Chapter 166 - Aicardi–Goutières syndrome
Introduction
In 1984, Jean Aicardi and Françoise Goutières 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 Goutières, 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-α (IFN-α) 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, Crow et al., 2006b). 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.
Section snippets
Presentation
The presentation of AGS can be broadly divided into two types:
Neuroimaging
The cardinal features of AGS on brain imaging are intracranial calcification, a leukodystrophy, and cerebral atrophy (Fig. 166.1, Fig. 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
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 and hands are also very cold, even in the absence of overt chilblains. The lesions probably result from an
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 (Goutières et al., 1998, Kumar et al., 1998). The finding of wedge-shaped infarctions together with patchy myelin loss and calcified deposits in the media, adventitia and perivascular space of small blood vessels led Barth et al.
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 these
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 (Lee-Kirsch et al., 2007). The
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
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 “band-like” calcification and polymicrogyria (which are not normally associated with AGS) (Briggs et al., 2008a). Other genetic conditions to consider include mitochondrial
Acknowledgments
I would like to thank all of the patients, families, and clinicians that have contributed to our work on Aicardi–Goutières 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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