RESUMO
Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS.
Assuntos
Astrócitos/metabolismo , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Animais , Doenças Autoimunes do Sistema Nervoso/complicações , Encefalite/complicações , Encefalite/metabolismo , Homeostase , Humanos , Inflamação/complicações , Inflamação/metabolismo , Interferon-alfa/metabolismo , Mutação , Malformações do Sistema Nervoso/complicações , Transdução de SinaisRESUMO
Chorea is defined as a syndrome characterized by brief, abrupt involuntary movements resulting from a continuous flow of random muscle contractions. There are genetic and non-genetic causes of chorea. The most common genetic cause of chorea is Huntington's disease (HD). Non-genetic forms of chorea include vascular choreas, auto-immune choreas, metabolic and toxic choreas, and drug-induced choreas. This chapter provides an overview of clinical features, pathogenesis and management of HD, other important genetic causes of chorea, Sydenham's chorea, other autoimmune choreas and vascular choreas.