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Aicardi–Goutières syndrome
Handbook of Clinical Neurology, Vol. 113 (3rd series) Pediatric Neurology Part III O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved
Chapter 166
Aicardi–Goutie`res syndrome YANICK J. CROW* Genetic Medicine, University of Manchester, St Mary’s Hospital, Manchester, UK
INTRODUCTION In 1984, Jean Aicardi and Franc¸oise Goutie`res 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 (Aicardi and Goutie`res, 1984). 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-a (IFN-a) in the CSF of affected children (Lebon et al., 1988). Other landmark clinical papers include the descriptions of chilblain lesions (Tolmie et al., 1995), occasional normocephaly and preservation of intellect (McEntagart et al., 1998), normal CSF white cell counts even in the early stages of the disease process (Crow et al., 2003), raised levels of CSF neopterin as a diagnostic marker (Blau et al., 2003), and intracerebral large vessel inflammatory disease associated with SAMHD1 mutations (Ramesh et al., 2010). The first gene localization for AGS was reported to chromosome 3p21 in 2000 (Crow et al., 2000), 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 (Ali et al., 2006). In 2006, four genes were identified which, when mutated, cause autosomal recessive AGS (Crow et al., 2006a, b). 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 (Rice et al., 2007a; Haaxma et al., 2010). A comprehensive genotype-phenotype analysis
(Rice et al., 2007b) showed that at least one further AGS-causing gene remained to be determined. In 2009, biallelic mutations in the SAMHD1 were identified in 13 families with AGS. Further genetic heterogeneity likely exists. The combined efforts of pediatric neurologists, clinical geneticists, innate immunologists, and cell biologists are producing rapid progress in the understanding of AGS which is now recognized to be an inflammatory immune disorder. These insights beg urgent questions about the use of immunosuppressive therapies in the treatment of AGS and related phenotypes.
NATURAL HISTORY OF AICARDI^GOUTIERES SYNDROME Presentation The presentation of AGS can be broadly divided into two types:
NEONATAL FORM A group of AGS patients, typically those with TREX1 mutations, present in the neonatal period with abnormal neurology manifest as jitteriness, poor feeding and neonatal seizures, features which are reflected in the finding of changes on brain imaging at birth. These infants frequently demonstrate hepatosplenomegaly with elevated liver enzymes, and thrombocytopenia with anemia necessitating recurrent platelet and red cell transfusion. 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 (Jepps et al., 2008).
*Correspondence to: Professor Yanick J. Crow, Genetic Medicine, University of Manchester, St Mary’s Hospital, Oxford Road, Manchester M13 9WL, UK. Tel: þ44-161-276-5165, Fax: þ44-161-276-6145, E-mail: [email protected]
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LATER ONSET FORM All other children 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. This encephalopathic phase usually lasts several months, after 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 following months of normal development raises the possibility that the condition might occur in considerably older individuals too (Orcesi et al., 2008). The stimulus for the disease onset is unknown, and why the disease tends to “burn out” after several months is also not understood. Recently, milder phenotypes have been associated with mutations in SAMHD1. Dale et al. (2010) reported two siblings compound heterozygous for null mutations in SAMHD1. The older girl showed mild intellectual disability with microcephaly. Her younger brother had significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains and recurrent mouth ulcers. One of the siblings had a chronic progressive deforming arthropathy of the small and large joints with secondary contractures. An additional previously undescribed feature of AGS, which so far seems to be exclusively related to SAMHD1 mutations, is intracranial large vessel disease causing both intracranial stenoses, in some cases reminiscent of moyamoya syndrome, and aneurysms (Ramesh et al., 2010).
