Giulia Amico
@gaslini.org
UOC Medical Genetics
IRCCS Giannina Gaslini
RESEARCH INTERESTS
Medical Genetics, stroke, mendelian diseases, population genetics, metabolic diseases
Scopus Publications
Scopus Publications
Giulia Amico, Wayne O. Hemphill, Mariasavina Severino, Claudio Moratti, Rosario Pascarella, Marta Bertamino, Flavia Napoli, Stefano Volpi, Francesca Rosamilia, Sara Signa,et al.
MDPI AG
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).
Moran Hausman-Kedem, Rachelle Herring, Marcela D Torres, Jonathan D. Santoro, Matsanga Leyila Kaseka, Carolina Vargas, Giulia Amico, Marta Bertamino, Deepti Nagesh, Jo Tilley,et al.
Elsevier BV
Francesco STILLO, Raul MATTASSI, Andrea DIOCIAIUTI, Iria NERI, Vittoria BARALDINI, Pietro DALMONTE, Bruno AMATO, Orsola AMETRANO, Giulia AMICO, Giuseppe BIANCHINI,et al.
Edizioni Minerva Medica
Matteo Paolucci, Chiara Vincenzi, Michele Romoli, Giulia Amico, Isabella Ceccherini, Simona Lattanzi, Anna Bersano, Marco Longoni, Simona Sacco, Fabrizio Vernieri,et al.
MDPI AG
Patent Foramen Ovale (PFO) is a common postnatal defect of cardiac atrial septation. A certain degree of familial aggregation has been reported. Animal studies suggest the involvement of the Notch pathway and other cardiac transcription factors (GATA4, TBX20, NKX2-5) in Foramen Ovale closure. This review evaluates the contribution of genetic alterations in PFO development. We systematically reviewed studies that assessed rare and common variants in subjects with PFO. The protocol was registered with PROSPERO and followed MOOSE guidelines. We systematically searched English studies reporting rates of variants in PFO subjects until the 30th of June 2021. Among 1231 studies, we included four studies: two of them assessed the NKX2-5 gene, the remaining reported variants of chromosome 4q25 and the GATA4 S377G variant, respectively. We did not find any variant associated with PFO, except for the rs2200733 variant of chromosome 4q25 in atrial fibrillation patients. Despite the scarceness of evidence so far, animal studies and other studies that did not fulfil the criteria to be included in the review indicate a robust genetic background in PFO. More research is needed on the genetic determinants of PFO.
Marta Bertamino, , Sara Signa, Marco Veneruso, Giulia Prato, Roberta Caorsi, Giuseppe Losurdo, Federica Teutonico, Silvia Esposito, Francesca Formica,et al.
Springer Science and Business Media LLC
Post-varicella arterial ischemic stroke (AIS) is considered an uncommon cause of pediatric stroke that is considered a self-limiting, monophasic disease. However, in a subset of patients, disease recurs; the prevalence of vasculopathy or AIS recurrence, severity of clinical outcomes, and standardized therapies have not been well characterized. Herein, we determined the clinical-neuroradiological features, long-term evolution, and relationship between acute phase treatment and vasculopathy recurrence in a pediatric population with post-varicella AIS. Clinical, laboratory, and neuroradiological features of 22 children with post-varicella AIS between 2010 and 2019 (16 males, mean age at stroke 4 years, range 1.7–10) were reviewed. Statistical analyses were performed using χ2 and Fisher exact tests. Of the 22 cases, mean time from varicella to stroke was 4.5 months with 3 cases presenting more than 12 months after rash; 21 (95%) were not vaccinated for varicella; 3 (13.6%) had posterior circulation involvement; and 5 (22.7%) had AIS or vasculopathy recurrence, of which 4 recurred 6.1 months to 2.8 years after initial clinical onset. Recurrence was associated with lack of antiviral treatment during the first episode (p = 0.02). Post-varicella AIS can occur months after rash making diagnosis challenging. Because recurrent vasculopathy was seen predominantly in cases not treated with antiviral therapy during initial presentation, it is important to rapidly diagnose post-varicella AIS through clinical criteria and/or virological testing then treat with antivirals to prevent recurrence.
