Aicardi Goutieres Syndrome

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Aicardi-Goutiressyndrome: animportant Mendelianmimic of congenitalinfection

Yanick J Crow* MBBS BMedSci MRCP PhD,

Leeds Institute of Molecular Medicine, St Jamess

University Hospital;

John H Livingston MBChB FRCP FRCPH, Department of

Paediatric Neurology, Leeds General Infirmary, Leeds, West

Yorkshire, UK.

*Correspondence to first author atLevel 9, Wellcome Trust

Brenner Building, Leeds Institute of Molecular Medicine,St Jamess University Hospital, Leeds, West Yorkshire

LS9 7TF, UK.

E-mail: [email protected]

DOI: 10.1111/j.1469-8749.2008.02062.x

Published online 14th April 2008

Aicardi-Goutires syndrome (AGS) is a rare, genetically

determined encephalopathy whose importance from a clinical

viewpoint is magnified because of the risk of misdiagnosis as

the sequelae of congenital infection. Recent molecular

advances have shown that AGS can be caused by mutations in

any one of at least five genes (four of which have so far been

identified), most commonly on a recessive basis but

occasionally as a dominant trait. Additionally, a recent

genotypephenotype correlation has shown that two clinical

presentations can be delineated; an early onset neonatal form

highly reminiscent of congenital infection seen particularly

with TREX1mutations, and a later-onset presentation,

sometimes occurring after several months of normal

development and occasionally associated with remarkably

preserved neurological function, most frequently due to

RNASEH2Bmutations. Evidence is emerging to show that

the nucleases defective in AGS are involved in removing

endogenous nucleic acid species produced during normal

cellular processing, and that a failure of this removal results

in inappropriate activation of the innate immune system. Thishypothesis explains the phenotypic overlap of AGS with

congenital infection and some aspects of systemic lupus

erythematosus, where a similar interferon alpha-mediated

innate immune response is triggered by viral and host nucleic

acids respectively.

In 1984, Jean Aicardi and Franoise Goutires, two eminent

French paediatric neurologists, described eight children from

five families with an early onset encephalopathy characterized

by basal ganglia calcification, white matter abnormalities, and

a chronic cerebrospinal fluid (CSF) lymphocytosis.1 The pres-

ence of sibling recurrences, affected females, and parental

consanguinity suggested that the condition was inherited asan autosomal recessive trait. However, the authors highlight-

ed the risk of misdiagnosis as the sequelae of congenital infec-

tion, an observation which led to the finding of raised levels of

the antiviral cytokine interferon alpha (IFN-) in the CSF of

affected children.2 Other landmark clinical papers include the

descriptions of chilblain lesions,3 occasional normocephaly

and preservation of intellect,4 normal CSF white cell counts

even in the early stages of the disease process,5 and raised lev-

els of CSF neopterin as a diagnostic marker.6

The first gene localization for AGS was reported to chromo-

some 3p21 in 2000,7 at which time it was also recognized that

the disease was genetically heterogeneous, i.e. mutations in

more than one gene cause the same clinical phenotype.Subsequently, a second locus was defined on chromosome 13q

with further genetic heterogeneity predicted.8 In 2006, four

genes were identified which, when mutated, cause autosomal

recessive AGS (Table I).9,10 In 2007, it was shown that rare cases

of AGS can arise due to heterozygousTREX1 mutations, i.e. as a

de novo dominant disorder.11 Most recently, a comprehensive

genotypephenotype analysis showed that at least one further

AGS-causing gene remains to be determined.12

Natural history of AGS

PRESENTATION

The presentation of AGS can be broadly divided into two types.

410 Developmental Medicine & Child Neurology 2008, 50: 410416

Review

See end of paper for list of abbreviations.


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Review 411

Neonatal form

A group of patients with AGS, typically those with TREX1

mutations, present in the neonatal period with abnormal

neurology which manifests as jitteriness, poor feeding, and

neonatal seizures, features which are reflected in the finding

of changes on brain imaging at birth (see below). These

infants frequently demonstrate hepatosplenomegaly with

elevated liver enzymes, and thrombocytopenia with anaemia

necessitating recurrent platelet and red cell transfusion

(Table II). Interestingly, these features of bone marrow sup-pression tend to resolve after the first few weeks of life. This

clinical picture is highly reminiscent of congenital infection.

