Publications by authors named "Enza Maria Valente"

213 Publications

Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study.

Mov Disord 2022 Jan 8. Epub 2022 Jan 8.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding.

Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR).

Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry).

Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029).

Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28902DOI Listing
January 2022

Adult onset familiar dystonia-plus syndrome: A novel presentation of IRF2BPL-associated neurodegeneration.

Parkinsonism Relat Disord 2021 Nov 14;94:22-24. Epub 2021 Nov 14.

Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Pathogenic variants of the IRF2BPL gene have been mostly associated with early onset epileptic encephalopathy. Movement disorders such as dystonia and ataxia were also reported, with symptoms mainly developing between childhood and adolescence. Here we describe a family with several members affected by a late onset dystonic and ataxic progressive syndrome, caused by a novel heterozygous pathogenic variant in the IRF2BPL gene.
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http://dx.doi.org/10.1016/j.parkreldis.2021.10.033DOI Listing
November 2021

Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing.

Cerebellum 2021 Nov 30. Epub 2021 Nov 30.

Deparment of Molecular Medicine, University of Pavia, via Forlanini 14, 27100, Pavia, Italy.

Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.
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http://dx.doi.org/10.1007/s12311-021-01350-8DOI Listing
November 2021

AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability.

Autophagy 2021 Nov 19:1-11. Epub 2021 Nov 19.

Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy.

PINK1 accumulation at the outer mitochondrial membrane (OMM) is a key event required to signal depolarized mitochondria to the autophagy machinery. How this early step is, in turn, modulated by autophagy proteins remains less characterized. Here, we show that, upon mitochondrial depolarization, the proautophagic protein AMBRA1 is recruited to the OMM and interacts with PINK1 and ATAD3A, a transmembrane protein that mediates mitochondrial import and degradation of PINK1. Downregulation of AMBRA1 expression results in reduced levels of PINK1 due to its enhanced degradation by the mitochondrial protease LONP1, which leads to a decrease in PINK1-mediated ubiquitin phosphorylation and mitochondrial PRKN/PARKIN recruitment. Notably, ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells upon mitochondrial damage. Overall, our findings underline an upstream contribution of AMBRA1 in the control of PINK1-PRKN mitophagy by interacting with ATAD3A and promoting PINK1 stability. This novel regulatory element may account for changes of PINK1 levels in neuropathological conditions.
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http://dx.doi.org/10.1080/15548627.2021.1997052DOI Listing
November 2021

PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum.

Am J Med Genet A 2022 02 29;188(2):635-641. Epub 2021 Oct 29.

Medical Genetics Unit, IRCCS Mondino Foundation, Pavia, Italy.

PUS3 encodes the pseudouridylate synthase 3, an enzyme catalyzing the formation of tRNA pseudouridine, which plays a critical role in tRNA structure, function, and stability. Biallelic pathogenic variants of PUS3 have been previously associated with severe intellectual disability, microcephaly, epilepsy, and short stature. We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia. This patient further expands the phenotypic spectrum of PUS3-related disorders to include a more severe syndromic presentation.
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http://dx.doi.org/10.1002/ajmg.a.62547DOI Listing
February 2022

haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.

J Med Genet 2021 Oct 21. Epub 2021 Oct 21.

Unit of Neurorehabilitation, Department of Neurosciences, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the gene in two families with mild JS. Recently, heterozygous truncating variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.

Methods: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.

Results: Heterozygous truncating and splice-site variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.

Conclusion: Heterozygous truncating or splice-site variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.
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http://dx.doi.org/10.1136/jmedgenet-2021-108114DOI Listing
October 2021

Social prediction in pediatric patients with congenital, non-progressive malformations of the cerebellum: From deficits in predicting movements to rehabilitation in virtual reality.

Cortex 2021 Nov 24;144:82-98. Epub 2021 Sep 24.

IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

It has been proposed that impairments of the predictive function exerted by the cerebellum may account for social cognition deficits. Here, we integrated cerebellar functions in a predictive coding framework to elucidate how congenital, non-progressive cerebellar alterations could affect the predictive processing of others' behavior. Experiment 1 demonstrated that cerebellar patients were impaired in relying on contextual information during prediction of other persons' movement, and this impairment was significantly associated with social cognition abilities. Experiment 2 indicated that children and adolescents with congenital, non-progressive cerebellar malformation showed a domain-general deficit in using contextual information to predict both others' movements and physical events, and that this impairment was independent from patients' cognitive abilities. Experiment 3 provided first evidence that a social-prediction training in virtual reality could boost the ability to use context-based predictions to understand others' intentions. These findings shed new light on the predictive role of the cerebellum and its contribution to social cognition, paving the way for new approaches to the rehabilitation of the Cerebellar Cognitive Affective Syndrome.
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http://dx.doi.org/10.1016/j.cortex.2021.08.008DOI Listing
November 2021

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease.

J Parkinsons Dis 2021 Oct 7. Epub 2021 Oct 7.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation.

Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases.

Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017).

Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking.

Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
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http://dx.doi.org/10.3233/JPD-212851DOI Listing
October 2021

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort.

Front Neurol 2021 9;12:710572. Epub 2021 Aug 9.

Department of Neurology, University Hospital Würzburg, Würzburg, Germany.

Pathogenic variants in the Leucine-rich repeat kinase 2 ( gene are the most common known monogenic cause of Parkinson's disease (PD). -linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of pathogenic variants using genetic and environmental data. Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with -linked PD, 200 with pathogenic variants but without PD, 100 PD patients with pathogenic variants in the or genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). LIPAD is a large-scale international scientific effort focusing on deep phenotyping of -linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity ClinicalTrials.gov, NCT04214509.
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http://dx.doi.org/10.3389/fneur.2021.710572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406937PMC
August 2021

haploinsufficiency causes periventricular nodular heterotopia with variable clinical expressivity.

J Med Genet 2021 Aug 5. Epub 2021 Aug 5.

Medical Genetics Unit, Foundation National Neurological Institute C Mondino Institute for Hospitalization and Care Scientific, Pavia, Italy

The primary anatomical defect leading to periventricular nodular heterotopia occurs within the neural progenitors along the neuroepithelial lining of the lateral ventricles and results from a defect in the initiation of neuronal migration, following disruption of the neuroependyma and impaired neuronal motility. Growing evidence indicates that the -dependent actin dynamics and regulation of vesicle formation and trafficking by activation of ADP-ribosylation factors (ARFs) can play an important role in this cortical malformation. We report the first inherited variant of in a girl with intellectual disability and periventricular nodular heterotopia who inherited the variant from the father with previously undiagnosed single nodular heterotopia and mild clinical expression. Additionally, both patients presented some features suggestive of hypohidrotic ectodermal dysplasia. These clinical features showed similarities to those of three previously reported cases with missense variants, confirming that haploinsufficiency of this gene causes a recognisable neurological disorder with abnormal neuronal migration and variable clinical expressivity.
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http://dx.doi.org/10.1136/jmedgenet-2021-107783DOI Listing
August 2021

Spectrum of Disease Severity in Nonsyndromic Patients With Mutations in the CEP290 Gene: A Multicentric Longitudinal Study.

Invest Ophthalmol Vis Sci 2021 07;62(9)

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.

Purpose: The purpose of this study was to perform a detailed longitudinal phenotyping and genetic characterization of 32 Italian patients with a nonsyndromic retinal dystrophy and mutations in the CEP290 gene.

Methods: We reviewed the clinical history and examinations of 32 patients with a nonsyndromic retinal dystrophy due to mutations in the CEP290 gene, followed up (mean follow-up: 5.9 years) at 3 Italian centers. The clinical examinations included: best corrected visual acuity (BCVA), optical coherence tomography (OCT), and full-field electroretinogram (ERG).

