Marcella Zollino

Catholic University of the Sacred Heart , Milano, Lombardy, Italy

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Publications (144)471.72 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mowat–Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the “unusual” patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 08/2014; · 2.30 Impact Factor
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    ABSTRACT: Objective Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K+/H+ exchange and in Ca2+ homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside.Methods Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array-comparative genomic hybridization (a-CGH). Real-time polymerase chain reaction (RT-PCR) on messanger RNA (mRNA) of LETM1 and CPLX1. Direct sequencing of LETM1.ResultsThree unusual 4p16.3 deletions were detected by array-CGH in absence of a obvious clinical diagnosis of WHS. Two of these, encompassing LETM1, were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM1, and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM1 had seizures, whereas seven of seven with interstitial deletions including LETM1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM1.SignificanceWe consider that haploinsufficiency not limited to LETM1 but including other genes acts as a risk factor for the WHS-associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM1.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
    Epilepsia 04/2014; · 3.96 Impact Factor
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    ABSTRACT: Background Classic clinical manifestations of HNPP are characterized by recurrent painless mononeuropathies, but a minority of patients presents with atypical clinical pattern, including CMT-like neuropathy, acute or chronic inflammatory demyelinating neuropathy-like polyneuropathy, carpal tunnel syndrome. Electrophysiological examination plays a central role in the diagnosis of HNPP, disclosing a non-uniform conduction slowing, more pronounced at entrapment sites. Patients and Methods We report clinical, electrophysiological and pathological findings from 73 patients with HNPP, coming from 53 unrelated families, followed in our Institute of Neurology over a 20-year period. Results Typical presentation with recurrent multiple mononeuropathies was observed in 28/64 (44%) patients. In the remaining 36/64 (56%), we observed an atypical clinical presentation, characterized by generalized weakness and cramps; chronic ulnar neuropathy; carpal tunnel syndrome; chronic sensory polyneuropathy; Guillain-Barrè-like presentation; CMT-like presentation. Nine patients were asymptomatic for neuropathic symptoms. Nerve conduction studies showed in all cases a sensori-motor demyelinating polyneuropathy with conduction abnormalities preferentially localized at common entrapment sites. When performed, sural nerve biopsy disclosed focal thickenings of the myelin sheath in all patients. Conclusions About half of patients with HNPP from our cohort showed an atypical clinical presentation. Neurophysiological examination represents the main tool for a proper diagnosis.
    Journal of the neurological sciences 01/2014; · 2.32 Impact Factor
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    ABSTRACT: We describe a family in which four individuals (the mother and three children) presented with an overlapping phenotype of minor physical anomalies and intellectual disability. Four previously unreported copy number variants were found inherited either from the affected mother or from the healthy father, consisting of a 3p22.3p22.2 deletion (2.5 Mb), a 3p24.3 deletion (0.55 Mb), a 6q22.31 duplication (0.74 Mb), all maternally inherited, and an 18q11.2 duplication (0.276 Mb) which was paternally inherited. The deletions on chromosome 3 were both found to segregate with the disease. However, being the 0.55 Mb deleted segment on 3p24.3 devoid of genes, we considered that the 2.5 Mb deletion on 3p22.3p22.2 acts as major pathogenic rearrangement in this condition. Among the transcribed genes residing in this interval, ARPP21 and CLASP2 are proposed as good candidate genes on the basis of their functional properties. A co-morbidity role for the other small rearrangements detected in the affected individuals in association with the 3p22.3p22.2 deletion is also suggested, according to a second-side model of pathogenesis. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2013; · 2.30 Impact Factor
  • American Journal of Medical Genetics Part A 10/2013; · 2.30 Impact Factor
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    ABSTRACT: To characterize epileptic phenotype, electroencephalography (EEG) features, and epileptic evolution in patients with ring 14 r(14) syndrome. Twenty-two patients with ring chromosome 14 were enrolled in the study. We examined age at onset, seizure semiology and frequency at onset and at follow-up, drug responsiveness/resistance, and interictal/ictal EEG data. The degree of severity of the epileptic phenotype negatively influences child cognitive development. The incidence of epilepsy in patients with r(14) syndrome is virtually 100%, characterized by early onset, polymorphic seizures, and drug-resistant seizures. In addition, we ascertained focal secondarily generalized epilepsy, seizure cluster tendency, frequent status epilepticus, and a rather typical epilepsy evolution. EEG abnormalities consisted of slow background activity with pseudoperiodic bursts of generalized slow waves in the early stage, focal frontotemporal or temporoposterior slow waves with multifocal spikes interposed, and unusual rhythmic fast recruiting posterior spikes followed by secondary generalization. The degree of severity of the epileptic phenotype negatively influences child cognitive development. This study provides a more precise definition of seizure types, natural history, and drug responsiveness of r(14) syndrome, a highly epileptogenic chromosomal condition.