Consequently, an absence of definitive evidence of an infec-

tious agent in such circumstances should always raise the

suspicion of AGS.

Later onset form

All other patients present at variable times beyond the first

few days of life, frequently after a period of normal develop-

ment. The majority of these later presenting cases exhibit a

severe encephalopathy with subacute onset which is charac-

terized by extreme irritability, intermittent sterile pyrexias, a

loss of skills, and a slowing of head growth (see Appendix I).This encephalopathic phase usually lasts several months,

beyond which time there appears to be no major disease pro-

gression.RNASEH2B mutations are associated with a signifi-

cantly later age at presentation, at or after the age of 12

months in several recorded cases. The onset of AGS after

many months of normal development raises the possibility

that the condition might occur in considerably older individ-

uals too.13 The stimulus for the disease onset is unknown,

and why the disease tends to burn out after several months

is also not understood.

LONG-TERM OUTCOME

The long-term neurological phenotype of all patients is con-

sistent although variations are observed in the severity of the

associated disability. Typically, patients are left with limb spas-

ticity, dystonic posturing, particularly of the upper limbs, trun-

cal hypotonia, and poor head control. Epileptic seizures arereported in around 50% of patients. A number of patients have

been noted to demonstrate a marked startle reaction to sud-

den noise and in some cases the differentiation from epilepsy

Table I: Genes, which when mutated, cause Aicardi-Goutires

syndromea

Gene Chromosome Other names % of

families with

mutations

AGS1 3b TREX1/DNaseIII 25

AGS2 13 RNASEH2B/FLJ11712 40AGS3 11 RNASEH2C/AYP1 14

AGS4 19 RNASEH2A


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can be difficult. At least one patient was initially diagnosed

with hyperekplexia.

The majority of patients are severely intellectually and

physically impaired. However, a few patients withRNASEH2B

mutations have relatively preserved intellectual function with

good comprehension and some retained communication.

One known patient with confirmed mutations is of normal

intelligence at age 19 years, his only features being those of a

spastic cerebral palsy with associated intracranial calcifica-

tion.4 It is of note that a discrepancy in the severity of the neu-rological outcome has been observed between siblings in

several families. Most patients exhibit a severe acquired micro-

cephaly, but in those patients with preserved intellect the head

circumference is normal. Hearing is reported as normal in the

majority of, but not all, cases. Visual function varies from nor-

mal to cortical blindness. Ocular structures are almost always

unremarkable. The lack of retinal changes and hearing loss are

useful differentiating features from congenital infection.RNASEH2B mutations are associated with a lower mortali-

ty rate, around 10%, than is seen with mutations in TREX1,

RNASEH2A, andRNASEH2C(34%). Interestingly, the opinion

of most pediatricians involved in the care of these patients is

that there is no disease progression beyond the encephalo-pathic period. Where death occurs, this seems usually not to

be due to a regressive process but secondary to the conse-

quences of neurological damage incurred during the initial

disease episode.

INVESTIGATIONS

Neuroimaging

The cardinal features of AGS on brain imaging are intracranial

calcification, white matter changes, and cerebral atrophy. The

distribution and extent of the calcification is variable. The basal

ganglia and deep white matter are frequently affected but in

some cases calcification is seen in a periventricular distribution

highly suggestive of congenital infection (Fig. 1). Affected sib-

ling pairs have been described as discordant for the presence of

intracranial calcification1 so this feature should not be consid-

ered a prerequisite for the diagnosis of AGS. Additionally,

intracranial calcification may only become evident over a peri-

od of months.13 Of particular importance, intracranial calcifica-

tion is not always recognized on magnetic resonance imaging(MRI), the initial imaging modality employed in most units.

Consequently, AGS should be considered in the differential

diagnosis of any unexplained leukoencephalopathy and com-

puted tomography (CT) is warranted in cases conforming to

the clinical scenarios outlined above. Most patients demon-

strate non-specific white matter changes in a periventricular

distribution. However, some patients show marked fronto-

temporal white matter involvement with cyst formation so that

Alexander disease, vanishing white matter disease, and mega-

lencephaly with cystic leukoencephalopathy have been consid-

ered and tested for (Fig. 2).

