Foundation of the Carlo Besta Neurological Institute

Milano, Italy

Foundation of the Carlo Besta Neurological Institute

Milano, Italy

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Bagatti D.,Foundation of the Carlo Besta Neurological Institute | Mazibrada J.,Foundation of the Carlo Besta Neurological Institute | Ligarotti G.K.,Foundation of the Carlo Besta Neurological Institute | Nazzi V.,Foundation of the Carlo Besta Neurological Institute | Franzini A.,Foundation of the Carlo Besta Neurological Institute
World neurosurgery | Year: 2016

BACKGROUND: Although syphilis has become a rare disease in the Western world since the Second World War, it is believed to have infected 12 million people in 1999, with greater than 90% of cases occurring in the developing world. Moreover, since the year 2000, the rates of syphilis have been increasing in the United States, the United Kingdom, Australia, and Europe. Because of the mimic nature of the disease and the overall low rate of occurrence of its manifestations in advanced stages, a proper diagnosis may prove difficult.CASE REPORT: We report the case of a 41-year-old African man affected by neurosyphilis that manifested itself through a meningovascular chronic inflammatory process, with the peculiar feature of a bilateral aneurysm of probable mycotic origin involving the distal tract of A2 segment of both anterior cerebral arteries.CONCLUSIONS: Because of the mostly nonspecific nature of clinical manifestations of syphilis (particularly advanced syphilis) and its consequent tendency to masquerade as many other diseases, even a skilled physician may find its diagnosis quite challenging; thus, thorough clinical and radiologic investigations should be supported by serologic testing for syphilis in all cases of cognitive impairment. Mycotic intracranial aneurysms in association with neurosyphilis rarely are reported; however, they require early diagnosis and meticulous, individualized treatment. Because syphilis appears to be on the raise, further studies on the topic are warranted. Copyright © 2016 Elsevier Inc. All rights reserved.


Bersano A.,C Mondino National Institute Of Neurology Foundation | Bersano A.,Foundation of the Carlo Besta Neurological Institute | Ranieri M.,University of Milan | Ciammola A.,IRCCS Instituto Auxologico Italiano | And 11 more authors.
Functional Neurology | Year: 2012

Some missense mutations and small deletions in the NOTCH3 gene, not involving cysteine residues, have been described in patients considered to be affected by paucisymptomatic CADASIL. However, the significance of such molecular variants is still unclear. We describe a 49-year-old woman with a CADASIL-like phenotype, carrying a novel cysteine-sparing mutation in exon 29 of the NOTCH3 gene, and discuss the possible pathogenetic role of this molecular variant. Even though atypical clinical and MRI findings make a diagnosis of CADASIL unlikely in this patient, our report nevertheless underlines the intriguing genotype-phenotype relationship in NOTCH3 mutations and the importance of functional investigation to ascertain the role of new NOTCH3 mutations in CADASIL pathogenesis. © CIC Edizioni Internazionali.


Zanellati M.C.,Foundation of the Carlo Besta Neurological Institute IRCCS | Monti V.,Foundation of the Carlo Besta Neurological Institute IRCCS | Barzaghi C.,Foundation of the Carlo Besta Neurological Institute IRCCS | Reale C.,Foundation of the Carlo Besta Neurological Institute IRCCS | And 5 more authors.
Frontiers in Genetics | Year: 2015

Mutations in PARK2, encoding Parkin, cause an autosomal recessive form of juvenile Parkinson Disease (JPD). The aim of the present study was to investigate the impact of PARK2 mutations on mitochondrial function and morphology in human skin fibroblasts. We analyzed cells obtained from four patients clinically characterized by JPD, harboring recessive mutations in PARK2. By quantitative PCR we found a reduction (<50%) of PARK2 transcript in all patients but one; however Western Blot analysis demonstrated the virtual absence of Parkin protein in all mutant fibroblasts. Respiration assays showed an increment of oxygen consumption, which was uncoupled to ATP cellular levels. This finding was probably due to presence of altered mitochondrial membrane potential (ΔΨm), confirmed by JC-1 analysis. The mitochondrial network was comparable between mutant and control cells but, interestingly, a "chain-like" network was found only in mutant fibroblasts. Dissipation of ΔΨm usually leads to mitochondrial fragmentation in healthy cells and eventually to mitophagy; however, this behavior was not observed in patients' fibroblasts. The absence of mitochondrial fragmentation in mutant Parkin fibroblasts could results in accumulation of damaged mitochondria not targeted to mitophagy. This condition should increase the oxidative stress and lead to cellular dysfunction and death. Our results suggest that PARK2 mutations cause mitochondrial impairment, in particular reduction in ATP cellular levels and alteration of ΔΨm, even in non-neuronal cells and confirm the hypothesis that Parkin holds a pivotal role in pro-fission events. © 2015 Zanellati, Monti, Barzaghi, Reale, Nardocci, Albanese, Valente, Ghezzi and Garavaglia.