Alessandro Iodice, Sara Signa, Mariasavina Severino, Domenico Tortora, Alice Zanetti, Giulia Amico, Gianluca Piatelli, Marta Bertamino, and Marco Pavanello
Elsevier BV
BACKGROUND
Post varicella angiopathy (PVA) is an underdiagnosed but potentially severe disease in both pediatric and adult settings. No guidelines are available for the medical and neurosurgical management of this condition. We report the first pediatric case with headache and PVA who was treated with surgical revascularization before the onset of ischemic events.
METHODS
This case report was conducted via retrospective chart review. A literature review was also completed, in order to identify previously described PVA undergone to revascularization.
RESULTS
We report on a 9-year-old boy presenting with a long history of headache and PVA involving the distal left middle cerebral artery. The arterial lesion rapidly worsened over a 10 months' period with formation of focal moyamoya-like collaterals, despite an adequate intravenous antiviral treatment. The pattern of headaches significantly changed with a clear left-side lateralization and a "re-build-up" phenomenon on EEG. The patient was treated with left superficial temporal artery - middle cerebral artery (STA-MCA) bypass and encephalo-duro-arterio-myo-pericranial-synangiosis. This combined treatment resulted in an immediate and persistent improvement of brain perfusion, accompanied by prompt resolution of neurological symptoms. Two cases who presented with Suzuki stage III (unilateral or bilateral) moyamoya PVA and recurrent strokes or transient ischemic attacks despite adequate pharmacological prophylaxis have been surgically treated using both indirect and direct revascularization technique. The outcome was good in both cases.
CONCLUSION
Surgical revascularization may have a role in the treatment of PVA and may prevent stroke. Given the lack of standardized treatment algorithms, individualized regimens should be formulated on a case-specific basis.
Marta Bertamino, Sara Signa, Giulia Vagelli, Roberta Caorsi, Alice Zanetti, Stefano Volpi, Giuseppe Losurdo, Giulia Amico, Icilio Dodi, Giulia Prato,et al.
AME Publishing Company
Post-varicella arterial ischemic stroke (AIS) is a rare but serious complication of varicella zoster virus (VZV) infection, with an estimated incidence of 1/15,000 children per year, and high risk of lifelong disability and increased mortality (1). Both in children and adults, the clinical diagnosis is based on neurological symptoms and signs due to AIS associated with a history of chickenpox or herpes zoster infection during the previous year, once other major causes for AIS are excluded (2-4). Of note, this diagnosis is often challenging since previous VZV rash may be absent in 30% of patients (5,6). Moreover, VZV DNA in cerebrospinal fluid (CSF) is positive in only 30% of subjects with VZV stroke, underlying that a negative PCR result does not exclude this diagnosis (5). The detection of anti-VZV IgG antibody in the CSF is the most sensitive diagnostic test, particularly when combined with demonstration of intrathecal synthesis (5-7). Qualitatively, the serum/CSF ratio of anti-VZV IgG antibody is compared with the serum/CSF ratio of albumin and total IgG, with a reduction of the former compared with the latter representing a positive result (8,9). A more quantitative assessment of intrathecal synthesis, the antibody index, has been described by Reiber and Lange: (CSF VZV IgG/serum VZV IgG)/(CSF total IgG or albumin/serum total IgG or albumin). An antibody index ≥1.5 is considered as positive (8). The underlying mechanism of VZV-associated AIS is not entirely clarified. Viral markers have been identified in patients’ CSF as well as viral DNA, antigens and particles in the wall of affected arteries (7). These findings support the hypothesis of a direct VZV arterial infection associated with variable indirect inflammatory responses (6), after transaxonal viral migration from the cranial nerve ganglia to the cerebral arterial walls (2). Indeed, inflammatory focal cerebral arteriopathy is the most common cerebrovascular manifestation attributed to VZV (10), classically involving the proximal middle cerebral artery (MCA) and/or other medium-sized vessels such as the terminal internal carotid Letter to the Editor
Patrizia Fiorio, Gloria Donarini, Ezio Fulcheri, Gabriella Meccariello, Elisa Tassano, Giulia Amico, and Dario Paladini
Wiley
