Publications by authors named "Nereo Bresolin"

331 Publications

Case Report: Efficacy of Rituximab in a Patient With Familial Mediterranean Fever and Multiple Sclerosis.

Front Neurol 2020 6;11:591395. Epub 2021 Jan 6.

Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Donato, Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit & MS Centre, Milan, Italy.

Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disease characterized by recurrent episodes of fever and serositis caused by mutations in the MEFV gene, while Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the CNS with genetic and environmental etiology. The two diseases rarely occur in association with relevant implications for clinical management and drug choice. In this paper, we present the case of a 53-year-old male with an autosomal dominant FMF since childhood who presented acute paresthesia at the right part of the body. He performed a brain and spinal cord MRI, which showed multiple brain lesions and a gd-enhancing lesion in the cervical spinal cord, and then received a diagnosis of MS. He then started Interferonβ-1a which was effective but not tolerated and caused hepatotoxicity, and then shifted to Rituximab with 3-month clinical and neuroradiological efficacy.
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http://dx.doi.org/10.3389/fneur.2020.591395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874168PMC
January 2021

Clinical features and disease course of patients with acute ischaemic stroke just before the Italian index case: Was COVID-19 already there?

Intern Emerg Med 2021 Feb 10. Epub 2021 Feb 10.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Since the end of February 2020, Italy has suffered one of the most severe outbreaks of coronavirus disease 2019 (COVID-19). However, what happened just before the Italian index case has not yet been investigated. To answer this question, we evaluated the potential impact of COVID-19 on the clinical features of a cohort of neurological inpatients admitted right before the Italian index case, as compared to the same period of the previous year. Demographic, clinical, treatment and laboratory data were extracted from medical records. The data collected included all inpatients who had been admitted to the Neurology and Stroke Units of the Ospedale Maggiore Policlinico, Milan, Italy, from December 15, 2018 to February 20, 2019 and from December 15, 2019 to February 20, 2020. Of the 248 patients, 97 subjects (39.1%) were admitted for an acute cerebrovascular event: 46 in the 2018/2019 period (mean [SD] age, 72.3 [15.6] years; 22 men [47.8%]), and 51 in the 2019/2020 interval (mean [SD] age, 72.8 [12.4] years; 24 men [47.1%]). The number of cryptogenic strokes has increased during the 2019-2020 year, as compared to the previous year (30 [58.8%] vs. 18 [39.1%], p = 0.05). These patients had a longer hospitalization (mean [SD] day, 15.7 [10.5] days vs. mean [SD] day, 11.7 [7.2] days, p = 0.03) and more frequent cerebrovascular complications (9 [30.0%] vs. 2 [11.1%]), but presented a lower incidence of cardiocerebral risk factors (18 [60.0%] vs. 14 [77.8%]). Right before the Italian index case, an increase in cryptogenic strokes has occurred, possibly due to the concomitant COVID-19.
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http://dx.doi.org/10.1007/s11739-021-02634-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872881PMC
February 2021

Posterior reversible encephalopathy syndrome and COVID-19: A series of 6 cases from Lombardy, Italy.

eNeurologicalSci 2021 Mar 22;22:100306. Epub 2020 Dec 22.

Neurology and Stroke Unit ASST, Lecco, Italy.

Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment.
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http://dx.doi.org/10.1016/j.ensci.2020.100306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806512PMC
March 2021

Unravelling Genetic Factors Underlying Corticobasal Syndrome: A Systematic Review.

Cells 2021 Jan 15;10(1). Epub 2021 Jan 15.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, 20122 Milan, Italy.

Corticobasal syndrome (CBS) is an atypical parkinsonian presentation characterized by heterogeneous clinical features and different underlying neuropathology. Most CBS cases are sporadic; nevertheless, reports of families and isolated individuals with genetically determined CBS have been reported. In this systematic review, we analyze the demographical, clinical, radiological, and anatomopathological features of genetically confirmed cases of CBS. A systematic search was performed using the PubMed, EMBASE, and Cochrane Library databases, included all publications in English from 1 January 1999 through 1 August 2020. We found forty publications with fifty-eight eligible cases. A second search for publications dealing with genetic risk factors for CBS led to the review of eight additional articles. was the most common gene involved in CBS, representing 28 out of 58 cases, followed by , and . A set of symptoms was shown to be significantly more common in -CBS patients, including visuospatial impairment, behavioral changes, aphasia, and language alterations. In addition, specific demographical, clinical, biochemical, and radiological features may suggest mutations in other genes. We suggest a diagnostic algorithm to help in identifying potential genetic cases of CBS in order to improve the diagnostic accuracy and to better understand the still poorly defined underlying pathogenetic process.
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http://dx.doi.org/10.3390/cells10010171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830591PMC
January 2021

A Novel Homozygous VPS11 Variant May Cause Generalized Dystonia.