Long-term outcome The long-term neurological phenotype of all patients is consistent, although variations are observed in the severity of the associated handicap. 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 children have been noted to demonstrate a marked startle reaction to sudden noise and in some cases the differentiation from epilepsy can be difficult. At least one child was initially diagnosed with hyperekplexia. Most patients are severely intellectually and physically impaired. However, some children with RNASEH2B and SAMHD1 mutations have relatively, sometimes perhaps completely, preserved intellectual
function with good comprehension and retained communication. For example, 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 (McEntagart et al., 1998). 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 children 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 although glaucoma is seen in some cases (Crow et al., 2004). 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, in most cases there appears to be no significant 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 Neuroimaging The cardinal features of AGS on brain imaging are intracranial calcification, a leukodystrophy, and cerebral atrophy (Figs 166.1 and 166.2). 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. Affected sibling pairs have been described as discordant for the presence of intracranial calcification so that 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. Of particular importance, intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units. Consequently, AGS should be considered in the differential diagnosis of any unexplained leukoencephalopathy and CT scanning is warranted in cases conforming to the clinical scenarios we have outlined above. Most patients demonstrate nonspecific white matter changes, symmetrically involving the lobar white matter with relative sparing of the strictly periventricular area, the corpus callosum, the capsules and the optic radiations. However, some patients show marked frontotemporal white matter involvement with
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Fig. 166.1. Examples of intracranial calcification on CT scan in patients with AGS. Calcification is seen in the basal ganglia (A, B), dentate nuclei of the cerebellum (C), in a periventricular distribution, (D) and within the deep white matter (E).
cyst formation, so that Alexander disease, vanishing white matter disease, and megalencephaly with cystic leukoencephalopathy have been considered and tested for. Additionally, we know of one affected child with a confirmed molecular diagnosis of AGS (RNASEH2B mutations) whose only clinical feature is a spastic diplegia and who has a completely normal cranial MRI at age 8 years. Cerebral atrophy is present in the majority of children and some demonstrate marked brainstem and cerebellar shrinkage also. Since limb dystonia is frequently seen in affected children, AGS should be considered in the differential diagnosis of pontocerebellar hypoplasia type II. As noted above, five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains
and ischemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral hemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin.
Cerebrospinal fluid: white cells, IFN-a, and neopterin A CSF lymphocytosis (5 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-a in the CSF of AGS patients falls to normal over the first few years of life. Moreover, in our
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Fig. 166.2. The spectrum of brain changes seen on MRI in patients with AGS. Hypointensity on T1-weighted imaging (A) and hyperintensity on T2-weighted imaging (B, C) of the white matter. Extensive bitemporal cystic lesions (D). Significant thinning of the brainstem and cerebellar atrophy (E).
series, a normal CSF white cell count was documented in the presence of elevated CSF IFN-a titers on 10% of occasions in the first year of life. 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-a appears to be a reliable marker of AGS. Again, titers tend to fall to normal after the first few years of life. Blau et al. described a possible variant of AGS associated with high levels of CSF pterins (2003). Subsequent studies in mutation-positive AGS cases show that CSF neopterin is consistently raised and is a thus a reliable disease marker (Rice et al., 2007b). Whether all or some
of the cases described by Blau et al. have AGS, or a separate condition, remains to be determined. Again, the level of neopterin tends to normalize over time.
ASSOCIATED FEATURES Chilblains Chilblains are seen in approximately 40% of AGS patients and can occur in association with mutations in any of the AGS1—4 genes. 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
AICARDI–GOUTIE`RES SYNDROME 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 complement in vessel walls. Treatment with antiinflammatory agents and vasodilators has generally been of little efficacy although no formal trials have been undertaken.
Other disease associations A small number of children with AGS have been recorded with raised levels of auto-antibodies, hypothyroidism, insulin dependent diabetes mellitus (IDDM), and hemolytic anemia. A polygammaglobulinemia is a common finding. Frank systemic lupus erythematosus (SLE) is very unusual (Aicardi and Goutie`res, 2000; Dale et al., 2000; De Laet et al., 2005; Rasmussen et al., 2005), but the identification of heterozygous TREX1 mutations in a cohort of SLE patients (LeeKirsch et al., 2007) (see below) indicates that AGS patients, and their parents, should be monitored for features of autoimmune disease. A small number of AGS patients have demonstrated glaucoma, neonatal cardiomyopathy and a demyelinating peripheral neuropathy.
NEUROPATHOLOGY The major features on post-mortem include brain atrophy, loss of myelin, infarction, and calcification. Calcium deposits can be seen in areas of infarction, in a perivascular distribution, or as small accretions not necessarily associated with necrosis or blood vessels (Goutie`res et al., 1998; Kumar et al., 1998). The finding of wedgeshaped infarctions together with patchy myelin loss and calcified deposits in the media, adventitia and perivascular space of small blood vessels led Barth et al. (1999) to postulate that Aicardi–Goutie`res syndrome might represent a primary genetic angiopathy. Such observations are interesting in view of the neuropathological changes seen in an astrocyte-specific IFN-a overproducing transgenic mouse (Akwa et al., 1998) and the known antiangiogenic effects of IFN-a.