Brea-Calvo G.,Pablo De Olavide University | Haack T.B.,Helmholtz Center for Environmental Research | Haack T.B.,TU Munich | Karall D.,Innsbruck Medical University | And 34 more authors.
American Journal of Human Genetics | Year: 2015

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency. © 2015 The Authors. This is an open access article under the CC BY-NC-ND license.


Canini M.,CNR Institute of Molecular Bioimaging and Physiology | Battista P.,CNR Institute of Molecular Bioimaging and Physiology | Della Rosa P.A.,CNR Institute of Molecular Bioimaging and Physiology | Catricala E.,Foundation of the Carlo Besta Neurological Institute | And 3 more authors.
Computational and Mathematical Methods in Medicine | Year: 2014

Digital technologies have opened new opportunities for psychological testing, allowing new computerized testing tools to be developed and/or paper and pencil testing tools to be translated to new computerized devices. The question that rises is whether these implementations may introduce some technology-specific effects to be considered in neuropsychological evaluations. Two core aspects have been investigated in this work: the efficacy of tests and the clinical ecology of their administration (the ability to measure real-world test performance), specifically (1) the testing efficacy of a computerized test when response to stimuli is measured using a touch-screen compared to a conventional mouse-control response device; (2) the testing efficacy of a computerized test with respect to different input modalities (visual versus verbal); and (3) the ecology of two computerized assessment modalities (touch-screen and mouse-control), including preference measurements of participants. Our results suggest that (1) touch-screen devices are suitable for administering experimental tasks requiring precise timings for detection, (2) intrinsic nature of neuropsychological tests should always be respected in terms of stimuli presentation when translated to new digitalized environment, and (3) touch-screen devices result in ecological instruments being proposed for the computerized administration of neuropsychological tests with a high level of preference from elderly people. © 2014 Matteo Canini et al.


Gnatkovsky V.,Foundation of the Carlo Besta Neurological Institute | De Curtis M.,Foundation of the Carlo Besta Neurological Institute | Pastori C.,Foundation of the Carlo Besta Neurological Institute | Cardinale F.,Niguarda Ca Granda Hospital | And 6 more authors.
Epilepsia | Year: 2014

Objective In one third of patients with a diagnosis of pharmacoresistant focal epilepsy who are candidates for therapeutic surgery, cerebral areas responsible for seizure generation can be defined exclusively with invasive intracranial recordings. A correct presurgical identification of the epileptogenic zone (EZ) with intracranial electrodes has a direct impact on postsurgical outcome. We aimed at identifying biomarkers of the EZ based on computer-assisted inspection of intracranial electroencephalography (EEG). Methods Computer-driven intracranial EEG analysis in the domains of time, frequency, and space was retrospectively applied to a population of 10 patients with focal epilepsy to detect EZ electrophysiologic markers. Next, a prospective study was performed on 14 surgery candidate patients. The stereo-EEG computer-assisted analysis of EZ boundaries performed blind from patients data was compared to that defined with the traditional visual inspection completed by neurophysiologists. Results In the retrospective study, the EZ was characterized by the combined detection of three biomarkers observed at seizure onset: (1) fast activity at 80-120 Hz associated with (2) very slow transient polarizing shift and (3) voltage depression (flattening). Correlations between these indexes were calculated for each seizure. In the prospective study, the quantified analysis based on the three biomarkers confirmed a complete overlap between leads within the EZ identified by expert clinicians. In 2 of 14 patients the proposed biomarkers partially identified the EZ. Significance Our findings demonstrate and validate with a prospective unbiased study the use of three neurophysiologic intracranial EEG parameters as excellent biomarkers of ictogenesis and as reliable indicators of EZ boundaries. © Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.