Ann Neurol 2021 Apr 2;89(4):834-839. Epub 2021 Feb 2.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.

In this work, we describe the association of a novel homozygous VPS11 variant with adult-onset generalized dystonia, providing a detailed clinical report and biological evidence of disease mechanism. Vps11 is a subunit of the homotypic fusion and protein sorting (HOPS) complex, which promotes the fusion of late endosomes and autophagosomes with the lysosome. Functional studies on mutated fibroblasts showed marked lysosomal and autophagic abnormalities, which improved after overexpression of the wild type Vps11 protein. In conclusion, a deleterious VPS11 variant, damaging the autophagic and lysosomal pathways, is the probable genetic cause of a novel form of generalized dystonia. ANN NEUROL 2021;89:834-839.
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http://dx.doi.org/10.1002/ana.26021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048445PMC
April 2021

A case report of late-onset cerebellar ataxia associated with a rare p.R342W TGM6 (SCA35) mutation.

BMC Neurol 2020 Nov 7;20(1):408. Epub 2020 Nov 7.

Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy.

Background: Mutations in TGM6 gene, encoding for transglutaminase 6 (TG6), have been implicated in the pathogenesis of spinocerebellar ataxia type 35 (SCA35), a rare autosomal dominant disease marked by cerebellar degeneration and characterized by postural instability, incoordination of gait, features of cerebellar dysfunction and pyramidal signs.

Case Presentation: Here we report the case of an Italian patient with late-onset, slowly progressive cerebellar features, including gait ataxia, scanning speech and ocular dysmetria and pyramidal tract signs. Whole exome sequencing revealed the rare heterozygous c.1024C > T (p.R342W) variant of TGM6, located at a highly evolutionary conserved position and predicted as pathogenic by in silico tools. Expression of TG6-R342W mutant in HEK293T cells led to a significant reduction of transamidase activity compared to wild-type TG6.

Conclusion: This finding extends SCA35 genetic landscape, highlighting the importance of TGM6 screening in undiagnosed late-onset and slowly progressive cerebellar ataxias.
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http://dx.doi.org/10.1186/s12883-020-01964-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648302PMC
November 2020

Hyperacute extensive spinal cord infarction and negative spine magnetic resonance imaging: a case report and review of the literature.

Medicine (Baltimore) 2020 Oct;99(43):e22900

Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, Neuroscience Section, University of Milan.

Rationale: Spinal cord infarction (SCI) accounts for only 1% to 2% of all ischemic strokes and 5% to 8% of acute myelopathies. Magnetic resonance imaging (MRI) holds a role in ruling out non-ischemic etiologies, but the diagnostic accuracy of this procedure may be low in confirming the diagnosis, even when extensive cord lesions are present. Indeed, T2 changes on MRI can develop over hours to days, thus accounting for the low sensitivity in the hyperacute setting (ie, within 6 hours from symptom onset). For these reasons, SCI remains a clinical diagnosis. Despite extensive diagnostic work-up, up to 20% to 40% of SCI cases are classified as cryptogenic. Here, we describe a case of cryptogenic longitudinally extensive transverse myelopathy due to SCI, with negative MRI and diffusion-weighted imaging at 9 hours after symptom onset.

Patient Concerns: A 51-year-old woman presented to our Emergency Department with acute severe abdominal pain, nausea, vomiting, sudden-onset of bilateral leg weakness with diffuse sensory loss, and paresthesias on the trunk and legs.

Diagnoses: On neurological examination, she showed severe paraparesis and a D6 sensory level. A 3T spinal cord MRI with gadolinium performed at 9 hours after symptom onset did not detect spinal cord alterations. Due to the persistence of a clinical picture suggestive of an acute myelopathy, a 3T MRI of the spine was repeated after 72 hours showing a hyperintense "pencil-like" signal mainly involving the grey matter from T1 to T6 on T2 sequence, mildly hypointense on T1 and with restricted diffusion.

