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Background: Type I interferonopathies including Aicardi-Goutiéres Syndrome (AGS) represent a heterogeneous group of clinical phenotypes. Herein, we present a Case with combined AGS and Cornelia de Lange Syndrome (CdLS)—a cohesinopathy—with comprehensive analysis of the immune and genomic abnormalities. Case and methods: A 20-year old man presented with chilblain lesions and resorption of distal phalanges of fingers and toes, somatic and psychomotor retardation, microcephaly, synophrys, hearing losing and other aberrancies consistent with the phenotype of CdLS. We used whole exome sequencing to genetically map the associated mutations and performed transcriptome profiling and enrichment analysis in CD14+ monocytes of the patient and immune phenotyping by mass cytometry (CyToF), comparing to healthy individuals and lupus patients as disease controls. DNA damage response was assayed by confocal microscopy in the peripheral blood of this patient. Results: Next generation exome sequencing confirmed a homozygous SAMHD1 gene mutation and a hemizygous non-synonymous mutation on SMC1A gene, responsible for the AGS and CdLS, respectively. Transcriptome profiling of CD14+ monocytes of the patient showed enrichment of type I IFN signaling and enhanced DNA damage response pathway. Broad immune phenotype of the peripheral blood of the patient revealed absence of activated T cell populations, increased frequency of NK cells and plasmablasts and enhanced granulocytic lineage. Further analysis suggested activation of the ATM branch of DNA damage response and increased apoptosis in the periphery of the patient. Conclusions: A rare case of a patient bearing two genetic lesions (responsible for AGS/CdLS syndromes) exhibits distinctive features of genomic damage and interferon responses. Immune phenotype revealed granulocytic skewing and absence of activated T cells compatible with chronic antigenic stimulation and/or homing of these cells at sites of inflammation. [ABSTRACT FROM AUTHOR]

Background: Aicardi-Goutières Syndrome is a monogenic type 1 interferonopathy with infantile onset, characterized by a variable degree of neurological damage. Approximately 7% of Aicardi-Goutières Syndrome cases are caused by pathogenic variants in the ADAR gene and are classified as Aicardi-Goutières Syndrome type 6. Here, we present a new homozygous pathogenic variant in the ADAR gene. Currently, Janus Kinase inhibitors have been proposed to treat selected interferonopathies such as Aicardi-Goutières Syndrome, although limited information is available on its use and results in the neonatal presentation of this disease. Case presentation: We present two siblings, a male neonate with congenital petechial rash, severe thrombopenia and generalized hypotonia and his deceased sister who had normal development until 5 months of age, when she suffered acute encephalopathy. We describe the clinical course, complementary examinations and follow-up with early treatment of the newborn with ruxolitinib. The homozygous variant c.2908G > A (p.Ala970Thr) in the ADAR gene was found in both siblings, parents were heterozygous carriers. Conclusions: The homozygous variant c.2908G > A (p.Ala970Thr) in the ADAR gene causes Aicardi-Goutières Syndrome type 6. Intrafamilial phenotypic spectrum of the disease varies among individuals with the same pathogenic variant. Early initiation of ruxolitinib improved systemic signs but did not prevent the progression of neurological disease. [ABSTRACT FROM AUTHOR]

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by excessive interferon-alpha production, leading to central nervous system damage, manifesting as subacute encephalopathy in infancy. Moreover, the phenotype includes frostbite-like skin lesions, hepatosplenomegaly, and endocrinopa­thies. Here we report a case of a patient with this syndrome and a concurrent urinary system malformation. A 3-year-old boy with AGS was referred to the nephrology clinic due to recurrent urinary tract infections. Diagnostics including voiding cystourethrography and renal scintigraphy revealed left-sided grade III vesicoureteral reflux and minor post-inflammatory lesions. Subsequent cystometry indicated subvesical obstruction, and posterior urethral valves were incised during cystoscopy. Since the initiation of treatment with furazidine, doxazosin and oxybutynin hydrochloride, the urinary tract infection has not recurred. Urinary system anomalies are a common issue in genetic syndromes. To date, urinary tract abnormalities have not been described as a part of the AGS phenotype.

ObjectiveTo explore the clinical and genetic features of Aicardi-Goutières syndrome (AGS) caused by IFIH1 gene mutation.MethodsWe analyzed the clinical features and genetic mutation results of a boy with AGS type 7 and conducted a retrospective review of the literature of the characteristics and clinical features of IFIH1 gene mutations in AGS type 7.ResultsIn the case of this report, the patient, 13-year-old boy, exhibited gait abnormalities at age 3. As the condition was progressive, the boy has paraplegia of the lower limbs. The first brain MRI showed no lesions.Rehabilitation therapy in the past several years has shown no improvement.Recent brain CT revealed multiple intracranial calcifications. The whole-exome sequencing identified a heterozygous mutation in the IFIH1 gene (c.2159G > A, p.R720Q)- a known pathogenic mutation. Through review of the literature, we identified 69 cases of AGS type 7 (including the case reported here)which showed that skin and neurological system involvement are most commonly seen. Among these 69 patients, there were 30 different mutations in the IFIH1 gene, all of which are missense mutations. Seven patients had the same gene mutation as the boy in this study does, but their clinical features differed. In terms of treatment, Janus kainase(JAK) inhibitors are commonly used.Additionally, recent reports showed that tocilizumab treatment have been used for this condition.ConclusionsAGS7 is a type of I interferonopathy. Growth retardation and nervous system involvement are the most prevalent.The condition usually involve the skin, blood system, digestive system, kidney, heart, and other organs. JAK inhibitors prove effective for this disease.

ABSTRACT Importance Aicardi–Goutières syndrome (AGS) is a rare genetic disorder mainly affecting the central nervous system and autoimmunity. However, research on AGS among Chinese patients is limited. Objective To summarize the neurologic phenotypes and genetic causes in pediatric AGS patients, providing insights for early recognition and diagnosis in the Chinese population. Methods Clinical features and neuroimaging results of the patients diagnosed with AGS from Beijing Children's Hospital between January 2018 and January 2022 were collected. Whole exome sequencing was used for genetic analysis. Results A total of 15 patients was included, all presenting with various neurological symptoms, including developmental delay (100%), motor skill impairment (100%), language disability (78.6%), dystonia (93.3%), microcephaly (73.3%), sleep disorders (26.7%), regression (20.0%), vessel disease (6.7%), and epilepsy (6.7%). Neuroimaging revealed intracranial calcification (86.7%), cerebral atrophy (73.3%), and leukodystrophy (73.3%). Seven genes were identified, with TREX1 being the most common (40.0%, 6/15), followed by IFIH1 (20.0%, 3/15). Variant c.294dupA (p.C99Mfs*3) was detected in four unrelated patients, accounting for 66.7% (4/6) patients with the TREX1 variant. A literature review showed that TREX1 gene mutations in 35.6% (21/59) of AGS patients among the Chinese population. Interpretation Neurological symptoms are the most prevalent and severe presentation of AGS. Diagnosis may be considered when symptoms such as developmental delay, dystonia, microcephaly, brain calcification, and leukodystrophy emerge. TREX1 mutations are predominant in the Chinese population.