GENETICS A comprehensive study of the mutation spectrum in 127 pedigrees with a clinical diagnosis of AGS was published in 2007 (Rice et al., 2007b). 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
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these families likely share a very distant common ancestor). De novo heterozygous TREX1 mutations causing AGS are an infrequent, but important, mechanism of AGS (Rice et al., 2007a). At least one further diseaserelated gene remains to be identified. 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 facilitates targeted gene testing. Mutations in SAMHD1 include missense and nonsense variants, as well as exonic deletions (Rice et al., 2009; Ramesh et al., 2010). There is a recurrent deletion of exon 1 in individuals of Ashkenazi Jewish ancestry.
PATHOGENESIS The pathology of the chilblain lesions and the observation of a small number of AGS children with autoantibodies, hypothyroidism, IDDM, and lupus suggests immune dysfunction is a major factor in AGS (Rice et al., 2007b). Interestingly, heterozygous TREX1 mutations have been described in an autosomal dominant cutaneous form of SLE called familial chilblain lupus (Rice et al., 2007a), and heterozygous TREX1 mutations have been reported in a cohort of lupus patients (LeeKirsch et al., 2007). The precise functions of TREX1 and the RNASEH2 complex proteins are unknown. However, it is predicted that they function as nucleases involved in removing endogenous nucleic acid species produced during normal cellular processes (Yang et al., 2007), and that a failure of this process results in inappropriate activation of the innate immune system (Stetson et al., 2008). This hypothesis would explain the phenotypic overlap of AGS with congenital infection and some aspects of SLE where an IFN-a mediated innate immune response is triggered by viral and host nucleic acids respectively. The finding that crosses of the Trex1 null mouse with animals either unable to signal through type I interferons or produce functional lymphocytes opens up exciting therapeutic possibilities requiring urgent attention.
MANAGEMENT The general management of children with AGS is similar to that of any child 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 children with the neonatal form of AGS. In relation to the chilblain lesions, neither immunosuppressive nor vasodilator therapy is useful therapeutically to our knowledge. Considering the evidence suggesting that AGS is an inflammatory disorder, the most pressing issue at this time
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regards the use of immunosuppression – particularly during the acute phase of the disease. At the moment the limited available evidence for the efficacy of steroids and other immunosuppressants is equivocal (D’Arrigo et al., 2008; Orcesi et al., 2008). The observation of progressive intracerebral large artery inflammatory disease indicates that treatment beyond the initial disease presentation may also be important – at least in the setting of SAMHD1-related AGS.
DIFFERENTIAL DIAGNOSIS The presence of intracranial calcification is not per se a particularly specific diagnostic sign. In the neonatal form of AGS, congenital infection represents the main differential diagnosis. We have recently delineated another congenital infection-like syndrome which can be differentiated from AGS by the presence of “bandlike” calcification and polymicrogyria (which are not normally associated with AGS) (Briggs et al., 2008a). Other 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 metabolism and celiac disease, and we have seen cases of both Coats plus (CRMCC, cerebroretinal microangiopathy with calcifications and cysts) and SPENCD (spondyloenochondrodysplasia) initially considered as AGS (Briggs et al., 2008b; Navarro et al., 2008). Cases with later onset of a nonspecific 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.
ACKNOWLEDGMENTS I would like to thank all of the patients, families, and clinicians that have contributed to our work on Aicardi– Goutie`res syndrome. I would also like to acknowledge funding support from many sources, but in particular the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement number 241779.