Cerebral atrophy is present in the majority of patients and

some also demonstrate marked brainstem and cerebellarshrinkage. Since limb dystonia is frequently seen in affected

patients, AGS should be considered in the differential diag-

nosis of pontocerebellar hypoplasia type II.

CSF, white cells, IFN-, and pterins

A CSF lymphocytosis (35 cells/mm3) was originally described

as a primary diagnostic feature of AGS. However, it is now

well recognized that the level of both white cells and IFN- in

the CSF of AGS patients falls to normal over the first few years


Table II: Features of patients with Aicardi-Goutires syndrome with mutations in TREX1, RNASEH2A, or RNASEH2C

presenting at birtha

Gene Gestation, Birthweight, Birth head Neonatal liver Platelets (lowest Neonatal

wks centile circum, centile involvement value recorded x109/l) seizures

TREX1 38 9th25th 9th25th HSM Low (39) Yes

TREX1 34 25th 50th HSM, ALFT Low (40) Yes

TREX1 36 97th 97th No Low (50) No

TREX1 nr nr nr No nr No

TREX1 nr nr nr No nr No

TREX1 37 9th 2nd No Low (38) Yes

TREX1 nr nr 25th HSM, ALFT Normal Yes

TREX1 40 2nd9th nr HSM, ALFT Normal No

TREX1 39 9th 9th Yes (unspecified) Normal No

TREX1 40 0.4th 2nd No Low (115) No

TREX1 38 2nd 2nd HSM Low (8). Tfs (plt and rc) Yes

TREX1 nr nr nr No Normal No

TREX1 40 0.4th2nd nr ALFT Low No

TREX1 40 2nd9th 0.4th HSM Low (53) No

TREX1 40


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of life. Moreover, in our recent series, a normal CSF white

cell count was documented in the presence of elevated CSF

IFN- titres on 10% of occasions in the first year of life (Table

III). Thus, a normal number of white cells in the CSF does

not rule out a diagnosis of AGS, even when measured in the

acute phase of the disease.

CSF IFN- appears to be a reliable marker of AGS.

Unfortunately, IFN- levels cannot be routinely determined

in most centres, but testing is available in Paris (e-mail on

request). Again, titres tend to fall to normal after the first fewyears of life.

Blau et al.6 recently described a possible variant of AGS

associated with high levels of CSF pterins. Subsequent stud-

ies in mutation-positive AGS cases show that CSF neopterin

is consistently raised and is a thus a reliable disease marker.12

Whether all or some of the cases described by Blau et al. have

AGS, or a separate condition, remains to be determined.

Pterin analysis is available as part of a neurotransmitter

screen (requested in a number of patients because of associ-

ated dystonia). Again, our data indicate that the level of

neopterin tends to normalize over time.

ASSOCIATED FEATURE SChilblains

Chilblains are seen in approximately 40% of AGS patients and

can occur in association with mutations in any of theAGS1-4

genes (Fig. 3). They are an extremely helpful diagnostic sign.

The lesions typically develop after the first year of life and are

seen especially on the toes and fingers, and sometimes on the

outer helix of the ears. They are worse in the winter months.

Frequently, the feet and hands are also very cold, even in the

absence of overt chilblains. The lesions probably result from

an inflammatory vasculopathy, and biopsy in a few cases has

demonstrated the deposition of immunoglobulin and com-

plement in vessel walls. Treatment with anti-inflammatory

agents and vasodilators has generally been of little efficacy

although no formal trials have been undertaken.

Other disease associations

A small number of patients with AGS have been recorded with

raised levels of autoantibodies, hypothyroidism, insulin

dependent diabetes mellitus (IDDM), and haemolytic

anaemia. A polygammaglobulinaemia is a common finding.Frank systemic lupus erythematosus (SLE) is very unusu-

al,1417 but the recent identification of heterozygous TREX1

mutations in a cohort of patients with SLE18 (see below) indi-

cates that patients with AGS, and their parents, should be

monitored for features of autoimmune disease. A small num-

ber of patients with AGS have demonstrated glaucoma, neona-

tal cardiomyopathy, and a demyelinating peripheral

neuropathy.

