Medical Genetics, stroke, mendelian diseases, population genetics, metabolic diseases
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Scopus Publications
Scopus Publications
ABCC6 Heterozygosity as Genetic Predisposition to Cerebrovascular Disease Across Ages Giulia Amico, Mariasavina Severino, Marta Bertamino, Rosario Pascarella, Domenico Tortora, et al. Genes, 2026 Background: Heterozygosity for pathogenic variants in the ABCC6 gene has been associated with an increased incidence of cerebrovascular diseases. This study aims to characterize the prevalence and clinical and neuroradiological phenotypes associated with monoallelic and biallelic ABCC6 variants in pediatric and adult patients presenting with arterial ischemic stroke or cerebral small vessel disease (CSVD). Methods: We conducted a retrospective observational study on 143 consecutive patients (48 pediatric, 24 juvenile, 71 adult) diagnosed with ischemic stroke or CSVD of unknown etiology. Clinical and neuroradiological data were collected and analyzed in relation to the identified genetic variants through next-generation sequencing. Results: Among the patients, 16 (11.2%) tested positive for causative variants in the ABCC6 gene, with 11 subjects carrying monoallelic variants and 5 carrying biallelic variants. Patients with biallelic variants exhibited severe and complex vasculopathy, with a high incidence of early ischemic events. In contrast, monoallelic carriers predominantly presented with microvascular disease manifestations, including lacunar strokes and signs of CSVD. Conclusions: The results suggest a significant age-dependent phenotypic divergence in patients with ABCC6 variants, highlighting the impact of heterozygosity on cerebrovascular health. Identifying these variants may enhance risk stratification and inform management strategies in patients with traditional vascular risk factors.
Arteriovenous cerebral high-flow shunts: genetic analysis of patients from a pediatric tertiary care center Ferruccio Romano, P. de Marco, Giulia Amico, M. Mallamaci, M. Pavanello, et al. Frontiers in Genetics, 2025 Introduction Arteriovenous cerebral high-flow shunts include the vein of Galen aneurysmal malformation (VGAM) and vein of Galen dilatation, which are considered secondary to arteriovenous malformations or arteriovenous fistulas. These entities are often sporadic but are found in association with variants of the RASA1 and EPHB4 genes (capillary malformation–arteriovenous malformation, CMAVM; OMIM #608354) or ACVRL1, ENG, and SMAD4 genes (hereditary hemorrhagic telangiectasia, HHT; OMIM #187300). The clinical phenotypes associated with these conditions are highly variable, with incomplete penetrance and mostly dependent on the hemodynamic consequences (including heart failure and cerebral hemorrhage) or management complications rather than anatomical vascular variations per se. The present study aimed to genetically characterize a cohort of 29 patients affected by arteriovenous cerebral high-flow shunts who were treated at a pediatric referral center. Methods The genetic techniques employed include next-generation sequencing, multiplex ligation-dependent probe amplification, and whole-exome sequencing. Results Of the 29 patients, 11 cases were found to have variants in genes associated with vascular functions, five cases received a genetic diagnosis, one case presented with a variant of uncertain significance in the EPHB4 gene, and five cases showed variants in novel genes possibly linked with cerebrovascular disorders. Discussion We provide extensive case descriptions and attempt to infer the genotype–phenotype correlations; variants in all of the known genes associated with arteriovenous cerebral shunts were reported in VGAM patients, while cutaneous angiomas were specific to RASA1 mutations. The genotypic and phenotypic descriptions of the affected individuals may thus have relevant implications in terms of better pathophysiological understanding, genotype–phenotype correlations, treatment strategies, and outcomes.
Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core Giulia Amico, Wayne O. Hemphill, Mariasavina Severino, Claudio Moratti, Rosario Pascarella, et al. Genes, 2022 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).
The genetic landscape of patent foramen ovale: A systematic review Matteo Paolucci, Chiara Vincenzi, Michele Romoli, Giulia Amico, Isabella Ceccherini, et al. Genes, 2021 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.
Expanding the clinical and neuroimaging features of post-varicella arteriopathy of childhood Marta Bertamino, Sara Signa, Marco Veneruso, Giulia Prato, Roberta Caorsi, et al. Journal of Neurology, 2021 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.
Combined medical therapy and neurosurgical revascularization preventing stroke in post-varicella angiopathy: Case report and review of literature Alessandro Iodice, Sara Signa, Mariasavina Severino, Domenico Tortora, Alice Zanetti, et al. Brain and Development, 2021 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.
An atypical case of post-varicella stroke in a child presenting with hemichorea followed by late-onset inflammatory focal cerebral arteriopathy Marta Bertamino, Sara Signa, Giulia Vagelli, Roberta Caorsi, Alice Zanetti, et al. Quantitative Imaging in Medicine and Surgery, 2021 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
Prenatal Diagnosis of an Uncommon 48,XX,+18+21 Karyotype in a Fetus With Malformations Typical of Both Trisomies Patrizia Fiorio, Gloria Donarini, Ezio Fulcheri, Gabriella Meccariello, Elisa Tassano, et al. Journal of Ultrasound in Medicine, 2020 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.
