Aicardi-goutières syndrome G31.8

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 30.09.2022

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Familial chiblain lupus; Familial Chilblain Lupus; OMIM: 610329

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Aicardi and Goutières, 1984

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Rare, genetically determined, hereditary (inheritance mostly autosomal recessive) disease of the brain and immune system with onset in early infancy (so-called type 1 interferonopathy). Affected children usually show severe physical and mental developmental delays. Onset is usually in the first 3 to 6 months of life with sudden onset of jerky movement disorders, crying attacks, sleep disturbances or seizures. Not infrequently, episodes of fever are also observed. The arms and legs show increasing stiffness or spasticity, while the trunk tends to be limp and children cannot hold their head or upper body upright properly. The disease typically progresses in relapses with periods of stabilization.

AGS clinically resembles a connatal viral infection without evidence of a corresponding causative agent (Crow YJ et al 2006). The disease may manifest intrauterine with cerebral calcifications or in the neonatal period with encephalopathy, hepatopathy, and thrombocytopenia. Pathognomonic are cold-induced cutaneous inflammatory lesions of the acras (signs of chilblain lupus) observed in about 20% of patients. Furthermore, other lupus-typical symptoms such as arthritis, antinuclear antibodies or lymphopenia may occur.

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To date, mutations in seven different genes(TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, IFIH1, ADAR) have been described. Evidence suggests that TREX1 deficiency leads to intracellular accumulation of single-stranded DNA. It is postulated that recognition of these pathologically accumulated nucleic acids by the innate immune system leads to a type I INF- response and thus to an autoimmunological reaction. The hallmark of immune activation is increased activity of type 1 interferon (type 1 interferonopathy).

AGS can also be described as an autoimmune encephalopathy. Why the inflammatory process primarily affects the brain is currently completely unclear.

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Some children are already conspicuous at birth. In most children, however, the disease begins in the first 3 to 6 months of life

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Chilblain symptomatology on acras - fingers, toes, nose and ears.

Clinical features
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Patients with familial Chilblain lupus (in contrast to sporadic Chilblain lupus) express a very pronounced phenotype of Chilblain lupus in early childhood. Initially, a Raynaud's syndrome is observed in most patients, which continues to accompany the later disease symptoms.

Typical are the classic, seasonally triggered (cold season) clinical signs of Chiblain's lupus in different, mostly severe manifestations with extensive, mostly spontaneously or on pressure painful redness with sometimes pillow-like swellings. Furthermore, acral, usually crust-covered, skin defects may occur, partly as rhagades or as extensive ulcers. In individual cases, larger necroses may occur on nasal tips or auricles. Sometimes amputation of finger and toe limbs are necessary due to the non-healing defects.

Other neurologic pathologies:

  • Bilateral striatal necrosis (13 patients; 3.6%).
  • Non-syndromic spastic paraparesis (12 patients; 3.4%).

Other clinical symptoms (Crow YJ et al 2015):

  • Glaucoma
  • Hypothyroidism
  • Cardiomyopathy
  • Intracerebral vasculitis
  • Peripheral neuropathy
  • Inflammatory bowel disease
  • Systemic lupus erythematosus.

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In addition to an interferon signature in the blood, system manifestations such as antinuclear antibodies, arthritis and cytopenia can also occur

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Detection of mutations in the previously known AGS-triggering genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, IFIH1, ADAR). The increased activity of type 1 interferon can be detected by determining the so-called "interferon signature" in the blood.

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  1. Aicardi J et al (1984) A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 15:49-5
  2. Aicardi J et al (2000) Systemic lupus erythematosus or Aicardi-Goutières syndrome? Aicardi J, Goutières F.Neuropediatrics 31:155-158.
  3. Crow YJ et al (2006) Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nature Genet. 38: 910-916
  4. Crow YJ et al (2015) Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A 167A:296-312.
  5. Gall A et al (2012) Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120-131
  6. Lee-Kirsch MA et al (2007a) A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med 85:531-537
  7. Lee-Kirsch MA et al (2006) Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet 79:731-737
  8. Ravenscroft JC et al (2011) Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A 155A:235-237.
  9. Yang YG et al (2007) Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873-886


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Last updated on: 30.09.2022