Interventions: The patient was given salicylic acid (100 mg/d), prophylactic low-molecular-weight heparin, and began neuromotor rehabilitation.

Outcomes: Two months later, a follow-up neurological examination revealed a severe spastic paraparesis, no evident sensory level, and poor sphincteric control with distended bladder.

Lessons: Regardless of its relatively low frequency in the general population, SCI should be suspected in every patient presenting with acute and progressive myelopathic symptoms, even in the absence of vascular risk factors. Thus, a clinical presentation consistent with a potential vascular syndrome involving the spinal cord overrides an initially negative MRI and should not delay timely and appropriate management.
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http://dx.doi.org/10.1097/MD.0000000000022900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581089PMC
October 2020

Expanding the clinical spectrum of the mitochondrial mutation A13084T in the gene.

Neurol Genet 2020 Oct 15;6(5):e511. Epub 2020 Sep 15.

Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1212/NXG.0000000000000511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524578PMC
October 2020

Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia.

Ageing Res Rev 2020 12 22;64:101172. Epub 2020 Sep 22.

Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy; Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy. Electronic address:

In 2011, a hexanucleotide repeat expansion (HRE) in the noncoding region of C9orf72 was associated with the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The main pathogenic mechanisms in C9-ALS/FTD are haploinsufficiency of the C9orf72 protein and gain of function toxicity from bidirectionally-transcribed repeat-containing RNAs and dipeptide repeat proteins (DPRs) resulting from non-canonical RNA translation. Additionally, abnormalities in different downstream cellular mechanisms, such as nucleocytoplasmic transport and autophagy, play a role in pathogenesis. Substantial research efforts using in vitro and in vivo models have provided valuable insights into the contribution of each mechanism in disease pathogenesis. However, conflicting evidence exists, and a unifying theory still lacks. Here, we provide an overview of the recently published literature on clinical, neuropathological and molecular features of C9-ALS/FTD. We highlight the supposed neuronal role of C9orf72 and the HRE pathogenic cascade, mainly focusing on the contribution of RNA foci and DPRs to neurodegeneration and discussing the several downstream mechanisms. We summarize the emerging biochemical and neuroimaging biomarkers, as well as the potential therapeutic approaches. Despite promising results, a specific disease-modifying treatment is still not available to date and greater insights into disease mechanisms may help in this direction.
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http://dx.doi.org/10.1016/j.arr.2020.101172DOI Listing
December 2020

Limb girdle muscular dystrophy due to gene mutations: new mutations expand the clinical spectrum of a still challenging diagnosis.

Acta Myol 2020 Jun 1;39(2):67-82. Epub 2020 Jun 1.

Dino Ferrari Center, Neurology Unit, Department of Pathophysiology and Transplantation, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy.

Mutations in gene, encoding merosin, are generally responsible of a severe congenital-onset muscular dystrophy (CMD type 1A) characterized by severe weakness, merosin absence at muscle analysis and white matter alterations at brain Magnetic Resonance Imaging (MRI). Recently, mutations have been acknowledged as responsible of LGMD R23, despite only few cases with slowly progressive adult-onset and partial merosin deficiency have been reported. We describe 5 independent Italian subjects presenting with progressive limb girdle muscular weakness, brain white matter abnormalities, merosin deficiency and gene mutations. We detected 7 different mutations, 6 of which are new. All patients showed normal psicomotor development and slowly progressive weakness with onset spanning from childhood to forties. Creatin-kinase levels were moderately elevated. One patient showed dilated cardiomyopathy. Muscle MRI allowed to evaluate the degree and pattern of muscular involvement in all patients. Brain MRI was fundamental in order to address and/or support the molecular diagnosis, showing typical widespread white matter hyperintensity in T2-weighted sequences. Interestingly these alterations were associated with central nervous system involvement in 3 patients who presented epilepsy and migraine. Muscle biopsy commonly but not necessarily revealed dystrophic features. Western-blot was usually more accurate than immunohystochemical analysis in detecting merosin deficiency. The description of these cases further enlarges the clinical spectrum of -related disorders. Moreover, it supports the inclusion of LGMD R23 in the new classification of LGMD. The central nervous system involvement was fundamental to address the diagnosis and should be always included in the diagnostic work-up of undiagnosed LGMD.
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http://dx.doi.org/10.36185/2532-1900-009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460730PMC
June 2020

Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase.

Acta Myol 2020 Jun 1;39(2):57-66. Epub 2020 Jun 1.

Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Italy.

Introduction: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic.

Methods: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials.

Results: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine.

Conclusions: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.
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http://dx.doi.org/10.36185/2532-1900-008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460733PMC
June 2020

Animal Models of CMT2A: State-of-art and Therapeutic Implications.

Mol Neurobiol 2020 Dec 27;57(12):5121-5129. Epub 2020 Aug 27.

Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.

Charcot-Marie-Tooth disease type 2A (CMT2A), arising from mitofusin 2 (MFN2) gene mutations, is the most common inherited axonal neuropathy affecting motor and sensory neurons. The cellular and molecular mechanisms by which MFN2 mutations determine neuronal degeneration are largely unclear. No effective treatment exists for CMT2A, which has a high degree of genetic/phenotypic heterogeneity. The identification of mutations in MFN2 has allowed the generation of diverse transgenic animal models, but to date, their ability to recapitulate the CMT2A phenotype is limited, precluding elucidation of its pathogenesis and discovery of therapeutic strategies. This review will critically present recent progress in in vivo CMT2A disease modeling, discoveries, drawbacks and limitations, current challenges, and key reflections to advance the field towards developing effective therapies for these patients.
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http://dx.doi.org/10.1007/s12035-020-02081-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541381PMC
December 2020

Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in ENG.

BMC Neurol 2020 Aug 26;20(1):316. Epub 2020 Aug 26.

Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy.

Background: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare disorder characterized by recurrent epistaxis, telangiectasias and systemic arteriovenous malformations (AVMs). HHT is associated with mutations in genes encoding for proteins involved in endothelial homeostasis such as ENG (endoglin) and ACVRL1 (activin receptor-like kinase-1).

Case Presentation: Here we describe a 22-year-old male presenting with a transient episode of slurred speech and left arm paresis. Brain MRI displayed polymicrogyria. A right-to-left shunt in absence of an atrial septum defect was noted. Chest CT revealed multiple pulmonary AVMs, likely causing paradoxical embolism manifesting as a transient ischemic attack. The heterozygous ENG variant, c.3G > A (p.Met1lle), was detected in the patient. This variant was also found in patient's mother and in his younger brother who displayed cortical dysplasia type 2.

Conclusions: The detection of cortical development malformations in multiple subjects from the same pedigree may expand the phenotypic features of ENG-related HHT patients. We suggest considering HHT in young patients presenting with acute cerebral ischemic events of unknown origin.
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http://dx.doi.org/10.1186/s12883-020-01890-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450577PMC
August 2020

Management of patients with neuromuscular disorders at the time of the SARS-CoV-2 pandemic.

J Neurol 2020 Aug 17. Epub 2020 Aug 17.

Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy.

The novel Coronavirus disease-19 (COVID-19) pandemic has posed several challenges for neuromuscular disorder (NMD) patients. The risk of a severe course of SARS-CoV-2 infection is increased in all but the mildest forms of NMDs. High-risk conditions include reduced airway clearance due to oropharyngeal weakness and risk of worsening with fever, fasting or infection Isolation requirements may have an impact on treatment regimens administered in hospital settings, such as nusinersen, glucosidase alfa, intravenous immunoglobulin, and rituximab infusions. In addition, specific drugs for SARS-CoV2 infection under investigation impair neuromuscular function significantly; chloroquine and azithromycin are not recommended in myasthenia gravis without available ventilatory support and prolonged prone positioning may influence options for treatment. Other therapeutics may affect specific NMDs (metabolic, mitochondrial, myotonic diseases) and experimental approaches for Coronavirus disease 2019 may be offered "compassionately" only after consulting the patient's NMD specialist. In parallel, the reorganization of hospital and outpatient services may change the management of non-infected NMD patients and their caregivers, favouring at-distance approaches. However, the literature on the validation of telehealth in this subgroup of patients is scant. Thus, as the first wave of the pandemic is progressing, clinicians and researchers should address these crucial open issues to ensure adequate caring for NMD patients. This manuscript summarizes available evidence so far and provides guidance for both general neurologists and NMD specialists dealing with NMD patients in the time of COVID-19.
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http://dx.doi.org/10.1007/s00415-020-10149-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429942PMC
August 2020

Extracellular vesicles and amyotrophic lateral sclerosis: from misfolded protein vehicles to promising clinical biomarkers.

Cell Mol Life Sci 2021 Jan 16;78(2):561-572. Epub 2020 Aug 16.

Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy.

Extracellular vesicles (EVs) are small reservoirs of different molecules and important mediators of cell-to-cell communication. As putative vehicles of misfolded protein propagation between cells, they have drawn substantial attention in the field of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Moreover, exosome-mediated non-coding RNA delivery may play a crucial role in ALS, given the relevance of RNA homeostasis in disease pathogenesis. Since EVs can enter the systemic circulation and are easily detectable in patients' biological fluids, they have generated broad interest both as diagnostic and prognostic biomarkers and as valuable tools in understanding disease pathogenesis. Here, after a brief introduction on biogenesis and functions of EVs, we aim to investigate their role in neurodegenerative disorders, especially ALS. Specifically, we focus on the main findings supporting EV-mediated protein and RNA transmission in ALS in vitro and in vivo models. Then, we provide an overview of clinical applications of EVs, summarizing the most relevant studies able to detect EVs in blood and cerebrospinal fluid (CSF) of ALS patients, underlying their potential use in aiding diagnosis and prognosis. Finally, we explore the therapeutic applications of EVs in ALS, either as targets or as vehicles of proteins, nucleic acids and molecular drugs.
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http://dx.doi.org/10.1007/s00018-020-03619-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872995PMC
January 2021

Late-onset leukoencephalopathy in a patient with recessive mutations.

Neurol Genet 2020 Oct 13;6(5):e488. Epub 2020 Jul 13.

Dino Ferrari Centre (E.M., D.R., F.A., G.P.C., N.B., A.D.F.), Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.F., M.G., F.A., G.P.C., N.B., A.D.F.), Neurology Unit; Department of Biomedical Sciences (L.S., S.D.), Humanitas University, Pieve Emanuele; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.S.), Neuroradiology Unit; and Humanitas Clinical and Research Center (S.D.), IRCCS, Rozzano, Milan, Italy.

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http://dx.doi.org/10.1212/NXG.0000000000000488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413628PMC
October 2020

Safety and efficacy of rt-PA treatment for acute stroke in pseudoxanthoma elasticum: the first report.

J Thromb Thrombolysis 2021 Jan;51(1):176-179

Dino Ferrari Centre, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Pseudoxanthoma elasticum is a rare cause for ischaemic stroke. Little is known about acute and secondary prevention strategies in these subjects given the increased risk of gastrointestinal and urinary bleedings. Here we present the case of a 62 years old man affected by pseudoxanthoma elasticum who presented with acute ischaemic stroke and was successfully treated with intravenous thrombolysis. Neurological signs improved after intravenous thrombolysis without bleeding complication. To our knowledge, this is the first case of pseudoxanthoma elasticum-related stroke undergoing intravenous thrombolysis.
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http://dx.doi.org/10.1007/s11239-020-02150-3DOI Listing
January 2021

The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer's Disease and Parkinson's Disease.

Mol Neurobiol 2020 Jul 22;57(7):2959-2980. Epub 2020 May 22.

Division of Neuroscience and Laboratory of Neurogenetics, National Institute on Aging, National Institute of Health, Bethesda, MD, USA.

Although the pathogenesis of neurodegenerative diseases is still widely unclear, various mechanisms have been proposed and several pieces of evidence are supportive for an important role of mitochondrial dysfunction. The present review provides a comprehensive and up-to-date overview about the role of mitochondria in the two most common neurodegenerative disorders: Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondrial involvement in AD is supported by clinical features like reduced glucose and oxygen brain metabolism and by numerous microscopic and molecular findings, including altered mitochondrial morphology, impaired respiratory chain function, and altered mitochondrial DNA. Furthermore, amyloid pathology and mitochondrial dysfunction seem to be bi-directionally correlated. Mitochondria have an even more remarkable role in PD. Several hints show that respiratory chain activity, in particular complex I, is impaired in the disease. Mitochondrial DNA alterations, involving deletions, point mutations, depletion, and altered maintenance, have been described. Mutations in genes directly implicated in mitochondrial functioning (like Parkin and PINK1) are responsible for rare genetic forms of the disease. A close connection between alpha-synuclein accumulation and mitochondrial dysfunction has been observed. Finally, mitochondria are involved also in atypical parkinsonisms, in particular multiple system atrophy. The available knowledge is still not sufficient to clearly state whether mitochondrial dysfunction plays a primary role in the very initial stages of these diseases or is secondary to other phenomena. However, the presented data strongly support the hypothesis that whatever the initial cause of neurodegeneration is, mitochondrial impairment has a critical role in maintaining and fostering the neurodegenerative process.
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http://dx.doi.org/10.1007/s12035-020-01926-1DOI Listing
July 2020

Microscopic Polyangiitis With Selective Involvement of Central and Peripheral Nervous System: A Case Report.