REFERENCES Aicardi J, Goutie`res F (1984). A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 15: 49–54. Aicardi J, Goutie`res F (2000). Systemic lupus erythematosus or Aicardi–Goutie`res syndrome? Neuropediatrics 31: 113. Akwa Y, Hassett DE, Eloranta ML et al. (1998). Transgenic expression of IFN-a in the central nervous system of mice protects against lethal neurotropic viral infection but
induces inflammation and neurodegeneration. J Immunol 161: 5016–5026. Ali M, Highet LJ, Lacombe D et al. (2006). A second locus for Aicardi–Goutie`res syndrome at chromosome 13q14-21. J Med Genet 43: 444–450. Barth PG, Walter A, van Gelderen I (1999). Aicardi–Goutie`res syndrome: a genetic microangiopathy? Acta Neuropathol 98: 212–216. Blau N, Bonafe L, Krageloh-Mann I et al. (2003). Cerebrospinal fluid pterins and folates in Aicardi–Goutie`res syndrome: a new phenotype. Neurology 61: 642–647. Briggs TA, Wolf NI, D’Arrigo S et al. (2008a). Band-like intracranial calcification with simplified gyration and polymicrogyria; a distinct “pseudo-TORCH” phenotype. Am J Med Genet 146A: 3173–3180. Briggs TA, Abdel-Salam GMH, Balicki M et al. (2008b). Cerebroretinal microangiopathy with calcification and cysts (CRMCC). Am J Med Genet 146A: 182–190. Crow YJ, Jackson A, Roberts E et al. (2000). Aicardi– Goutie`res syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21. Am J Hum Genet 67: 213–221. Crow YJ, Black DN, Bond J et al. (2003). Cree encephalitis is allelic with Aicardi–Goutie`res syndrome; implications for the pathogenesis of disorders of interferon alpha metabolism. J Med Genet 40: 183–187. Crow YJ, Massey RF, Innes JR et al. (2004). Congenital glaucoma and brain stem atrophy as features of Aicardi– Goutie`res syndrome. Am J Med Genet 129: 303–307. Crow YJ, Hayward BE, Parmar R et al. (2006a). Mutations in the gene encoding the 3’–5’ DNA exonuclease TREX1 cause Aicardi–Goutie`res syndrome at the AGS1 locus. Nat Genet 38: 917–920. Crow YJ, Leitch A, Hayward BE et al. (2006b). Mutations in genes encoding ribonuclease H2 subunits cause Aicardi– Goutie`res syndrome and mimic congenital viral brain infection. Nat Genet 38: 910–916. D’Arrigo S, Riva D, Bulgheroni S et al. (2008). Aicardi– Goutie`res syndrome: description of a late onset case. Dev Med Child Neurol 50: 631–634. Dale RC, Tang SP, Heckmatt JZ et al. (2000). Familial systemic lupus erythematosus and congenital infection-like syndrome. Neuropediatrics 31: 155–158. Dale RC Gornall H, Singh-Grewal D et al. (2010). Familial Aicardi–Goutie`res syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures. Am J Med Genet A 152A: 938–942. De Laet C, Goyens P, Christophe C et al. (2005). Phenotypic overlap between infantile systemic lupus erythematosus and Aicardi–Goutie`res syndrome. Neuropediatrics 36: 399–402. Goutie`res F, Aicardi J, Barth PG et al. (1998). Aicardi– Goutie`res syndrome: an update and results of interferonalpha studies. Ann Neurol 44: 900–907. Haaxma CA, Crow YJ, van Steensel MA et al. (2010). A de novo Asp18Asn mutation in TREX1 in a patient with Aicardi–Goutie`res syndrome. Am J Med Genet 152A: 2612–2627.
AICARDI–GOUTIE`RES SYNDROME Jepps H, Seal S, Hattingh L et al. (2008). The neonatal form of Aicardi–Goutie`res syndrome masquerading as congenital infection. Early Hum Dev 84: 783–785. Kumar D, Rittey C, Cameron AH et al. (1998). Recognisable inherited syndrome of progressive central nervous system degeneration and generalised intracranial calcification with overlapping phenotype of the syndrome of Aicardi and Goutie`res. Am J Med Genet 75: 508–515. Lebon P, Badoual J, Ponsot G et al. (1988). Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 84: 201–208. Lee-Kirsch MA, Gong M, Chowdhury D et al. (2007). Mutations in the gene encoding the 30 –50 DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39: 1065–1067. McEntagart M, Kamel H, Lebon P et al. (1998). Aicardi– Goutie`res syndrome: an expanding phenotype. Neuropediatrics 29: 163–167. Navarro V, Scott C, Briggs TA et al. (2008). Two further cases of spondyloenchondrodysplasia (SPENCD) with immune dysregulation. Am J Med Genet 146A: 2810–2815. Orcesi S, Pessagno A, Biancheri R et al. (2008). Aicardi– Goutie`res syndrome presenting atypically as a subacute leukoencephalopathy. Eur J Paediatr Neurol 12: 408–411. Ramesh V, Bernardi B, Stafa A et al. (2010). Intracerebral large artery disease in Aicardi–Goutie`res syndrome implicates
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SAMHD1 in vascular homeostasis. Dev Med Child Neurol 52: 725–732. Rasmussen M, Skullerud K, Bakke SJ et al. (2005). Cerebral thrombotic microangiopathy and antiphospholipid antibodies in Aicardi–Goutie`res syndrome – reports of two sisters. Neuropediatrics 36: 40–44. Rice G, Newman WG, Dean J et al. (2007a). Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi–Goutie`res syndrome. Am J Hum Genet 80: 811–815. Rice G, Patrick T, Parmar R et al. (2007b). Clinical and molecular phenotype of Aicardi–Goutie`res syndrome. Am J Hum Genet 81: 713–725. Rice GI, Bond J, Asipu A et al. (2009). Mutations involved in Aicardi–Goutie`res syndrome implicate SAMHD1 as regulator of the immune response. Nat Genet 41: 829–832. Stetson DB, Ko JS, Heidmann T et al. (2008). Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134: 587–598. Tolmie JL, Shillito P, Hughes-Benzie R et al. (1995). The Aicardi–Goutie`res syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis). J Med Genet 32: 881–884. Yang YG, Lindahl T, Barnes DE (2007). Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131: 873–886.
