What is Aicardi-Goutieres syndrome?

Aicardi-Goutieres Syndrome (AGS)

Aicardi-Goutieres syndrome is a rare genetic neurological disorder characterized by encephalopathy, acquired microcephaly, intracranial calcifications, white matter abnormalities, and elevated interferon-alpha levels in cerebrospinal fluid, often mistaken for congenital infection. 1

Definition and Genetics

• AGS is classified as a type I interferonopathy, listed among the defects of innate immunity in the WHO/IUIS classification of primary immunodeficiencies 2
• It is an autosomal recessive disorder in most cases, with rare autosomal dominant "de novo" cases 1
• Currently, seven genes have been identified that, when mutated, can cause AGS 1, 3:
  • AGS1: TREX1 deficiency 2
  • AGS2: RNASEH2B deficiency 2
  • AGS3: RNASEH2C deficiency 2
  • AGS4: RNASEH2A deficiency 2
  • AGS5: SAMHD1 deficiency 2
  • AGS6: ADAR1 deficiency 2
  • A seventh gene is believed to exist 3

Epidemiology

• AGS has a prevalence of approximately 1-5 in 10,000 live births 4
• Nearly 200 cases have been reported worldwide 1
• The International Aicardi-Goutieres Syndrome Association (IAGSA) was founded in 2000 to track and study cases 1

Clinical Presentation

Neurological Manifestations

• Progressive encephalopathy with onset typically in the first year of life 4, 1
• Severe psychomotor retardation and developmental regression 4
• Acquired microcephaly (develops after birth) 1, 3
• Spastic tetraparesis and pyramidal dysfunction 4
• Dystonic movements and abnormal tone (axial hypotonia with hypertonia of extremities) 4
• Intermittent nystagmus may be present 4

Radiological Findings

• Intracranial calcifications, particularly in the basal ganglia 4, 1
• White matter abnormalities (leukodystrophy) 1, 3
• Cerebral atrophy 1, 3
• These findings can be detected by transfontanelar ultrasound in infants and by MRI 4

Extraneurological Manifestations

• Chilblain-like skin lesions on fingers, toes, and ears 3, 5
• Some patients develop features overlapping with systemic lupus erythematosus (SLE) 1, 5
• Photosensitivity and cutaneous vasculitis may be present 5

Diagnostic Approach

• Cerebrospinal fluid analysis showing:
  • Chronic lymphocytosis 1, 3
  • Elevated levels of interferon-alpha (IFN-α) 1, 3
• Neuroimaging (MRI) revealing:
  • Intracranial calcifications 4, 1
  • White matter involvement 1
  • Brain atrophy 1, 3
• Genetic testing to identify mutations in the known AGS genes 2, 4
• Ophthalmological examination should be performed as eye abnormalities are common in conditions with microcephaly 2

Differential Diagnosis

• Congenital infections (TORCH) must be excluded through serological testing 1, 3
• Other causes of microcephaly, including:
  • Non-genetic causes (intrauterine teratogen exposure, perinatal brain injuries) 2
  • Chromosomal abnormalities 2
  • Single gene disorders 2

Pathophysiology

• The genes involved in AGS are related to nucleic acid metabolism and repair mechanisms 1, 6
• Defects in these genes lead to inappropriate activation of the innate immune system 1, 3
• This results in increased production and secretion of type I interferons, particularly IFN-α 6, 3
• The elevated interferon levels are believed to be responsible for the neurological damage and other clinical features 6, 3

Management and Treatment

• Currently, there is no curative treatment for AGS 6, 3
• Immunosuppressive therapy during the active phase has not shown significant benefit in altering the disease course 3
• Management is primarily supportive and focused on:
  • Controlling symptoms 6
  • Managing complications 6
  • Physical and occupational therapy for motor impairments 6
• Research is ongoing to develop targeted therapies based on understanding of the molecular mechanisms 6, 3

Prognosis

• AGS typically has a severe prognosis with high morbidity and mortality 6
• The disease often "burns out" after several months, but leaves permanent neurological damage 3
• Some patients with RNASEH2B mutations (as in the case report) may have a more stable course after initial progression 4

Genetic Counseling

• Genetic counseling is essential for families with affected children 2
• For autosomal recessive cases with identified mutations:
  • Recurrence risk for siblings is 25% if both parents are carriers 2
  • Carrier testing for family members should be offered 2
• Prenatal diagnosis is possible when the causative mutation is known 2

Common Pitfalls

• Misdiagnosis as congenital infection due to similar clinical and laboratory findings 1, 3
• Delayed diagnosis due to the rarity of the condition and variable presentation 1
• Failure to recognize the relationship between AGS and autoimmune disorders like SLE 1, 5
• The diagnostic significance of key signs (elevated IFN-α, basal ganglia calcifications) varies at different stages of the disease 3