Review

Aicardi-Goutires syndrome: an important Mendelian mimic of congenital infection

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 at Level 9, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, St Jamess University Hospital, Leeds, West Yorkshire LS9 7TF, UK. E-mail: Yanickcrow@mac.com 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 TREX1 mutations, 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 RNASEH2B mutations. 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. This hypothesis 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 presence of sibling recurrences, affected females, and parental consanguinity suggested that the condition was inherited as an autosomal recessive trait. However, the authors highlighted the risk of misdiagnosis as the sequelae of congenital infection, 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 levels of CSF neopterin as a diagnostic marker.6 The first gene localization for AGS was reported to chromosome 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 heterozygous TREX1 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

See end of paper for list of abbreviations.

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

410

Developmental Medicine & Child Neurology 2008, 50: 410416

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 suppression 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 infectious 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 development. The majority of these later presenting cases exhibit a severe encephalopathy with subacute onset which is characterized 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 progression. RNASEH2B mutations are associated with a significantly 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 consistent although variations are observed in the severity of the associated disability. Typically, patients are left with limb spasticity, dystonic posturing, particularly of the upper limbs, truncal hypotonia, and poor head control. Epileptic seizures are reported in around 50% of patients. A number of patients have been noted to demonstrate a marked startle reaction to sudden 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 25 40 14 <4 17

AGS1 AGS2 AGS3 AGS4 AGS5

3b 13 11 19 Unknown

TREX1/DNaseIII RNASEH2B/FLJ11712 RNASEH2C/AYP1 RNASEH2A

aData taken from Rice et al.12 with permission from the University of Chicago Press. bThree cases of AGS are known to us due to de novo heterozygous TREX1 mutations, i.e. these mutations cause AGS as a dominant disorder. See Rice et al.11

Figure 1: Examples of intracranial calcification on computed tomography scan in patients with Aicardi-Goutires syndrome. Calcification is seen in (a, b) basal ganglia, (c) dentate nuclei of cerebellum, in (d) periventricular distribution, and (e) within deep white matter.

Review 411

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 with RNASEH2B 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 calcification.4 It is of note that a discrepancy in the severity of the neurological outcome has been observed between siblings in several families. Most patients exhibit a severe acquired microcephaly, 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 normal 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 mortality rate, around 10%, than is seen with mutations in TREX1, RNASEH2A, and RNASEH2C (34%). Interestingly, the opinion of most pediatricians involved in the care of these patients is that there is no disease progression beyond the encephalopathic period. Where death occurs, this seems usually not to be due to a regressive process but secondary to the consequences of neurological damage incurred during the initial disease episode.
INVESTIGATIONS

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 sibling pairs have been described as discordant for the presence of intracranial calcification1 so this feature should not be considered a prerequisite for the diagnosis of AGS. Additionally, intracranial calcification may only become evident over a period of months.13 Of particular importance, intracranial calcification 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 computed tomography (CT) is warranted in cases conforming to the clinical scenarios outlined above. Most patients demonstrate non-specific white matter changes in a periventricular distribution. However, some patients show marked frontotemporal white matter involvement with cyst formation so that Alexander disease, vanishing white matter disease, and megalencephaly with cystic leukoencephalopathy have been considered and tested for (Fig. 2). Cerebral atrophy is present in the majority of patients and some also demonstrate marked brainstem and cerebellar shrinkage. Since limb dystonia is frequently seen in affected patients, AGS should be considered in the differential diagnosis 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

Neuroimaging The cardinal features of AGS on brain imaging are intracranial calcification, white matter changes, and cerebral atrophy. The

Table II: Features of patients with Aicardi-Goutires syndrome with mutations in TREX1, RNASEH2A, or RNASEH2C presenting at birtha
Gene Gestation, wks 38 34 36 nr nr 37 nr 40 39 40 38 nr 40 40 40 38 31 27 36 38 nr 40 37 Birthweight, centile 9th25th 25th 97th nr nr 9th nr 2nd9th 9th 0.4th 2nd nr 0.4th2nd 2nd9th <0.4th 50th 0.4th 0.4th2nd 91st 9th nr 25th 2nd Birth head circum, centile 9th25th 50th 97th nr nr 2nd 25th nr 9th 2nd 2nd nr nr 0.4th <0.4th 50th 0.4th 2nd9th 50th 9th25th nr 25th <0.4th Neonatal liver involvement HSM HSM, ALFT No No No No HSM, ALFT HSM, ALFT Yes (unspecified) No HSM No ALFT HSM HSM, ALFT No HSM HSM, ALFT No HSM, ALFT HSM HSM HSM Platelets (lowest value recorded x109/l) Low (39) Low (40) Low (50) nr nr Low (38) Normal Normal Normal Low (115) Low (8). Tfs (plt and rc) Normal Low Low (53) Pancytopenia. Tfs (plt, rc) Normal Low Low (15). Tfs (plt) Low (37). Tfs (plt) Low (47) Normal Low (30) Pancytopenia. Tfs (plt, rc) Neonatal seizures Yes Yes No No No Yes Yes No No No Yes No No No No No No No No Yes Yes No Yes

TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 TREX1 RNASEH2C RNASEH2C RNASEH2C RNASEH2A

aData taken from Rice et al.12 with permission from the University of Chicago Press. WCC, white cell count; IFN-; interferon alpha;

HSM, hepatosplenomegaly; ALFT, abnormal liver function tests; Tfs, transfusion; plt, platelets; rc, red cells; na, not analyzed; nr, not recorded.

