.T Med Genet 1995;32:881-884

Syndrome of the month

The Aicardi-Goutieres syndrome (familial, earlyonset encephalopathy with calcifications of thebasal ganglia and chronic cerebrospinal fluidlymphocytosis)

J L Tolmie, Paul Shillito, Rhiannon Hughes-Benzie, J B P Stephenson

AbstractAicardi-Goutieres syndrome (Mendelianinheritance in man Catalog No *225750)is an autosomal recessive encephalopathywhich causes developmental arrest, intra-cerebral calcification, and white matterdisease in the presence of chronic cer-ebrospinal fluid lymphocytosis, and araised level of cerebrospinal fluid inter-feron-alpha (IFN-a). Diagnosis requiresthe presence of progressive encephalo-pathy with onset shortly after birth, andcharacteristic clinical neurological andneuroimaging signs together with chronicCSF.lymphocytosis. The syndrome has su-perficial resemblance to the neurologicalsequelae of congenital infection, thus arigorous search for microbiological andserological evidence of embryopathic in-fections should be carried out in each case.

(J Med Genet 1995;32:881-884)

cerebrospinal fluid lymphocytosis an absoluterequirement for diagnosis? Nevertheless, al-lowing some latitude in the interpretation ofpre-1984 publications and also other reportswhere cases have been investigated to a variableextent, there are nearly 30 reported cases.'-"Although Aicardi-Goutieres syndrome is rare,its clinical genetic importance is exaggeratedby the high chance that its symptoms and signsmay be mistaken for the neurological sequelaeof a non-genetic congenital infection.

Clinical features and natural historyTypically, the antenatal history is uneventfuland birth weight at term is normal. The headcircumference (OFC) at birth is usually normal

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Duncan GuthrieInstitute of MedicalGenetics and Fraser ofAllander Unit(PaediatricNeurology),Yorkhill HospitalsNHS Trust,Glasgow G3 8SJ, UKJ L TolmieP ShillitoR Hughes-BenzieJ B P Stephenson

Correspondence to:Dr Tolmie.

Jean Aicardi and Francoise Goutieres are em-inent French paediatric neurologists who de-scribed the syndrome bearing their name in1984.' Their original report was a detailedaccount of eight children affected by a verysevere, familial encephalopathy diagnosedshortly after birth which was fatal or causedpersistent vegetative state from early child-hood. The neurological phenotype comprisedacquired microcephaly with intracerebral cal-cification and white matter disease, spasticity,dystonia, visual inattention, and abnormal eyemovements. A most striking abnormality waschronic cerebrospinal fluid lymphocytosis inthe absence of other evidence of infection byany known embryopathic pathogen.Although Aicardi and Goutieres identified

cases with a similar clinical course and in-tracranial calcification in older neurologicalpublications,2`5 their syndrome is uncommon.Since 1984 we have observed only two casesin our catchment population where there are30 000 births per year. The total number ofpublished cases is also uncertain because ofdifficulties with case definition, for example, is

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Figure 1 Non-dysmorphic, hypotonic infant with theencephalopathy of Aicardi-Goutieres syndrome (see fig 3for cranial CT appearance).

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Figure 2 Severe, unexplained chilblains which developed after the second birthday of theinfant depicted in fig 1.

or slightly reduced in comparison with thebirth weight centile. Presenting symptoms andneurological signs of encephalopathy are notedin the first days or weeks of life with poorfeeding, irritability, and truncal hypotonia co-inciding with the onset ofpoor head growth (fig1). Limb spasticity and intermittent dystonicposturing are usual but seizures are not prom-inent and the electroencephalographic recordis frequently unremarkable apart from somediffuse slow wave activity. Abnormal eye move-ments with visual inattention are typically pres-ent by the age of 3 months but ophthal-mological examination and visual evoked po-tentials are normal. Rapid progression to apersistent vegetative state is usual. Death oc-curs in the first year in about 25% of cases.Tube feeding has been used to overcome oralfeeding difficulties and an affected infant maythrive, although head growth virtually ceasesand the OFC may decline to 7 SD below themean. In two older affected children, we notedthe development of severe chilblains and acro-cyanosis of the feet (fig 2). This occurred intheir third year and, curiously, the chilblains

were not associated with any coolness of theextremities nor any detectable immunologicalabnormality. Furthermore, the lesions did notrespond to vasodilator therapy.