Front Neurol 2020 28;11:269. Epub 2020 Apr 28.

Neuroscience Section, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Microscopic polyangiitis (MPA) is a necrotizing vasculitis that affects predominantly small-sized vessels in many organ systems. The disease generally causes glomerulonephritis, pulmonary damage, arthritis, and neuropathy. An exclusive involvement of both central nervous system (CNS) and peripheral nervous system (PNS) is extremely rare. A 62-year-old woman was admitted to our hospital with a 3 months history of right foot drop, recently complicated by intense myalgia, arthralgia, and allodynia to tactile, vibratory, and pressure stimuli. Since blood tests revealed elevated inflammatory indexes, we suspected either infectious or immune-mediated disorders. Chest radiograph, blood culture series, and echocardiogram revealed normal findings, while urinalysis showed a bacterial infection that was successfully treated. The neurophysiological findings were compatible with multiple mononeuritis, and a brain MRI evidenced ischemic lesions of both basal ganglia and thalamus. A wide-spectrum autoantibody assay revealed the presence of high-titer perinuclear anti-neutrophil cytoplasmic antibodies specific for myeloperoxidase (MPO-ANCA). According to these findings, the diagnosis of MPA was made, and the patient was successfully treated with intravenous (IV) methylprednisolone, followed by two doses of rituximab. An assessment of both CNS and PNS should be included in the diagnostic evaluation of MPA. The involvement of the PNS may raise the risk of a relapsing course and treatment failure, therefore it should be considered in the choice of induction and maintenance therapy.
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http://dx.doi.org/10.3389/fneur.2020.00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198731PMC
April 2020

Neural Stem Cell Transplantation for Neurodegenerative Diseases.

Int J Mol Sci 2020 Apr 28;21(9). Epub 2020 Apr 28.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Via Francesco Sforza 35, 20122 Milan, Italy.

Neurodegenerative diseases are disabling and fatal neurological disorders that currently lack effective treatment. Neural stem cell (NSC) transplantation has been studied as a potential therapeutic approach and appears to exert a beneficial effect against neurodegeneration via different mechanisms, such as the production of neurotrophic factors, decreased neuroinflammation, enhanced neuronal plasticity and cell replacement. Thus, NSC transplantation may represent an effective therapeutic strategy. To exploit NSCs' potential, some of their essential biological characteristics must be thoroughly investigated, including the specific markers for NSC subpopulations, to allow profiling and selection. Another key feature is their secretome, which is responsible for the regulation of intercellular communication, neuroprotection, and immunomodulation. In addition, NSCs must properly migrate into the central nervous system (CNS) and integrate into host neuronal circuits, enhancing neuroplasticity. Understanding and modulating these aspects can allow us to further exploit the therapeutic potential of NSCs. Recent progress in gene editing and cellular engineering techniques has opened up the possibility of modifying NSCs to express select candidate molecules to further enhance their therapeutic effects. This review summarizes current knowledge regarding these aspects, promoting the development of stem cell therapies that could be applied safely and effectively in clinical settings.
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http://dx.doi.org/10.3390/ijms21093103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247151PMC
April 2020

Noncoding RNAs in Duchenne and Becker muscular dystrophies: role in pathogenesis and future prognostic and therapeutic perspectives.

Cell Mol Life Sci 2020 Nov 29;77(21):4299-4313. Epub 2020 Apr 29.

Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Noncoding RNAs (ncRNAs), such as miRNAs and long noncoding RNAs, are key regulators of gene expression at the post-transcriptional level and represent promising therapeutic targets and biomarkers for several human diseases, including Duchenne and Becker muscular dystrophies (DMD/BMD). A role for ncRNAs in the pathogenesis of muscular dystrophies has been suggested, even if it is still incompletely understood. Here, we discuss current progress leading towards the clinical utility of ncRNAs for DMD/BMD. Long and short noncoding RNAs are differentially expressed in DMD/BMD and have a mechanism of action via targeting mRNAs. A subset of muscle-enriched miRNAs, the so-called myomiRs (miR-1, miR-133, and miR-206), are increased in the serum of patients with DMD and in dystrophin-defective animal models. Interestingly, myomiRs might be used as biomarkers, given that their levels can be corrected after dystrophin restoration in dystrophic mice. Remarkably, further evidence demonstrates that ncRNAs also play a role in dystrophin expression; thus, their modulations might represent a potential therapeutic strategy with the aim of upregulating the dystrophin protein in combination with other oligonucleotides/gene therapy approaches.
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http://dx.doi.org/10.1007/s00018-020-03537-4DOI Listing
November 2020

Dystonia-ataxia syndrome with permanent torsional nystagmus caused by ECHS1 deficiency.

Ann Clin Transl Neurol 2020 05 24;7(5):839-845. Epub 2020 Apr 24.

Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Biallelic mutations in ECHS1, encoding the mitochondrial enoyl-CoA hydratase, have been associated with mitochondrial encephalopathies with basal ganglia involvement. Here, we describe a novel clinical presentation consisting of dystonia-ataxia syndrome with hearing loss and a peculiar torsional nystagmus observed in two adult siblings. The presence of a 0.9-ppm peak at MR spectroscopy analysis suggested the accumulation of branched-chain amino acids. Exome sequencing in index probands identified two ECHS1 mutations, one of which was novel (p.V82L). ECHS1 protein levels and residual activities were reduced in patients' fibroblasts. This paper expands the phenotypic spectrum observed in patients with impaired valine catabolism.
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http://dx.doi.org/10.1002/acn3.51025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261751PMC
May 2020

Glial cells involvement in spinal muscular atrophy: Could SMA be a neuroinflammatory disease?

Neurobiol Dis 2020 07 12;140:104870. Epub 2020 Apr 12.

Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, Neuroscience Section, University of Milan, Milan, Italy.; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.

Spinal muscular atrophy (SMA) is a severe, inherited disease characterized by the progressive degeneration and death of motor neurons of the anterior horns of the spinal cord, which results in muscular atrophy and weakness of variable severity. Its early-onset form is invariably fatal in early childhood, while milder forms lead to permanent disability, physical deformities and respiratory complications. Recently, two novel revolutionary therapies, antisense oligonucleotides and gene therapy, have been approved, and might prove successful in making long-term survival of these patients likely. In this perspective, a deep understanding of the pathogenic mechanisms and of their impact on the interactions between motor neurons and other cell types within the central nervous system (CNS) is crucial. Studies using SMA animal and cellular models have taught us that the survival and functionality of motor neurons is highly dependent on a whole range of other cell types, namely glial cells, which are responsible for a variety of different functions, such as neuronal trophic support, synaptic remodeling, and immune surveillance. Thus, it emerges that SMA is likely a non-cell autonomous, multifactorial disease in which the interaction of different cell types and disease mechanisms leads to motor neurons failure and loss. This review will introduce the different glial cell types in the CNS and provide an overview of the role of glial cells in motor neuron degeneration in SMA. Furthermore, we will discuss the relevance of these findings so far and the potential impact on the success of available therapies and on the development of novel ones.
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http://dx.doi.org/10.1016/j.nbd.2020.104870DOI Listing
July 2020

SLC25A46 mutations in patients with Parkinson's Disease and optic atrophy.

Parkinsonism Relat Disord 2020 05 2;74:1-5. Epub 2020 Apr 2.

IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. Electronic address:

Mutations in the gene encoding the mitochondrial carrier protein SLC25A46 are known to cause optic atrophy associated with peripheral neuropathy and congenital pontocerebellar hypoplasia. We found novel biallelic SLC25A46 mutations (p.H137R, p.A401Sfs*17) in a patient with Parkinson's disease and optic atrophy. Screening of six unrelated patients with parkinsonism and optic atrophy allowed us to identify two additional mutations (p.A176V, p.K256R) in a second patient. All identified variants are predicted likely pathogenic and affect very conserved protein residues. These findings suggest for the first time a possible link between Parkinson's Disease and SLC25A46 mutations. Replication in additional studies is needed to conclusively prove this link.
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http://dx.doi.org/10.1016/j.parkreldis.2020.03.018DOI Listing
May 2020

Mental health and coping strategies in families of children and young adults with muscular dystrophies.

J Neurol 2020 Jul 28;267(7):2054-2069. Epub 2020 Mar 28.

Neuromuscular Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.

