Publications by authors named "Silvia Esposito"

47 Publications

Plasma Lipid Profiling Contributes to Untangle the Complexity of Moyamoya Arteriopathy.

Int J Mol Sci 2021 Dec 14;22(24). Epub 2021 Dec 14.

Laboratory of Neurobiology and UCV, Neurology IX Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved in MA. Our aim is to evaluate angiogenic/vasculogenic/inflammatory proteins and lipid profile in plasma of MA patients and control subjects (healthy donors HD or subjects with atherosclerotic cerebrovascular disease ACVD). Angiogenic and inflammatory protein levels were measured by ELISA and a complete lipidomic analysis was performed on plasma by mass spectrometry. ELISA showed a significant decrease for MMP-9 released in plasma of MA. The untargeted lipidomic analysis showed a cumulative depletion of lipid asset in plasma of MA as compared to HD. Specifically, a decrease in membrane complex glycosphingolipids peripherally circulating in MA plasma with respect to HD was observed, likely suggestive of cerebral cellular recruitment. The quantitative targeted approach demonstrated an increase in free sphingoid bases, likely associated with a deregulated angiogenesis. Our findings indicate that lipid signature could play a central role in MA and that a detailed biomarker profile may contribute to untangle the complex, and still obscure, pathogenesis of MA.
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http://dx.doi.org/10.3390/ijms222413410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708587PMC
December 2021

Expanding the clinical and neuroimaging features of post-varicella arteriopathy of childhood.

J Neurol 2021 Dec 27;268(12):4846-4865. Epub 2021 May 27.

Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Objective: 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.

Methods: 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 χ and Fisher exact tests.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1007/s00415-021-10606-6DOI Listing
December 2021

A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia.

Neuropediatrics 2021 12 14;52(6):484-488. Epub 2021 Apr 14.

Department of Developmental Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with gene. Alterations of have been linked to neurodevelopmental disorders, ranging from developmental delay, to autism spectrum disorder, to attention deficit/hyperactivity disorder. The underlying mechanism is not yet fully understood, as it has been hypothesized a fully dominant effect, a risk factor role of partially penetrating variants, and a recessive inheritance pattern. We report a novel and de novo mutation in a child affected by severe neurodevelopmental disorder and with brain magnetic resonance imaging evidence of mega cisterna magna and mild cerebellar hypoplasia. This case strengthens the hypothesis that dominant variants may lead to neurodevelopmental disruption; furthermore, given the strong interaction between and , we discuss as posterior fossa anomalies may also be part of the phenotype of -related syndrome.
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http://dx.doi.org/10.1055/s-0041-1725964DOI Listing
December 2021

CGH Findings in Children with Complex and Essential Autistic Spectrum Disorder.

J Autism Dev Disord 2021 Jan 4. Epub 2021 Jan 4.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a strong genetic basis. We accurately assessed 209 ASD subjects, categorized in complex (47) and essential (162), and performed array comparative genomic hybridization to identify pathogenic and recurrent Copy Number Variants (CNVs). We found 117 CNVs in 75 patients, 11 classified as pathogenic. The complex ASD subjects have higher frequency of pathogenic CNVs with a diagnostic yield of 12.8%. Familiality, cognitive and verbal abilities, severity of autistic symptoms, neuroimaging and neurophysiological findings are not related to genetic data. This study identifies loci of interest for ASD and highlights the importance of a careful phenotypic characterization, as complex ASD is related to higher rate of pathogenic CNVs.
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http://dx.doi.org/10.1007/s10803-020-04833-5DOI Listing
January 2021

Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant.

Eur J Med Genet 2021 Jan 8;64(1):104116. Epub 2020 Dec 8.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p. Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p. Pro260Leu variant, suggesting a possible role of the p. Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder.
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http://dx.doi.org/10.1016/j.ejmg.2020.104116DOI Listing
January 2021

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer.

J Exp Clin Cancer Res 2020 Sep 7;39(1):180. Epub 2020 Sep 7.

Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", CNR, Via S. Pansini 5, 80131, Naples, Italy.

Background: Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC.

Methods: The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4 T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4 T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed.

Results: We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8 + T cells and reducing FOXP3 + Treg cells.

Conclusion: Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first time an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.
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http://dx.doi.org/10.1186/s13046-020-01694-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487859PMC
September 2020

Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells.