Chapter 166
Aicardi–Goutie`res syndrome YANICK J. CROW* Genetic Medicine, University of Manchester, St Mary’s Hospital, Manchester, UK
INTRODUCTION In 1984, Jean Aicardi and Franc¸oise Goutie`res 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 (Aicardi and Goutie`res, 1984). 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-a (IFN-a) in the CSF of affected children (Lebon et al., 1988). Other landmark clinical papers include the descriptions of chilblain lesions (Tolmie et al., 1995), occasional normocephaly and preservation of intellect (McEntagart et al., 1998), normal CSF white cell counts even in the early stages of the disease process (Crow et al., 2003), raised levels of CSF neopterin as a diagnostic marker (Blau et al., 2003), and intracerebral large vessel inflammatory disease associated with SAMHD1 mutations (Ramesh et al., 2010). The first gene localization for AGS was reported to chromosome 3p21 in 2000 (Crow et al., 2000), 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 (Ali et al., 2006). In 2006, four genes were identified which, when mutated, cause autosomal recessive AGS (Crow et al., 2006a, b). 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 (Rice et al., 2007a; Haaxma et al., 2010). A comprehensive genotype-phenotype analysis
(Rice et al., 2007b) showed that at least one further AGS-causing gene remained to be determined. In 2009, biallelic mutations in the SAMHD1 were identified in 13 families with AGS. Further genetic heterogeneity likely exists. The combined efforts of pediatric neurologists, clinical geneticists, innate immunologists, and cell biologists are producing rapid progress in the understanding of AGS which is now recognized to be an inflammatory immune disorder. These insights beg urgent questions about the use of immunosuppressive therapies in the treatment of AGS and related phenotypes.
NATURAL HISTORY OF AICARDI^GOUTIERES SYNDROME Presentation The presentation of AGS can be broadly divided into two types:
NEONATAL FORM A group of AGS patients, typically those with TREX1 mutations, present in the neonatal period with abnormal neurology manifest as jitteriness, poor feeding and neonatal seizures, features which are reflected in the finding of changes on brain imaging at birth. These infants frequently demonstrate hepatosplenomegaly with elevated liver enzymes, and thrombocytopenia with anemia necessitating recurrent platelet and red cell transfusion. 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 (Jepps et al., 2008).
*Correspondence to: Professor Yanick J. Crow, Genetic Medicine, University of Manchester, St Mary’s Hospital, Oxford Road, Manchester M13 9WL, UK. Tel: þ44-161-276-5165, Fax: þ44-161-276-6145, E-mail: [email protected]
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LATER ONSET FORM All other children 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. This encephalopathic phase usually lasts several months, after 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 following months of normal development raises the possibility that the condition might occur in considerably older individuals too (Orcesi et al., 2008). The stimulus for the disease onset is unknown, and why the disease tends to “burn out” after several months is also not understood. Recently, milder phenotypes have been associated with mutations in SAMHD1. Dale et al. (2010) reported two siblings compound heterozygous for null mutations in SAMHD1. The older girl showed mild intellectual disability with microcephaly. Her younger brother had significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains and recurrent mouth ulcers. One of the siblings had a chronic progressive deforming arthropathy of the small and large joints with secondary contractures. An additional previously undescribed feature of AGS, which so far seems to be exclusively related to SAMHD1 mutations, is intracranial large vessel disease causing both intracranial stenoses, in some cases reminiscent of moyamoya syndrome, and aneurysms (Ramesh et al., 2010).