Results: Patients (mean age = 19.0 ± 3.4 years) had a mean BCVA of 1.73 ± 0.20 logMAR. Longitudinal analysis of BCVA showed a nonsignificant decline. Central retinal thickness (CRT) declined significantly with age at an exponential rate of 1.0%/year (P = 0.001). At disease onset, most patients (19/32; 49.4%) had nystagmus. The absence of nystagmus was significantly associated with better BCVA and more preserved CRT (P < 0.05). ERG showed undetectable responses in most patients (64.0%), whereas reduced scotopic and photopic responses were observed in four patients (16.0%) who had no nystagmus. We identified 35 different variants, among which 12 were novel. Our genotype-phenotype correlation analysis shows a significantly worse BCVA in patients harboring a loss-of-function mutation and the deep-intronic variant c.2991+1655A>G.

Conclusions: Our study highlights a mild phenotype of the disease, characterized by absence of nystagmus, good visual acuity, considerably preserved retinal morphology, and recordable ERG, confirming the wide spectrum of CEP290-related retinal dystrophies. Finally, in our cohort, the deep intronic variant c.2991+1655A>G was associated with a more severe phenotype.
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http://dx.doi.org/10.1167/iovs.62.9.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267213PMC
July 2021

Establishment of three Joubert syndrome-derived induced pluripotent stem cell (iPSC) lines harbouring compound heterozygous mutations in CC2D2A gene.

Stem Cell Res 2021 07 16;54:102430. Epub 2021 Jun 16.

Angelo Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Italy.

We have developed Joubert syndrome (JS)-derived induced pluripotent stem cell (iPSC) lines from dermal fibroblasts biopsied from a female patient harbouring novel compound heterozygous mutations in CC2D2A gene. The newly established iPSC lines provide tremendous promises for development of JS-derived neuronal cell lines to uncover the molecular and cellular mechanisms underlying the pathogenesis of JS and to develop therapeutic interventions for treatment of JS.
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http://dx.doi.org/10.1016/j.scr.2021.102430DOI Listing
July 2021

Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study.

J Med Genet 2021 Mar 5. Epub 2021 Mar 5.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes.

Methods: We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters.

Results: A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was , which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in and pathogenic variants in accounted for 18% and 9% of cases, respectively. , and were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with and lower motor neuron signs with . When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for .

Conclusion: represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between and -associated disorders.
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http://dx.doi.org/10.1136/jmedgenet-2020-107497DOI Listing
March 2021

Diagnostic Yield and Cost-Effectiveness of "Dynamic" Exome Analysis in Epilepsy with Neurodevelopmental Disorders: A Tertiary-Center Experience in Northern Italy.

Diagnostics (Basel) 2021 May 25;11(6). Epub 2021 May 25.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, 27100 Pavia, Italy.

Background: The advent of next-generation sequencing (NGS) techniques in clinical practice led to a significant advance in gene discovery. We aimed to describe diagnostic yields of a "dynamic" exome-based approach in a cohort of patients with epilepsy associated with neurodevelopmental disorders.

Methods: We conducted a retrospective, observational study on 72 probands. All patients underwent a first diagnostic level of a 135 gene panel, a second of 297 genes for inconclusive cases, and finally, a whole-exome sequencing for negative cases. Diagnostic yields at each step and cost-effectiveness were the objects of statistical analysis.

Results: Overall diagnostic yield in our cohort was 37.5%: 29% of diagnoses derived from the first step analysis, 5.5% from the second step, and 3% from the third. A significant difference emerged between the three diagnostic steps ( < 0.01), between the first and second ( = 0.001), and the first and third ( << 0.001). The cost-effectiveness plane indicated that our exome-based "dynamic" approach was better in terms of cost savings and higher diagnostic rate.

Conclusions: Our findings suggested that "dynamic" NGS techniques applied to well-phenotyped individuals can save both time and resources. In patients with unexplained epilepsy comorbid with NDDs, our approach might maximize the number of diagnoses achieved.
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http://dx.doi.org/10.3390/diagnostics11060948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228291PMC
May 2021

Challenges and resources in adult life with Joubert syndrome: issues from an international classification of functioning (ICF) perspective.