412

Developmental Medicine & Child Neurology 2008, 50: 410416

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 few years of life. Blau et al.6 recently described a possible variant of AGS associated with high levels of CSF pterins. Subsequent studies 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 associated dystonia). Again, our data indicate that the level of neopterin tends to normalize over time.
ASSOCIATED FEATURES

demonstrated the deposition of immunoglobulin and complement 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 unusual,1417 but the recent identification of heterozygous TREX1 mutations in a cohort of patients with SLE18 (see below) indicates that patients with AGS, and their parents, should be monitored for features of autoimmune disease. A small number of patients with AGS have demonstrated glaucoma, neonatal cardiomyopathy, and a demyelinating peripheral neuropathy.
GENETICS

Chilblains Chilblains are seen in approximately 40% of AGS patients and can occur in association with mutations in any of the AGS1-4 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 Table II: continued
CSF WCC/mm3 (age) CSF IFN- IU/l (age) Status (age) Alive (11y) Dead (6y) Alive (7y) Alive (3y) Dead (2y) Alive (18mo) Alive (3y) Dead (6y) Alive (6y) Dead (13y) Alive (10mo) Alive (3y) Alive (9y) Alive (9y) Alive (6mo) Alive (1y) Alive (4mo) Dead (4.5mo) Alive (2mo) Dead (2y 11mo) Dead (2y 8mo) Alive (1y) Dead (7y)

We recently performed mutation screening in 127 pedigrees with a clinical diagnosis of AGS.12 Autosomal recessive inheritance was confirmed in 99 families by identifying mutations on both alleles. RNASEH2B mutations were seen most frequently, while TREX1 mutations were also common, especially in families 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 with de novo heterozygous TREX1 mutations, thus indicating this is an infrequent, but important, mechanism of AGS.11 From a practical point of view, although the disease is genetically heterogeneous, the small size of TREX1, the clustering of mutations in exons 2, 6, and 7 of RNASEH2B, and the observation of a recurrent mutation in RNASEH2C means 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

52 (2wk) na 1 (25mo); 2 (30mo) 50 (25mo) 27 (1wk); 17 (1mo); 4 (8mo) 2550 (8mo) nr nr 12 (4mo) 200 (4mo) 17 (2wk) 400 (2mo) na na 0 (11mo) 3 (11mo) 18 (14mo) 9 (14mo) 3 (2d); 25 (7d) 100 (2wk) 12 (2wk) 200 (2wk) 14 (4mo); 25 (11mo) 100 (4mo) 17 (5mo); 6 (17mo) na 57 (1d); 124 (3wk); 15 (1mo); 10 (9mo) 50 (9mo) 0 (2mo) 75 (2mo) 108 (15d); 20 (28d); 6 (37d) 36 (1mo) 0 (1d); 2 (1mo) 20 (1mo) na na 21 (2wk) 200 (2wk) 25 (11d); 70 (3wk); 63 (2mo) na na na nr 150 (3mo) 25 (1d) na

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 heterozygous TREX1 mutations have now been reported in a cohort of lupus patients.18 The precise functions of the TREX1 and RNASEH2 complex proteins are unknown. Table III: Number of normal cerebrospinal fluid white cell and interferon alpha (IFN-) examinations in mutationpositive patients with Aicardi-Goutires syndromea
Age range (y) 01 13 4 WCC <5/mm3 (total recordings) 9 (87) 12 (35) 11 (15) IFN- <2 IU/l (total recordings) 0 (44) 3 (26) 4 (11)

aData taken from Rice et al.12 with permission from the University of Chicago Press. WCC, white cell count.

Review 413

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 system. 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 triggered 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

cytopathies, Cockayne syndrome, and Hoyeraal-Hreidarsson syndrome. In older children, intracranial calcification can occur in association with abnormalities of parathyroid metabolism, and we have seen cases of both Coats plus/CRMCC (cerebroretinal microangiopathy with calcification and cysts) and SPENCD (spondyloenchondrodysplasia) initially considered 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 importance of considering AGS in this situation. Conclusion AGS is an important disease to recognize because of the associated 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 frontotemporal cystic changes in severe cases, the clinical diagnosis can be aided by the observation of chilblain lesions and the analysis of CSF white cells, pterins, and IFN-. In some patients, especially those where the diagnosis has been considered in retrospect, the only way to confirm the diagnosis is through mutation analysis. The incidence of AGS is currently

The general management of young patients with AGS is similar to that of any patient with a severe and chronic neurological 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 immunosuppressive nor vasodilator therapy are useful therapeutically to our knowledge.
DIFFERENTIAL DIAGNOSIS

The presence of intracranial calcification per se is not a particularly specific diagnostic sign. In the neonatal form of AGS, congenital infection represents the main differential diagnosis while genetic conditions to consider include mitochondrial

Figure 2: Spectrum of brain changes seen on magnetic resonance imaging in patients with AicardiGoutires 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.

