The neuropathology of Aicardi-Goutières syndrome

doi:10.1053/ejpn.2002.0570

European Journal of Paediatric Neurology

Volume 6, Supplement A, May 2002, Pages A27-A31

https://doi.org/10.1053/ejpn.2002.0570 Get rights and content

Abstract

Aicardi-Goutières syndrome is an autosomal recessive neurodegenerative disorder with unique characteristics which include cerebrospinal fluid lymphocytosis, cytokine involvement (interferon-alpha in plasma and in cerebrospinal fluid), a unique distribution of cerebral calcifications, and early loss of myelin. Surprisingly only a very small number of detailed neuropathological studies are available. This paper summarizes the findings. Calcifications are both present as concretions and as perivascular cuffs of calcium surrounding small vessels. Small vessel involvement (microangiopathy) is apparent from a typical distribution of microinfarctions in at least one case studied. Together with signs of extracerebral vascular involvement known from earlier reports this finding points to microangiopathy as an important pathogenic mechanism in Aicardi-Goutières syndrome.

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Cited by (35)

Degenerative Disorders of the Newborn
2018, Volpe's Neurology of the Newborn
Degenerative disorders of the newborn are relatively rare. Nonetheless, they are important to recognize because a few are treatable when diagnosed early. Dividing these disorders into those that primarily affect gray matter, white matter, or both is useful. Disorders of gray matter are characterized by seizures, myoclonus, spikes, or sharp activity on electroencephalogram, failure of cognitive development, and retinal disease. Some are accompanied by visceral storage including GM₁ gangliosidosis, GM₂ gangliosidosis, Niemann-Pick disease, Gaucher disease, Farber disease, and infantile sialic acid storage disease. Other gray matter disorders such as Tay-Sachs disease, congenital neuronal ceroid-lipofuscinosis, Alpers disease, and Menkes disease lack visceral storage. White matter disorders are characterized by marked motor deficits and slow activity on electroencephalogram and include Canavan disease, Alexander disease, Krabbe disease, Pelizaeus-Merzbacher disease, and Aicardi-Goutieres disease. Disorders that affect both white and gray matter often target subcellular structures (mitochondria, peroxisomes), target amino acid or neurotransmitter synthesis pathways, and can have regional selectivity for the cerebellum, pons, or basal ganglia. Examples include neonatal adrenoleukodystrophy, Zellweger syndrome, Leigh syndrome, mitochondrial encephalopathies, congenital disorders of glycosylation, pontocerebellar hypoplasias, neurotransmitter defects including serine synthesis deficiency, and Rett syndrome in males. We discuss each of these disorders briefly, focusing on clinical features, diagnosis, genetics, neuropathology, neuroimaging findings, current treatments, and emerging therapies.
Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha: Relationship to Monoamines and Depression
2009, Biological Psychiatry
Citation Excerpt :
Given microglial expression of IFN-alpha receptors (50), direct effects of IFN-alpha on microglial cytokine production including IL-6 may also be involved. Interferon-alpha has been detected in CSF of patients with a number of infectious diseases, including viral and bacterial meningitis as well as systemic lupus erythematosis and Aicardi-Goutieres syndrome, where high concentrations of blood and CSF IFN-alpha are associated with diffuse neuropathology (29,51–55). In HIV infection, CSF IFN-alpha was found to be significantly higher in subjects with HIV dementia compared with patients without dementia and control subjects (28,29).
Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established.
Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after ∼12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale.
Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r² = −.25, p < .05).
These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.
Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?
2008, DNA Repair
The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurodegenerative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi–Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.
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^f1: Correspondence: Prof. Peter G Barth, Department of Pediatric Neurology, Emma Children's Hospital/ AMC, University of Amsterdam, PO Box 22700,1100DE Amsterdam, The Netherlands. Tel: +31 20 5667508; Fax: +31 20 6917735e-mail:[email protected]

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Review articleThe neuropathology of Aicardi-Goutières syndrome

Abstract

Review article
The neuropathology of Aicardi-Goutières syndrome