アイカルディ症候群

Background: Aicardi-Goutières syndrome (AGS) is a neurogenetic leukoencephalopathy that typically manifests within the first 6 months of life. Classically, AGS presents with an early encephalopathic episode characterised by feeding difficulties, irritability and psychomotor regression or delay. Cutaneous lesions affecting the extremities and epilepsy are common, with symptoms usually evolving over weeks to months before stabilising. Milder phenotypes have been described, often demonstrating relative preservation of language and cognitive function. Case presentation: Here, we report a case of a 31-year-old woman with compound heterozygous variants in the ADAR gene: (GRCh38) NM_001111.4:c.577C>G p.(Pro193Ala) and (GRCh38) NM_001111.4:c.1111_1112del p.(Ser371Cysfs*3), consistent with AGS. The developmental history revealed normal early motor milestones. At age 3, she developed progressive ataxia and hypotonia. Over time, she exhibited spasticity, dystonia and learning difficulties, along with significant cardiac valvular calcification. Conclusions: The patient was recently referred for consideration of treatment with baricitinib, a selective JAK1/JAK2 inhibitor. This case underscores the importance of considering AGS in individuals with non-classical presentations, particularly when extracerebral calcification is a notable feature.

PURPOSE OF REVIEW: Genetic autoinflammatory conditions constitute an increasing field. Among them, type I interferonopathies (IFNp-I) were conceptualized 15 years ago as inborn errors of immunity due to chronic activation of the type I interferon (IFN-I) signalling pathway. Here, we provide recent insights in genetic mechanisms, clinical phenotypes and therapeutic options for these severe and rare disorders. RECENT FINDINGS: We will cover the novel findings into disease mechanisms, particularly the role of PTP1B in STING and IFNAR signalling, as well as the contribution of endosomal TLR pathways. We will also discuss the expanding phenotypic spectrum highlighted by recent case reports and cohort studies, together with the topic of clinical expressivity, including clinical non-penetrance, and possible mechanistic explanations such as monoallelic expression, the STING HAQ haplotype, and innovative approaches to characterise disease variability. Finally, we discuss current targeted therapeutic approaches for these disabling conditions, as well as potential new treatments for the future. SUMMARY: Overall, these findings highlight the need to consider these rare diseases across a wide range of clinical phenotypes. Advances in next-generation sequencing have enabled a genetic diagnosis in suspected cases and the implementation of targeted treatments, thereby reducing diagnostic uncertainty and providing the possibility of genetic counselling.

Type I diabetes (T1D) is an autoimmune disorder in which the insulin producing cells of the pancreas are attacked and destroyed by autoreactive T cells. The innate immune mechanisms that contribute to T1D remain incompletely defined. Genome-wide association studies in humans have identified alleles of the IFIH1 gene, which encodes the intracellular RNA sensor MDA5, that are strongly associated with development of T1D. We previously found that MDA5 signaling drives disease and mortality in a mouse model of Aicardi-Goutieres Syndrome (AGS) caused by mutations in the ADAR1 RNA editing enzyme. Genetic dissection of disease in this ADAR1 mutant mouse model revealed that the double stranded RNA-activated kinase PKR and the RNA sensor ZBP1 are also essential for disease. To test the role of intracellular RNA detection in T1D in the nonobese diabetic (NOD) mouse model, we used CRISPR targeting to generate NOD mice targeted for Ifih1, Eif2ak2 (PKR) and Zbp1 . We found that haploinsufficiency for Ifih1 resulted in modest but significant protection from T1D only in male NOD mice, but neither PKR nor ZBP1 contributed to T1D onset or incidence. Moreover, treatment of NOD mice with a pharmacological inhibitor of the integrated stress response (ISR) had no effect on T1D incidence in female NOD mice, but accelerated and exacerbated disease in male NOD mice. Together, our findings demonstrate that MDA5 and the ISR contribute to sex-specific disease incidence in NOD mice.

SAMHD1 is the lone human dNTP triphosphohydrolase and is linked to antiviral defense, nucleotide pool homeostasis, chemotherapy resistance, and the autoinflammatory Aicardi-Goutières syndrome. Although its substrate specificity and nucleotide-dependent oligomerization have been extensively studied, the identity and mechanistic roles of its metal cofactors remain poorly understood. Here, we integrate selective metal enrichment, spectroscopy, biochemical reconstitution, and enzyme kinetics to define the metal requirements underlying SAMHD1 activation and catalysis. We show that robust SAMHD1 activity is preferentially supported by transition metals and that the enzyme readily assembles multiple iron-containing dinuclear active sites in solution. Iron preferentially binds to one position of the bimetallic core and promotes recruitment of a second divalent metal required for catalysis. Although manganese can substitute for iron, it alters metal-binding equilibria and less efficiently supports dinuclear cofactor assembly, highlighting a specialized organizational role for iron. In contrast, the second site remains comparatively permissive and accommodates various divalent metal ions with distinct functional consequences. Mixed-metal active sites further retain catalytic activity across redox conditions that otherwise suppress activity in homodinuclear diiron configurations, suggesting that metal plasticity buffers SAMHD1 against oxidative inhibition. Transition metals additionally act as higher-affinity allosteric activators than Mg2+, revealing that metal identity contributes to both catalytic and regulatory layers of SAMHD1 function. Cumulatively, these findings redefine the metal requirements of SAMHD1 and establish a framework in which iron-dependent active site organization and mixed-metal flexibility cooperate to sustain dNTP hydrolysis under changing cellular environments and metal flux conditions.

Adenosine deaminase acting on RNA 1 (ADAR1), which mediates adenosine-to-inosine RNA editing, is expressed as two isoforms, p110 and p150. Deletion of Adar1 p150 in mice results in embryonic lethality caused by aberrant activation of melanoma differentiation-associated protein 5 (MDA5)-mediated sensing of unedited endogenous transcripts, whereas Adar1 p110-specific deficient mice die postnatally through RNA editing-independent mechanisms. ADAR1 mutations cause Aicardi-Goutières syndrome (AGS), a congenital autoinflammatory disease accompanied by encephalopathy with a type I interferon (IFN) signature. However, the roles of ADAR1 in neurons remain elusive. Here, we show that neuron-specific deletion of Adar1 (both p110 and p150) in mice caused early postnatal lethality with elevated expression of type I IFN-stimulated genes (ISGs). Ventricular obstruction due to hypoplasia of the choroid plexus and ependymal cells, which was accompanied by gliosis, was observed. Of note, both selective restoration of ADAR1 p150 function and deletion of MDA5 largely normalized type I ISG expression and ameliorated ventricular obstruction but failed to rescue early postnatal lethality. Furthermore, selective restoration of RNA editing-independent function of ADAR1 p110 was also insufficient to rescue the early postnatal lethality, suggesting that both ADAR1 p110 and p150 in neurons are essential for postnatal survival.