Importance: Aicardi–Goutières syndrome (AGS) is a rare genetic disorder mainly affecting the central nervous system and autoimmunity. However, research on AGS among Chinese patients is limited. Objective: To summarize the neurologic phenotypes and genetic causes in pediatric AGS patients, providing insights for early recognition and diagnosis in the Chinese population. Methods: Clinical features and neuroimaging results of the patients diagnosed with AGS from Beijing Children's Hospital between January 2018 and January 2022 were collected. Whole exome sequencing was used for genetic analysis. Results: A total of 15 patients was included, all presenting with various neurological symptoms, including developmental delay (100%), motor skill impairment (100%), language disability (78.6%), dystonia (93.3%), microcephaly (73.3%), sleep disorders (26.7%), regression (20.0%), vessel disease (6.7%), and epilepsy (6.7%). Neuroimaging revealed intracranial calcification (86.7%), cerebral atrophy (73.3%), and leukodystrophy (73.3%). Seven genes were identified, with TREX1 being the most common (40.0%, 6/15), followed by IFIH1 (20.0%, 3/15). Variant c.294dupA (p.C99Mfs*3) was detected in four unrelated patients, accounting for 66.7% (4/6) patients with the TREX1 variant. A literature review showed that TREX1 gene mutations in 35.6% (21/59) of AGS patients among the Chinese population. Interpretation: Neurological symptoms are the most prevalent and severe presentation of AGS. Diagnosis may be considered when symptoms such as developmental delay, dystonia, microcephaly, brain calcification, and leukodystrophy emerge. TREX1 mutations are predominant in the Chinese population. [ABSTRACT FROM AUTHOR]

The critical need for awareness and genetic testing of the SAMHD1 deletion in Ashkenazi Jewish patients is highlighted owing to its relatively high carrier frequency. Early detection can prevent severe disease complications through targeted therapy.

Aicardi-Goutières Syndrome is a rare autosomal recessive disorder characterized by a triad of partial or complete agenesis of the corpus callosum, infantile spasms, and chorioretinal lacunae. The condition predominantly affects females, as males often do not survive the embryonic period. Intellectual disability associated with the syndrome ranges from mild to moderate. There is limited information in the literature regarding the oral manifestations of this syndrome. This case report aims to provide insights into the development of primary dentition in patients with Aicardi-Goutières Syndrome and to raise awareness about the oral and dental health needs of these rare pediatric patients, particularly during early childhood. In this case report, it was observed that the primary teeth of a 2-year-5-month-old patient had not yet erupted. Notably, even at 3 years and 1 month old, the patient's primary dentition remained incomplete despite continued monitoring during follow-up examinations. These patients often have limited ability to cooperate with dental treatments due to their intellectual disability, which complicates the process. Furthermore, due to the respiratory risks associated with the syndrome, dental treatments under general anesthesia are generally not preferred. In this context, maintaining the oral health of these patients and implementing preventive strategies, including topical fluoridation, along with appropriate oral hygiene instructions and dietary modifications, are crucial in managing patients with Aicardi-Goutières Syndrome. Pediatric dentists are responsible for educating families on these matters, and caregivers play a vital role in maintaining the oral health of these patients by collaborating closely with dental specialists. [ABSTRACT FROM AUTHOR]

Objectives Mutations in the TREX1 gene cause Aicardi-Goutières syndrome (AGS) 1, associated with a spectrum of autoimmune and neurodegenerative manifestations. AGS 1, the most severe neonatal type of AGS, is characterized by abnormal neurologic findings, visual inattention, hepatosplenomegaly, thrombocytopenia, skin rash, restlessness, and fever. Materials & Methods The present study described two affected siblings from an Iranian family whose phenotypes overlap with intrauterine infections. They had almost similar presentations, including developmental delay, microcephaly, no fix and follow epileptic seizures and the same pattern of brain CT scan involvements. Following clinical and paraclinical assessments, whole-exome sequencing was employed to determine the disease-causing variant, and subsequently, PCR-Sanger sequencing was performed to indicate the segregation pattern of the candidate variant in family members. Results Genetic analysis revealed a novel homozygous missense variant (c.461A>C; p.D154A) in the TREX1 gene in affected family members. Sanger sequencing of other family members showed the expected zygosities. Conclusion This study identifies a novel mutation in the TREX1 gene in this family and highlights the efficiency of next-generation sequencing-based techniques for obtaining a definite diagnosis in patients with early-onset encephalopathy. [ABSTRACT FROM AUTHOR]

Abstract Background Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy characterized by upregulation of the type I interferon pathway, poorly responsive to conventional immunosuppression. Case presentation We describe a 7-year-old Chinese boy who developed symptoms at the age of 6 months. He presented with a chilblain-like rash, leukopenia, neutropenia, elevated liver enzymesgrowth retardation, microcephaly, elevated acute phase reactants, intracranial calcification and leukodystrophy. At the age of 3 years old, whole-exome sequencing confirmed a de novo heterozygous gain-of-function mutation, c.1016 C > A (p.Ala339Asp), in the IFIH1 gene, and he was diagnosed with AGS7. He was treated with ruxolitinib accompanied by steroids and thalidomide for about four years. The rash, hematological manifestations, and the liver function were all improved, but the erythrocyte sedimentation rate remained consistently elevated until the addition of tocilizumab, a monoclonal antibody against interleukin 6. Conclusions Ruxolitinib was not successful in suppressing the inflammatory process, and tocilizumab produced highly encouraging results in reducing the inflammatory reaction of AGS. The study makes a significant contribution to the literature because we may found a potential alternative therapeutic option for AGS.

Aicardi–Goutières syndrome (AGS) is an autosomal recessive disease that mimics congenital viral infection and mainly affects the brain, immune system, and skin. The dominant clinical symptom is the subacute onset of severe encephalopathy, which manifests as irritability, loss of ability, slowing of head growth, and poor nutrition. Arteriopathy in AGS is an uncommon manifestation usually associated with mutations in the SAMHD1 gene. We present a rare case of a 3-year-old male due to failure to thrive, global developmental delay, microcephaly, poor vision, upper and lower limbs spasticity, and gastroesophageal reflux disease (GERD), who harbored early stenotic lesions of the large and medium intracranial arteries with ischemic sequelae in the early postnatal life. Performed genetic testing confirmed homozygous gene mutation, SAMHD1 associated with AGS type 5. By reviewing the available literature, we were able to find only one patient whose arterial lesions were diagnosed after 6 months. [ABSTRACT FROM AUTHOR]