Double trisomy (DT), defined as the coexistence of 2 numeric chromosomal abnormalities in the same individual, is a rare condition frequently leading to early spontaneous miscarriage. In general, DT pregnancies reaching the end of first trimester are exceptionally rare, but milder conditions, possibly compatible with survival, have been described when sex chromosomes and autosomes are together affected. The exclusive involvement of 2 autosomes results in more severe malformations mainly associated with only 1 of the 2 aneuploidies. Here we describe the uncommon case of a first-trimester fetus with a 48,XX,+18+21 karyotype, presenting prenatal ultrasound (US) evidence of congenital anomalies typical of both 18 and 21 autosomal trisomies. The mother, 45 years old (gravida 2 para 1), was referred to the Fetal Medicine Unit of our institution for a pregnancy evaluation due to advanced age. Conception was spontaneous, and the couple did not report consanguinity. The first child was a healthy boy. The first transvaginal US examination was performed in our institute at a gestational age of 10 weeks 6 days. Thickened nuchal translucency with subcutaneous edema extending caudally to the whole fetal trunk was observed, together with an anomaly of one forearm, possibly consistent with radial aplasia. On the basis of the overall US findings, the couple was counseled about the high probability of a fetus affected with trisomy 18 and agreed on the decision to proceed directly with chorionic villus sampling. At 12 weeks 4 days, chorionic villus sampling was performed, and a further US evaluation confirmed severe nuchal thickening (6.2 mm), a crown-rump length of 52 mm, subcutaneous edema, absence of the nasal bone, and a flat facial profile (Figure 1A). The heart could not be thoroughly investigated, although the suspicion of unilateral radial aplasia was confirmed (Figure 1B), despite the presence of a thumb finger. Particularly, the latter is unusual in trisomy 18, raising the doubt that other rarer genetic conditions, such as Fanconi anemia and thrombocytopenia–absent radius, syndrome, may have been present. Ductus venous velocimetric findings were abnormal, with pronounced reversal of the A wave and a high peak velocity in the hepatic artery (65 cm/s; Figure 1C). A cytogenetic analysis on the chorionic villi was performed, following standard protocols, after setting up chromosome preparations. The karyotype result was 48,XX,+18+21 in 25 metaphases from a shortterm culture and in 16 metaphases from 2 independent long-term cultures. Fetal demise was revealed at 13 weeks 4 days, and then medical termination was performed. Subsequent necropsy confirmed only some of the anomalies detected by US because of prolonged retention of the dead fetus and the early gestational age. The fetal weight was 3.2 g, and the crown-rump length was 47 mm. Advanced maceration prevented a detailed gross anatomic assessment involving the upper and, to a lesser extent, lower limbs as well. However, serial sections of the upper limb, which showed radial aplasia at the US evaluations, were obtained. The histologic examination highlighted the copresence of a single ossified bone, consistent with the ulna, and normal cartilage (Figure 1D, left panel) but also immature cartilage without any sign of growth located in the radius site (Figure 1D, right panel). The concurrent presence of DT in the same individual has been described in 0.2% to 2.8% of miscarried fetuses and in an even lower percentage of term neonates. The first report about DT, published in 1959, described Klinefelter and Down syndromes (48,XXY,+21). To our knowledge, only 1 case of trisomy 18 and trisomy 21, diagnosed in a 13-month-old girl by a cytogenetic analysis performed to confirm the Down syndrome phenotype, has been described. Moreover, only a few cases of DT mosaicism have been reported so far. In prenatal diagnosis, DT involving trisomy 18 or trisomy 21 was reported only in association with a sex chromosome imbalance, probably because when it involves 2 autosomes, it leads to early pregnancy failure. In our case, US first showed a fetus with concurrent anomalies typical of trisomy 18 and trisomy 21. In particular, a flat profile, enlarged nuchal translucency, and trunk edema are common to both aneuploidies; absence of the nasal bone and a high peak velocity in the hepatic artery are typical of trisomy 21; whereas radial aplasia is usually associated with trisomy 18.
