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Aicardi-Goutieres syndrome 2(AGS2)

MedGen UID:
483677
Concept ID:
C3489724
Disease or Syndrome
Synonym: Aicardi-Goutieres Syndrome 2
 
Gene (location): RNASEH2B (13q14.3)
 
Monarch Initiative: MONDO:0012429
OMIM®: 610181

Disease characteristics

Excerpted from the GeneReview: Aicardi-Goutières Syndrome
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known. [from GeneReviews]
Authors:
Yanick J Crow   view full author information

Additional descriptions

From OMIM
Aicardi-Goutieres syndrome (AGS) is an autosomal recessive early-onset encephalopathy characterized by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serologic investigations for common prenatal infections (summary by Ali et al., 2006). Severe neurologic dysfunction becomes clinically apparent in infancy and manifests as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood (summary by Crow et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).  http://www.omim.org/entry/610181
From MedlinePlus Genetics
As a result of the severe neurological problems that are usually associated with Aicardi-Goutières syndrome, most people with this disorder do not survive past childhood. However, some affected individuals with the later-onset form of the condition and milder neurological problems can live into adolescence or adulthood.

People with the later-onset form of Aicardi-Goutières syndrome typically have normal development in infancy. In these individuals, encephalopathy typically occurs after 1 year of age. Similar to those with the early-onset form, babies with the later-onset form experience irritability, poor feeding, and sterile pyrexias. Over time, affected individuals show developmental delays and regression. They may also have spasticity and hypotonia, and the growth of the brain and head may slow leading to microcephaly. The health and developmental problems in people with the later-onset form are typically not as severe as those in individuals with the early-onset form, though the severity can vary among affected individuals.

Affected babies are usually extremely irritable and do not feed well. They also have muscle stiffness (spasticity), involuntary tensing of various muscles (dystonia), and weak muscle tone (hypotonia). They can have vision problems including vision loss and increased pressure in the eye (glaucoma).

In about 20 percent of cases, the early-onset form of Aicardi-Goutières syndrome begins prenatally. Slow growth (intrauterine growth retardation) and brain abnormalities, especially brain calcification, may be seen on ultrasound imaging. These individuals have the most severe neurological problems and the highest risk for early death.

About 40 percent of people with the early-onset form of Aicardi-Goutières syndrome develop a skin problem called chilblains. Chilblains are painful, itchy skin lesions that are puffy and red, and they usually appear on the fingers, toes, nose, and ears. They are caused by inflammation of small blood vessels and may be brought on or made worse by exposure to cold temperatures. 

In some affected newborns, white blood cells, interferon proteins, and other immune system molecules can be detected in the cerebrospinal fluid, which is the fluid that surrounds the brain and spinal cord (central nervous system). These findings are consistent with inflammation and tissue damage in the central nervous system.

Some newborns have a combination of features that include an enlarged liver and spleen (hepatosplenomegaly), elevated blood levels of liver enzymes, and a shortage of blood cells called platelets that are needed for normal blood clotting (thrombocytopenia). They may develop intermittent fevers in the absence of infection (sterile pyrexias). While this combination of signs and symptoms is typically associated with the immune system's response to a viral infection that is present at birth (congenital), no actual infection is found in these infants. For this reason, Aicardi-Goutières syndrome is sometimes referred to as a "mimic of congenital infection."

Individuals with the early-onset form of Aicardi-Goutières syndrome can experience severe brain dysfunction (encephalopathy) within the first months of life. This encephalopathic phase of the disorder can last for weeks or months. Affected infants stop developing new skills and begin losing skills they had already acquired (developmental regression). Infants with this form can have seizures. Medical imaging reveals loss of white matter in the brain (leukodystrophy). White matter consists of nerve cells covered by myelin, which is a substance that protects nerves and allows them to rapidly transmit nerve impulses. Growth of the brain and skull slows down, resulting in an abnormally small head size (microcephaly). Affected individuals may have abnormal deposits of calcium (calcification) in the brain. As a result of this neurological damage, most people with Aicardi-Goutières syndrome have profound intellectual disabilities.

