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Aicardi-Goutieres syndrome 9(AGS9)

MedGen UID:
1794176
Concept ID:
C5561966
Disease or Syndrome
Synonyms: AGS9; AICARDI-GOUTIERES SYNDROME 9
 
Gene (location): RNU7-1 (12p13.31)
 
Monarch Initiative: MONDO:0030362
OMIM®: 619487

Definition

Aicardi-Goutieres syndrome-9 (AGS9) is a type I interferonopathy characterized by severe developmental delay and progressive neurologic deterioration. Patients present in infancy with irritability and spasticity. Brain imaging shows diffusely abnormal white matter, cerebral atrophy, and intracranial calcification. Premature death has been associated with renal and/or hepatic failure (Uggenti et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750). [from OMIM]

Clinical features

From HPO
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Glomerular sclerosis
MedGen UID:
61248
Concept ID:
C0178664
Disease or Syndrome
Accumulation of scar tissue within the glomerulus.
Recurrent urinary tract infections
MedGen UID:
120466
Concept ID:
C0262655
Disease or Syndrome
Repeated infections of the urinary tract.
Thickened glomerular basement membrane
MedGen UID:
488906
Concept ID:
C0445347
Finding
Prominent glomerular basement membrane (GBM), reflecting an increase in thickness (subjective estimate) of the basal lamina of the glomerulus of the kidney.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Hyperechogenic kidneys
MedGen UID:
477530
Concept ID:
C3275899
Finding
An increase in amplitude of waves returned in ultrasonography of the kidney, which is generally displayed as increased brightness of the signal.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Lower limb hypertonia
MedGen UID:
375612
Concept ID:
C1845245
Finding
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Portal hypertension
MedGen UID:
9375
Concept ID:
C0020541
Disease or Syndrome
Increased pressure in the portal vein.
Pericardial effusion
MedGen UID:
10653
Concept ID:
C0031039
Disease or Syndrome
Accumulation of fluid within the pericardium.
Left ventricular hypertrophy
MedGen UID:
57442
Concept ID:
C0149721
Disease or Syndrome
Enlargement or increased size of the heart left ventricle.
Increased blood pressure
MedGen UID:
635666
Concept ID:
C0497247
Finding
Abnormal increase in blood pressure. An individual measurement of increased blood pressure does not necessarily imply hypertension. In practical terms, multiple measurements are recommended to diagnose the presence of hypertension.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Weight loss
MedGen UID:
853198
Concept ID:
C1262477
Finding
Reduction of total body weight.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Ascites
MedGen UID:
416
Concept ID:
C0003962
Disease or Syndrome
Accumulation of fluid in the peritoneal cavity.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Hepatic fibrosis
MedGen UID:
116093
Concept ID:
C0239946
Disease or Syndrome
The presence of excessive fibrous connective tissue in the liver. Fibrosis is a reparative or reactive process.
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
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 diplegia
MedGen UID:
44181
Concept ID:
C0023882
Disease or Syndrome
Spasticity (neuromuscular hypertonia) primarily in the muscles of the legs, hips, and pelvis.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Self-mutilation
MedGen UID:
19925
Concept ID:
C0036601
Injury or Poisoning
Deliberate harm to one's body resulting in tissue damage, without a conscious intent to die.
Sleep abnormality
MedGen UID:
52372
Concept ID:
C0037317
Sign or Symptom
An abnormal pattern in the quality, quantity, or characteristics of sleep.
Sensory neuropathy
MedGen UID:
101791
Concept ID:
C0151313
Disease or Syndrome
Peripheral neuropathy affecting the sensory nerves.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Spastic tetraparesis
MedGen UID:
658719
Concept ID:
C0575059
Disease or Syndrome
Spastic weakness affecting all four limbs.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Lateral ventricle dilatation
MedGen UID:
383904
Concept ID:
C1856409
Pathologic Function
Diffuse leukoencephalopathy
MedGen UID:
358229
Concept ID:
C1868514
Finding
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Hemolytic anemia
MedGen UID:
1916
Concept ID:
C0002878
Disease or Syndrome
A type of anemia caused by premature destruction of red blood cells (hemolysis).
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Cerebral calcification
MedGen UID:
124360
Concept ID:
C0270685
Finding
The presence of calcium deposition within the cerebrum.
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.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Acute pancreatitis
MedGen UID:
7872
Concept ID:
C0001339
Disease or Syndrome
A acute form of pancreatitis.
Chilblains
MedGen UID:
886
Concept ID:
C0008058
Injury or Poisoning
Chilblains, also called perniosis, are an inflammatory skin condition related to an abnormal vascular response to the cold. We are unaware of a reliable estimate of incidence. It typically presents as tender, pruritic red or bluish lesions located symmetrically on the dorsal aspect of the fingers, toes, ears and nose. Less commonly, reports describe involvement of the thighs and buttocks. The lesions present hours after exposure to cold and usually resolve spontaneously in one to three weeks.
Pericarditis
MedGen UID:
18377
Concept ID:
C0031046
Disease or Syndrome
Inflammation of the sac-like covering around the heart (pericardium).
Edema
MedGen UID:
4451
Concept ID:
C0013604
Pathologic Function
An abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduction in the concentration of albumin in the blood.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Poikiloderma
MedGen UID:
97905
Concept ID:
C0392777
Disease or Syndrome
Poikiloderma refers to a patch of skin with (1) reticulated hypopigmentation and hyperpigmentation, (2) wrinkling secondary to epidermal atrophy, and (3) telangiectasias.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Chorioretinal atrophy
MedGen UID:
884881
Concept ID:
C4048273
Disease or Syndrome
Atrophy of the choroid and retinal layers of the fundus.

