Nucleotide metabolism, leukodystrophies, and CNS pathology

Abstract

The balance between a protective and a destructive immune response can be precarious, as exemplified by inborn errors in nucleotide metabolism. This class of inherited disorders, which mimics infection, can result in systemic injury and severe neurologic outcomes. The most common of these disorders is Aicardi Goutières syndrome (AGS). AGS results in a phenotype similar to "TORCH" infections (Toxoplasma gondii, Other [Zika virus (ZIKV), human immunodeficiency virus (HIV)], Rubella virus, human Cytomegalovirus [HCMV], and Herpesviruses), but with sustained inflammation and ongoing potential for complications. AGS was first described in the early 1980s as familial clusters of "TORCH" infections, with severe neurology impairment, microcephaly, and basal ganglia calcifications (Aicardi & Goutières, Ann Neurol, 1984;15:49-54) and was associated with chronic cerebrospinal fluid (CSF) lymphocytosis and elevated type I interferon levels (Goutières et al., Ann Neurol, 1998;44:900-907). Since its first description, the clinical spectrum of AGS has dramatically expanded from the initial cohorts of children with severe impairment to including individuals with average intelligence and mild spastic paraparesis. This broad spectrum of potential clinical manifestations can result in a delayed diagnosis, which families cite as a major stressor. Additionally, a timely diagnosis is increasingly critical with emerging therapies targeting the interferon signaling pathway. Despite the many gains in understanding about AGS, there are still many gaps in our understanding of the cell-type drivers of pathology and characterization of modifying variables that influence clinical outcomes and achievement of timely diagnosis.

Keywords: Aicardi Goutieres syndrome; inborn error of metabolism; leukodystrophy; type I interferonopathy.

FIGURE 1

Molecular mechanism of Aicardi Goutières syndrome (AGS). A pathogenic variant in any of nine genes attributed to AGS result in dysfunction in RNA/DNA metabolism and subsequent activation of the Type I interferon pathway. Normally this pathway is an essential part of the antiviral response, but in AGS, this pathway is constitutively active. This similarity in mechanism (and phenotype) has led to AGS being referred to as a “pseudo-TORCH” infection. dNTP, deoxynucleotide triphosphate; dsDNA, double-stranded DNA; dsRNA, double-stranded RNA; IFN, interferon; IRF9, interferon regulatory factor; ISG, interferon signaling gene; ISRE, interferon-sensitive response element; JAK, Janus kinase; ssDNA, single-stranded DNA; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2.

FIGURE 2

Cellular mechanisms of AGS. The pathophysiology of AGS occurs by direct mutation-related dysfunction, IFNα production and action, and autoimmune-mediated tissue injury. While disease-causing genes are expressed by most cells in the brain, astrocytes and microglia are the primary sources of IFNα in AGS. Causal mutations can promote nucleic acid accumulation and disordered nucleic acid sensing ultimately leading to type I IFN release. This release promotes ISG expression via interferon-α/β receptor (IFNAR) signaling and cytokine production by microglia, astrocytes, and endothelial cells. Though the precise mechanisms are poorly understood, this leads to feedforward gliosis, blood–brain barrier dysfunction, perivascular calcification, and neuron and oligodendrocyte death. Systemic IFN production can directly cause CNS endothelial dysfunction and impair productive adaptive immune responses—promoting CNS infiltration of “peripheral” immune cells (lymphocytes, dendritic cells, macrophages), and in some cases, enhanced antigen presentation and autoimmunity. Current therapies are supportive or work to disrupt IFNAR signaling by JAK inhibition. How each cellular component of the runaway inflammatory response leads from gene mutation to AGS neuropathology is unclear, but is critical to improve therapies and disrupt disease pathogenesis. B, B cell; CNS, central nervous system; DC, dendritic cell; M0, macrophage; T, T cell.

FIGURE 3

AGS results in systemic inflammation. AGS is a multisystemic disease of immune dysfunction. While not all organs are affected in all individuals, systemic screening of treatable complications is critical. Common complications include chilblains of the skin, cytopenias, and inflammatory hepatitis. Severe, but rare sequelae include moyamoya syndrome and pulmonary hypertension, both of which can be fatal. Many of the systemic complications of AGS are shared across the type I interferonopathies.