Abstract Background Aicardi–Goutières syndrome (AGS) is a rare, autosomal recessive, hereditary neurodegenerative disorder. It is characterized mainly by early onset progressive encephalopathy, concomitant with an increase in interferon-α levels in the cerebrospinal fluid. Preimplantation genetic testing (PGT) is a procedure that could be used to choose unaffected embryos for transfer after analysis of biopsied cells, which prevents at-risk couples from facing the risk of pregnancy termination. Methods Trio-based whole exome sequencing, karyotyping and chromosomal microarray analysis were used to determine the pathogenic mutations for the family. To block the inheritance of the disease, multiple annealing and looping-based amplification cycles was used for whole genome amplification of the biopsied trophectoderm cells. Sanger sequencing and next-generation sequencing (NGS)-based single nucleotide polymorphism (SNP) haplotyping were used to detect the state of the gene mutations. Copy number variation (CNV) analysis was also carried out to prevent embryonic chromosomal abnormalities. Prenatal diagnosis was preformed to verify the PGT outcomes. Results A novel compound heterozygous mutation in TREX1 gene was found in the proband causing AGS. A total of 3 blastocysts formed after intracytoplasmic sperm injection were biopsied. After genetic analyses, an embryo harbored a heterozygous mutation in TREX1 and without CNV was transferred. A healthy baby was born at 38th weeks and prenatal diagnosis results confirmed the accuracy of PGT. Conclusions In this study, we identified two novel pathogenic mutations in TREX1, which has not been previously reported. Our study extends the mutation spectrum of TREX1 gene and contributes to the molecular diagnosis as well as genetic counseling for AGS. Our results demonstrated that combining NGS-based SNP haplotyping for PGT-M with invasive prenatal diagnosis is an effective approach to block the transmission of AGS and could be applied to prevent other monogenic diseases.

Background: Aicardi–Goutières syndrome (AGS) is a rare genetic disorder characterized by microcephaly, white matter lesions, numerous intracranial calcifications, chilblain skin lesions and high levels of interferon-α (IFN-α) in the cerebrospinal fluid (CSF). However, ocular involvement is reported significantly less frequently. Case presentation: We present a case of a neonate with hypotrophy, microcephaly, frostbite-like skin lesions, thrombocytopenia, elevated liver enzymes and hepatosplenomegaly. Magnetic resonance imaging (MRI) of the brain showed multiple foci of calcification, white matter changes, cerebral atrophy, and atrophic dilatation of the ventricular system. The inflammatory parameters were not elevated, and the infectious etiology was excluded. Instead, elevated levels of IFN-α in the serum were detected. Based on the related clinical symptoms, imaging and test findings, the diagnosis of AGS was suspected. Genetic testing revealed two pathogenic mutations, c.490C>T and c.222del (novel mutation), in the three prime repair exonuclease 1 (TREX1) gene, confirming AGS type 1 (AGS1). An ophthalmologic examination of the child at 10 months of age revealed an impaired pupillary response to light, a corneal haze with Haab lines in the right eye (RE), pale optic nerve discs and neuropathy in both eyes (OU). The intraocular pressure (IOP) was 51 mmHg in the RE and 49 in the left eye (LE). The flash visual evoked potential (FVEP) showed prolonged P2 latencies of up to 125% in the LE and reduced amplitudes of up to approximately 10% OU. This girl was diagnosed with congenital glaucoma, and it was managed with a trabeculectomy with a basal iridectomy of OU, resulting in a reduction and stabilization in the IOP to 12 mmHg in the RE and 10 mmHg in the LE without any hypotensive eyedrops. Conclusions: We present the clinical characteristics, electrophysiological and imaging findings, as well as the genetic test results of a patient with AGS1. Our case contributes to the extended ophthalmic involvement of the pathogenic c.490C>T and c.222del mutations in TREX1. [ABSTRACT FROM AUTHOR]

Background: Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy characterized by upregulation of the type I interferon pathway, poorly responsive to conventional immunosuppression. Case presentation: We describe a 7-year-old Chinese boy who developed symptoms at the age of 6 months. He presented with a chilblain-like rash, leukopenia, neutropenia, elevated liver enzymesgrowth retardation, microcephaly, elevated acute phase reactants, intracranial calcification and leukodystrophy. At the age of 3 years old, whole-exome sequencing confirmed a de novo heterozygous gain-of-function mutation, c.1016 C > A (p.Ala339Asp), in the IFIH1 gene, and he was diagnosed with AGS7. He was treated with ruxolitinib accompanied by steroids and thalidomide for about four years. The rash, hematological manifestations, and the liver function were all improved, but the erythrocyte sedimentation rate remained consistently elevated until the addition of tocilizumab, a monoclonal antibody against interleukin 6. Conclusions: Ruxolitinib was not successful in suppressing the inflammatory process, and tocilizumab produced highly encouraging results in reducing the inflammatory reaction of AGS. The study makes a significant contribution to the literature because we may found a potential alternative therapeutic option for AGS. [ABSTRACT FROM AUTHOR]

Abstract Aicardi-Goutières syndrome (AGS) is a rare genetic disorder involving the central nervous system and autoimmune abnormalities, leading to severe intellectual and physical disability with poor prognosis. AGS has a phenotype similar to intrauterine viral infection, which often leads to delays in genetic counseling. In this study, we report a case with a prenatal diagnosis of AGS. The first fetal ultrasound detected bilateral lateral ventricle cystic structures, and fetal MRI was performed to identify other signs. The right parietal lobe signal showed cerebral white matter abnormalities, and fetal brain development level was lower than that of normal fetuses of the same gestational age. Whole-exome sequencing revealed that the fetus carried the TREX1:NM_033629.6:exon2:c.294dup:p. C99Mfs*3 variant, suggesting that the c.294dup mutation of the TREX1 gene was the pathogenic mutation site, and the final comprehensive diagnosis was AGS1. In this article, we also reviewed the previous literature for possible phenotypes in the fetus and found that microcephaly and intrauterine growth retardation may be the first and most important markers of the intrauterine phenotype of AGS.

Biallelic pathogenic variants in RNASEH2C cause Aicardi‐Goutières syndrome 3 (AGS3, MIM #610329), a rare early‐onset encephalopathy characterized by intermittent unexplained fever, chilblains, irritability, progressive microcephaly, dystonia, spasticity, severe psychomotor retardation and abnormal brain imaging. Currently, approximately 50 individuals with AGS3 and 19 variants in RNASEH2C have been revealed. Here, we reported the novel clinical manifestations and genotypic information of three unrelated Chinese patients with AGS3 caused by pathogenic variants in RNASEH2C. In addition to three novel missense variants (c.101G>A, p.Cys34Tyr; c.401T>A, p.Leu134Gln and c.434G>T, p.Arg145Leu), one missense variant (c.194G>A, p.Gly65Asp) reoccurred in all patients but was completely absent in South Asian and other ethnicities. Our study expanded the variant spectrum of RNASEH2C and identified RNASEH2C c.194G>A as a Chinese‐specific founder mutation. The novel phenotypes, including mouth ulcers, hip dysplasia, retarded dentition and hypogonadism, observed in our patients greatly enriched the clinical characteristics of AGS3. [ABSTRACT FROM AUTHOR]

