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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]

A number of systemic autoinflammatory diseases arise from gain-of-function mutations in genes encoding IL-1–activating inflammasomes or cytoplasmic nucleic acid sensors including the receptor and sensor STING and result in increased IL-1 and type I interferon production, respectively. Blocking these pathways in human diseases has provided proof-of-concept, confirming the prominent roles of these cytokines in disease pathogenesis. Recent insights into the multilayered regulation of these sensor pathways and insights into their role in amplifying the disease pathogenesis of monogenic and complex genetic diseases spurred new drug development targeting the sensors. This review provides insights into the pathogenesis and genetic causes of these "prototypic" diseases caused by gain-of function mutations in IL-1–activating inflammasomes (inflammasomopathies) and in interferon-activating pathways (interferonopathies) including STING-associated vasculopathy with onset in infancy, Aicardi-Goutieres syndrome, and proteasome-associated autoinflammatory syndromes that link activation of the viral sensors STING, "self" nucleic acid metabolism, and the ubiquitin-proteasome system to "type I interferon production" and human diseases. Clinical responses and biomarker changes to Janus kinase inhibitors confirm a role of interferons, and a growing number of diseases with "interferon signatures" unveil extensive cross-talk between major inflammatory pathways. Understanding these interactions promises new tools in tackling the significant clinical challenges in treating patients with these conditions. [ABSTRACT FROM AUTHOR]

Aicardi-Goutières syndrome (AGS) is a hereditary inflammatory encephalopathy resulting in severe neurological damage in the majority of cases. We report on two siblings with AGS6 due to compound heterozygosity for a known and a novel mutation in the ADAR gene and a strikingly variable phenotype. The first sibling presented at 12 months of age with a subacute encephalopathy following a mild respiratory infection. The child developed a spastic tetraparesis, generalized dystonia and dysarthria. In contrast, the younger sibling presented with an acute episode of neurological impairment in his third year of life, from which he recovered without sequelae within a few weeks. These findings illustrate a striking intrafamilial phenotypic variability in patients with AGS6 and describe the first case of a full recovery from an acute encephalopathy in an AGS patient. Our findings also suggest that AGS should be considered as an important differential diagnosis of an infection-triggered encephalopathy in infancy despite the absence of typical neuroimaging findings. [ABSTRACT FROM AUTHOR]

Background Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutières syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. Patients and Methods We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. Results All patients were found to carry biallelic mutations of RNASET2 . Conclusions Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2 -related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation. [ABSTRACT FROM AUTHOR]

Aicardi-Goutières syndrome (AGS) is a rare, autosomal recessively inherited, immune-mediated neurodevelopmental disorder. The syndrome causes infantileonset progressive encephalopathy characterized by the neuroradiologic features of basal ganglia and periventricular white matter calcification, leucodystrophy and cerebral atrophy. Lymphocytosis and elevated levels of interferon alpha (IFN-alpha) in the cerebrospinal fluid are supplementary findings of AGS. It is frequently misdiagnosed as sequelae of congenital infection (pseudo-TORCH) and mostly recognized later. We describe three AGS cases with different clinical presentation, two male siblings with RNASEH2C mutation and a boy with TREX1 mutation. These cases highlight the importance of considering AGS in the differential diagnosis of unexplained leukoencephalopathy and developmental delay. We suggest to search for intracranial calcification, especially if there are more than one affected cases in a family. [ABSTRACT FROM AUTHOR]

Abstract: Background: Aicardi–Goutières syndrome (AGS) is a genetically determined early-onset encephalopathy with variable phenotype, including neurologic manifestations such as dystonia, spasticity, epileptic seizures, progressive microcephaly, and severe developmental delay. The aim of our study was the characterization of epilepsy, one of the most frequent and severe AGS manifestations, in molecularly confirmed patients. Methods: We reviewed the medical records, EEG, and CT/MRI findings in 16 patients aged 1–22 years that carried AGS1-5 mutations. Results: Epilepsy manifested in 12 (75%) patients and took a refractory course in 9 (56%). 4 (25%) patients presented with seizures in the first four weeks and 11 (69%) altogether in the first year of life. Spasms were reported in 3 (19%) patients, focal seizures in 4 (25%), myoclonic in 5 (31%), symmetric or asymmetric tonic in 11 (69%), generalized tonic–clonic in 3 (19%) and status epilepticus in 4 (25%). EEG recordings initially showed a slow and disorganized background, followed by a regional intermittent theta/delta slow, while obvious multifocal or generalized epileptic discharges were only observed at follow-up. None of these EEG features were specific of AGS. There was no discernible correlation between the genotype and epilepsy onset, seizure types and epilepsy evolution. Epilepsy severity did not correspond to neuroimaging pathology. Discussion: Epilepsy constitutes a cardinal feature of AGS, characterized by early onset, predominantly tonic semiology and a refractory course. The early discrimination of epileptic seizures from paroxysmal dystonia poses a challenge for neuropaediatricians, considering the initially inconspicuous or non-specific EEG findings. This study underlines the necessity of a more systematic serial evaluation of AGS patients using long-term video-EEG recordings. [Copyright &y& Elsevier]