Disabil Rehabil 2021 May 19:1-8. Epub 2021 May 19.

Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.

Background: Joubert Syndrome (JS) is a rare inherited neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation (i.e. the molar tooth sign) and variable organ involvement. The aim of the present study was to describe functional limitations and disabilities in a large sample of adult patients with a diagnosis of JS.

Methods: We administered the International Classification of Functioning (ICF) checklist to thirty-six adult Italian patients with JS or their caregivers through telephone calls.

Results: None-to-mild impairment was documented for basic cognitive and mental functions, whereas severe deficit emerged for higher-order skills and language. A mismatch between individuals' capacity for daily activity and social participation and the actual performance in these fields emerged, suggesting that adults with JS may greatly benefit from external support from the caring environment. Indeed, specific facilitators were highlighted, including communication technologies as well as family members, healthcare professionals and peers support. Mild-to-severe barriers have been identified by adult patients with JS in the domains of services, systems and policies.

Conclusions: These findings highlight challenges and barriers for adults with JS in areas of daily functioning that may be improved by investing in rehabilitation care models that embed social support programs and policies into clinical interventions.IMPLICATIONS FOR REHABILITATIONChildren with Joubert Syndrome, a child-onset rare inherited neurodevelopmental condition, are growing up and becoming adults; a life course approach in rehabilitation is needed;There is a substantial lack of information on the long-term adaptive daily functioning of children with a diagnosis of Joubert Syndrome;In this paper, the International Classification of Functioning (ICF) was applied to assess the daily functioning in people with JS;Severe deficits emerged for high-order skills and language, whereas the use of communication technologies and the engagement of family members were highlighted as key facilitators;These findings highlight the need for a change of paradigm in the care model of subjects with JS, with the embedding of social support in rehabilitation programs.
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http://dx.doi.org/10.1080/09638288.2021.1922516DOI Listing
May 2021

WITHDRAWN: Schuurs-Hoeijmakers syndrome: Severe expression of the recurrent PACS1 c.607C>T mutation.

Brain Dev 2021 May 14. Epub 2021 May 14.

Medical Genetics Unit, IRCCS Mondino Foundation, Pavia, Italy; Dept. of Molecular Medicine, University of Pavia, Pavia, Italy.

This article has been withdrawn at the request of the authors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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http://dx.doi.org/10.1016/j.braindev.2021.04.006DOI Listing
May 2021

RFC1 expansions are a common cause of idiopathic sensory neuropathy.

Brain 2021 06;144(5):1542-1550

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren's syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies.
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http://dx.doi.org/10.1093/brain/awab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262986PMC
June 2021

Histologic heterogeneity and syndromic associations of non-ampullary duodenal polyps and superficial mucosal lesions.

Dig Liver Dis 2021 Dec 1;53(12):1647-1654. Epub 2021 Apr 1.

First Department of Internal Medicine, University of Pavia, IRCCS San Matteo Hospital Foundation, Viale Golgi 19, 27100, Italy.

Background: Duodenal polyps and superficial mucosal lesions (DP/SMLs) are poorly characterised.

Aims: To describe a series of endoscopically-diagnosed extra-ampullary DPs/SMLs.

Methods: This is a retrospective study conducted in a tertiary referral Endoscopy Unit, including patients who had DPs or SMLs that were biopsied or removed in 2010-2019. Age, gender, history of familial polyposis syndromes, DP/SML characteristics were recorded. Histopathological, immunohistochemical and molecular analyses were performed.

Results: 399 non-ampullary DP/SMLs from 345 patients (60.6% males; median age 67 years) were identified. Gastric foveolar metaplasia represented the most frequent histotype (193 cases, 48.4%), followed by duodenal adenomas (DAs; 77 cases, 19.3%). Most DAs (median size 6 mm) were sessile (Paris Is; 48%), intestinal-type (96.1%) with low-grade dysplasia (93.5%). Among syndromic DAs (23%), 15 lesions occurred in familial adenomatous polyposis 1, two were in MUTYH-associated polyposis and one was in Peutz-Jeghers syndrome (foveolar-type, p53-positive, low-grade dysplasia). Only one (3.3%) tubular, low-grade DA showed mismatch repair deficiency (combined loss of MLH1 and PMS2, heterogeneous MSH6 expression), and it was associated with a MLH1 gene germline mutation (Lynch syndrome).