GENETICS

We recently performed mutation screening in 127 pedigrees

with a clinical diagnosis of AGS.12Autosomal recessive inheri-

tance was confirmed in 99 families by identifying mutations onboth alleles.RNASEH2Bmutations were seen most frequently,

whileTREX1 mutations were also common, especially in fami-

lies of northern European origin. A recurrent RNASEH2C

mutation was seen in Pakistani families suggesting an ancient

founder effect (i.e. all these families likely share a very distant

common ancestor). We know of three patients withde novo

heterozygous TREX1 mutations, thus indicating this is an

infrequent, but important, mechanism of AGS.11 From a prac-

tical point of view, although the disease is genetically hetero-

geneous, the small size ofTREX1, the clustering of mutations

in exons 2, 6, and 7 ofRNASEH2B, and the observation of a

recurrent mutation inRNASEH2Cmeans that gene testing is a

relatively minor undertaking. An NHS diagnostic service for

AGS mutation screening is now available in Leeds(http://www.leedsdna.info).

PATHOGENESIS

The pathology of the chilblain lesions and the observation of

a small number of children with AGS and autoantibodies,

hypothyroidism, and IDDM suggests immune dysfunction is

a major factor in AGS. Interestingly, we recently described

heterozygous TREX1 mutations in an autosomal dominant

cutaneous form of SLE called familial chilblain lupus,11 and

heterozygousTREX1 mutations have now been reported in a

cohort of lupus patients.18 The precise functions of theTREX1 and RNASEH2 complex proteins are unknown.

Review 413

Table II: continued

CSF WCC/mm3 (age) CSF IFN-IU/l Status

(age) (age)

52 (2wk) na Alive (11y)

1 (25mo); 2 (30mo) 50 (25mo) Dead (6y)

27 (1wk); 17 (1mo); 4 (8mo) 2550 (8mo) Alive (7y)

nr nr Alive (3y)

12 (4mo) 200 (4mo) Dead (2y)

17 (2wk) 400 (2mo) Alive (18mo)

na na Alive (3y)

0 (11mo) 3 (11mo) Dead (6y)

18 (14mo) 9 (14mo) Alive (6y)

3 (2d); 25 (7d) 100 (2wk) Dead (13y)

12 (2wk) 200 (2wk) Alive (10mo)

14 (4mo); 25 (11mo) 100 (4mo) Alive (3y)

17 (5mo); 6 (17mo) na Alive (9y)

57 (1d); 124 (3wk); 15 (1mo); 10 (9mo) 50 (9mo) Alive (9y)

0 (2mo) 75 (2mo) Alive (6mo)

108 (15d); 20 (28d); 6 (37d) 36 (1mo) Alive (1y)

0 (1d); 2 (1mo) 20 (1mo) Alive (4mo)

na na Dead (4.5mo)

21 (2wk) 200 (2wk) Alive (2mo)

25 (11d); 70 (3wk); 63 (2mo) na Dead (2y 11mo)

na na Dead (2y 8mo)

nr 150 (3mo) Alive (1y)

25 (1d) na Dead (7y)

Table III: Number of normal cerebrospinal fluid white cell

and interferon alpha (IFN-) examinations in mutation-positive patients with Aicardi-Goutires syndromea

Age range WCC


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However, we predict that these nucleases are involved in

removing endogenous nucleic acid species produced during

normal cellular processing, and that a failure of this removal

results in inappropriate activation of the innate immune sys-

tem. This hypothesis would explain the phenotypic overlap

of AGS with congenital infection and some aspects of SLE

where an IFN- mediated innate immune response is trig-

gered by viral and host nucleic acids respectively.19 Indeed,

the recent findings of Yang et al.20 show that TREX1 null cells

accumulate large amounts of single stranded DNA (ssDNA)produced during cell replication.

MANAGEMENT

The general management of young patients with AGS is simi-

lar to that of any patient with a severe and chronic neurologi-

cal disease. Obvious issues relate to seizure control, feeding,

and the development of scoliosis. Glaucoma should be

actively considered in patients with the neonatal form of

AGS.21 In relation to the chilblain lesions, neither immuno-

suppressive nor vasodilator therapy are useful therapeutical-

ly to our knowledge.

