Search

Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) 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.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant condition, characterized by the presence of unexplained left ventricular hypertrophy. This condition is usually associated with electrocardiographic abnormalities including QTc prolongation reported in the 13% of HCM patients. The main explanation for QTc prolongation in HCM is myocardial hypertrophy and the related structural damage. However, mechanisms other than myocardial hypertrophy, including long QT syndrome (LQTS) gene mutations, may also be involved. The addictive effect of 2 disease-causing mutations has been already reported in other pathological conditions. In the present study we investigated the possible co-inheritance of pathogenic variants associated with both LQTS and HCM, exploring the hypothesis of a distinct genetic basis underlying QTc prolongation in HCM. For this purpose, we considered a cohort of 150 HCM patients carrying pathogenic variants in sarcomeric genes. Out of them we selected 25 patients carrying a QTc prolongation not explained by any other cause (drugs, etc). The QTc was considered prolonged if greater than 450 ms in males and greater than 470 ms in females. NGS analysis was performed with Illumina TrueSight Cardio panel genes on Illumina MiniSeq platform to evaluate the presence of pathogenetic variants in LQTS related genes. We identified pathogenic/likely pathogenic variants in LQTS related gene KCNQ1 (c.1781G>A, p. Arg594Gln; c.532G>A, p. Ala178Thr) in two patients (8%) and uncertain significant variants in SCN5A, KCNJ5, AKAP9 and ANK2 in four patients (16%). Although the results of our study are limited by the small number of patients included in the analysis, they highlight a minor contribution of LQTS genes in HCM patients with a QTc prolongation. The screening for ion channel gene mutations should be considered in HCM patients with QTc prolongation, not explained by any other cause. This strategy may be important for risk stratification and treatment planning.

Background: It is a well-known fact that the information obtained from a survey can be used in a healthcare organizational analysis; however, it is very difficult to compare the different results found in the literature to each other, even through the use of metanalysis, as the methodology is often not consistent. Methods: Data from a survey analyzing the organizational and managerial responses adopted in pathology-specific clinical pathways (CPs) during the first two waves of the COVID-19 pandemic were used for constructing a decisional matrix, a tool called SPRIS system, consisting of four different sheets. The first sheet reports the results of the survey and, using a streetlight color system, identifies strengths and weaknesses; the second one, by assigning a priority score, establishes the priority of intervention on each of the strengths and weaknesses identified; the third sheet reports the subjective items of the questionnaire in order to identify threats and opportunities and their probability of happening; in the last sheet, a SWOT Analysis is used to calculate the performance index of the whole organization. Results: The SPRIS system, applied to data concerning the adaptation of four CPs to the COVID-19 pandemic, showed that, whereas all the CPs had a good performance index, some concerns remained unsolved and need be addressed. Conclusions: The SPRIS system showed to be an easily constructed tool that is able to give an overview of the organization analyzed by the survey and to produce an index that can be used in a direct quality comparison between different services or organizations.

Hypertrophic cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are inherited diseases characterized by a wide genetic heterogeneity. Based on the separate incidence of these pathologies and on the absence of linkage, the occurrence of both diseases in the same individual has an incidence of about 1/250000. We describe a rare case report of a 24 years-old patient with maternal familiarity for type 1 LQTS (mother carrier of KCNQ1 c.1781G>A) and paternal familiarity for HCM (father carrier of TNNI3 c.592C>G mutation) who inherited both gene mutations and was diagnosed with HCM and LQTS later in adolescence, after clinical and genetic evaluations.

Objective The main limitation of neuromodulation techniques is inter-subject variability. Combining theta-burst stimulation (TBS) with gamma-transcranial alternating current stimulation (γ-tACS) allows to shape cortical plasticity. However, it is unknown whether γ-tACS modifies TBS-induced response variability. In this study, we measured the inter-subject variability of TBS-γ tACS and controlled the effect of the Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism. Methods Intermittent TBS (iTBS)-sham tACS, iTBS-γ tACS, continuous TBS (cTBS)-sham tACS, and cTBS-γ tACS were applied in randomised sessions. Inter-subject variability was measured using grand average and clustering methods. TBS-γ tACS effects on motor evoked potentials (MEP) were compared between Val/Val and Met carriers. Results We found that γ-tACS boosted iTBS-induced MEP facilitation and cancelled cTBS-induced MEP depression. Grand average analysis showed that γ-tACS prominently increased the percentage of iTBS responders and cTBS non-responders. The clustering method demonstrated that TBS-γ tACS response varied between subjects, a phenomenon unrelated to the BDNF genotype. Conclusions Enhancing γ oscillations through tACS boosts iTBS-induced LTP-like plasticity and suppresses cTBS-induced LTD-like plasticity of the primary motor cortex in a reliable manner. The BDNF Val66Met polymorphism does not influence these effects. Significance Since γ-tACS significantly increases the number of iTBS responders, it may be used in clinical settings.