Int J Mol Sci 2020 Aug 11;21(16). Epub 2020 Aug 11.

Laboratory of Cellular Neurobiology, Neurology IX Unit, UCV, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45CD34CD133 mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.
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http://dx.doi.org/10.3390/ijms21165763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460840PMC
August 2020

Teaching NeuroImages: Symmetrical abnormalities of the globi pallidi in succinic semialdehyde dehydrogenase deficiency.

Neurology 2020 10 17;95(16):e2316-e2317. Epub 2020 Jul 17.

From the Developmental Neurology Unit (S.E., E.G., C.P.), Neuroradiology Department (M.M., L.F.), Unit of Medical Genetics and Neurogenetics (C.C., C.G.), and Unit of Child Neurology (A.A.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan; and Neuroimaging Laboratory (L.F.), IRCCS Fondazione Santa Lucia, Rome, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000010367DOI Listing
October 2020

The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein.

Int J Mol Sci 2020 Jan 21;21(3). Epub 2020 Jan 21.

Dipartimento di Scienze Motorie e del Benessere, Universita' "Parthenope", Via Medina 40, 80133 Napoli, Italy.

Thyroid carcinoma is the most common endocrine cancer and includes different forms. Among these, anaplastic thyroid carcinoma (ATC) is the rarest but the most lethal subtype, compared to papillary thyroid carcinoma (PTC) which shows an overall good prognosis. We have previously showed that Tumor Suppressor Candidate 2 (TUSC2), a known tumour suppressor gene, is downregulated in human PTC and ATC compared to normal thyroid samples. The aim of this study was to gain insight into the molecular mechanisms induced by TUSC2 in thyroid cancer cells. Here, we stably transfected TUSC2 in papillary (TPC-1) and in anaplastic (8505C) thyroid cancer cell lines and studied its effects on several biological processes, demonstrating that TUSC2 overexpression decreased thyroid cancer cell proliferation, migration and invasion. Through the proteome profiler apoptosis array, we observed that TUSC2 increased sensitivity to apoptosis by increasing the SMAC/DIABLO and CYTOCHROME C proteins. On the other hand, transient silencing of TUSC2, by siRNA, in an immortalized thyroid follicular epithelial cell line (Nthy-ori 3-1) showed the opposite effect. Finally modulation of SMAC/DIABLO partially rescued the biological effects of TUSC2. Thus, our data highlight a tumour suppressor role of TUSC2 in thyroid carcinogenesis, suggesting that it could be a promising target and biomarker for thyroid carcinoma.
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http://dx.doi.org/10.3390/ijms21030702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037188PMC
January 2020

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype-Phenotype Correlations in A Large Independent Cohort.

Cancers (Basel) 2019 11 21;11(12). Epub 2019 Nov 21.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20121 Milan, Italy.

The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring mutations in the 5' tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of mutation with the development of OPG was analysed using the χ2 test and Fisher's exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni's correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype-phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.
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http://dx.doi.org/10.3390/cancers11121838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966666PMC
November 2019

Brain Tumors in NF1 Children: Influence on Neurocognitive and Behavioral Outcome.

Cancers (Basel) 2019 Nov 11;11(11). Epub 2019 Nov 11.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

Neurofibromatosis type-1 (NF1) is a monogenic tumor-predisposition syndrome creating a wide variety of cognitive and behavioral abnormalities, such as decrease in cognitive functioning, deficits in visuospatial processing, attention, and social functioning. NF1 patients are at risk to develop neurofibromas and other tumors, such as optic pathway gliomas and other tumors of the central nervous system. Few studies have investigated the impact of an additional diagnosis of brain tumor on the cognitive outcome of children with NF1, showing unclear results and without controlling by the effect of surgery, radio- or chemotherapy. In the present mono-institutional study, we compared the behavioral and cognitive outcomes of 26 children with neurofibromatosis alone (NF1) with two age-matched groups of 26 children diagnosed with NF1 and untreated optic pathway glioma (NF1 + OPG) and 19 children with NF1 and untreated other central nervous system tumors (NF1 + CT). NF1 + CT and NF1 + OPG showed significantly impaired cognitive abilities compared to NF1 group, with weaknesses in visuo-spatial abilities, visual scanning and verbal working memory, while general verbal abilities are preserved. Moreover, NF1 + OPG patients present more frequent internalizing problems and increased oppositional-deviant behaviors. These results suggest that the co-diagnosis of a brain tumor in NF1 children may partially worsen the cognitive and emotional outcome.
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http://dx.doi.org/10.3390/cancers11111772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896178PMC
November 2019

Non-Coding RNA and Tumor Development in Neurofibromatosis Type 1: Rs2151280 Is Associated with Optic Glioma Development and a Mild Phenotype in Neurofibromatosis Type 1 Patients.