Professional guidelines

PubMed

de Barcelos IP, Woidill S, Gavazzi F, Modesti NB, Sevagamoorthy A, Vanderver A, Adang L
Mol Genet Metab 2024 May;142(1):108346. Epub 2024 Feb 13 doi: 10.1016/j.ymgme.2024.108346. PMID: 38368708

Recent clinical studies

Etiology

Baide-Mairena H, Marti-Sánchez L, Marcé-Grau A, Cazurro-Gutiérrez A, Sanchez-Montanez A, Delgado I, Moreno-Galdó A, Macaya-Ruiz A, García-Arumí E, Pérez-Dueñas B; Childhood Basal Ganglia Disease Group
Dev Med Child Neurol 2022 Jun;64(6):743-752. Epub 2022 Jan 5 doi: 10.1111/dmcn.15125. PMID: 34988976
De Giorgis V, Varesio C, Viri M, Giordano L, La Piana R, Tonduti D, Roncarolo F, Masnada S, Pichiecchio A, Veggiotti P, Fazzi E, Orcesi S; Italian AGS Study Group
Seizure 2021 Mar;86:197-209. Epub 2020 Dec 1 doi: 10.1016/j.seizure.2020.11.019. PMID: 33589296
Piccoli C, Bronner N, Gavazzi F, Dubbs H, De Simone M, De Giorgis V, Orcesi S, Fazzi E, Galli J, Masnada S, Tonduti D, Varesio C, Vanderver A, Vossough A, Adang L
Pediatr Neurol 2021 Feb;115:1-6. Epub 2020 Nov 2 doi: 10.1016/j.pediatrneurol.2020.10.012. PMID: 33307271Free PMC Article
Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Ramantani G, Maillard LG, Bast T, Husain RA, Niggemann P, Kohlhase J, Hertzberg C, Ungerath K, Innes MA, Walkenhorst H, Bevot A, von Stülpnagel C, Thomas K, Niemann F, Ergun MA, Tacke U, Häusler M, Ikonomidou C, Korinthenberg R, Lee-Kirsch MA
Eur J Paediatr Neurol 2014 Jan;18(1):30-7. Epub 2013 Sep 5 doi: 10.1016/j.ejpn.2013.07.005. PMID: 24011626

Diagnosis

Panigrahy N, Bakhru S, Lingappa L, Chirla D
BMJ Case Rep 2022 Dec 29;15(12) doi: 10.1136/bcr-2022-249192. PMID: 36581356Free PMC Article
Adang LA, Gavazzi F, D'Aiello R, Isaacs D, Bronner N, Arici ZS, Flores Z, Jan A, Scher C, Sherbini O, Behrens EM, Goldbach-Mansky R, Olson TS, Lambert MP, Sullivan KE, Teachey DT, Witmer C, Vanderver A, Shults J
Mol Genet Metab 2022 Aug;136(4):324-329. Epub 2022 Jun 16 doi: 10.1016/j.ymgme.2022.06.003. PMID: 35786528Free PMC Article
De Giorgis V, Varesio C, Viri M, Giordano L, La Piana R, Tonduti D, Roncarolo F, Masnada S, Pichiecchio A, Veggiotti P, Fazzi E, Orcesi S; Italian AGS Study Group
Seizure 2021 Mar;86:197-209. Epub 2020 Dec 1 doi: 10.1016/j.seizure.2020.11.019. PMID: 33589296
Piccoli C, Bronner N, Gavazzi F, Dubbs H, De Simone M, De Giorgis V, Orcesi S, Fazzi E, Galli J, Masnada S, Tonduti D, Varesio C, Vanderver A, Vossough A, Adang L
Pediatr Neurol 2021 Feb;115:1-6. Epub 2020 Nov 2 doi: 10.1016/j.pediatrneurol.2020.10.012. PMID: 33307271Free PMC Article
Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048