Objective: To report a series of atypical presentations of Aicardi–Goutières syndrome. Methods: Clinical, neuroimaging, and genetic data. Results: We report a series of six unrelated patients (five males) with a subacute loss of developmental milestones, pyramidal signs, and regression of communication abilities, with onset at ages ranging from 7 to 20 months, reaching a nadir after 4 to 24 weeks. A remarkable improvement of lost abilities occurred in the follow-up, and they remained with residual spasticity and dysarthria but preserved cognitive function. Immunization or febrile illness occurred before disease onset in all patients. CSF was normal in two patients, and in four, borderline or mild lymphocytosis was present. A brain CT scan disclosed a subtle basal ganglia calcification in one of six patients. Brain MRI showed asymmetric signal abnormalities of white matter with centrum semi-ovale involvement in five patients and a diffuse white matter abnormality with contrast enhancement in one. Four patients were diagnosed and treated for acute demyelinating encephalomyelitis (ADEM). Brain imaging was markedly improved with one year or more of follow-up (average of 7 years), but patients remained with residual spasticity and dysarthria without cognitive impairment. Demyelination relapse occurred in a single patient four years after the first event. Whole-exome sequencing (WES) was performed in all patients: four of them disclosed biallelic pathogenic variants in RNASEH2B (three homozygous p.Ala177Thr and one compound heterozygous p.Ala177Thr/p.Gln58*) and in two of them the same homozygous deleterious variants in RNASEH2A (p.Ala249Val). Conclusions: This report expands the phenotype of AGS to include subacute developmental regression with partial clinical and neuroimaging improvement. Those clinical features might be misdiagnosed as ADEM. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Baricitinib, a Janus kinase inhibitor (JAK‐inhibitor), seems to contribute to an improvement of a child affected by Aicardi‐Goutières syndrome (AGS), reducing the interferon score and determining a recovery of cognitive, communicative, and relational dysfunctions, while the gross motor deficit persisted. We report the treatment response to baricitinib, a JAK‐inhibitor, in a 4‐year‐old girl affected by Aicardi‐Goutières syndrome (AGS2, RNASEH2B mutation). Using quantitative measures, we detected a significant amelioration characterized by a complete recovery of cognitive, communicative, and relational skills after 8 and 16 months from the beginning of therapy. [ABSTRACT FROM AUTHOR]

Background: Aicardi–Goutières syndrome (AGS) is a rare, autosomal recessive, hereditary neurodegenerative disorder. It is characterized mainly by early onset progressive encephalopathy, concomitant with an increase in interferon-α levels in the cerebrospinal fluid. Preimplantation genetic testing (PGT) is a procedure that could be used to choose unaffected embryos for transfer after analysis of biopsied cells, which prevents at-risk couples from facing the risk of pregnancy termination. Methods: Trio-based whole exome sequencing, karyotyping and chromosomal microarray analysis were used to determine the pathogenic mutations for the family. To block the inheritance of the disease, multiple annealing and looping-based amplification cycles was used for whole genome amplification of the biopsied trophectoderm cells. Sanger sequencing and next-generation sequencing (NGS)-based single nucleotide polymorphism (SNP) haplotyping were used to detect the state of the gene mutations. Copy number variation (CNV) analysis was also carried out to prevent embryonic chromosomal abnormalities. Prenatal diagnosis was preformed to verify the PGT outcomes. Results: A novel compound heterozygous mutation in TREX1 gene was found in the proband causing AGS. A total of 3 blastocysts formed after intracytoplasmic sperm injection were biopsied. After genetic analyses, an embryo harbored a heterozygous mutation in TREX1 and without CNV was transferred. A healthy baby was born at 38th weeks and prenatal diagnosis results confirmed the accuracy of PGT. Conclusions: In this study, we identified two novel pathogenic mutations in TREX1, which has not been previously reported. Our study extends the mutation spectrum of TREX1 gene and contributes to the molecular diagnosis as well as genetic counseling for AGS. Our results demonstrated that combining NGS-based SNP haplotyping for PGT-M with invasive prenatal diagnosis is an effective approach to block the transmission of AGS and could be applied to prevent other monogenic diseases. [ABSTRACT FROM AUTHOR]

Type 1 interferonopathy is a novel context reflecting a group of inborn disorders sharing common pathway disturbances. This group of diseases is characterized by autoimmunity and autoinflammation caused by an upregulation of type 1 interferons (IFN)s due to certain genetic mutations. Several features are common in most of the diseases in this group, such as vasculitic skin changes, including chilblains, panniculitis, interstitial lung disease, basal ganglion calcifications, neuromotor impairments, epilepsy, stroke, and recurrent fever. Family history and consanguineous marriage are also common. IFN signature is a useful diagnostic tool and is positive in almost all patients with type 1 interferonopathies. Although IFN signature is a sensitive test, its specificity is relatively low. It can also be positive in viral infections and several connective tissue diseases. Therefore, next-generation sequence methods, whole exome sequencing (WES) in particular, are required for the ultimate diagnosis. The optimal treatment regime is still under debate due to a lack of clinical trials. Although high-dose steroids, anti-IL-1 and anti-IL-6 treatments, and reverse transcriptase inhibitors are used, JAK inhibitors are highly promising. Additionally, monoclonal antibodies against IFN-alpha and interferon-α receptor (IFNAR) are currently underway. [ABSTRACT FROM AUTHOR]

Retroelements are mobile genomic components requiring an RNA intermediate which is reverse-transcribed into complementary DNA for transposition. Human genome contains a vast amount of retroelements including retrotransposons and endogenous retroviruses. These elements are categorized according to presence or absence of long terminal repeats, LTRs or non-LTRs, as well as autonomous and non-autonomous according to involvement of reverse transcriptase. The retroelements have been accumulated in mammalian genomes over all evolutionary times through vertical transmission, and many of them were inactivated through accumulation of mutations. However, the retroelements entered into genome within the last 200,000 years are mostly functional. Some of the active retroelements are associated with varying autoimmune diseases because anti-retroelement antibodies might cross-react with other proteins in the human body. For instance, autoimmunity and inflammation could be stimulated by increased expression of long interspersed element 1 (LINE-1 or L1) or decreased L1 degradation. Different regulation of L1 expression might be related to the genetic and sex-related variations or environmental factors. Activation of retroelements is also controlled by epigenetic silencing mechanisms such as histone modification. Elevated levels of L1 retroelements could trigger the production of type I interferon, a crucial innate defense mechanism in mammals against viruses, and systemic autoimmune response is induced. Loss-of-function in some deoxyribonucleases (DNases) such as three prime repair exonuclease 1 that degrades reverse-transcribed DNA is also related to autoimmune diseases. Additionally, human endogenous retroviruses also play a role in autoimmune diseases. Involvement of retroelements in autoimmune disorders is exemplified with three diseases, i.e. systemic lupus erythematosus, Aicardi–Goutières syndrome, and multiple sclerosis.