Neuroimaging investigationsWhen the encephalopathy is first diagnosed, askull x ray may show numerous small areas ofintracranial calcification while cranial ultra-sound scan may confirm periventricular cal-cification with normal ventricles and little orno atrophy. Alternatively, calcification may beabsent from these initial images.'6 Progressiveperiventricular and basal ganglia calcificationis the most constant finding but there may alsobe calcification in the cerebrum and cere-bellum. However, the extent of intracerebralcalcification does not correlate with the severityof the clinical picture. Serial cranial CT scansshow progressive cerebral atrophy with lossof white matter (fig 3). Magnetic resonancestudies have confirmed the white matter ab-normalities with increased intensity of the T2weighted signal.9

InvestigationsTo clinch the diagnosis of Aicardi-Gouti&ressyndrome, serial lumbar punctures are requiredto establish that sterile, chronic cerebrospinalfluid lymphocytosis is present. The cell countvaries from 20 to 80 per cubic mm, lymphocytesmake up 80% or more of the total, and, in onecase, there were decreased subpopulations ofactivated and avid T cells and a predominanceof non-T, non-B, and null lymphocytes.8 Assayof cerebrospinal fluid IFN-cx provides usefuladditional evidence if the level is significantlyabove the normal value of less than 2 IU.Overall, these results are compatible with alocalised inflammatory process, yet protein andglucose levels are normal in most cases andno infectious agent has ever been identified.Nevertheless, important additional investiga-tions to undertake are microbiological and sero-logical tests for prenatal infection with toxo-plasma, rubella, cytomegalovirus, and herpes

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Figure 3 Serial cranial CT scans showing periventricular calcification (left), progressive loss of central white matter

(centre and right), and progressive calcification in the dentate nuclei (centre and right). Scans were performed on thepatient depicted in fig 1.

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The Aicardi-Goutieres syndrome

Differential diagnoses ofAicardi-Goutieres syndrome (categories 1-3 were derived from Billard et al'3).

Clinical syndrome

(1) Cerebral calcification, demyelination, andprominent additional features such as retinaldystrophy

(2) Cerebral calcification with CT or MRIevidence of prenatal anoxic-ischaemic lesions

(3) Cerebral calcification, acquired microcephaly,encephalopathy, and CSF lymphocytosis

(4) Cerebral calcification and leucodystrophy withor without a high CSF protein level, butnormal CSF cell count

(5) Other cerebral calcification syndromes closelymimicking sequelae of intrauterine infection

(6) Miscellaneous syndromes causingencephalopathy in infancy or intracranialcalcification or both

simplex virus which should be negative inblood, urine, and other body secretions. Fur-ther serological tests for human immuno-deficiency virus should also be demonstrablynormal. To date, no chromosomal abnormalityhas been found.

Neuropathological findings have not beenpresented in recently described cases ofAicardi-Goutieres syndrome. However, amongreports of infants with similar findings"142-14(comprising leucoencephalopathy and cerebralcalcifications with or without raised CSF pro-tein levels but no mention ofCSF leucocytosis),documented brain histological abnormalitiesinclude calcifications of the basal ganglia, ce-rebral and cerebellar hemispheres, reducedwhite matter with poorly staining myelin andgliosis, and an inflammatory type meningealreaction.

Differential diagnosisPatients with neurodegeneration and cerebralcalcifications have presented long standing no-sological problems and an informative reviewwas written 35 years ago by Melchior et al.4These authors noted that Fahr's disease was theeponym given to cases with the predominantfinding of "idiopathic nonarteriosclerotic cal-cifications of the brain", following Fahr's de-scription ofa 55 year old man with symmetricalcalcification of the basal ganglia and rapidlyprogressive neurological disease. Melchior etal4 also distinguished from Fahr's disease afamilial genetic encephalopathy ofinfancy, akinto Aicardi-Goutieres syndrome, with de-myelination and cerebral calcification. On itsown, intracerebral calcification is not a par-ticularly good diagnostic handle and an ex-tensive list of nearly 100 causes was supplied ina case report of a child with dysosteosclerosis. 15Fortunately, though, the vast majority of theselisted syndromes are easily distinguished if theAicardi-Goutieres syndrome is defined as asevere, progressive encephalopathy diagnosedshortly after birth with calcification in the basalnuclei and chronic excess of white cells in

