Georgia Ramantani

Bio: Georgia Ramantani is an academic researcher from Boston Children's Hospital. The author has contributed to research in topics: Epilepsy & Epilepsy surgery. The author has an hindex of 26, co-authored 82 publications receiving 1904 citations. Previous affiliations of Georgia Ramantani include University Medical Center Freiburg & Aarhus University Hospital.

Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome.

Abstract: Objective Aicardi-Goutieres syndrome (AGS) is an early-onset encephalopathy resembling congenital viral infection that is characterized by basal ganglia calcifications, loss of white matter, cerebrospinal fluid (CSF) lymphocytosis, and elevated interferon-α levels in the CSF. Studies have shown that AGS is an autosomal-recessive disease linked to mutations in 5 genes, encoding the 3′-repair DNA exonuclease 1 (TREX1), the 3 subunits of ribonuclease H2 (RNASEH2A–C), and sterile alpha motif domain and HD domain–containing protein 1 (SAMHD1). In this study we further characterized the phenotypic spectrum of this disease. Methods Clinical and laboratory data were obtained from 26 patients fulfilling the clinical diagnostic criteria for AGS. Genomic DNA was screened for mutations in all 5 AGS genes by direct sequencing, and sera were analyzed for autoantibodies. Results In 20 patients with AGS, 20 mutations, 12 of which were novel, were identified in all 5 AGS genes. Clinical and laboratory investigations revealed a high prevalence of features (some not previously described in patients with AGS) that are commonly seen in patients with systemic lupus erythematosus (SLE), such as thrombocytopenia, leukocytopenia, antinuclear antibodies, erythematous lesions, oral ulcers, and arthritis, which were observed in 12 (60%) of 20 patients with AGS. Moreover, the coexistence of AGS and SLE, was for the first time, demonstrated in 2 patients with molecularly proven AGS. Conclusion These findings expand the phenotypic spectrum of lupus erythematosus in AGS and provide further insight into its disease mechanisms by showing that activation of the innate immune system as a result of inherited defects in nucleic acid metabolism could lead to systemic autoimmunity.

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Abstract: Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutieres syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.

Focal cortical dysplasia: prevalence, clinical presentation and epilepsy in children and adults

Abstract: Focal cortical dysplasias (FCD) are defined as circumscribed malformations of cortical development. They result from an impairment of neuronal proliferation, migration and differentiation. In the diagnosis of focal epilepsy FCD prevalence ranges between 5% and 25%, depending on patient collective and imaging techniques. Several 'cryptogenic' epilepsies may be caused by FCD but have not been diagnosed because of the lack of high-quality magnetic resonance imaging assessment. Retrospective analysis of patients who have undergone epilepsy surgery can be biased because of the fact that they represent a mere subset of potential FCD diagnoses. Epilepsy typically manifests within the first years of life, but has been documented up to the age of 60 years. Cognitive impairment commonly accompanies early onset. Epilepsy is often refractory to antiepileptic drug (AED) treatment. Clinical observations and pathophysiological findings illustrate intrinsic epileptogenicity. Upregulation of drug transporter proteins has been found in FCD tissue. There is no specific drug treatment in FCD, as any AED used in focal epilepsy could prove effective. A sequential AED therapy should be designed individually and take side effects as well as developmental progresses into consideration. Fifty to sixty-five percent of FCD patients are rendered seizure-free after surgery. Presurgical evaluation should be initiated after two unsuccessful AED trials. Both risks and potential benefits regarding seizure control and developmental impairment need to be considered on an individual basis when deciding between surgical intervention and conservative treatment. Current knowledge on epilepsy course and psychomotor development in FCD is limited in the absence of qualified long-term studies combining imaging with cognitive evaluation.

Catching the Invisible: Mesial Temporal Source Contribution to Simultaneous EEG and SEEG Recordings

Abstract: Mesial temporal sources are presumed to escape detection in scalp electroencephalographic recordings. This is attributed to the deep localization and infolded geometry of mesial temporal structures that leads to a cancellation of electrical potentials, and to the blurring effect of the superimposed neocortical background activity. In this study, we analyzed simultaneous scalp and intracerebral electroencephalographic recordings to delineate the contribution of mesial temporal sources to scalp electroencephalogram. Interictal intracerebral spike networks were classified in three distinct categories: solely mesial, mesial as well as neocortical, and solely neocortical. The highest and earliest intracerebral spikes generated by the leader source of each network were marked and the corresponding simultaneous intracerebral and scalp electroencephalograms were averaged and then characterized both in terms of amplitude and spatial distribution. In seven drug-resistant epileptic patients, 21 interictal intracerebral networks were identified: nine mesial, five mesial plus neocortical and seven neocortical. Averaged scalp spikes arising respectively from mesial, mesial plus neocortical and neocortical networks had a 7.1 (n = 1,949), 36.1 (n = 628) and 10 (n = 1,471) µV average amplitude. Their scalp electroencephalogram electrical field presented a negativity in the ipsilateral anterior and basal temporal electrodes in all networks and a significant positivity in the fronto-centro-parietal electrodes solely in the mesial plus neocortical and neocortical networks. Topographic consistency test proved the consistency of these different scalp electroencephalogram maps and hierarchical clustering clearly differentiated them. In our study, we have thus shown for the first time that mesial temporal sources (1) cannot be spontaneously visible (mean signal-to-noise ratio −2.1 dB) on the scalp at the single trial level and (2) contribute to scalp electroencephalogram despite their curved geometry and deep localization.

CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling

Abstract: CRISPR-Cas9 is a versatile genome editing technology for studying the functions of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse. We demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells. Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung adenocarcinoma. Delivery of a single AAV vector in the lung generated loss-of-function mutations in p53 and Lkb1, as well as homology-directed repair-mediated KrasG12D mutations, leading to macroscopic tumors of adenocarcinoma pathology. Together, these results suggest that Cas9 mice empower a wide range of biological and disease modeling applications.

New insights into the immunopathogenesis of systemic lupus erythematosus

Abstract: In this Review, Tsokos et al. describe recent advances in our understanding of systemic lupus erythematosus (SLE) that are driving repurposing of existing drugs as well as development of new treatments. Cytokines, tolerance pathways, local tissue mediators, and epigenetic mechanisms all show promise as novel targeted therapies that could lead to individualized care in SLE.

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Abstract: Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutieres syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

Aicardi–Goutières syndrome and the type I interferonopathies

Abstract: This Review describes the type I interferonopathies — a set of Mendelian disorders associated with the upregulation of type I interferon activity. The authors explain how defects in key components of innate immune signalling pathways can lead to these diseases and discuss the immunological insights that have resulted from their study.