Conclusion: DPs/SMLs are heterogeneous lesions, most of which showing foveolar metaplasia, followed by low-grade, intestinal-type, non-syndromic DAs. MMR-d testing may identify cases associated with Lynch syndrome.
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http://dx.doi.org/10.1016/j.dld.2021.03.011DOI Listing
December 2021

GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson's Disease.

Int J Mol Sci 2021 Feb 23;22(4). Epub 2021 Feb 23.

Cellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy.

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson's disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal-lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD.
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http://dx.doi.org/10.3390/ijms22042215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927041PMC
February 2021

CASK related disorder: Epilepsy and developmental outcome.

Eur J Paediatr Neurol 2021 Mar 19;31:61-69. Epub 2021 Feb 19.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genova, Italy; Unit of Child Neuropsychiatry, ASST Fatebenefratelli Sacco, Milano, Italy.

Objective: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay.

Methods: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature.

Results: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy.

Conclusions: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.006DOI Listing
March 2021

Novel unconventional variants expand the allelic spectrum of OPHN1 gene.

Am J Med Genet A 2021 05 27;185(5):1575-1581. Epub 2021 Feb 27.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Mutations in the OPHN1 gene cause a rare X-linked recessive neurodevelopmental disorder characterized by intellectual disability, variably associated with cerebellar hypoplasia and distinctive facial appearance. In most of cases so far reported, the identified genomic variants involve the region encoding the central RhoGAP domain of the oligophrenin-1 protein, and are predicted to result in a complete loss of function. By using a NGS-based diagnostic approach, we identified three male and a female patients from two unrelated families carrying novel non-disruptive OPHN1 variants (the in-frame c.116_127 deletion and the missense c.2129C>T change, respectively), affecting either the BAR domain or the C-terminus proline-rich domain of the protein. Clinical and neuroimaging findings in the patients recapitulated the main features of OPHN1-related syndrome, including developmental delay, intellectual disability, behavioral disorder, dysmorphic features, seizures, cerebellar hypoplasia, and ventriculomegaly. Yet, we observed a wide variability even among affected siblings, confirming the lack of clear genotype-phenotype correlation. Our results expand the allelic spectrum of OPHN1 and illustrate the challenges for clinical interpretation of non-disruptive variants affecting X-linked genes.
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http://dx.doi.org/10.1002/ajmg.a.62144DOI Listing
May 2021

Profiling the Biochemical Signature of GBA-Related Parkinson's Disease in Peripheral Blood Mononuclear Cells.

Mov Disord 2021 05 22;36(5):1267-1272. Epub 2021 Feb 22.

Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Background: GBA mutations are the commonest genetic risk factor for Parkinson's disease (PD) and also impact disease progression.

Objective: The objective of this study was to define a biochemical profile that could distinguish GBA-PD from non-mutated PD.

Methods: 29 GBA-PD, 37 non-mutated PD, and 40 controls were recruited; α-synuclein levels in plasma, exosomes, and peripheral blood mononuclear cells were analyzed, GCase and main GCase-related lysosomal proteins in peripheral blood mononuclear cells were measured.

Results: Assessment of plasma and exosomal α-synuclein levels did not allow differentiation between GBA-PD and non-mutated PD; conversely, measurements in peripheral blood mononuclear cells clearly distinguished GBA-PD from non-mutated PD, with the former group showing significantly higher α-synuclein levels, lower GCase activity, higher LIMP-2, and lower Saposin C levels.

Conclusion: We propose peripheral blood mononuclear cells as an easily accessible and manageable model to provide a distinctive biochemical profile of GBA-PD, potentially useful for patient stratification or selection in clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247888PMC
May 2021

Genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome: A Next Generation Sequencing study.