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder involving the central nervous system and autoimmune abnormalities, leading to severe intellectual and physical disability with poor prognosis. AGS has a phenotype similar to intrauterine viral infection, which often leads to delays in genetic counseling. In this study, we report a case with a prenatal diagnosis of AGS. The first fetal ultrasound detected bilateral lateral ventricle cystic structures, and fetal MRI was performed to identify other signs. The right parietal lobe signal showed cerebral white matter abnormalities, and fetal brain development level was lower than that of normal fetuses of the same gestational age. Whole-exome sequencing revealed that the fetus carried the TREX1:NM_033629.6:exon2:c.294dup:p. C99Mfs*3 variant, suggesting that the c.294dup mutation of the TREX1 gene was the pathogenic mutation site, and the final comprehensive diagnosis was AGS1. In this article, we also reviewed the previous literature for possible phenotypes in the fetus and found that microcephaly and intrauterine growth retardation may be the first and most important markers of the intrauterine phenotype of AGS. [ABSTRACT FROM AUTHOR]

Since their original discovery, type I interferons (IFN-Is) have been closely associated with antiviral immune responses. However, their biological functions go far beyond this role, with balanced IFN-I activity being critical to maintain cellular and tissue homeostasis. Recent findings have uncovered a darker side of IFN-Is whereby chronically elevated levels induce devastating neuroinflammatory and neurodegenerative pathologies. The underlying causes of these 'interferonopathies' are diverse and include monogenetic syndromes, autoimmune disorders, as well as chronic infections. The prominent involvement of the CNS in these disorders indicates a particular susceptibility of brain cells to IFN-I toxicity. Here we will discuss the current knowledge of how IFN-Is mediate neurotoxicity in the brain by analyzing the cell-type specific responses to IFN-Is in the CNS, and secondly, by exploring the spectrum of neurological disorders arising from increased IFN-Is. Understanding the nature of IFN-I neurotoxicity is a crucial and fundamental step towards development of new therapeutic strategies for interferonopathies. [ABSTRACT FROM AUTHOR]

Background: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases., Results: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases., Conclusions: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases., (© 2025 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: To estimate the incidence of Aicardi-Goutières syndrome (AGS) and potassium sodium-activated channel subfamily T member 1 (KCNT1)-related epilepsy in Denmark and to characterize the patients diagnosed with AGS and KCNT1-related epilepsy. Background: AGS and KCNT1-related epilepsy are 2 distinct rare genetic disorders. Due to the rarity of AGS and KCNT1-related epilepsy, the epidemiology remains unclear. The incidences for these diseases or the carriers with disease-related genetic variants remain unknown. Materials and methods: This is a retrospective, non-interventional, population-based study using aggregate data from the Danish population register and hospital-based patient-level data in Denmark to identify persons with genetically confirmed AGS between January 2010 to December 2020 and KCNT1-related epilepsies between January 2012 to December 2020. Cases of these disorders were identified from in-hospital databases, and pathogenic variants were identified and confirmed by Sanger and/or whole exome (panel-based) sequencing. The incidence of AGS and KCNT1-related epilepsy were estimated in separate statistical analyses. Results: A total of 7 AGS patients were identified. The mean age at AGS diagnosis was 19.4 months (median age 14 months). TREX1 (n

Aicardi–Goutières syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in RNASEH2B and RNASEH2A genes. Lymphoblastoid cell lines (LCLs) from RNASEH2A- and RNASEH2B-mutated patients and healthy control were used. Transmission Electron Microscopy (TEM) and flow cytometry were used to assess morphological alterations, reactive oxygen species (ROS) production and mitochondrial membrane potential variations. Seahorse Analyzer was used to investigate metabolic alterations, and mtDNA oxidation and VDAC1 oligomerization were assessed by immunofluorescence. Western blot and RT-qPCR were used to quantify mtTFA protein and mtDNA release. Morphological alterations of mitochondria were observed in both mutated LCLs, and loss of physiological membrane potential was mainly identified in RNASEH2A LCLs. ROS production and 8-oxoGuanine levels were increased in RNASEH2B LCLs. Additionally, the VDAC1 signal was increased, suggesting a mitochondrial pore formation possibly determining mtDNA release. Indeed, higher cytoplasmic mtDNA levels were found in RNASEH2B LCLs. Metabolic alterations confirmed mitochondrial damage in both LCLs. Data highlighted mitochondrial alterations in AGS patients' LCLs suggesting a pivotal role in AGS pathogenesis. [ABSTRACT FROM AUTHOR]

Three-prime repair exonuclease 1 (TREX1) is an anti-viral enzyme that cleaves nucleic acids in the cytosol, preventing accumulation and a subsequent type I interferon-associated inflammatory response. Autoimmune diseases, including Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus, can arise when TREX1 function is compromised. AGS is a neuroinflammatory disorder with severe and persistent intellectual and physical problems. Here we generated a human AGS model that recapitulates disease-relevant phenotypes using pluripotent stem cells lacking TREX1. We observed abundant extrachromosomal DNA in TREX1-deficient neural cells, of which endogenous Long Interspersed Element-1 retrotransposons were a major source. TREX1-deficient neurons also exhibited increased apoptosis and formed three-dimensional cortical organoids of reduced size. TREX1-deficient astrocytes further contributed to the observed neurotoxicity through increased type I interferon secretion. In this model, reverse-transcriptase inhibitors rescued the neurotoxicity of AGS neurons and organoids, highlighting their potential utility in therapeutic regimens for AGS and related disorders.

Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. The existence of these sensors raises fundamental questions about self/nonself discrimination because of the abundance of self-DNA and self-RNA that occupy these same compartments. Recent advances have revealed that enzymes that metabolize or modify endogenous nucleic acids are essential for preventing inappropriate activation of the innate antiviral response. In this review, we discuss rare human diseases caused by dysregulated nucleic acid sensing, focusing primarily on intracellular sensors of nucleic acids. We summarize lessons learned from these disorders, we rationalize the existence of these diseases in the context of evolution, and we propose that this framework may also apply to a number of more common autoimmune diseases for which the underlying genetics and mechanisms are not yet fully understood.

The TREX1 exonuclease degrades DNA to prevent aberrant nucleic-acid sensing through the cGAS-STING pathway, and dominant Aicardi–Goutières Syndrome type 1 (AGS1) represents one of numerous TREX1-related autoimmune diseases. Monoallelic TREX1 mutations were identified in patients showing early-onset cerebrovascular disease, ascribable to small vessel disease, and CADASIL-like neuroimaging. We report the clinical-neuroradiological features of two patients with AGS-like (Patient A) and CADASIL-like (Patient B) phenotypes carrying the heterozygous p.A136V and p.R174G TREX1 variants, respectively. Genetic findings, obtained by a customized panel including 183 genes associated with monogenic stroke, were combined with interferon signature testing and biochemical assays to determine the mutations' effects in vitro. Our results for the p.A136V variant are inconsistent with prior biochemistry-pathology correlates for dominant AGS-causing TREX1 mutants. The p.R174G variant modestly altered exonuclease activity in a manner consistent with perturbation of substrate interaction rather than catalysis, which represents the first robust enzymological data for a TREX1 variant identified in a CADASIL-like patient. In conclusion, functional analysis allowed us to interpret the impact of TREX1 variants on patients' phenotypes. While the p.A136V variant is unlikely to be causative for AGS in Patient A, Patient B's phenotype is potentially related to the p.R174G variant. Therefore, further functional investigations of TREX1 variants found in CADASIL-like patients are warranted to determine any causal link and interrogate the molecular disease mechanism(s). [ABSTRACT FROM AUTHOR]