Genes (Basel) 2019 11 5;10(11). Epub 2019 Nov 5.

Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, via F.lli Cervi 93, Segrate, 20090 Milan, Italy.

Non-coding RNAs (ncRNAs) are known to regulate gene expression at the transcriptional and post-transcriptional levels, chromatin remodeling, and signal transduction. The identification of different species of ncRNAs, microRNAs (miRNAs), circular RNAs (circRNAs), and long ncRNAs (lncRNAs)-and in some cases, their combined regulatory function on specific target genes-may help to elucidate their role in biological processes. NcRNAs' deregulation has an impact on the impairment of physiological programs, driving cells in cancer development. We here carried out a review of literature concerning the implication of ncRNAs on tumor development in neurofibromatosis type 1 (NF1), an inherited tumor predisposition syndrome. A number of miRNAs and a lncRNA has been implicated in NF1-associated tumors, such as malignant peripheral nerve sheath tumors (MPNSTs) and astrocytoma, as well as in the pathognomonic neurofibromas. Some authors reported that the lncRNA was deregulated in the blood of NF1 patients with plexiform neurofibromas (PNFs), even if its role should be further elucidated. We here provided original data concerning the association of a specific genotype about rs2151280 with the presence of optic gliomas and a mild expression of the NF1 phenotype. We also detected the LOH of in different tumors from NF1 patients, supporting the involvement of in some NF1-associated tumors. Our results suggest that rs2151280 may be a potential diagnostic and prognostic marker, addressing early diagnosis of optic glioma and predicting the phenotype severity in NF1 patients.
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http://dx.doi.org/10.3390/genes10110892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895873PMC
November 2019

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

Hum Mutat 2020 01 26;41(1):299-315. Epub 2019 Oct 26.

Department of Dermatology and Venereology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
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http://dx.doi.org/10.1002/humu.23929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973139PMC
January 2020

Consolidating the Role of TDP2 Mutations in Recessive Spinocerebellar Ataxia Associated with Pediatric Onset Drug Resistant Epilepsy and Intellectual Disability (SCAR23).

Cerebellum 2019 Oct;18(5):972-975

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133, Milan, Italy.

Spinocerebellar Ataxia 23 (SCAR23) is a newly described condition caused by mutations in TDP2 gene. To date, only four patients from two families have been reported, all carrying the same homozygous mutation. We describe a fifth patient, carrying a novel mutation in the same gene, thus confirming the role of TDP2 mutations in determining the disease and defining the main features SCAR23: pediatric onset ataxia and drug-resistant epilepsy and intellectual disability. We further show the clinical presentation which is associated with the neuroradiological evidence of progressive cerebellar atrophy, giving the evidence that SCAR23 can be classified as a degenerative condition.
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http://dx.doi.org/10.1007/s12311-019-01069-7DOI Listing
October 2019

Pott's Disease: An Emerging Source of Potentially Inappropriate Treatment.

Neuropediatrics 2019 10 29;50(5):334-335. Epub 2019 May 29.

Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, Milan, Italy.

Spinal Tuberculosis in children is uncommon, even more so in cases of involvement of posterior vertebral elements, and its diagnosis is often delayed. Here we report the case of a young female presenting neuroradiological features and clinical symptoms suspicious for malignant tumor. Histological examination of biopsy specimen evidenced a Pott's disease. We highlight the importance of suspecting this disorder in children with both aspecific systemic and neurological symptoms, in order to reach a timely diagnosis for appropriate and targeted intervention, avoiding the risk of overtreatment and malpractice claims.
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http://dx.doi.org/10.1055/s-0039-1691833DOI Listing
October 2019

miR-650 promotes motility of anaplastic thyroid cancer cells by targeting PPP2CA.