Comment

Different autosomal recessive varieties, for example, early onsetCockayne syndrome'6 or encephalopathy with growth hormonedeficiency." Necropsy important to identify autosomal recessivesudanophilic leucodystrophies (MIM 260600)Sporadic disorders,' antenatal and perinatal history frequentlyuninformative but non-progressive neurological signs and absence ofprogressive brain atrophy on neuroimaging are highly suggestiveAutosomal recessive Aicardi-Goutieres syndrome: encephalopathy withwhite matter disease and progressive brain atrophyAutosomal recessive inheritance: note similarity of cases'2'4 to Aicardi-Goutieres. Also, note reports of cerebral calcifications with cerebellarhypoplasia" and autosomal recessive leucoencephalopathy affectingNorth American Indians."920 Measurement of fluid IFN-cx should beconsidered (P Lebon, personal communication)Autosomal recessive, with prominent hepatosplenomegaly andhaematological abnormalities,2 22 but reports of affected brothers withseizures and no haematological abnormalities may suggest an X linkedvariety23 24Many metabolic, neuroectodermal, and dysmorphic syndromes diagnosedby history, clinical and biochemical findings.2" Fumarase deficiency(MIM 136850), multiple carboxylase deficiency (MIM 253260 &253270), molybdenum cofactor deficiency (MIM 252150), pyruvatedehydrogenase deficiency (MIM 312170), and mitochondrial cytopathy(MIM 516060) are notable causes of early onset encephalopathy whilecarbonic anhydrase II deficiency (MIM 259730) and dysosteosclerosis"present later with prominent cerebral calcifications.

cerebrospinal fluid. The table provides a shorterlist of references to groups of disorders whichneed to be considered in the differential diag-nosis of Aicardi-Goutieres syndrome.

Aetiology and geneticsCase reports have documented parental con-sanguinity and the recurrence of the syndromein sibs of diverse ethnic origins.'7'1 Thus, thereis general agreement that an autosomal re-cessive gene causes this condition. Never-theless, the syndrome's resemblance to neuro-degeneration caused by embryopathic infectionis long appreciated.' Moreover, there is a puzz-ling rise of cerebrospinal fluid IFN-oL," a cy-tokine which has the ability to protect cellsagainst a wide range ofDNA and RNA virusesas well as having antitumour and immuno-modulatory effects through binding specific re-ceptors on target cells and altering gene ex-pression and post-transcriptional proteinexpression.26 Raised levels of IFN-oa, but notIFN-y, were found in cerebrospinal fluid orsera or both in seven out of eight patientswith Aicardi-Goutieres syndrome with negativeserology tests." The IFN-oa levels in cer-ebrospinal fluid were high at birth and thenslowly declined but were still present in twoout of three patients tested at the age of 5 years.The reason for persistent production of IFN-a in patients with familial encephalopathy isunknown but it is speculated that there maybe an underlying pleiotropic inherited defectwhich causes leucodystrophy and defective re-gulation of IFN-oa synthesis, or an unknownviral infection associated with an autosomalrecessive abnormality of host response.''

Prenatal diagnosis of Aicardi-Goutieres syn-drome has not been accomplished althoughconsideration may be given to measuring IFN-ot in a sample of fetal blood or cerebrospinalfluid. This procedure would be risky and spec-ulative, so it is gratifying to record that Pro-fessor Lebon has started collection of DNAsamples from suitable families for the purposeof molecular genetic studies.

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We thank Professors Aicardi, Goutieres, and Lebon and DrBryony Fredericks for commenting on clinical and radiologicalfeatures of our cases and also for assaying IFN-o levels in bloodand CSF.

1 Aicardi J, Goutieres F. A progressive familial encephalopathyin infancy with calcifications of the basal ganglia andchronic cerebrospinal fluid lymphocytosis. Ann Neurol1984;15:49-54.

2 Hallervorden I. Uber diffuse symmetrische kalkabla-gerungen bei einem krankheitsbild mit mikrocephalieundmeningoencephalitis. Arch Psychiatr Zeitschr Neurol 1950;184:579-600.

3 Jervis GA. Microcephaly with extensive calcium depositsand demyelination. J Neuropathol Exp Neurol 1954;13:318-29.

4 Melchior JC, Benda CE, Yakovlev PI. Familial idiopathiccalcifications in childhood. Am .7 Dis Child 1960;99: 101-17.

5 Lyon G, Robain 0, Phillipart M, Sarlieve L. Leuko-dystrophie avec calcifications strio-cerebelleuses, micro-cephalie et nanism. Rev Neurol (Paris) 1968;119:197-210.