Parkinsonism Relat Disord 2021 03 2;84:82-90. Epub 2021 Feb 2.

Center for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry, Neuroscience Section, University of Salerno, Italy. Electronic address:

Objective: To perform the genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome.

Methods: A Next Generation Sequencing - based targeted sequencing of 32 genes associated to various neurodegenerative phenotypes, plus a screening for SNCA Copy Number Variations and C9orf72 repeat expansion, was applied in a cohort of 85 Italian patients presenting with parkinsonism and cognitive and/or behavioral syndrome and a positive familial history for any neurodegenerative disorder (i.e., dementia, movement disorders, amyotrophic lateral sclerosis).

Results: Through this combined genetic approach, we detected potentially relevant genetic variants in 25.8% of patients with familial parkinsonism and cognitive and/or behavioral syndrome. Peculiar phenotypes are described (Cortico-basal syndrome with APP, Posterior Cortical Atrophy with GBA, Progressive Supranuclear Palsy-like with GRN, Multiple System Atrophy with TARDBP). The majority of patients presented a rigid-bradykinetic parkinsonian syndrome, while rest tremor was less common. Myoclonic jerks, pyramidal signs, dystonic postures and vertical gaze disturbances were more frequently associated with the presence of a pathogenic variant in one of the tested genes.

Conclusions: Given the syndromic approach adopted in our study, we were able to provide a detailed clinical description of patients beyond the boundaries of specific clinical diagnoses and describe peculiar phenotypes. This observation further supports the knowledge that genetic disorders present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria defining sharp boundaries between distinct conditions.
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http://dx.doi.org/10.1016/j.parkreldis.2021.01.024DOI Listing
March 2021

Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS).

Int J Mol Sci 2021 Jan 26;22(3). Epub 2021 Jan 26.

Istituto Auxologico Italiano IRCCS, Bioinformatics and Statistical Genomics Unit, Cusano Milanino, 20095 Milano, Italy.

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. , , and gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.
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http://dx.doi.org/10.3390/ijms22031190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866060PMC
January 2021

Posterior Cortical Atrophy phenotype in a GBA N370S mutation carrier: a case report.

BMC Neurol 2021 Jan 12;21(1):17. Epub 2021 Jan 12.

Center for Neurodegenerative diseases (CEMAND), Department of Medicine, Surgery and Dentistry, Neuroscience section, University of Salerno, Baronissi, Salerno, Italy.

Background: Glucocerebrosidase (GBA) heterozygous variants are the most important genetic risk factor for the development of alpha-synucleinopathies (i.e., Parkinson's disease and Dementia with Lewy Bodies). Herein, we report for the first time on a patient with a clinical diagnosis of Posterior Cortical Atrophy, carrier of the common GBA heterozygous variant N370S (c.1226A > G).

Case Presentation: A 44-year-old woman with positive familial history for Dementia with Lewy Bodies disclosed three related signs characterizing the Balint's syndrome: ocular apraxia, optic ataxia and simultanagnosia. Over 2-year follow up, overt gaze apraxia (psychic paralysis of gaze) appeared leading to functional blindness. Given her young age at onset and positive familial history, she underwent a next-generation-sequencing (NGS) based screening of a panel of 32 genes related to neurodegenerative conditions within the ANAMNESYS (An origiNal Approach to study faMiliarity in NEurodegenerative SYndromeS) study. NGS demonstrated the N370S variant in the GBA gene (rs76763715), confirmed by Sanger sequencing. This is a relatively common variant, with predicted mild impact, already reported to occur in 2.4% of PD Italian patients; however, neither this nor other GBA variants have ever been reported to date in patients with Posterior Cortical Atrophy. Glucocerebrosidase activity was investigated and found to be significantly reduced (4.72 nmol/h/mg) compared to healthy controls as well as patients affected by neurodegenerative diseases, further supporting pathogenicity of the GBA variant.