DIFFERENTIAL DIAGNOSISThe presence of intracranial calcification per se is not a partic-

ularly specific diagnostic sign. In the neonatal form of AGS,

congenital infection represents the main differential diagnosis

while genetic conditions to consider include mitochondrial

cytopathies, Cockayne syndrome, and Hoyeraal-Hreidarsson

syndrome. In older children, intracranial calcification can

occur in association with abnormalities of parathyroid metab-

olism, and we have seen cases of both Coats plus/CRMCC

(cerebroretinal microangiopathy with calcification and cysts)

and SPENCD (spondyloenchondrodysplasia) initially consid-

ered as AGS.22,23 Patients with later onset of a non-specific

leukoencephalopathy, where intracranial calcification may

not be observed and CSF white cells may be normal, invoke a

wide differential diagnosis and we emphasize the importanceof considering AGS in this situation.

Conclusion

AGS is an important disease to recognize because of the associ-

ated high risk of recurrence in most cases. The disease should

be considered in neonates with features of congenital infection

where a pathogen has not been isolated. Additionally, patients

can present after many months of normal development with a

non-specific leukoencephalopathy of subacute onset. Along

with the observation of intracranial calcification, which is not

always present, and white matter changes, including fron-

totemporal cystic changes in severe cases, the clinical diagnosis

can be aided by the observation of chilblain lesions and theanalysis of CSF white cells, pterins, and IFN-. In some

patients, especially those where the diagnosis has been consid-

ered in retrospect, the only way to confirm the diagnosis is

through mutation analysis. The incidence of AGS is currently


Figure 2:Spectrum of

brain changes seen on

magnetic resonance

imaging in patients

with Aicardi-

Goutires syndrome.

Hypointensity on (a)T1-weighted imaging

and hyperintensity on

(b, c) T2

-weighted

imaging of white

matter. (d) Extensive

bitemporal cystic

lesions. (e) Significant

thinning of brainstem

and cerebellar

atrophy.

a b c

d e


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unknown and we request that new patients be notified to the

British Paediatric Neurology Surveillance Unit reporting

scheme system (http://www.bpnsu.co.uk/). Undoubtedly,

cases of AGS remain undiagnosed, with the risk of recurrence

unrecognized until the birth of a second affected child.

Accepted for publication 18th December 2007.

AcknowledgementsWe sincerely thank all patients with AGS and their families for the

use of genetic samples and clinical information. We thank allclinicians for contributing samples and data on which thismanuscript is based.

References

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2. Lebon P, Badoual J, Ponsot G, Goutires F, Hemeury-Cukier F,Aicardi J. Intrathecal synthesis of interferon-alpha in infants withprogressive familial encephalopathy.J Neurol Sci 1988;84: 20108.

3. Tolmie JL, Shillito P, Hughes-Benzie R, Stephenson JB. The Aicardi-Goutires syndrome (familial, early onset encephalopathy withcalcifications of the basal ganglia and chronic cerebrospinal fluidlymphocytosis).J Med Genet1995; 32: 88184.

4. McEntagart M, Kamel H, Lebon P, King MD. Aicardi-Goutiressyndrome: an expanding phenotype.Neuropediatrics 1998;29: 16367.

5. Crow YJ, Black DN, Bond J, et al. Cree encephalitis is allelic withAicardi-Goutires syndrome; implications for the pathogenesis ofdisorders of interferon alpha metabolism.J Med Genet2003;40: 18387.

6. Blau N, Bonafe L, Krageloh-Mann I, et al. Cerebrospinal fluidpterins and folates in Aicardi-Goutires syndrome: a newphenotype.Neurology 2003; 61: 64267.

7. Crow YJ, Jackson A, Roberts E, et al. Aicardi-Goutires syndrome

displays genetic heterogeneity with one locus (AGS1) onchromosome 3p21.Am J Hum Genet2000; 67: 21321.