    Epilepsia 10/2013; · 3.96 Impact Factor
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    ABSTRACT: Mutations in the gene encoding FUS have been identified in a subset of patients with sporadic and familial Amyotrophic Lateral Sclerosis (ALS). Variants in the 3' Untranslated Region (3'UTR) of FUS have also been reported in ALS patients, but their pathogenic role has not been assessed.We sequenced the whole 3'UTR of FUS in 420 ALS patients who were negative for mutations in the currently known ALS genes and in 480 ethnically matched controls. We detected four 3'UTR variants (c.*48 G>A, c.*59 G>A, c.*108 C>T and c.*110 G>A) in four sporadic and in one familial ALS patients compared to none in controls (p=0.02).We investigated whether these variants impaired FUS expression in primary fibroblast cultures from three patients harbouring the c.*59 G>A, c.*108 C>T and c.*110 G>A variants, respectively. The pattern of FUS expression was also investigated in fibroblasts from one ALS patient with FUS R521C mutation, in two ALS patients without mutations in the known ALS genes and in four control individuals. By immunostaining and immunoblotting, large amounts of FUS were observed in both the cytoplasm and nuclei of mutant 3'UTR FUS fibroblasts. In FUS R521C mutant fibroblasts we observed a slight increase of FUS in the cytoplasm associated with a remarkable loss of detection in nuclei.Our findings show that mutations in 3'UTR of FUS are overrepresented in ALS patients and result into translation de-regulation of FUS. Overexpression and mislocalization of wild type FUS likely contribute to ALS pathogenesis in these cases.
    Human Molecular Genetics 07/2013; · 7.69 Impact Factor
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    ABSTRACT: The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be proposed to asymptomatic at-risk subjects, unless they request it or are enrolled in research programmes. Genetic counselling in ALS should take into account the uncertainties about the pathogenicity and penetrance of some genetic mutations; the possible presence of mutations of different genes in the same individual; the poor genotypic/phenotypic correlation in most ALS genes; and the phenotypic pleiotropy of some genes. Though psychological, social and ethical implications of genetic testing are still relatively unexplored in ALS, we recommend multidisciplinary counselling that addresses all relevant issues, including disclosure of tests results to family members and the risk for genetic discrimination.
    Journal of neurology, neurosurgery, and psychiatry 07/2013; · 4.87 Impact Factor
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    ABSTRACT: We report on a young woman admitted to our Cardiology Unit because of an episode of cardiac arrest related to a long-QT syndrome (LQTS). This manifestation was part of a broader phenotype, which was recognized as a mild form of Beckwith-Wiedemann syndrome (BWS). Molecular analysis confirmed the diagnosis of BWS owing to a maternally inherited deletion of the centromeric imprinting center, or ICR2, an extremely rare genetic mechanism in BWS. The deletion interval (198 kb) also included exons 11-16 of the KCNQ1 gene, known to be responsible for LQTS at locus LQT1. No concomitant mutations were found in any other of the known LQT genes. The proposita's mother carries the same deletion in her paternal chromosome and shows manifestations of the Silver-Russell syndrome (SRS). This report describes the smallest BWS-causing ICR2 deletion and provides the first evidence that a paternal deletion of ICR2 leads to a SRS-like phenotype. In addition, our observation strongly suggests that in cases of LQTS due to mutation of the KCNQ1 gene (LQT1), an accurate clinical genetic evaluation should be done in order to program the most appropriate genetic tests.European Journal of Human Genetics advance online publication, 20 March 2013; doi:10.1038/ejhg.2012.280.
    European journal of human genetics: EJHG 03/2013; · 3.56 Impact Factor
  • M Sabatelli, A Conte, M Zollino
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    ABSTRACT: Though clinical picture of ALS is a stereotypical one, resulting from combination of signs secondary to dysfunction of both upper and lower motor neurons, clinical heterogeneity is a consistent feature of the disease. Age of onset, relative mix of upper and lower motor neuron signs, duration of the disease and association with other conditions are major factors contributing to variable clinical phenotypes. Genetically, familial forms of ALS are associated with a large number of pleiotropic genes whose mutations impair different biochemical pathways, resulting in overlapping clinical and pathological phenotypes. Over the last few years contribution of large- and low-effect genes to sporadic ALS is increasingly recognized.