414

Developmental Medicine & Child Neurology 2008, 50: 410416

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. Acknowledgements We sincerely thank all patients with AGS and their families for the use of genetic samples and clinical information. We thank all clinicians for contributing samples and data on which this manuscript is based. References 1. Aicardi J, Goutires F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 1984; 15: 4954. 2. Lebon P , Badoual J, Ponsot G, Goutires F, Hemeury-Cukier F, Aicardi J. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 1988; 84: 20108. 3. Tolmie JL, Shillito P , Hughes-Benzie R, Stephenson JB. The AicardiGoutires syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis). J Med Genet 1995; 32: 88184.

4. McEntagart M, Kamel H, Lebon P , King MD. Aicardi-Goutires syndrome: an expanding phenotype. Neuropediatrics 1998; 29: 16367. 5. Crow YJ, Black DN, Bond J, et al. Cree encephalitis is allelic with Aicardi-Goutires syndrome; implications for the pathogenesis of disorders of interferon alpha metabolism. J Med Genet 2003; 40: 18387. 6. Blau N, Bonafe L, Krageloh-Mann I, et al. Cerebrospinal fluid pterins and folates in Aicardi-Goutires syndrome: a new phenotype. Neurology 2003; 61: 64267. 7. Crow YJ, Jackson A, Roberts E, et al. Aicardi-Goutires syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21. Am J Hum Genet 2000; 67: 21321. 8. Ali M, Highet LJ, Lacombe D, et al. A second locus for AicardiGoutires syndrome at chromosome 13q14-21. J Med Genet 2006; 43: 44450. 9. Crow YJ, Hayward BE, Parmar R, et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutires syndrome at the AGS1 locus. Nat Genet 2006; 38: 91720. 10. Crow YJ, Leitch A, Hayward BE, et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutires syndrome and mimic congenital viral brain infection. Nat Genet 2006; 38: 91016. 11. Rice G, Newman WG, Dean J, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant AicardiGoutires syndrome. Am J Hum Genet 2007; 80: 81115.

Figure 3: Examples of chilblain lesions seen in patients with Aicardi-Goutires syndrome.

Review 415

12. Rice G, Patrick T, Parmar R, et al. Clinical and molecular phenotype of Aicardi-Goutires syndrome. Am J Hum Genet 2007; 81: 71325. 13. Orcesi S, Pessagno A, Biancheri R, et al. Aicardi-Goutires syndrome presenting atypically as a sub-acute leukoencephalopathy. Eur J Paediatr Neurol 2007; (Epub ahead of print). 14. Dale RC, Tang SP , Heckmatt JZ, Tatnall FM. Familial systemic lupus erythematosus and congenital infection-like syndrome. Neuropediatrics 2000; 31: 15558. 15. Aicardi J, Goutires F. Systemic lupus erythematosus or AicardiGoutires syndrome? Neuropediatrics 2000; 31: 113. 16. De Laet C, Goyens P , Christophe C, Ferster A, Mascart F, Dan B. Phenotypic overlap between infantile systemic lupus erythematosus and Aicardi-Goutires syndrome. Neuropediatrics 2005; 36: 399402. 17. Rasmussen M, Skullerud K, Bakke SJ, Lebon P , Jahnsen FL. Cerebral thrombotic microangiopathy and antiphospholipid antibodies in Aicardi-Goutires syndrome reports of two sisters. Neuropediatrics 2005; 36: 4044. 18. Lee-Kirsch MA, Gong M, Chowdhury D, et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 2007; 39: 106567. 19. Alarcn-Riquelme ME. Nucleic acid by-products and chronic inflammation. Nat Genet 2006; 38: 86667. 20. Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 2007; 131: 87386. 21. Crow YJ, Massey RF, Innes JR, et al. Congenital glaucoma and brain stem atrophy as features of Aicardi-Goutires syndrome. Am J Med Genet 2004; 129: 30307. 22. Briggs TA, Abdel-Salam GMH, Balicki M, et al. Cerebroretinal microangiopathy with calcification and cysts (CRMCC). Am J Med Genet 2008; 146: 18290. 23. Crow YJ, Rice GI, Navarro V . SPENCD: another immunoosseous dysplasia; normal AGS1-4 sequence in an affected female. British Society of Human Genetics Abstracts. J Med Genet 2007; 44 (Suppl. 1): S50.

Appendix I: Verbatim quotes from medical staff and parents describing the stereotyped presentation of later onset AicardiGoutires 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 less frequently. 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.

List of abbreviations
AGS CSF IFN- SLE Aicardi-Goutires syndrome Cerebrospinal fluid Interferon alpha Systemic lupus erythematosus

416

Developmental Medicine & Child Neurology 2008, 50: 410416