6 Giroud M, Gouyon JB, Chaumet F, et al. A case of familialencephalopathy in infancy with calcification of the basalganglia and chronic cerebrospinal fluid lymphocytosis.Child' Nerv Syst 1986;2:47-8.

7 Mehta L, Trounce JQ, Moore JR, Young ID. Familialcalcification of the basal ganglia with cerebrospinal fluidpleocytosis. I Med Genet 1986;23:157-60.

8 Diament AJ, Machado LR, Cypel S, Ramos JLA. Sindromede calcificac6es dos ganglios da base, leucodistrofia epleocitose linfomonocitaria cr6nicqa do liquido ce-falorraqueano. Arq Neuropsiquitar 1986;44: 185-90.

9 Bonnemann CG, Meinecke P. Encephalopathy of infancywith intracerebral calcification and chronic spinal fluidlymphocytosis - another case of the Aicardi-Gouti&ressyndrome. Neuropediatrics 1992;23: 157-61.

10 Babbit DP, Tang T, Dobbs J, Berk R. Idiopathic familialcerebrovascular ferrocalcinosis (Fahr's disease) and reviewof differential diagnosis of intracranial calcification inchildren. Am 7 Radiol 1969;1O5:352-8.

11 Lebon P, Badoual J, Ponsot G, Goutieres F, Hemeury-Cukier F, Aicardi J. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy..7 Neurol Sci 1988;84:201-8.

12 Razavi-Encha F, Larroche JC, Gaillard D. Infantile familialencephalopathy with cerebral calcifications and leuko-dystrophy. Neuropediatnics 1988;19:72-9.

13 Billard C, Dulac 0, Bouloche J, et al. Encephalopathy withcalcifications of the basal ganglia in children. A reappraisalof Fahr's syndrome with respect to 14 new cases. Neuro-pediatrics 1989;20:12-19.

14 Bolthauser E, Steinlin M, Boesch C, Martin E, Schubiger G.Magnetic resonance imaging in infantile encephalopathywith cerebral calcification and leukodystrophy. Neuro-pediatrics 1991;22:33-5.

15 Chitayat D, Silver K, Azouz EM. Skeletal dysplasia, in-tracerebral calcifications, optic atrophy, hearing im-pairment and mental retardation: nosology ofdysosteosclerosis. Am _7 Med Genet 1992;43:517-23.

16 Patton MA, Gianelli F, Francis AJ, et al. Early onset Cock-ayne syndrome: case reports with neuropathological andfibroblast studies. _7 Med Genet 1989;26:154-9.

17 Bonnemann CG, Meinecke P. Reich H. Encephalopathywith intracerebral calcification, white matter lesions,growth hormone deficiency, microcephaly and retinal de-generation. Two siblings confirming a probably distinctentity. JMed Genet 1991;28:708-11.

18 Troost D, van Rossum A, Veiga Pires J, Willemse J. Cerebralcalcifications and cerebellar calcification in two children:clinical radiologic and neuropathological studies: a sep-arate neurodevelopmental entity. Neuropediatrics 1984;15:102-9.

19 Black DN, Booth F, Watters GV, et al. Leucoencephalopathyamong native Indian infants in northern Quebec andManitoba. Ann Neurol 1988;24:483-9.

20 Black DN, Watters GV, Andermann E, et al. Encephalitisamong Cree children in Northern Quebec. Ann Neural1988;24:483-9.

21 Bum J, Wickramasinghe HT, Harding B, Baraitser M. Asyndrome with intracranial calcification and microcephalyin two sibs, resembling intrauterine infection. Clin Genet1986;30: 112-16.

22 Reardon W, Hockey A, Silbertstein P, et al. Autosomalrecessive congenital intrauterine infection-like syndromeof microcephaly, intracranial calcification and CNS dis-ease. Am JMed Genet 1994;52:58-65.

23 Baraitser M, Brett EM, Piesowicz AT. Microcephaly andintracranial calcification in two brothers. .7 Med Genet1983;20:2 10-12.

24 Ishitsu TS, Chikazawa I, Matsuda I. Two siblings withmicrocephaly associated with calcification of the cerebralwhite matter. .7pn .7 Hum Genet 1985;30:213-17.

25 Stephenson JBP, King MD. Handbook of neurological in-vestigations. Revised edition London: Butterworth-Hei-nemann, 1992.

26 Pfeffer LM, Constantinescu SN, Wang C. Transmembranesignalling by IFN-o. ProgMol Subcell Biol 1994;14:242-59.

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