    Clinical Genetics 02/2013; · 4.25 Impact Factor
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    ABSTRACT: Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2013; · 2.30 Impact Factor
  • Amyotrophic lateral sclerosis and frontotemporal degeneration. 01/2013;
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    ABSTRACT: The gene expression pattern of glioblastoma (GBM) is well documented but the expression profile of brain adjacent to tumor is not yet analysed. This may help to understand the oncogenic pathway of GBM development. We have established the genome-wide expression profiles of samples isolated from GBM tumor mass, white matter adjacent to tumor (apparently free of tumor cells), and white matter controls by using the Affymetrix HG-U133 arrays. Array-CGH (aCGH) was also performed to detect genomic alterations. Among genes dysregulated in peritumoral white matter, 15 were over-expressed, while 42 were down-regulated when compared to white matter controls. A similar expression profile was detected in GBM cells. Growth, proliferation and cell motility/adhesion-associated genes were up-regulated while genes involved in neurogenesis were down-regulated. Furthermore, several tumor suppressor genes along with the (a member of natural killer receptor) were also down-regulated in the peritumoral brain tissue. Several mosaic genomic lesions were detected by aCGH, mostly in tumor samples and several GBM-associated mosaic genomic lesions were also present in the peritumoral brain tissue, with a similar mosaicism pattern. Our data could be explained by a dilution of genes expressed from tumor cells infiltrating the peritumour tissue. Alternatively, these findings could be substained by a relevant amount of "apparently normal" cells presenting a gene profile compatible with a precancerous state or even "quiescent" cancer cells. Otherwise, the recurrent tumor may arise from both infiltrating tumor cells and from an interaction and recruitment of apparently normal cells in the peritumor tissue by infiltrating tumor cells.
    PLoS ONE 01/2013; 8(3):e57145. · 3.53 Impact Factor
  • Neurological Sciences 12/2012; · 1.41 Impact Factor
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    ABSTRACT: The present study focussed on a specific type of rare genetic condition: chromosome 14 deletions. Children with this genetic condition often show developmental delays and brain and neurological problems, although the type and severity of symptoms varies depending on the size and location of the deleted genetic material. The specific aim of the present study was to describe the developmental trajectories of language skills in a group of children with linear 14q deletions. Four children with an interstitial deletion of the long arm of chromosome 14 were followed for 1 year. Data collected from psychomotor and linguistic assessments highlight a large individual variability. Considering the children's genetic and clinical conditions, findings revealed that the size of the deleted area is not related to outcome. However, the developmental trajectories of language development are deeply influenced by the presence of clinical conditions, such as autism spectrum disorders.
    Clinical Linguistics & Phonetics 12/2012; 26(11-12):962-74. · 0.78 Impact Factor
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    ABSTRACT: Autism spectrum disorders (ASDs) include three main conditions: autistic disorder (AD), pervasive developmental disorder, not otherwise specified (PDD-NOS), and Asperger syndrome. It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3. We screened this last gene in two cohorts of ASD patients (133 patients from US and 88 from Italy). We found 5/221 (2.3%) cases with pathogenic alterations: a 106 kb deletion encompassing the SHANK3 gene, two frameshift mutations leading to premature stop codons, a missense mutation (p.Pro141Ala), and a splicing mutation (c.1820-4 G>A). Additionally, in 17 patients (7.7%) we detected a c.1304+48C>T transition affecting a methylated cytosine in a CpG island. This variant is reported as SNP rs76224556 and was found in both US and Italian controls, but it results significantly more frequent in our cases than in the control cohorts. The variant is also significantly more common among PDD-NOS cases than in AD cases. We also screened this gene in an independent replication cohort of 104 US patients with ASDs, in which we found a missense mutation (p.Ala1468Ser) in 1 patient (0.9%), and in 8 patients (7.7%) we detected the c.1304+48C>T transition. While SHANK3 variants are present in any ASD subtype, the SNP rs76224556 appears to be significantly associated with PDD-NOS cases. This represents the first evidence of a genotype-phenotype correlation in ASDs and highlights the importance of a detailed clinical-neuropsychiatric evaluation for the effective genetic screening of ASD patients.European Journal of Human Genetics advance online publication, 15 August 2012; doi:10.1038/ejhg.2012.175.
    European journal of human genetics: EJHG 08/2012; · 3.56 Impact Factor
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    ABSTRACT: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels widely expressed throughout the mammalian brain, including bulbar and spinal motor neurons. They are involved in neuroprotection and in control of release of many neurotransmitters, including glutamate. Previous data raised the hypothesis that rare variants in the region coding the intracellular loop subunits of nAChRs might represent one of several genetic risk factors for SALS. The aim of present study was to replicate the study in an independent cohort of ALS patients. We analysed 718 sporadic ALS patients from five Italian ALS centres and 1300 ethnically matched controls. We focused primarily on CHRNA4, encoding α4 subunit, since most mutations were previously detected in this gene. We observed a significant association between CHRNA4 mutations and ALS (OR 2.91; 95% CI 1.4080-6.0453; p = 0.0056). Most mutations detected in patients were not present in the dbSNP134 and in 3500 ethnically matched control chromosomes and affected evolutionary conserved amino acid residues. In conclusion, the present data confirm that CHRNA4 variants are overrepresented in SALS strengthening the hypothesis can they act as predisposing genetic factors for SALS.