Long-term outcome The long-term neurological phenotype of all patients is consistent, although variations are observed in the severity of the associated handicap. 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 children have been noted to demonstrate a marked startle reaction to sudden noise and in some cases the differentiation from epilepsy can be difficult. At least one child was initially diagnosed with hyperekplexia. Most patients are severely intellectually and physically impaired. However, some children with RNASEH2B and SAMHD1 mutations have relatively, sometimes perhaps completely, preserved intellectual
function with good comprehension and retained communication. For example, 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 (McEntagart et al., 1998). 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 children 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 although glaucoma is seen in some cases (Crow et al., 2004). 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, in most cases there appears to be no significant 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 Neuroimaging The cardinal features of AGS on brain imaging are intracranial calcification, a leukodystrophy, and cerebral atrophy (Figs 166.1 and 166.2). 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. Affected sibling pairs have been described as discordant for the presence of intracranial calcification so that 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. Of particular importance, intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units. Consequently, AGS should be considered in the differential diagnosis of any unexplained leukoencephalopathy and CT scanning is warranted in cases conforming to the clinical scenarios we have outlined above. Most patients demonstrate nonspecific white matter changes, symmetrically involving the lobar white matter with relative sparing of the strictly periventricular area, the corpus callosum, the capsules and the optic radiations. However, some patients show marked frontotemporal white matter involvement with
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Fig. 166.1. Examples of intracranial calcification on CT scan in patients with AGS. Calcification is seen in the basal ganglia (A, B), dentate nuclei of the cerebellum (C), in a periventricular distribution, (D) and within the deep white matter (E).
cyst formation, so that Alexander disease, vanishing white matter disease, and megalencephaly with cystic leukoencephalopathy have been considered and tested for. Additionally, we know of one affected child with a confirmed molecular diagnosis of AGS (RNASEH2B mutations) whose only clinical feature is a spastic diplegia and who has a completely normal cranial MRI at age 8 years. Cerebral atrophy is present in the majority of children and some demonstrate marked brainstem and cerebellar shrinkage also. Since limb dystonia is frequently seen in affected children, AGS should be considered in the differential diagnosis of pontocerebellar hypoplasia type II. As noted above, five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains
and ischemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral hemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin.
Cerebrospinal fluid: white cells, IFN-a, and neopterin A CSF lymphocytosis (5 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-a in the CSF of AGS patients falls to normal over the first few years of life. Moreover, in our
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Fig. 166.2. The spectrum of brain changes seen on MRI in patients with AGS. Hypointensity on T1-weighted imaging (A) and hyperintensity on T2-weighted imaging (B, C) of the white matter. Extensive bitemporal cystic lesions (D). Significant thinning of the brainstem and cerebellar atrophy (E).
series, a normal CSF white cell count was documented in the presence of elevated CSF IFN-a titers on 10% of occasions in the first year of life. 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-a appears to be a reliable marker of AGS. Again, titers tend to fall to normal after the first few years of life. Blau et al. described a possible variant of AGS associated with high levels of CSF pterins (2003). Subsequent studies in mutation-positive AGS cases show that CSF neopterin is consistently raised and is a thus a reliable disease marker (Rice et al., 2007b). Whether all or some
of the cases described by Blau et al. have AGS, or a separate condition, remains to be determined. Again, the level of neopterin tends to normalize over time.
ASSOCIATED FEATURES Chilblains Chilblains are seen in approximately 40% of AGS patients and can occur in association with mutations in any of the AGS1—4 genes. 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
AICARDI–GOUTIE`RES SYNDROME 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 complement in vessel walls. Treatment with antiinflammatory agents and vasodilators has generally been of little efficacy although no formal trials have been undertaken.
Other disease associations A small number of children with AGS have been recorded with raised levels of auto-antibodies, hypothyroidism, insulin dependent diabetes mellitus (IDDM), and hemolytic anemia. A polygammaglobulinemia is a common finding. Frank systemic lupus erythematosus (SLE) is very unusual (Aicardi and Goutie`res, 2000; Dale et al., 2000; De Laet et al., 2005; Rasmussen et al., 2005), but the identification of heterozygous TREX1 mutations in a cohort of SLE patients (LeeKirsch et al., 2007) (see below) indicates that AGS patients, and their parents, should be monitored for features of autoimmune disease. A small number of AGS patients have demonstrated glaucoma, neonatal cardiomyopathy and a demyelinating peripheral neuropathy.