Therapy

Cusack SV, Gavazzi F, de Barcelos IP, Modesti NB, Woidill S, Formanowski B, DeMauro SB, Lorch S, Vincent A, Jawad AF, Estilow T, Glanzman AM, Vanderver A, Adang LA
J Child Neurol 2024 Mar;39(3-4):147-154. Epub 2024 Mar 27 doi: 10.1177/08830738241241786. PMID: 38532733Free PMC Article
Kanazawa N, Ishii T, Takita Y, Nishikawa A, Nishikomori R
Pediatr Rheumatol Online J 2023 Apr 22;21(1):38. doi: 10.1186/s12969-023-00817-8. PMID: 37087470Free PMC Article
Adang LA, Gavazzi F, D'Aiello R, Isaacs D, Bronner N, Arici ZS, Flores Z, Jan A, Scher C, Sherbini O, Behrens EM, Goldbach-Mansky R, Olson TS, Lambert MP, Sullivan KE, Teachey DT, Witmer C, Vanderver A, Shults J
Mol Genet Metab 2022 Aug;136(4):324-329. Epub 2022 Jun 16 doi: 10.1016/j.ymgme.2022.06.003. PMID: 35786528Free PMC Article
He T, Xia Y, Yang J
Pediatr Rheumatol Online J 2021 Jan 22;19(1):9. doi: 10.1186/s12969-021-00497-2. PMID: 33482855Free PMC Article
Henrickson M, Wang H
Clin Rheumatol 2017 Jun;36(6):1445-1451. Epub 2017 Mar 13 doi: 10.1007/s10067-017-3600-2. PMID: 28289923Free PMC Article

Prognosis

Abraham SSC, Yoganathan S, Koshy B, Oommen SP, Simon A, Mathai S, Korula S, Mathew L, Sathishkumar D, Jasper A, George R, Danda S
Eur J Med Genet 2021 Sep;64(9):104291. Epub 2021 Jul 22 doi: 10.1016/j.ejmg.2021.104291. PMID: 34303877
Vanderver A, Prust M, Kadom N, Demarest S, Crow YJ, Helman G, Orcesi S, La Piana R, Uggetti C, Wang J, Gordisch-Dressman H, van der Knaap MS, Livingston JH
J Child Neurol 2015 Sep;30(10):1343-8. Epub 2014 Dec 22 doi: 10.1177/0883073814562252. PMID: 25535058Free PMC Article
Ramantani G, Maillard LG, Bast T, Husain RA, Niggemann P, Kohlhase J, Hertzberg C, Ungerath K, Innes MA, Walkenhorst H, Bevot A, von Stülpnagel C, Thomas K, Niemann F, Ergun MA, Tacke U, Häusler M, Ikonomidou C, Korinthenberg R, Lee-Kirsch MA
Eur J Paediatr Neurol 2014 Jan;18(1):30-7. Epub 2013 Sep 5 doi: 10.1016/j.ejpn.2013.07.005. PMID: 24011626
Takanohashi A, Prust M, Wang J, Gordish-Dressman H, Bloom M, Rice GI, Schmidt JL, Crow YJ, Lebon P, Kuijpers TW, Nagaraju K, Vanderver A
Neurology 2013 Mar 12;80(11):997-1002. Epub 2013 Feb 13 doi: 10.1212/WNL.0b013e3182872694. PMID: 23408864Free PMC Article
McEntagart M, Kamel H, Lebon P, King MD
Neuropediatrics 1998 Jun;29(3):163-7. doi: 10.1055/s-2007-973555. PMID: 9706629

Clinical prediction guides

Cusack SV, Gavazzi F, de Barcelos IP, Modesti NB, Woidill S, Formanowski B, DeMauro SB, Lorch S, Vincent A, Jawad AF, Estilow T, Glanzman AM, Vanderver A, Adang LA
J Child Neurol 2024 Mar;39(3-4):147-154. Epub 2024 Mar 27 doi: 10.1177/08830738241241786. PMID: 38532733Free PMC Article
Baide-Mairena H, Marti-Sánchez L, Marcé-Grau A, Cazurro-Gutiérrez A, Sanchez-Montanez A, Delgado I, Moreno-Galdó A, Macaya-Ruiz A, García-Arumí E, Pérez-Dueñas B; Childhood Basal Ganglia Disease Group
Dev Med Child Neurol 2022 Jun;64(6):743-752. Epub 2022 Jan 5 doi: 10.1111/dmcn.15125. PMID: 34988976
Bajad P, Jantsch MF, Keegan L, O'Connell M
RNA Biol 2017 Sep 2;14(9):1223-1231. Epub 2017 Mar 27 doi: 10.1080/15476286.2017.1306173. PMID: 28346055Free PMC Article
Vanderver A, Prust M, Kadom N, Demarest S, Crow YJ, Helman G, Orcesi S, La Piana R, Uggetti C, Wang J, Gordisch-Dressman H, van der Knaap MS, Livingston JH
J Child Neurol 2015 Sep;30(10):1343-8. Epub 2014 Dec 22 doi: 10.1177/0883073814562252. PMID: 25535058Free PMC Article
Ramantani G, Maillard LG, Bast T, Husain RA, Niggemann P, Kohlhase J, Hertzberg C, Ungerath K, Innes MA, Walkenhorst H, Bevot A, von Stülpnagel C, Thomas K, Niemann F, Ergun MA, Tacke U, Häusler M, Ikonomidou C, Korinthenberg R, Lee-Kirsch MA
Eur J Paediatr Neurol 2014 Jan;18(1):30-7. Epub 2013 Sep 5 doi: 10.1016/j.ejpn.2013.07.005. PMID: 24011626

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