Adenosine (A) to inosine (I) RNA editing is important for life in metazoan organisms. Dysregulation or mutations that compromise the efficacy of A to I editing results in neurological disorders and a shorten life span. These reactions are catalyzed by adenosine deaminases acting on RNA (ADARs), which hydrolytically deaminate adenosines in regions of duplex RNA. Because inosine mimics guanosine in hydrogen bonding, this prolific RNA editing alters the sequence and structural information in the RNA landscape. Aicardi-Goutières syndrome (AGS) is a severe childhood autoimmune disease that is one of a broader set of inherited disorders characterized by constitutive upregulation of type I interferon (IFN) referred to as type I interferonopathies. AGS is caused by mutations in multiple genes whose protein products, including ADAR1, are all involved in nucleic acid metabolism or sensing. The recent crystal structures of human ADAR2 deaminase domain complexed with duplex RNA substrates enabled modeling of how AGS causing mutations may influence RNA binding and catalysis. The mutations can be broadly characterized into three groups; mutations on RNA-binding loops that directly affect RNA binding, "second-layer" mutations that can alter the disposition of RNA-binding loops, and mutations that can alter the position of an α-helix bearing an essential catalytic residue.

Abstract Introduction Aicardi-Goutières (AGS) is a rare immune dysregulated disease due to mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1. Clinical features include basal ganglia calcifications, white matter abnormalities, and cerebral atrophy. Severe systemic inflammation and chronic kidney disease (CKD) are extremely rare in AGS. Herein, we report a patient presenting with systemic inflammation and CKD to broaden the clinical phenotype spectrum of the RNASEH2B defect. Methods All testing and molecular genetic analysis were performed after obtaining the informed consent of the parents. Demographic, clinical, and laboratory findings were abstracted from outpatient and inpatient encounters. Cerebral magnetic resonance imaging (MRI), computed tomography (CT) scans, and renal biopsy histopathology reports were reviewed and summarized. Whole exome sequencing (WES) was performed on peripheral blood cells. After exposure to cGAMP in vitro for 24 h, mRNA expression of 12 IFN-stimulated cytokine genes in PBMCs was assessed. Serum cytokine levels were detected by Milliplex. Results A 11-year-old girl presented with recurrent aseptic fever, arthritis, chilblains, failure to thrive, mild hearing loss, and neurological manifestations. Laboratory and immunologic findings demonstrated lymphopenia, low complement levels, positive autoantibodies, elevated levels of acute-phase reactants and inflammatory cytokines. Cerebral imaging showed cerebral atrophy, white matter abnormalities, and intracranial calcification. Renal biopsy showed glomerular sclerosis in 3 of 14 glomeruli, infiltration of lymphocytes and other mononuclear cells. WES revealed a homozygous and heterozygous mutations in RNASEH2B. Over-expression of IFN-stimulated cytokine genes was observed, including IFI44, IFI27, IFIT1, IFIT2, IFIT3, ISG15, OAS1, and SIGLEC1. Conclusions To date, only two cases with AGS have been reported to have renal disease. Here, we describe a patient with both homozygous and heterozygous variants in RNASEH2B, presenting with neurological manifestations, persistently systemic autoinflammation, and CKD. CKD has never been reported in patients with AGS due to the RNASEH2B defect. Trial registration Not applicable; this was a retrospective study.

Abstract Background Type I interferonopathies are a group of rare autoimmune diseases characterised by excessive activation of type I interferon that leads to disturbances in immune function. Three prime repair exonuclease 1 (TREX1) is an important exonuclease and plays an important role in DNA damage repair. TREX1 mutations are associated with many type I interferonopathies. Studies have been published on the effectiveness of tofacitinib in the treatment of type I interferonopathies. The aim of this study is to identify the pathogenic variation in a Chinese family with type I interferonopathies and to observe the therapeutic effects of tofacitinib. Methods A Chinese family with two members with type I interferonopathies was investigated. Whole exome sequencing and Sanger sequencing were applied for mutation screening using peripheral blood DNA of the patient and her family members. Sequencing results were analysed using bioinformatics software tools including VarCards and PolyPhen-2. Close clinical follow-up and observation were used to record changes in the disease before and after treatment with tofacitinib. Results Compound heterozygous variants of TREX1 were observed in the patient’s genome. One was a missense variant (NM_016381; c.C227T; p.Ala76Val) from the patient’s father, and the other was a frameshift variant (NM_016381; c.458dupA; p.Gln153Glnfs*3) from the patient’s mother. One of the proband’s elder brothers with similar skin lesions also carried these two variants. This brother of the proband had more serious cutaneous involvement with the comorbidity of cerebral palsy. These TREX1 variants have not been reported in previous studies and are predicted to be highly pathogenic. The proband was given tofacitinib that led to a marked improvement. Conclusions We identified two novel complex heterozygous variants in the TREX1 gene, which may underlie the molecular pathogenesis of the type I interferonopathies observed in members of this family. Tofacitinib could be an alternative treatment for this disease.

One of the oldest mechanisms of immune defense against pathogens is through detection of foreign DNA. Since human DNA is compartmentalized into the nucleus, its presence in the cytosol heralds a potential threat. The cGAS-STING pathway is one of the most important cytosolic DNA sensing pathways and leads to interferon signaling, inflammasome activation, autophagy, and cell death. While STING signaling is protective at physiologic levels, chronic activation of this pathway can instead drive autoinflammation and autoimmunity. Here we discuss several monogenic disorders of the STING pathway that highlight its impact on both innate and adaptive immunity in the progressive loss of tolerance. The potential relevance of STING signaling in systemic lupus erythematosus is then discussed with a focus on future avenues for monitoring and targeting this pathway. [ABSTRACT FROM AUTHOR]

Background: Pseudo-TORCH syndrome (PTS) is a group of autosomal recessive disorders that clinically and radiologically mimic TORCH congenital infections. The prevalence of pseudo-TORCH syndrome 2 is 1 in 1,000,000 cases worldwide. This novel disorder is extremely rare, and is generally detected by prenatal diagnosis through next generation sequencing (NGS) during pregnancy. In this study, a familial case of pseudo-TORCH syndrome 2 with novel non-sense mutation in the ubiquitin-specific peptidase 18 (USP 18) gene in the parents was reported, who are heterozygous asymptomatic carriers; however, all children have inherited a homozygous pathogenic form of USP18, which is an important negative regulator of type I interferon (IFN) signal transduction. To the best of our knowledge, this is the first case of a novel mutation of USP18 seen in a family with pseudo-TORCH syndrome 2 (PTS 2) from India. Case Presentation: A 23-year-old pregnant woman with bad obstetric history, including intrauterine and neonatal mortality was referred to the Institute of Genetics in the year 2021 for clinical and genetic evaluation. Advanced clinical exome sequencing of the parents and the fetus revealed heterozygous carrier status in parents and homozygous mutation in USP 18 gene in the progeny leading to pseudoTORCH-2 syndrome. Conclusion: The present case highlights the significance of carrier screening, prenatal diagnosis, and genetic counseling in couples with bad obstetric history for the detection of rare genetic disorders with poor prognosis. [ABSTRACT FROM AUTHOR]