Endocrine 2019 09 29;65(3):582-594. Epub 2019 Mar 29.

IRCCS SDN, Napoli, Via Emanuele Gianturco 113, 80143, Napoli, Italy.

Purpose: Aberrant expression of miRNAs is crucial in several tissues tumorigenesis including thyroid. Recent studies demonstrated that miR-650 plays different role depending on the cancer type. Herein, we investigated the role of miR-650 in thyroid carcinoma.

Methods: The expression of miR-650 was analyzed in human thyroid tissues by q-RT-PCR. Anaplastic (8505C, CAL62, SW1736) and papillary (TPC-1) thyroid cancer cell lines were used to dissect the role of miR-650 on malignant hallmarks of transformation. Label-free proteomic analysis was exploited to unravel the targets of miR-650, while luciferase reporter assay and functional experiments were performed to confirm a selected target. Spearman's rank correlation test was used to assess the association between miR-650 and its target in human thyroid cancer tissues.

Results: miR-650 is over-expressed in anaplastic (ATC) thyroid carcinoma where it enhances cell migration and invasion. Proteomic label-free and bioinformatics analysis revealed that the serine-threonine protein phosphatase 2 catalytic subunit alpha (PPP2CA) is a target of miR-650; these finding were confirmed by luciferase assay. Restoration of PPP2CA mRNA, deprived of its 3'UTR, is able to revert the malignant phenotype induced by miR-650 in HEK-293 cells. Importantly, PPP2CA is down-regulated in ATC tissues and is inversely correlated with miR-650.

Conclusions: miR-650 displayed oncogenic activity in ATC cells through targeting PPP2CA phosphatase. These results suggest that miR-650/PPP2CA axis could be modulated to interfere with motile ability of thyroid carcinoma cells.
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http://dx.doi.org/10.1007/s12020-019-01910-3DOI Listing
September 2019

Visuoperceptual Impairment in Children with NF1: From Early Visual Processing to Procedural Strategies.

Behav Neurol 2019 13;2019:7146168. Epub 2019 Jan 13.

Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

Visual-spatial impairment has long been considered a hallmark feature of neurofibromatosis type 1 (NF1). No study investigating the cognitive and neuropsychological profile of NF1 used the Rey Complex Figure Test (RCFT) task as the primary measure of visual-perceptual abilities taking into consideration all functions involved including the strategic processing style. We compared 18 children with NF1, 17 siblings (S), and 18 typically developing children (TD) at intelligence scale and RCFT copy, recall, and recognition trials; we also evaluated the copy strategy as a measure of a visual-processing style. Children with NF1 had normal total IQ, with cognitive weaknesses in the perceptual organization and working memory in line with the existing literature. At the RCFT copy, immediate and delay recall scores are significantly lower in NF1 than S and TD, while recognition is in the normal range in all groups. Copy style was poor and less efficient in children with NF1 and correlated to copy and recall ability, but the effect of the group in the RCFT copy and recall remained significantly controlling for strategic approach. The present study confirms visuospatial impairment in children with NF1, due to a deficit in perceptual analysis of shape and their spatial features, in visuomotor integration efficiency and strategies, in recall memory, while recognition memory is preserved. A more configural/holistic style may facilitate both the visual-perceptual and visuomotor ability and the recall process. Visuoperceptual impairment in NF1 seems to be a unified process from early visual processing to higher order functions (planning, strategy, and executive functioning).
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http://dx.doi.org/10.1155/2019/7146168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348799PMC
July 2019

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

Neurol Sci 2019 Mar 3;40(3):561-570. Epub 2019 Jan 3.

Stroke Unit, Nuovo Ospedale Civile S Agostino Estense, University Hospital of Modena, Modena, Italy.

Background: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results.

Methods: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies.

Results: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed.

Conclusion: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.
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http://dx.doi.org/10.1007/s10072-018-3664-zDOI Listing
March 2019

Clinical spectrum of PTEN mutation in pediatric patients. A bicenter experience.

Eur J Med Genet 2019 Dec 4;62(12):103596. Epub 2018 Dec 4.

Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Objective Of The Study: To give a full overview of the clinical presentation of PTEN mutations in pediatric patients and to propose a pediatric follow-up protocol.