Amico, Brandas, Moran, and Baroni
MDPI AG
Cystic fibrosis (CF) is a genetic disease associated with the defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that causes obstructive disease and chronic bacterial infections in airway epithelia. The most prevalent CF-causing mutation, the deletion of phenylalanine at position 508 (F508del), leads to CFTR misfolding, trafficking defects and premature degradation. A number of correctors that are able to partially rescue F508del-CFTR processing defects have been identified. Clinical trials have demonstrated that, unfortunately, mono-therapy with the best correctors identified to date does not ameliorate lung function or sweat chloride concentration in homozygous F508del patients. Understanding the mechanisms exerted by currently available correctors to increase mutant F508del-CFTR expression is essential for the development of new CF-therapeutics. We investigated the activity of correctors on the mutant F508del and wild type (WT) CFTR to identify the protein domains whose expression is mostly affected by the action of correctors, and we investigated their mechanisms of action. We found that the four correctors under study, lumacaftor (VX809), the quinazoline derivative VX325, the bithiazole compound corr4a, and the new molecule tezacaftor (VX661), do not influence either the total expression or the maturation of the WT-CFTR transiently expressed in human embryonic kidney 293 (HEK293) cells. Contrarily, they significantly enhance the expression and the maturation of the full length F508del molecule. Three out of four correctors, VX809, VX661 and VX325, seem to specifically improve the expression and the maturation of the mutant CFTR N-half (M1N1, residues 1–633). By contrast, the CFTR C-half (M2N2, residues 837–1480) appears to be the region mainly affected by corr4a. VX809 was shown to stabilize both the WT- and F508del-CFTR N-half isoforms, while VX661 and VX325 demonstrated the ability to enhance the stability only of the mutant F508del polypeptide.
Denise Lasigliè, Anna Mensa-Vilaro, Denise Ferrera, Roberta Caorsi, Federica Penco, Giuseppe Santamaria, Marco Di Duca, Giulia Amico, Kenji Nakagawa, Francesca Antonini,et al.
The Journal of Rheumatology
Objective.To evaluate the rate of somatic NLRP3 mosaicism in an Italian cohort of mutation-negative patients with cryopyrin-associated periodic syndrome (CAPS).Methods.The study enrolled 14 patients with a clinical phenotype consistent with CAPS in whom Sanger sequencing of the NLRP3 gene yielded negative results. Patients’ DNA were subjected to amplicon-based NLRP3 deep sequencing.Results.Low-level somatic NLRP3 mosaicism has been detected in 4 patients, 3 affected with chronic infantile neurological cutaneous and articular syndrome and 1 with Muckle-Wells syndrome. Identified nucleotide substitutions encode for 4 different amino acid exchanges, with 2 of them being novel (p.Y563C and p.G564S). In vitro functional studies confirmed the deleterious behavior of the 4 somatic NLRP3 mutations. Among the different neurological manifestations detected, 1 patient displayed mild loss of white matter volume on brain magnetic resonance imaging.Conclusion.The allele frequency of somatic NLRP3 mutations occurs generally under 15%, considered the threshold of detectability using the Sanger method of DNA sequencing. Consequently, routine genetic diagnostic of CAPS should be currently performed by next-generation techniques ensuring high coverage to identify also low-level mosaicism, whose actual frequency is yet unknown and probably underestimated.