Recent studies have suggested an association between intestinal microbiota composition and human disease, however causality remains to be proven. With hindsight, the application of fecal transplantation (FMT) does indeed suggest a causal relation between interfering with gut microbiota composition and a resultant cure of several disease states. In this review, we aim to show the available evidence regarding the involvement of intestinal microbiota and human (autoimmune) disease. Moreover, we refer to (mostly case report) studies showing beneficial or adverse effects of fecal transplantation on clinical outcomes in some of these disease states. If these findings can be substantiated in larger randomized controlled double blind trials also implementing gut microbiota composition before and after intervention, fecal transplantation might provide us with novel insights into causally related intestinal microbiota, that might be serve as future diagnostic and treatment targets in human disease. [ABSTRACT FROM AUTHOR]

Abstract: Aicardi–Goutières syndrome is an autosomal recessive encephalopathy characterised by acquired microcephaly, basal ganglia calcifications, leukodystrophy, cerebral atrophy, chronic cerebrospinal lymphocytosis, and raised titres of interferon alpha in the cerebrospinal fluid. The disease onset is generally within the first months of life. We here report a case of Aicardi–Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy following satisfactory psychomotor development up to the age of 16 months. This case highlights the importance of considering Aicardi–Goutières syndrome in the differential diagnosis of an unexplained leukoencephalopathy and the possibility of later onset of the disease. [Copyright &y& Elsevier]

Abstract: In 1984, Jean Aicardi and Françoise Goutières described 8 children showing both severe brain atrophy and chronic cerebrospinal fluid lymphocytosis, with basal ganglia calcification in at least one member of each affected family. The course was rapid to death or a vegetative outcome. Aicardi and Goutières correctly predicted that the disorder would be genetic, but emphasised that “some features, especially the pleocytosis, may erroneously suggest an inflammatory condition”. The increased interferon-alpha in affected children (Pierre Lebon, Paris) mimicked congenital viral infection, but the associated chilblains (pernio) pointed to lupus erythematosus and an autoimmune mechanism. Genetic research led by Yanick Crow has clarified these puzzling relationships in Aicardi–Goutières syndrome, a syndrome that now includes conditions previously known as microcephaly-intracranial calcification syndrome, pseudo-TORCH and Cree encephalitis. At the time of writing, Crow''s team has discovered that over 80% of families with Aicardi–Goutières syndrome have mutations in one of four nuclease genes, the exonuclease TREX1 and the genes for all three subunits of the ribonuclease H2 enzyme complex. Aicardi–Goutières syndrome is both genetically and phenotypically heterogeneous, with a range of severity from life-threatening perinatal illness to mild late infancy onset. All infants of whatever genotype have increased interferon-alpha in the first year of life and this appears to be the final common pathway that links Aicardi–Goutières syndrome, congenital virus infection and systemic lupus erythematosus. [Copyright &y& Elsevier]