Conclusions: We report on a patient with a clinical diagnosis of Posterior Cortical Atrophy, carrier of the GBA heterozygous variant N370S (c.1226A > G; p.Asn409Ser) determining reduced GCase activity. This report also confirms the role of NGS-based targeted gene analysis in detecting peculiar clinical phenotypes associated with known pathogenic mutations and reinforces the knowledge that carriers of genetic variants often present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria in defining boundaries between distinct conditions and the difficulties of clinicians in reaching the best clinical diagnosis.
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http://dx.doi.org/10.1186/s12883-020-02023-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802182PMC
January 2021

Mitochondria and Parkinson's disease: a complex (III) liaison.

Brain 2020 12;143(11):3175-3178

IRCCS Mondino Foundation, Pavia, Italy.

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http://dx.doi.org/10.1093/brain/awaa324DOI Listing
December 2020

Visual Evoked Potentials in Joubert Syndrome: A Suggested Useful Method for Evaluating Future Approaches Targeted to Improve Visual Pathways' Function.

Adv Ther 2021 01 24;38(1):278-289. Epub 2020 Oct 24.

Department of Surgical and Clinical, Diagnostic and Pediatric Sciences, Section of Ophthalmology, University of Pavia, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

Introduction: Joubert syndrome (JS) is a recessive disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features including optic nerve morphologic abnormalities. The function of the visual pathways, including the optic nerve, can be objectively evaluated by visual evoked potential (VEP) recordings. Our work aims to employ VEP to evaluate the neural conduction along the visual pathways in JS patients with or without optic nerve morphologic abnormalities (ONMA).

Methods: In this observational and prospective study, 18 children with genetic diagnosis of JS (mean age 8.78 ± 5.87 years) and 17 healthy age-similar control subjects (control group, 9.05 ± 6.02 years) were enrolled. Based on presence/absence of ONMA at fundus examination, JS patients were divided into two groups: the JS-A group (eight patients with ONMA) and JS-N group (ten patients without ONMA). Following the ISCEV standards, pattern VEPs were recorded in patients and controls in response to 60' and 15' checks to obtain a prevalent activation of large or small axons, respectively.

Results: Compared to controls, both the JS-A and JS-N groups showed significant abnormalities in 60' and 15' VEP implicit time and amplitude. Only in the JS-N group were values of 15' VEP implicit significantly correlated with the corresponding values of visual acuity.

Conclusions: Our results suggest that a visual pathways dysfunction (of both large and small axons) detectable by VEP may occur in JS patients regardless of the presence of ONMA. Since clinical trials are envisaged in the near future to address JS-related ocular problems, our results might provide information about the potential usefulness of VEP recordings to assess the efficacy of treatments targeted to improve the visual pathways' function.
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http://dx.doi.org/10.1007/s12325-020-01534-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854410PMC
January 2021

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism.

Brain 2020 10;143(10):3041-3051

Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.

There is increasing evidence for a role of inflammation in Parkinson's disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson's disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson's disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson's disease patients. These results highlight the potential of IL6 as progression marker in Parkinson's disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson's disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson's disease and Parkinson's disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson's disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson's disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson's disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson's disease, at least in this subset of patients.
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http://dx.doi.org/10.1093/brain/awaa246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586086PMC
October 2020

Generation of induced pluripotent stem cell (iPSC) lines from a Joubert syndrome patient with compound heterozygous mutations in C5orf42 gene.

Stem Cell Res 2020 12 22;49:102007. Epub 2020 Sep 22.

Angelo Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Italy.

We have generated new disease-specific induced pluripotent stem cell (iPSC) lines from skin fibroblasts obtained from a female patient with Joubert syndrome (JS) caused by compound heterozygous mutations in C5orf42 gene. The generated iPSCs offer an unprecedented opportunity to obtain iPSC-derived neurons to investigate the pathogenesis of JS in vitro and to develop therapeutic strategies.
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http://dx.doi.org/10.1016/j.scr.2020.102007DOI Listing
December 2020
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