Methods: Recruitment of 16 PTEN mutated children (age 6 months-11 years) from two pediatric centers in Milan (Italy) between 2006 and 2017. All the patients underwent clinical and neurologic evaluations, cognitive and behavioral tests, and brain MRI; they are currently following an oncologic follow-up.

Results: Extreme macrocephaly is present in all the patients (69% HC above +4 SD). Neuropsychiatric issues have high prevalence, with 56% of patients showing developmental delay and 25% showing autism spectrum disorder. Brain MRI reveals in 75% of the patients at least one of the following: enlarged perivascular spaces, white matter anomalies, and/or downward displacement of the cerebellar tonsils through the foramen magnum, resulting in Chiari I malformation in two patients. Vascular malformations have a prevalence of 19%, with further evidence that complex cardiovascular malformations may be related to PTEN mutations; 31% of patients present hamartomas. None of our patients have so far experienced any oncologic complication.

Conclusions: We suggest to screen for PTEN mutations all children presenting macrocephaly and one of the following: neurodevelopmental issues, one of the three major brain MRI anomalies, cutaneous lesions, vascular malformations, family history positive for PTEN related malignancies; or also with macrocephaly alone when exceeding +3 SD. Basing on our cohort results and further recent studies on the condition, we recommend a follow-up protocol that includes annual clinical and dermatological examination, thyroid and abdominal US, and Fecal Occult Blood test plus neurodevelopmental evaluation, heart US (to exclude congenital heart malformations), and brain MRI (to exclude Chiari I malformation) at diagnosis.
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http://dx.doi.org/10.1016/j.ejmg.2018.12.001DOI Listing
December 2019

The noncoding RNA AK127244 in 2p16.3 locus: A new susceptibility region for neuropsychiatric disorders.

Am J Med Genet B Neuropsychiatr Genet 2018 09 14;177(6):557-562. Epub 2018 Aug 14.

Laboratory of Clinical Pathology and Medical Genetics, Foundation IRCCS C. Besta Neurological Institute, Milan, Italy.

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions.
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http://dx.doi.org/10.1002/ajmg.b.32649DOI Listing
September 2018

Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Eur J Hum Genet 2018 10 28;26(10):1462-1477. Epub 2018 Jun 28.

Genome Damage & Stability Centre, University of Sussex, Brighton, UK.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
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http://dx.doi.org/10.1038/s41431-018-0185-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138755PMC
October 2018

Correction: The absence that makes the difference: choroidal abnormalities in Legius syndrome.

J Hum Genet 2018 03 7;63(3):391. Epub 2018 Feb 7.

Medical Genetics Unit Woman, Child and Newborn department, IRCSS Foundation, Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.

Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78.
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http://dx.doi.org/10.1038/s10038-017-0369-8DOI Listing
March 2018

A PDE10A de novo mutation causes childhood-onset chorea with diurnal fluctuations.

Mov Disord 2017 11 26;32(11):1646-1647. Epub 2017 Sep 26.

Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.1002/mds.27175DOI Listing
November 2017

The absence that makes the difference: choroidal abnormalities in Legius syndrome.

J Hum Genet 2017 Nov 27;62(11):1001-1004. Epub 2017 Jul 27.

Medical Genetics Unit Woman, Child and Newborn department, IRCSS Foundation, Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.

Neurofibromatosis type 1 (NF1) is an hereditary disorder characterized by abnormal proliferation of multiple tissues of neural crest origin, and presents mainly with multiple café-au-lait macules, axillary freckling and neurofibromas. Choroidal involvement in NF1 patients has been studied, thanks to the development of non-invasive tools such as infrared monochromatic light during fundus examination, which showed bright patchy lesions consistent with choroidal nodules. Choroidal abnormalities identified with near-infrared reflectance have reported with a frequency of up to 100% in NF1, and have been recently been proposed as a novel diagnostic criterion for NF1. Legius syndrome can be clinically indistinguishable from NF1 and results in a small percentage of individuals being misdiagnosed. We investigated the presence of choroidal abnormalities in Legius syndrome to determine their specificity to NF1 and their potential usefulness as a novel diagnostic criterion for NF1. We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. No abnormalities were observed, confirming the diagnostic value of choroidal abnormalities for the diagnosis of NF1.
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http://dx.doi.org/10.1038/jhg.2017.78DOI Listing
November 2017

Chiari I malformation in a child with PTEN hamartoma tumor syndrome: Association or coincidence?