Abstract Background Familial chilblain lupus (FCL) is a rare, chronic form of cutaneous lupus erythematosus, which is characterized by painful bluish-red inflammatory cutaneous lesions in acral locations. Mutations in TREX1, SAMHD1 and STING have been described in FCL patients. Less than 10 TREX1 mutation positive FCL families have been described in the literature. Case presentation Genetic study was performed in a large, nonconsanguineous Chinese family with 13 members over 4 generations affected by chilblain lupus. Whole exome sequencing was performed for the index patient. Significant variant detection was subsequently validated by resequencing using Sanger sequencing in the index patient and other family members. A novel pathogenic mutation TREX1 p.Asp18His was iditified in the index patient. The mutation was present in affected individuals and was absent in non-affected individuals in the familiy. Conclusions We present a four-generation Chinese family with FCL caused by a novel heterozygous mutation TREX1 p.Asp18His, which had been reported in a patient with Aicardi–Goutie’res syndrome. This is the first reported Chinese family with FCL based on mutation in TREX1.

Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy. The syndrome was first described in 1984, and is characterised by upregulation of the type I interferon (IFN) pathway, which is involved in the host immune response against viral infections, including SARS-CoV-2. Whilst defects in type I IFN pathways have been described in association with severe coronavirus disease 2019 (COVID-19), less is known about the outcomes of upregulation. We describe an unusual case of generalised panniculitis as a post-COVID-19 phenomenon in a child with AGS. Our patient was initially managed with systemic steroid therapy, but due to relapse of symptoms on weaning, an alternative therapy was sought. In this case, a novel use of ruxolitinib, a JAK inhibitor, has resulted in lasting remission without complications. We discuss the probable protective role of IFN upregulation following COVID-19 infection in AGS and possible immunological mechanisms driving the panniculitis and therapeutic response in our case.

Microglia, the brain's resident macrophages, can be reconstituted by surrogate cells - a process termed "microglia replacement." To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived (BMD) macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system's power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1 -mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi-Goutières Syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo - phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.

Aicardi-Goutières syndrome (AGS) is a severe childhood inflammatory disorder that shows clinical and genetic overlap with systemic lupus erythematosus (SLE). AGS is thought to arise from the accumulation of incompletely metabolized endogenous nucleic acid species owing to mutations in nucleic acid-degrading enzymes TREX1 (AGS1), RNase H2 (AGS2, 3 and 4), and SAMHD1 (AGS5). However, the identity and source of such immunogenic nucleic acid species remain undefined. Using genome-wide approaches, we show that fibroblasts from AGS patients with AGS1-5 mutations are burdened by excessive loads of RNA:DNA hybrids. Using MethylC-seq, we show that AGS fibroblasts display pronounced and global loss of DNA methylation and demonstrate that AGS-specific RNA:DNA hybrids often occur within DNA hypomethylated regions. Altogether, our data suggest that RNA:DNA hybrids may represent a common immunogenic form of nucleic acids in AGS and provide the first evidence of epigenetic perturbations in AGS, furthering the links between AGS and SLE.

Type I Interferonopathies comprise inherited inflammatory diseases associated with perturbation of the type I IFN response. Use of Janus kinase (JAK) inhibitors has been recently reported as possible tools for treating some of those rare diseases. We describe herein the clinical picture and treatment response to the JAK-inhibitor ruxolitinib in a 5-year-old girl affected by Aicardi-Goutières Syndrome type 6 (AGS6) due to ADAR1 mutation. The girl's interferon score (IS) was compared with that of her older brother, suffering from the same disorder, who was not treated. We observed a limited, but distinct neurological improvement (Gross Motor Function and Griffiths Mental Development Scales). Analysis of IS values of the two siblings during the treatment showed several changes, especially related to infections; the IS values of the child treated with ruxolitinib were consistently lower than those measured in her brother. Based on these observations we suggest that the use of ruxolitinib in children with the same condition might be effective in inhibiting type I interferon response and that starting this therapy at early age in children with AGS could mitigate the detrimental effects of type I interferon hyperproduction.

Abstract Transposable Elements (TEs) are mobile genetic elements whose sequences constitute nearly half of the human genome. Each TE copy can be present in hundreds to thousands of locations within the genome, complicating the genetic and genomic studies of these highly repetitive sequences. The recent development of better tools for evaluating TE derived sequences in genomic studies has enabled an increasing appreciation for the contribution of TEs to human development and disease. While some TEs have contributed novel and beneficial host functions, this review will summarize the evidence for detrimental TE activity in neurodegenerative disorders. Much of the evidence for pathogenicity implicates endogenous retroviruses (ERVs), a subset of TEs that entered the genome by retroviral infections of germline cells in our evolutionary ancestors and have since been passed down as a substantial fraction of the human genome. Human specific ERVs (HERVs) represent some of the youngest ERVs in the genome, and thus are presumed to retain greater function and resultant pathogenic potential.

Abstract Background Ribonucleases (RNases) are crucial for degradation of ribosomal RNA (rRNA). RNASET2 as a subtype of RNASEs is a 256 amino acid protein, encoded by RNASET2 gene located on chromosome six. Defective RNASET2 leads to RNASET2-deficient leukoencephalopathy, a rare autosomal recessive neurogenetic disorder with psychomotor delay as its main clinical symptom. The clinical findings can be similar to congenital cytomegalovirus (CMV) infection and Aicardi-Goutieres syndrome (AGS). Methods Herein, we presented a patient with motor delay, neurological regression, infrequent seizures and microcephaly at 5 months of age. Brain imaging showed white matter involvement, calcification and anterior temporal cysts. Basic metabolic tests, serum and urine CMV polymerase chain reaction (PCR) were requested. According to clinical and imaging findings, screening of RNASET2 and RMND1 genes were performed. The clinical data and magnetic resonance imaging (MRI) findings of previous reported individuals with RNASET2-deficient leukodystrophy were also reviewed and compared to the findings of our patient. Results Brain MRI findings were suggestive of RNASET2-deficient leukoencephalopathy, AGS and CMV infection. Basic metabolic tests were normal and CMV PCR was negative. Molecular study revealed a novel homozygous variant of c.233C > A; p.Ser78Ter in exon 4 of RNASET2 gene compatible with the diagnosis of RNASET2-deficient leukoencephalopathy. Conclusions RNASET2-deficiency is a possible diagnosis in an infant presented with a static leukoencephalopathy and white matter involvement without megalencephaly. Due to overlapping clinical and radiologic features of RNASET2-deficient leukoencephalopathy, AGS and congenital CMV infections, molecular study as an important and helpful diagnostic tool should be considered to avoid misdiagnosis.