Verrotti A.,University of Perugia | Cusmai R.,Bambino Gesu Childrens Hospital | Nicita F.,University of Rome La Sapienza | Pizzolorusso A.,University of Chieti Pescara | And 17 more authors.
Journal of Pediatrics | Year: 2013

Objective To describe the electroclinical features and the long-term outcomes of epilepsy in a large cohort of males and females with Down syndrome who developed epilepsy in childhood. Study design Subjects with Down syndrome and cryptogenic epilepsy with onset in childhood were identified retrospectively from the databases of 16 Italian epilepsy centers over a 40-year period. For each subject, age at onset of seizures, seizure semiology and frequency, electroencephalography characteristics, treatment with antiepileptic drugs, and long-term clinical and electroencephalography outcomes were analyzed. Results A total of 104 subjects (64 males [61.5%], 40 females [38.5%]) were identified. Seizure onset occurred within 1 year of birth in 54 subjects (51.9%), between 1 and 12 years in 42 subjects (40.4%), and after 12 years in 8 subjects (7.7%). Males had a younger age of seizure onset than females. Of the 104 subjects, 51 (49.0%) had infantile spasms (IS), 35 (33.7%) had partial seizures (PS), and 18 (17.3%) had generalized seizures (GS). Febrile seizures were recorded in 5 (4.8%) subjects. Intractable seizures were observed in 23 (22.1%) subjects, including 5 (9.8%) with IS, 8 (44.4%) with PS, and 10 (31.3%) with GS. Conclusion Cryptogenic epilepsy in Down syndrome may develop during the first year of life in the form of IS or, successively, as PS or GS. Electroclinical features of IS resemble those of idiopathic West syndrome, with a favorable response to treatment with adrenocorticotropic hormone seen. Patients experiencing PS and GS may be resistant to therapy with antiepileptic drugs. © 2013 Mosby Inc. All rights reserved.


Zambrelli E.,San Paolo Hospital | Vignoli A.,San Paolo Hospital | Vignoli A.,University of Milan | Nobili L.,Niguarda Hospital | And 7 more authors.
Functional Neurology | Year: 2013

Ring chromosome 20 [r(20)] syndrome is a chromosomal disorder characterized by epilepsy and intellectual disability. Distinctive electroclinical features and wakefulness EEG patterns have been described. The EEG features of sleep have not yet been evaluated. We studied the pattern of sleep in six patients aged 2-59 years who underwent at least one polysomnographic recording. Their sleep pattern evolution is described as deterioration ranging from normal to destructured NREM/REM sleep. NREM sleep alterations were observed from childhood and were more evident in adulthood. EEG abnormalities detected during wakefulness persisted, with morphological changes, during sleep. During NREM sleep all the subjects presented high amplitude delta sequences with a sharply contoured or notched appearance, prevalent over frontal regions. The theta rhythm of wakefulness was seen to persist during REM sleep. Ring chromosome 20 syndrome shows sleep alterations that seem to be age-related. A potential role of cortical and thalamocortical dysfunction is discussed.


Although syphilis has become a rare disease in the Western world since the Second World War, it is believed to have infected 12 million people in 1999, with greater than 90% of cases occurring in the developing world. Moreover, since the year 2000, the rates of syphilis have been increasing in the United States, the United Kingdom, Australia, and Europe. Because of the mimic nature of the disease and the overall low rate of occurrence of its manifestations in advanced stages, a proper diagnosis may prove difficult.We report the case of a 41-year-old African man affected by neurosyphilis that manifested itself through a meningovascular chronic inflammatory process, with the peculiar feature of a bilateral aneurysm of probable mycotic origin involving the distal tract of A2 segment of both anterior cerebral arteries.Because of the mostly nonspecific nature of clinical manifestations of syphilis (particularly advanced syphilis) and its consequent tendency to masquerade as many other diseases, even a skilled physician may find its diagnosis quite challenging; thus, thorough clinical and radiologic investigations should be supported by serologic testing for syphilis in all cases of cognitive impairment. Mycotic intracranial aneurysms in association with neurosyphilis rarely are reported; however, they require early diagnosis and meticulous, individualized treatment. Because syphilis appears to be on the raise, further studies on the topic are warranted.


PubMed | Innsbruck Medical University, University of Bari, Klinikum Reutlingen, Saitama University and 8 more.
Type: Case Reports | Journal: American journal of human genetics | Year: 2015

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations inCOQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.

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