NEUROPATHOLOGY The major features on post-mortem include brain atrophy, loss of myelin, infarction, and calcification. Calcium deposits can be seen in areas of infarction, in a perivascular distribution, or as small accretions not necessarily associated with necrosis or blood vessels (Goutie`res et al., 1998; Kumar et al., 1998). The finding of wedgeshaped infarctions together with patchy myelin loss and calcified deposits in the media, adventitia and perivascular space of small blood vessels led Barth et al. (1999) to postulate that Aicardi–Goutie`res syndrome might represent a primary genetic angiopathy. Such observations are interesting in view of the neuropathological changes seen in an astrocyte-specific IFN-a overproducing transgenic mouse (Akwa et al., 1998) and the known antiangiogenic effects of IFN-a.
GENETICS A comprehensive study of the mutation spectrum in 127 pedigrees with a clinical diagnosis of AGS was published in 2007 (Rice et al., 2007b). 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
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these families likely share a very distant common ancestor). De novo heterozygous TREX1 mutations causing AGS are an infrequent, but important, mechanism of AGS (Rice et al., 2007a). At least one further diseaserelated gene remains to be identified. 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 facilitates targeted gene testing. Mutations in SAMHD1 include missense and nonsense variants, as well as exonic deletions (Rice et al., 2009; Ramesh et al., 2010). There is a recurrent deletion of exon 1 in individuals of Ashkenazi Jewish ancestry.
PATHOGENESIS The pathology of the chilblain lesions and the observation of a small number of AGS children with autoantibodies, hypothyroidism, IDDM, and lupus suggests immune dysfunction is a major factor in AGS (Rice et al., 2007b). Interestingly, heterozygous TREX1 mutations have been described in an autosomal dominant cutaneous form of SLE called familial chilblain lupus (Rice et al., 2007a), and heterozygous TREX1 mutations have been reported in a cohort of lupus patients (LeeKirsch et al., 2007). The precise functions of TREX1 and the RNASEH2 complex proteins are unknown. However, it is predicted that they function as nucleases involved in removing endogenous nucleic acid species produced during normal cellular processes (Yang et al., 2007), and that a failure of this process results in inappropriate activation of the innate immune system (Stetson et al., 2008). This hypothesis would explain the phenotypic overlap of AGS with congenital infection and some aspects of SLE where an IFN-a mediated innate immune response is triggered by viral and host nucleic acids respectively. The finding that crosses of the Trex1 null mouse with animals either unable to signal through type I interferons or produce functional lymphocytes opens up exciting therapeutic possibilities requiring urgent attention.
MANAGEMENT The general management of children with AGS is similar to that of any child 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 children with the neonatal form of AGS. In relation to the chilblain lesions, neither immunosuppressive nor vasodilator therapy is useful therapeutically to our knowledge. Considering the evidence suggesting that AGS is an inflammatory disorder, the most pressing issue at this time
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regards the use of immunosuppression – particularly during the acute phase of the disease. At the moment the limited available evidence for the efficacy of steroids and other immunosuppressants is equivocal (D’Arrigo et al., 2008; Orcesi et al., 2008). The observation of progressive intracerebral large artery inflammatory disease indicates that treatment beyond the initial disease presentation may also be important – at least in the setting of SAMHD1-related AGS.
DIFFERENTIAL DIAGNOSIS The presence of intracranial calcification is not per se a particularly specific diagnostic sign. In the neonatal form of AGS, congenital infection represents the main differential diagnosis. We have recently delineated another congenital infection-like syndrome which can be differentiated from AGS by the presence of “bandlike” calcification and polymicrogyria (which are not normally associated with AGS) (Briggs et al., 2008a). Other 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 metabolism and celiac disease, and we have seen cases of both Coats plus (CRMCC, cerebroretinal microangiopathy with calcifications and cysts) and SPENCD (spondyloenochondrodysplasia) initially considered as AGS (Briggs et al., 2008b; Navarro et al., 2008). Cases with later onset of a nonspecific 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.
ACKNOWLEDGMENTS I would like to thank all of the patients, families, and clinicians that have contributed to our work on Aicardi– Goutie`res syndrome. I would also like to acknowledge funding support from many sources, but in particular the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement number 241779.
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