Aicardi-goutières syndrome G31.8

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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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 (heredity mostly autosomal recessive) disease of the brain and immune system with onset in early infancy (so-called type 1 interferonopathy). The affected children usually show severe physical and mental developmental delays. It usually begins in the first 3 to 6 months of life with sudden jerky movement disorders, crying attacks, sleep disorders or seizures. Frequently, fever attacks are also observed. The arms and legs show increasing stiffness or spasticity, while the trunk is rather flaccid and the children cannot hold their head or upper body properly upright. The disease typically progresses in relapses with phases of stabilization.

The AGS is clinically similar to a connatal viral infection, without a corresponding pathogen being detectable (Crow YJ et al. 2006). The disease can manifest itself already intrauterine with cerebral calcifications or in the newborn with encephalopathy, hepatopathy and thrombocytopenia. Pathognomonic are cold-induced cutaneous inflammatory lesions of the acres, so-called chilblain lesions, which are observed in only about 20% of patients, as well as other lupus-typical symptoms such as arthritis, antinuclear antibodies or lymphopenia.

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So far, mutations have been described in seven different genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, IFIH1, ADAR). TREX1 deficiency has been shown to lead to an intracellular accumulation of single-stranded DNA. It is postulated that the 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. Characteristic of the immune activation is the increased activity of type 1 interferon (type 1 interferonopathy). AGS can also be described as an autoimmune encephalopathy. Why the inflammatory process mainly affects the brain is currently still 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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Akren - fingers, toes, nose and ears.

Clinical features
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Patients with familial chilblain lupus express (in contrast to the sporadically occurring chilblain lupus) a very distinct phenotype of chilblain lupus from early childhood. Initially, most patients are observed to have Raynaud's syndrome, which continues to accompany the later symptoms of the disease. Typical are the classical, seasonally triggered (cold season) clinical signs of Chiblain-Lupus in different, mostly severe manifestations with flat, mostly spontaneous or on pressure painful redness with partly cushion-like swellings. In addition, acral, usually crust-covered skin defects may occur, sometimes as rhagades or as flat ulcers. In individual cases, larger necroses may occur at the tips of the nose or ear. Sometimes amputation of finger and toe limbs is necessary due to the non-healing defects. Other organ manifestations are missing.

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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, Goutières F (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, Goutières F (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. Gall A et al (2012) Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120-131
  5. Lee-Cherry 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
  6. Lee-Cherry MA et al (2006) Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. At J Hum Genet 79:731-737
  7. 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
  8. 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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Chilblain lupus;


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Last updated on: 29.10.2020