Aicardi-Goutières syndrome is often divided into two types, which are distinguished by the severity of features and the age at which they begin: the early-onset form (sometimes called the classic form) and the later-onset form. 

Aicardi-Goutières syndrome is a disorder with variable signs and symptoms, but it primarily affects the brain, the immune system, and the skin.  https://medlineplus.gov/genetics/condition/aicardi-goutieres-syndrome

Clinical features

From HPO
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Chronic CSF lymphocytosis
MedGen UID:
869799
Concept ID:
C4024229
Finding
Chronic cerebrospinal fluid (CSF) lymphocytosis is defined as the finding, in at least two serial CSF examinations, of more than 5 cells per cubic millimeter.
Basal ganglia calcification
MedGen UID:
234651
Concept ID:
C1389280
Pathologic Function
The presence of calcium deposition affecting one or more structures of the basal ganglia.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Lymphocytosis
MedGen UID:
9834
Concept ID:
C0024282
Disease or Syndrome
Increase in the number or proportion of lymphocytes in the blood.

Professional guidelines

PubMed

Dell'Isola GB, Dini G, Culpepper KL, Portwood KE, Ferrara P, Di Cara G, Verrotti A, Lodolo M
World J Pediatr 2023 Jul;19(7):635-643. Epub 2023 Jan 17 doi: 10.1007/s12519-022-00679-2. PMID: 36650407Free PMC Article
Cetin Gedik K, Lamot L, Romano M, Demirkaya E, Piskin D, Torreggiani S, Adang LA, Armangue T, Barchus K, Cordova DR, Crow YJ, Dale RC, Durrant KL, Eleftheriou D, Fazzi EM, Gattorno M, Gavazzi F, Hanson EP, Lee-Kirsch MA, Montealegre Sanchez GA, Neven B, Orcesi S, Ozen S, Poli MC, Schumacher E, Tonduti D, Uss K, Aletaha D, Feldman BM, Vanderver A, Brogan PA, Goldbach-Mansky R
Ann Rheum Dis 2022 May;81(5):601-613. Epub 2022 Jan 27 doi: 10.1136/annrheumdis-2021-221814. PMID: 35086813Free PMC Article
Lanzi G, D'Arrigo S, Drumbl G, Uggetti C, Fazzi E
Funct Neurol 2003 Apr-Jun;18(2):71-5. PMID: 12911136

Recent clinical studies

Etiology

Ait El Cadi C, Dafrallah L, Amalou G, Charif M, Charoute H, Araqi-Houssaini A, Lakhiari H, Lenaers G, Barakat A
Rev Neurol (Paris) 2023 Oct;179(8):902-909. Epub 2023 Jun 7 doi: 10.1016/j.neurol.2023.01.728. PMID: 37296061

Diagnosis

Svingen L, Goheen M, Godfrey R, Wahl C, Baker EH, Gahl WA, Malicdan MCV, Toro C
Dev Med Child Neurol 2017 Dec;59(12):1307-1311. Epub 2017 Aug 1 doi: 10.1111/dmcn.13509. PMID: 28762473Free PMC Article

Prognosis

Ait El Cadi C, Dafrallah L, Amalou G, Charif M, Charoute H, Araqi-Houssaini A, Lakhiari H, Lenaers G, Barakat A
Rev Neurol (Paris) 2023 Oct;179(8):902-909. Epub 2023 Jun 7 doi: 10.1016/j.neurol.2023.01.728. PMID: 37296061

Clinical prediction guides

Ait El Cadi C, Dafrallah L, Amalou G, Charif M, Charoute H, Araqi-Houssaini A, Lakhiari H, Lenaers G, Barakat A
Rev Neurol (Paris) 2023 Oct;179(8):902-909. Epub 2023 Jun 7 doi: 10.1016/j.neurol.2023.01.728. PMID: 37296061

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