Summary: Loss of function of adenosine deaminase acting on double-stranded RNA (dsRNA)-1 (ADAR1) causes the severe autoinflammatory disease Aicardi-Goutières syndrome (AGS). ADAR1 converts adenosines into inosines within dsRNA. This process called A-to-I editing masks self-dsRNA from detection by the antiviral dsRNA sensor MDA5. ADAR1 binds to dsRNA in both the canonical A-form and the poorly defined Z conformation (Z-RNA). Mutations in the Z-RNA-binding Zα domain of ADAR1 are common in patients with AGS. How loss of ADAR1/Z-RNA interaction contributes to disease development is unknown. We demonstrate that abrogated binding of ADAR1 to Z-RNA leads to reduced A-to-I editing of dsRNA structures formed by base pairing of inversely oriented short interspersed nuclear elements. Preventing ADAR1 binding to Z-RNA triggers an MDA5/MAVS-mediated type I interferon response and leads to the development of lethal autoinflammation in mice. This shows that the interaction between ADAR1 and Z-RNA restricts sensing of self-dsRNA and prevents AGS development.

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMPGMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi–Goutière’s syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2′3′-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2′3′-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, over expression of cGAS-STING, or SAVI STING mutants. In Trex1−/− mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease. [ABSTRACT FROM AUTHOR]

The IFIH1 gene encodes melanoma differentiation-associated gene 5 (MDA5) and has been associated with Aicardi-Goutières syndrome (AGS), Singleton-Merten syndrome (SMS), and other autoimmune diseases. The mechanisms responsible for how a functional change in a single gene can cause so many different phenotypes remain unknown. Moreover, there is significant controversy as to whether these distinct phenotypes represent the same disease continuum or mutation-specific disorders. Here, we describe the case of a patient with a novel c.1465G > T (p.Ala489Ser) mutation in the IFIH1 gene. The patient presented with spastic paraplegia, dystonia, psychomotor retardation, joint deformities, intracranial calcification, abnormal dentition, characteristic facial features, lymphadenopathy, and autoimmunity. His phenotype appeared to represent an overlap of the phenotypes for AGS and SMS. The patient also experienced unexplained pancytopenia, suggesting that the hemic system may have been affected by a gain-of-function mutation in the IFIH1 gene. In summary, we provide further evidence that SMS and AGS exhibit the same disease spectrum following a gain-of-function mutation in the IFIH1 gene. Our data highlight the genetic heterogeneity of these conditions and expand our knowledge of differential phenotypes created by IFIH1 gain-of-function mutation.

TREX1 (three prime repair exonuclease 1) gene encodes DNA 3′ end repair exonuclease that plays an important role in DNA repair. Mutations in TREX1 gene have been identified as the cause of a rare autoimmune neurological disease, Aicardi-Goutières syndrome (AGS). Here, we report an AGS case of a 6-month-old Chinese girl with novel TREX1 variants. The patient had mild rashes on the face and legs, increased muscle tensions in the limbs, and positive cervical correction reflex. Cranial magnetic resonance imaging showed that there were patches of slightly longer T1 and T2 signals in the bilateral cerebral hemisphere and brainstem white matter, mainly in the frontotemporal lobe, together with decreased white matter volume, enlarged ventricles, and widened sulcus fissure. Total exon sequencing showed that the TREX1 gene of the child had mutations of c.137_138insC and c.292_293insA, which had not been reported before. In addition, elevated type I interferons were detected by using enzyme-linked immunosorbent assay in the patient's serum. Together, our study demonstrated that novel TREX1 variants (c.137_138insC and c.292_293insA) cause AGS for the first time.

Aicardi–Goutières Syndrome (AGS) is a rare disorder characterized by neurological and immunological signs. In this study we have described a child with a phenotype consistent with AGS carrying a novel compound heterozygous mutation in RNASEH2B gene. Next Generation Sequencing revealed two heterozygous variants in RNASEH2B gene. We also highlighted a reduction of RNase H2B transcript and protein levels in all the family members. Lower protein levels of RNase H2A have been observed in all the members of the family as well, whereas a deep depletion of RNase H2C has only been identified in the affected child. The structural analysis showed that both mutations remove many intramolecular contacts, possibly introducing conformational rearrangements with a decrease of the stability of RNase H2B and strongly destabilizing the RNase H2 complex. Taken together, these results highlight the importance of an integrated diagnostic approach which takes into consideration clinical, genetic, and molecular analyses.

Notable advances in gene sequencing methods in recent years have permitted enormous progress in the phenotypic and genotypic characterization of autoinflammatory syndromes. Interferonopathies are a recent group of inherited autoinflammatory diseases, characterized by a dysregulation of the interferon pathway, leading to constitutive upregulation of its activation mechanisms or downregulation of negative regulatory systems. They are clinically heterogeneous, but some peculiar clinical features may lead to suspicion: a familial “idiopathic” juvenile arthritis resistant to conventional treatments, an early necrotizing vasculitis, a non-infectious interstitial lung disease, and a panniculitis associated or not with a lipodystrophy may represent the “interferon alarm bells.” The awareness of this group of diseases represents a challenge for pediatricians because, despite being rare, a differential diagnosis with the most common childhood rheumatological and immunological disorders is mandatory. Furthermore, the characterization of interferonopathy molecular pathogenetic mechanisms is allowing important steps forward in other immune dysregulation diseases, such as systemic lupus erythematosus and inflammatory myositis, implementing the opportunity of a more effective target therapy.

The IFIH1 gene encodes melanoma differentiation-associated gene 5 (MDA5) and has been associated with Aicardi-Goutières syndrome (AGS), Singleton-Merten syndrome (SMS), and other autoimmune diseases. The mechanisms responsible for how a functional change in a single gene can cause so many different phenotypes remain unknown. Moreover, there is significant controversy as to whether these distinct phenotypes represent the same disease continuum or mutation-specific disorders. Here, we describe the case of a patient with a novel c.1465G > T (p.Ala489Ser) mutation in the IFIH1 gene. The patient presented with spastic paraplegia, dystonia, psychomotor retardation, joint deformities, intracranial calcification, abnormal dentition, characteristic facial features, lymphadenopathy, and autoimmunity. His phenotype appeared to represent an overlap of the phenotypes for AGS and SMS. The patient also experienced unexplained pancytopenia, suggesting that the hemic system may have been affected by a gain-of-function mutation in the IFIH1 gene. In summary, we provide further evidence that SMS and AGS exhibit the same disease spectrum following a gain-of-function mutation in the IFIH1 gene. Our data highlight the genetic heterogeneity of these conditions and expand our knowledge of differential phenotypes created by IFIH1 gain-of-function mutation. [ABSTRACT FROM AUTHOR]