    Amyotrophic Lateral Sclerosis 08/2012; 13(6):580-4. · 3.40 Impact Factor
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    ABSTRACT: OBJECTIVE: To classify familial amyotrophic lateral sclerosis (FALS) on the base of family history, and to determine whether frequency of mutations in major amyotrophic lateral sclerosis (ALS) genes varies in different FALS categories. METHODS: Included in the study are 53 FALS families. Patients were classified as definite, probable and possible FALS, according to recently proposed criteria. Seven ALS-associated genes, including SOD1, TARDBP, FUS, ANG, ATXN2, OPTN and C9ORF72, were analysed. RESULTS: Thirteen patients (24.5%) were included in the definite group. The great majority of our FALS cases (40/53, 75.5%) were families with only two affected relatives; of these, 31 (58.5%) were included in the probable, and 9 (17%) in the possible FALS categories. The percentage of mutations was 61.5% in definite, 41.9% in probable and 11.1% in possible FALS. With respect to probable FALS, if cases with parent-to-child transmission of the disease were considered separately, the mutational load increased to 61.5%, as observed in definite FALS. CONCLUSIONS: Our findings provide evidence that frequency of mutations in currently known ALS genes varies widely among different FALS categories. Families with only two affected relatives have heterogeneous genetic components, the chance to detect mutations being higher in cases with parent-to-child transmission.
    Journal of neurology, neurosurgery, and psychiatry 07/2012; · 4.87 Impact Factor
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    ABSTRACT: To quantify the overall contribution of mutations in the currently known amyotrophic lateral sclerosis (ALS) genes in a large cohort of sporadic patients and to make genotype-phenotype correlations. Screening for SOD1, TARDBP, FUS, ANG, ATXN2, OPTN, and C9ORF72 was carried out in 480 consecutive patients with sporadic ALS (SALS) and in 48 familial ALS (FALS) index patients admitted to a single Italian referral center. Mutations were detected in 53 patients, with a cumulative frequency of 11. Seven of them were novel. The highest frequencies of positive cases were obtained in TARDBP (2.7%), C9ORF72 (2.5%), and SOD1 (2.1%). The overall group of mutated patients was indistinguishable from that without mutations as no significant differences were observed with regard to age and site of onset, frequency of clinical phenotypes, and survival. However, by separately evaluating genotype-phenotype correlation in single genes, clinical differences were observed among different genes. Duration of disease was significantly shorter in patients harboring the C9ORF72 expansion and longer in the SOD1 group. A high frequency of predominant upper motor neuron phenotype was observed among patients with TARDBP mutations. Two patients, 1 with C9ORF72 and 1 with SOD1 mutation, had concurrent ANG mutations. Mutations were detected in 43.7% of patients with FALS. A considerable proportion of patients with SALS harbored mutations in major ALS genes. This result has relevant implications in clinical practice, namely in genetic counseling. The detection of double mutations in 2 patients raises the hypothesis that multiple mutations model may explain genetic architecture of SALS.
    Neurology 06/2012; 79(1):66-72. · 8.30 Impact Factor
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    ABSTRACT: It has been recently reported that a large proportion of patients with familial and sporadic amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) carries the hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We describe a patient with a complex phenotype characterized by behavioural variant of FTD, Parkinsonism and ALS with predominant lower motor neuron involvement in which the C9ORF72 expansion was detected.
    Amyotrophic Lateral Sclerosis 06/2012; · 3.40 Impact Factor

Publication Stats

2k Citations
471.72 Total Impact Points

Institutions

  • 1989–2014
    • Catholic University of the Sacred Heart
      • • Institute of Medical Genetics
      • • Institute of Neurology
      • • Institute of Clinical Pediatrics
      • • Faculty of Medicine and Surgery
      • • School of Hematology
      • • Institute of Pathological Anatomy
      Milano, Lombardy, Italy
  • 2013
    • Institute of Neurology
      Moskva, Moscow, Russia
    • University of Florence
      Florens, Tuscany, Italy
  • 2012
    • Università degli Studi di Milano-Bicocca
      • Department of Psychology
      Milano, Lombardy, Italy
    • Università degli Studi di Torino
      • Dipartimento di Neuroscienze
      Torino, Piedmont, Italy
  • 1998–2011
    • The Catholic University of America
      Washington, Washington, D.C., United States
  • 2007–2009
    • Azienda Ospedaliera Santa Maria Nuova di Reggio Emilia
      Reggio nell'Emilia, Emilia-Romagna, Italy
  • 2008
    • ARUP Laboratories: A National Reference Laboratory
      Salt Lake City, Utah, United States
  • 1991
    • St. Helena Hospital
      Saint Helena, California, United States