8. Ali M, Highet LJ, Lacombe D, et al. A second locus for Aicardi-Goutires syndrome at chromosome 13q14-21.J Med Genet2006; 43: 44450.

9. Crow YJ, Hayward BE, Parmar R, et al. Mutations in the geneencoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutiressyndrome at the AGS1 locus.Nat Genet2006; 38:91720.

10. Crow YJ, Leitch A, Hayward BE, et al. Mutations in genesencoding ribonuclease H2 subunits cause Aicardi-Goutiressyndrome and mimic congenital viral brain infection.Nat Genet2006; 38: 91016.

11. Rice G, Newman WG, Dean J, et al. Heterozygous mutations inTREX1 cause familial chilblain lupus and dominant Aicardi-Goutires syndrome.Am J Hum Genet2007; 80: 81115.

Review 415

Figure 3:Examples of

chilblain lesions seen

in patients with

Aicardi-Goutires

syndrome.


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12. Rice G, Patrick T, Parmar R, et al. Clinical and molecularphenotype of Aicardi-Goutires syndrome.Am J Hum Genet2007; 81: 71325.

13. Orcesi S, Pessagno A, Biancheri R, et al. Aicardi-Goutiressyndrome presenting atypically as a sub-acuteleukoencephalopathy.Eur J Paediatr Neurol2007; (Epub aheadof print).

14. Dale RC, Tang SP, Heckmatt JZ, Tatnall FM. Familial systemiclupus erythematosus and congenital infection-like syndrome.Neuropediatrics 2000; 31: 15558.

15. Aicardi J, Goutires F. Systemic lupus erythematosus or Aicardi-

Goutires syndrome?Neuropediatrics 2000; 31: 113.16. De Laet C, Goyens P, Christophe C, Ferster A, Mascart F, Dan B.

Phenotypic overlap between infantile systemic lupuserythematosus and Aicardi-Goutires syndrome.Neuropediatrics 2005; 36: 399402.

17. Rasmussen M, Skullerud K, Bakke SJ, Lebon P, Jahnsen FL.Cerebral thrombotic microangiopathy and antiphospholipidantibodies in Aicardi-Goutires syndrome reports of twosisters.Neuropediatrics 2005; 36: 4044.

18. Lee-Kirsch MA, Gong M, Chowdhury D, et al. Mutations in thegene encoding the 3'-5' DNA exonuclease TREX1 are associated

with systemic lupus erythematosus.Nat Genet2007;39: 106567.

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20. Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degradesssDNA to prevent chronic checkpoint activation andautoimmune disease. Cell2007; 131: 87386.

21. Crow YJ, Massey RF, Innes JR, et al. Congenital glaucoma andbrain stem atrophy as features of Aicardi-Goutires syndrome.Am J Med Genet2004; 129: 30307.

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List of abbreviations

AGS Aicardi-Goutires syndrome

CSF Cerebrospinal fluidIFN- Interferon alpha

SLE Systemic lupus erythematosus

Appendix I: Verbatim quotes from medical staff and parents

describing the stereotyped presentation of later onset Aicardi-

Goutires syndrome

At age 2 months she has spent several days in our paediatric ward

under observation because of periods of intense irritability.

Over the last few weeks the patients father states that the patient

has had changes in his behaviour. He has become quite irritable and

cries a lot. He has cried for up to 30 to 37 hours at a time with only

short naps in between. He has an increased startle to noise.

For first week he seemed fine. Then he began to cry relentlessly. Very

irritable. Inconsolable, really for over a year. Then things settled.

From 3 months of age she screamed for 18 hours a day and became

very difficult to feed.

He was normal until 2 and a half months. Then he would cry solid

for 2 days, develop a fever and then sleep for 3 or 4 days, then

recover, then the same again. This cycle continued until he was 9

months or so. With the fevers he lost all his abilities.

She sat with support at 6 months and independently soon after.

Then her parents began to notice scissoring for the first time. At that

time she became more irritable, screaming and also cooing lessfrequently.

Until age 1.5 years he was very restless and crying whole days and

nights.

She was well until 3 months. Then, after her vaccination, she cried

day and night. She had fevers which came and went for several

months. At a year and a half the crying stopped.

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Aicardi Goutieres Syndrome