Eur J Med Genet 2017 May 7;60(5):261-264. Epub 2017 Mar 7.

Neuroradiology Department, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy.

PTEN hamartoma tumor syndrome (PHTS) refers to a group of clinical conditions caused by germline mutations in the PTEN tumor suppressor gene. Increasing evidence has documented that PHTS may be associated with a broader spectrum of structural brain abnormalities, including dysplastic gangliocytoma of the cerebellum, brain tumors, vascular malformations, white matter abnormalities, dilated perivascular spaces and cortical dysplasia. We report a PTEN-mutated child showing macrocephaly, mild intellectual disability and epilepsy symptomatic of right occipital polymicrogyria, who also developed Chiari I Malformation (CIM) that repeatedly required surgical correction. We suppose that the association between PHTS and CIM could be not coincidental, thus extending the spectrum of neurological manifestations of PHTS and highlighting the role of brain MRI in the management of PHTS patients. We suggest that genes within the RAS-MAPK and PI3-AKT pathways might have a significant role in the pathogenesis of CIM in such patients.
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http://dx.doi.org/10.1016/j.ejmg.2017.03.002DOI Listing
May 2017

The Key Search Subtest of the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C) Instrument Reveals Impaired Planning Without External Constraints in Children With Neurofibromatosis Type 1.

J Child Neurol 2017 03 20;32(4):387-396. Epub 2016 Dec 20.

1 Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.

Studies of executive function and its relationship with brain T2-weighted hyperintensities in children with neurofibromatosis type 1 (NF1) have yielded inconsistent results. We examined 16 children with NF1 aged 8 to 15 years, of normal intelligence, and compared their findings to those of 16 siblings and 16 typically developing children using the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C). NF1 patients had an adequate overall score at BADS-C, but showed significantly lower performance than typical peers in the Key Search subtest. This is a task that must be solved without any given rules, in which subjects must devise a strategy and an efficient search pattern transferable to other similar real situations. The Key Search scores were not correlated with number and signal characteristics of T2-weighted hyperintensities. Planning without external indications is impaired in children with NF1 because they have to rely entirely on self-organization and monitoring; this study provides information for remediation programs designed to improve functioning in daily life.
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http://dx.doi.org/10.1177/0883073816683322DOI Listing
March 2017

The Arabidopsis THO/TREX component TEX1 functionally interacts with MOS11 and modulates mRNA export and alternative splicing events.

Plant Mol Biol 2017 Feb 21;93(3):283-298. Epub 2016 Dec 21.

Department of Cell Biology and Plant Biochemistry, Biochemistry Centre, University of Regensburg, Universitätsstr. 31, 93053, Regensburg, Germany.

Key Message: We identify proteins that associate with the THO core complex, and show that the TEX1 and MOS11 components functionally interact, affecting mRNA export and splicing as well as plant development. TREX (TRanscription-EXport) is a multiprotein complex that plays a central role in the coordination of synthesis, processing and nuclear export of mRNAs. Using targeted proteomics, we identified proteins that associate with the THO core complex of Arabidopsis TREX. In addition to the RNA helicase UAP56 and the mRNA export factors ALY2-4 and MOS11 we detected interactions with the mRNA export complex TREX-2 and multiple spliceosomal components. Plants defective in the THO component TEX1 or in the mRNA export factor MOS11 (orthologue of human CIP29) are mildly affected. However, tex1 mos11 double-mutant plants show marked defects in vegetative and reproductive development. In tex1 plants, the levels of tasiRNAs are reduced, while miR173 levels are decreased in mos11 mutants. In nuclei of mos11 cells increased mRNA accumulation was observed, while no mRNA export defect was detected with tex1 cells. Nevertheless, in tex1 mos11 double-mutants, the mRNA export defect was clearly enhanced relative to mos11. The subnuclear distribution of TEX1 substantially overlaps with that of splicing-related SR proteins and in tex1 plants the ratio of certain alternative splicing events is altered. Our results demonstrate that Arabidopsis TEX1 and MOS11 are involved in distinct steps of the biogenesis of mRNAs and small RNAs, and that they interact regarding some aspects, but act independently in others.
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http://dx.doi.org/10.1007/s11103-016-0561-9DOI Listing
February 2017

Interleukin-30 Promotes Breast Cancer Growth and Progression.

