basal ganglia and periventricular white matter on CT, leukodystrophy and atrophy on MRI.
• Gene panel or exome sequencing for the known genes.
• Exclusion of congenital infection: cytomegalovirus, toxoplasma, rubella, syphilis and herpes.
• Liver tests, platelets, thyroid function and autoantibodies.
• Ophthalmology with intraocular pressure.

Differential diagnosis.

• Congenital infection (TORCH) and HIV encephalopathy
• Cree encephalitis
• Pseudo-TORCH syndromes (OCLN, USP18) and Coats plus syndrome
• Other leukodystrophies and mitochondrial disease
• Systemic lupus erythematosus and familial chilblain lupus

• Immunomodulation: Janus kinase inhibitors (baricitinib, ruxolitinib) lower the interferon signature and improve skin, fever and some neurological function when started early. Baricitinib is given as 2 to 4 mg orally once daily, chosen by age and weight, with infection screening, blood count and liver tests before starting and every 3 months. Dose and age limits require specialist confirmation.
• Other immunosuppression: methylprednisolone 30 mg/kg (maximum 1 g) intravenously daily for 3 days in acute inflammatory episodes, followed by prednisolone 1 mg/kg daily with taper.
• Chilblains: avoid cold, keep extremities warm, and give nifedipine modified release 30 mg daily in adults.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Spasticity and dystonia: baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg), physiotherapy and botulinum toxin.
• Feeding and gastrointestinal care: gastrostomy for unsafe swallow, and omeprazole 0.7 to 1 mg/kg daily for reflux.
• Sleep and irritability: melatonin 2 to 5 mg 30 to 60 minutes before bed (up to 10 mg if needed).
• Endocrine care: levothyroxine for hypothyroidism, and diabetes treatment where needed.
• Eye care: intraocular pressure measurement, topical latanoprost for glaucoma, and surgery if needed.
• Vaccination: routine immunisation, with live vaccines avoided on a Janus kinase inhibitor.
• Genetic counselling: a 25% recurrence risk for recessive forms and a 50% risk for dominant forms from an affected parent, with prenatal diagnosis available.

Special groups.

• Infants with encephalopathy, calcification and negative infection screen: send the interferon signature and gene testing early, because treatment is most useful before brain injury.

Monitoring. Neurological status, seizures and development every 3 months. Blood count, liver tests and infection surveillance every 3 months on Janus kinase inhibitors, with thyroid function and intraocular pressure yearly.

Referral and escalation. Refer to clinical genetics, paediatric neurology, rheumatology and ophthalmology. Emergency for sepsis on immunosuppression, status epilepticus or acute neurological deterioration.