The leukodystrophies are a heterogeneous group of diseases, which primarily affect white matter. An integrated description of the clinical, neuroimaging and pathophysiological features is crucial for categorizing these disorders. A group of leukoencephalopathies are associated with calcifications. In this article, we review these disorders briefly. Aicardi-Goutieres Syndrome: Aicardi-Goutieres syndrome (AGS) is a genetically heterogeneous autosomal recessive group of encephalopathies with 5 subtypes. Classic AGS is characterized by cerebral atrophy, white matter abnormalities, intracranial calcifications, chronic CSF lymphocytosis, and elevated CSF alphainterferon. Broadly speaking, 2 clinical presentations have been delineated: an early onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurologic function. Severe neurologic dysfunction becomes clinically apparent in infancy, and manifests as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood. Outside the nervous system, thrombocytopenia, hepatosplenomegaly, and elevated hepatic transaminases along with intermittent fever may also erroneously suggest an infective process. It is important to exclude of pre-/perinatal infections, in particular the TORCH complex. Genetic screening for mutations in the four genes known to cause AGS allows definitive confirmation of the diagnosis in the majority (83%). Cockayne ‘s syndrome: Cockayne syndrome is an autosomal recessive disease due to a DNA repair defect. Patients show psychomotor developmental delay, dwarfism, progeroid appearance, microcephaly, deafness, pigmentary retinal degeneration, optic atrophy, and photosensitivity. Abnormal peripheral nerve conduction is due to a demyelinating polyneuropathy. Neuroimaging shows brain atrophy of variable degree, namely in brainstem and cerebellum; abnormally high signal intensity on T2-weighted images throughout the hemispherical white matter; late involvement of the subcortical fibers; abnormal hyperintensity on T1-weighted images in the basal ganglia corresponding to calcification. Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy): It is caused by homozygous or compound heterozygous mutation in the RNASET2 gene on chromosome 6q27. Neurologic deficits were noted within the first months of life, and included severe intellectual impairment, motor retardation, and spasticity. Brain MRI showed extensive cysts within the anterior temporal lobes, ventricular enlargement, and white matter disease. The signal intensities of the cysts were identical to those of cerebrospinal fluid. CT scans showed intracranial calcifications in some subjects. Cerebrotendinous xanthomatosis: Also called cerebral cholesterosis, is an autosomal recessive form of xanthomatosis. it is characterized by progressive cerebellar ataxia beginning after puberty and by juvenile cataracts, juvenile or infantile onset chronic diarrhea, childhood neurological deficit, and tendineous or tuberous xanthomas. The initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy. In 75% of cases, cataract is the first finding, often appearing in childhood. Pyramidal signs and/or cerebellar ataxia are present in the 20s or 30s. Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy. MRI shows bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter. Leukoencephalopathy with calcifications and cysts: Triad of leukoencephalopathy, cerebral calcifications and cysts (LCC) is a recently reported rare disease named ‘Labrune syndrome’. The clinical presentation is insidious and variable. Typically, initial symptoms are of raised intracranial pressure, later followed by focal neurologic deficits resulting in spasticity, dystonia, seizures, and cognitive decline. Cerebroretinal microangiopathy with calcifications and cysts, an autosomal recessive disorder caused by mutation in the CTC1 gene that shows phenotypic similarities to Labrune syndrome. CRMCC includes the neurologic findings of intracranial calcifications, leukodystrophy, and brain cysts, but also includes retinal vascular abnormalities and other systemic manifestations, such as osteopenia with poor bone healing, a high risk of gastrointestinal bleeding, hair, skin, and nail changes, and anemia and thrombocytopenia. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic. Naku-Hakola’s disease: Affected patients had onset in the third decade of pain and swelling following strain of the wrist or ankle; fractures occurred after minor accidents. Radiographs showed cystic rarefactions in the epiphyseal regions of bones. The cysts contained jellylike material and microscopically showed membranous and lamellar structures between fatty and collagenous connective tissue. In the fourth decade, patients developed neuropsychiatric symptoms, including memory impairment, euphoria, loss of social inhibitions, and impotency or frigidity. Neurologic examination showed exaggerated deep tendon reflexes, pathologic reflexes, and dysplasia. Patients usually die between ages 35 and 45, and the later features of the disorder resemble those of Alzheimer disease. Globoid Cell Leukodystrophy (Krabbe Disease): The manifestations of Krabbe disease are due to accumulation of galactocerebrosides and galactosylsphingosine, which in turn leads to loss of oligodendrocytes. Infantile Krabbe disease presents in the first 6 months of life as hyperirritability, increased muscular tone, fever, and developmental arrest. As the disease progresses, there is further cognitive decline, myoclonus, opisthotonus, nystagmus, and optic atrophy. Patients diagnosed in infancy rarely survive beyond 2 years. In an estimated 10% of cases, symptoms begin after the patient has begun to walk; these are considered “late-onset.” Central motor signs include spasticity, ataxia, and weakness. Of late-onset patients, 20% have abnormal peripheral nerve conduction studies with uniform slowing of conduction velocities. Demyelination of the deep WM, progressively involving the subcortical white matter. Calcifications within the thalami, basal ganglia, and corona radiata shown by CT scan. [ABSTRACT FROM AUTHOR]