Cancer Res 2016 11 22;76(21):6218-6229. Epub 2016 Aug 22.

Department of Medicine and Sciences of Aging, Division of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.

The inflammatory tissue microenvironment that promotes the development of breast cancer is not fully understood. Here we report a role for elevated IL30 in supporting the breast cancer cell viability and invasive migration. IL30 was absent in normal mammary ducts, ductules, and acini of histologically normal breast and scanty in the few stromal infiltrating leukocytes. In contrast, IL30 was expressed frequently in breast cancer specimens where it was associated with triple-negative and HER2 molecular subtypes. In stromal leukocytes found in primary tumors or tumor-draining lymph nodes, which included mainly CD14 monocytes, CD68 macrophages, and CD33/CD11b myeloid cells, IL30 levels increased with disease stage and correlated with recurrence. A negative correlation was determined between IL30 expression by nodal stromal leukocytes and overall survival. In vitro studies showed that human recombinant IL30 upregulated expression of a pro-oncogenic program, including especially IL6 in both triple-negative and HER2 breast cancer cells. In triple-negative breast cancer cells, IL30 boosted a broader program of proliferation, invasive migration, and an inflammatory milieu associated with KISS1-dependent metastasis. Silencing of STAT1/STAT3 signaling hindered the regulation of the primary growth and progression factors in breast cancer cells. IL30 administration in vivo fostered the growth of triple-negative breast cancer by promoting proliferation and vascular dissemination of cancer cells and the accumulation of intratumoral CD11b/Gr1 myeloid cell infiltrates. Overall, our results show how IL30 regulates breast cancer cell viability, migration, and gene expression to promote breast cancer growth and progression and its impact on patient outcome. Cancer Res; 76(21); 6218-29. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0189DOI Listing
November 2016

Vasculogenic and Angiogenic Pathways in Moyamoya Disease.

Curr Med Chem 2016 ;23(4):315-45

Laboratory of Cellular Neurobiology, Neurology Unit, UCV, Neurological Institute "C. Besta" IRCCS Foundation, Via Celoria 11, Milan 20133, Italy.

Background: Moyamoya disease (MMD) is a slowly progressing steno-occlusive cerebrovascular disease. The typical moyamoya vessels, which originate from an initial stenosis of the internal carotid, highlight that increased and/or abnormal angiogenic, vasculogenic and arteriogenic processes are involved in the disease pathophysiology.

Objective: Herein, we summarize the current knowledge on the most important signaling pathways involved in MMD vessel formation, particularly focusing on the expression of growth factors and function of endothelial progenitor cells (EPCs).

Methods And Results: Higher plasma concentrations of vascular endothelial growth factor, matrix metalloproteinase, hepatocyte growth factor, and interleukin-1β were reported in MMD. A specific higher level of basic fibroblast growth factor was also found in the cerebrospinal fluid of these patients. Finally, the number and the functionality of EPCs were found to be increased. In spite of the available data, the approaches and findings reported so far do not give an evident correlation between the expression levels of the aforementioned growth factors and MMD severity. Furthermore, the controversial results provided by studies on EPCs, do not permit to understand the true involvement of these cells in MMD pathophysiology.

Conclusion: Further studies should thus be implemented to extend our knowledge on processes regulating both the arterial stenosis and the excessive formation of collateral vessels. Moreover, we suggest advances of integrated approaches and functional assays to correlate biological and clinical data, arguing for the development of new therapeutic applications for MMD.
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http://dx.doi.org/10.2174/092986732304160204181543DOI Listing
October 2016

126 novel mutations in Italian patients with neurofibromatosis type 1.

Mol Genet Genomic Med 2015 Nov 7;3(6):513-25. Epub 2015 Jul 7.

Molecular Neuro-oncology IRCCS Foundation, "C. Besta" Neurological Institute Milan Italy.

Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation-dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970_2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA-based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients.
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http://dx.doi.org/10.1002/mgg3.161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694136PMC
November 2015
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