Susanna Lualdi, Genny Del Zotto, Olga Zegarra-Moran, Nicoletta Pedemonte, Fabio Corsolini, Maurizio Bruschi, Valeria Tomati, Giulia Amico, Giovanni Candiano, Andrea Dardis,et al.
Wiley
The transfer of genomic information into the primary RNA sequence can be altered by RNA editing. We have previously shown that genomic variants can be RNA‐edited to wild‐type. The presence of distinct “edited” iduronate 2‐sulfatase (IDS) mRNA transcripts ex vivo evidenced the correction of a nonsense and frameshift variant, respectively, in three unrelated Hunter syndrome patients. This phenomenon was confirmed in various patient samples by a variety of techniques, and was quantified by single‐nucleotide primer extension. Western blotting also confirmed the presence of IDS protein similar in size to the wild‐type. Since preliminary experimental evidence suggested that the “corrected” IDS proteins produced by the patients were similar in molecular weight and net charge to their wild‐type counterparts, an in vitro system employing different cell types was established to recapitulate the site‐specific editing of IDS RNA (uridine to cytidine conversion and uridine deletion), and to confirm the findings previously observed ex vivo in the three patients. In addition, confocal microscopy and flow cytometry analyses demonstrated the expression and lysosomal localization in HEK293 cells of GFP‐labeled proteins translated from edited IDS mRNAs. Confocal high‐content analysis of the two patients’ cells expressing wild‐type or mutated IDS confirmed lysosomal localization and showed no accumulation in the Golgi or early endosomes.
Giulia Amico, Serena Grossi, Raymon Vijzelaar, Federica Lanza, Raffaella Mazzotti, Fabio Corsolini, Mirjam Ketema, and Mirella Filocamo
Elsevier BV
The chromosomal region, in which the GBA gene is located, is structurally subject to misalignments, reciprocal and nonreciprocal homologous recombination events, leading to structural defects such as deletions, duplications and gene-pseudogene complex rearrangements causing Gaucher Disease (GD). Interestingly deletions and duplications, belonging to the heterogeneous group of structural defects collectively termed Copy Number Variations (CNVs), together with gene-pseudogene complex rearrangements represent the main cause of pitfalls in GD mutational analysis. In the present study, we set up and validate a Multiplex Ligation-dependent Probe Amplification (MLPA)-based approach to simultaneously investigate the potential occurrence of CNVs and complex rearrangements in 8 unrelated GD patients who had still not-well-characterized or uncharacterized alleles. The findings allowed us to complete the mutational analysis in 4 patients, identifying a rare deletion (g.-3100_+834del3934) and 2 novel recombinant alleles (g.4356_7031conJ03060.1:g.2544_4568; g.1942_7319conJ03060.1:g.1092_4856). These results demonstrate the diagnostic usefulness of MLPA in the detection of GBA deletions and recombinations. In addition, MLPA findings have also served as a basis for developing molecular approaches to precisely pinpoint the breakpoints and characterize the underlying mechanism of copy number variations.
Martina Cesani, Laura Lorioli, Serena Grossi, Giulia Amico, Francesca Fumagalli, Ivana Spiga, Mirella Filocamo, and Alessandra Biffi
Wiley
Metachromatic leukodystrophy is a neurodegenerative disorder characterized by progressive demyelination. The disease is caused by variants in the ARSA gene, which codes for the lysosomal enzyme arylsulfatase A, or, more rarely, in the PSAP gene, which codes for the activator protein saposin B. In this Mutation Update, an extensive review of all the ARSA‐ and PSAP‐causative variants published in the literature to date, accounting for a total of 200 ARSA and 10 PSAP allele types, is presented. The detailed ARSA and PSAP variant lists are freely available on the Leiden Online Variation Database (LOVD) platform at http://www.LOVD.nl/ARSA and http://www.LOVD.nl/PSAP, respectively.