Background: Living with a progressive disease as muscular dystrophy (MD) can be challenging for the patient and the entire family from both emotional and practical point of view. We aimed to extend our previously published data about mental health in patients with MDs, also investigating coping profiles of both themselves and their parents. Furthermore, we wanted to verify whether psychological adaptation of patients can be predicted by coping strategies, taking also into account physical impairment, cognitive level and socioeconomic status.

Methods: 112 patients with MDs, aged 2-32 were included. Their emotional and behavioural features were assessed through parent- and self-report Achenbach System for Empirically Based Assessment questionnaires and Strength and Difficulties Questionnaires. Development and Well-Being Assessment or Autism Diagnostic Observation Schedule were administered to confirm suspected diagnoses. Coping profile of both parents and patients was assessed through the self-administered New Italian Version of the Coping Orientation to the Problems Experienced questionnaire and its relationship with emotional/behavioural outcome was examined in linear regression analyses.

Results: High prevalence of intellectual disability and autism spectrum disorders was confirmed in Duchenne MD. Despite the high rate of internalizing symptomatology, we did not report higher rate of psychopathological disorders compared to general population. Parents tend to rely more on positive reinterpretation and less on disengagement coping. Avoidance coping, whether used by parents or patients, and ID, predicted increased emotional/behavioural problems.

Conclusions: Psychosocial interventions should address problems of anxiety and depression that people with MDs frequently experience, even through fostering parents' and childrens' engagement coping over disengagement coping.
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http://dx.doi.org/10.1007/s00415-020-09792-6DOI Listing
July 2020

Silence superoxide dismutase 1 (SOD1): a promising therapeutic target for amyotrophic lateral sclerosis (ALS).

Expert Opin Ther Targets 2020 04 14;24(4):295-310. Epub 2020 Mar 14.

Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, Neuroscience Section, University of Milan, Milan, Italy.

: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disorder that targets upper and lower motor neurons and leads to fatal muscle paralysis. Mutations in the superoxide dismutase 1 (SOD1) gene are responsible for 15% of familial ALS cases, but several studies have indicated that SOD1 dysfunction may also play a pathogenic role in sporadic ALS. SOD1 induces numerous toxic effects through the pathological misfolding and aggregation of mutant SOD1 species, hence a reduction of the levels of toxic variants appears to be a promising therapeutic strategy for SOD1-related ALS. Several methods are used to modulate gene expression ; these include RNA interference, antisense oligonucleotides (ASOs) and CRISPR/Cas9 technology.: This paper examines the current approaches for gene silencing and the progress made in silencing SOD1 . It progresses to shed light on the key results and pitfalls of these studies and highlights the future challenges and new perspectives for this exciting research field.: Gene silencing strategies targeting SOD1 may represent effective approaches for familial and sporadic ALS-related neurodegeneration; however, the risk of off-target effects must be minimized, and effective and minimally invasive delivery strategies should be fine-tuned.
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http://dx.doi.org/10.1080/14728222.2020.1738390DOI Listing
April 2020

Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Cell Mol Life Sci 2020 Sep 2;77(17):3351-3367. Epub 2020 Mar 2.

Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy.

Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.
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http://dx.doi.org/10.1007/s00018-020-03492-0DOI Listing
September 2020

Nusinersen treatment and cerebrospinal fluid neurofilaments: An explorative study on Spinal Muscular Atrophy type 3 patients.

J Cell Mol Med 2020 03 7;24(5):3034-3039. Epub 2020 Feb 7.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.

The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme-linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response.
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http://dx.doi.org/10.1111/jcmm.14939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077557PMC
March 2020

Herpes Simplex virus type 2 myeloradiculitis with a pure motor presentation in a liver transplant recipient.

Transpl Infect Dis 2020 Feb 1;22(1):e13236. Epub 2020 Jan 1.

Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, Neuroscience Section, University of Milan, Milan, Italy.

In this case report, we describe the first PCR-confirmed case of HSV2 myeloradiculitis with a purely motor presentation, occurring in a 68-year-old liver transplant recipient. The patient reported ascending weakness with no sensory nor sphincteric symptoms, thereby resembling acute demyelinating inflammatory neuropathy, or Guillain-Barré syndrome. HSV2 was detected in cerebrospinal fluid by PCR, and the patient was successfully treated with intravenous Acyclovir.
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http://dx.doi.org/10.1111/tid.13236DOI Listing
February 2020