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by hyperplastic polyps in the upper and lower gastrointestinal (GI) tract with a high risk of developing GI cancers. We have described a three-generation Italian family with all the spectrum of SMAD4 phenotype. A multigene panel test was performed on the genomic DNA of the proband by next-generation sequencing, including genes related to hereditary GI tumor syndromes. Molecular analysis revealed the presence of the c.1140-2A>G substitution in the SMAD4 gene, a novel splice variant that has never been described before. Our family is remarkable in that it illustrates the variable expressivity of the SMAD4 phenotype within the same family. The possibility of phenotype variability should also be considered within family members carrying the same mutation. In JPS, a timely genetic diagnosis allows clinicians to better manage patients and to provide early surveillance and intervention for their asymptomatic mutated relatives in the early decades of life.

We describe the unusual presentation of familial early-onset gastric cancer due to a heterozygous pathogenic variant in the ATM gene. The proband had gastric cancer (age 45), and reported a sister deceased for diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next Generation Sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, TP53) identified the truncating c.5944C>T, p.(Gln1982*) variant in ATM (NM_000051.3; NP_000042.3) in the proband. The variant segregated in the living affected sister and in the unaffected daughter of the deceased sister. Heterozygous ATM variants appear to significantly increase the risk for pancreatic, breast, gastric and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. Familial gastric cancer is an unusual presentation for ATM. The occurrence of gastric cancer in this family suggests that individual variants may result in different, specific risks. Genotype-phenotype correlations are challenging, given the low penetrance and variable expressivity for ATM variants. Careful family history assessment is pivotal for prevention planning, strengthened by the availability of molecular diagnoses.

Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or multiplex ligation-dependent probe amplification and qPCR. Eighty-seven disease-causative variants (55 novel and 32 known) were identified including frameshift (42%), nonsense (32%), missense (11%), splicing (10%) variants and genomic rearrangements (5%). Informative clinical features were available for 42 EXT1 and 27 EXT2 subjects. Osteochondromas were more frequent in EXT1 as compared to EXT2 patients. Anatomical distribution of lesions showed significant differences based on causative gene. Microscopy analysis for selected EXT1 and EXT2 variants verified that EXT1 and EXT2 mutants failed to co-localize each other and loss Golgi localization by surrounding the nucleus and/or assuming a diffuse intracellular distribution. In a cell viability study, cells expressing EXT1 and EXT2 mutants proliferated more slowly than cells expressing wild-type proteins. This confirms the physiological relevance of EXT1 and EXT2 Golgi co-localization and the key role of these proteins in the cell cycle. Taken together, our data expand genotype-phenotype correlations, offer further insights in the pathogenesis of HMO and open the path to future therapies.

QTc prolongation is reported in patients with hypertrophic cardiomyopathy (HCM). However, the causes of the QTc interval increase remain unclear. The main contribution to QTc prolongation in HCM is attributed to the myocardial hypertrophy and related structural damage. In a 24-year-old male proband, affected by HCM and long QTc, we identified by Next Generation Sequencing a pathogenic variant in gene TNNI3 co-inherited with a damaging variant in KCNQ1 gene. This evidence suggests the possibility that QTc interval prolongation and its dispersion in HCM could be associated not only to the severity of left ventricular hypertrophy but also to the co-inheritance of pathogenic variants related to both long QT Syndrome (LQTS) and HCM. Although the simultaneous presence of pathogenic variants in genes related to different heart diseases is extremely rare, counseling and genetic testing appear crucial for the clinical diagnosis. Screening of LQTS genes should be considered in HCM patients to clarify the origin of long QTc, to provide more information about the clinical presentation and to evaluate the incidence of the co-existence of LQTS/HCM gene variants that could occur more frequently than so far reported.

The identification of the p.A53T mutation in the SNCA gene encoding alpha-synuclein (alpha-syn), as causative of autosomal dominant Parkinson disease (PD) represented a fundamental milestone, which paved the way to the extremely prolific field of PD genetics. Despite being the oldest player in this field and only a rare cause of inherited PD, research on alpha-syn has remained incredibly active over nearly twenty decades, leading to identify alpha-syn aggregation as a key mechanism in PD pathogenesis. The past two years have witnessed new exciting findings, with the discovery of at least three novel pathogenic mutations (p.H50Q, p.G51D and p.A53E) causative of complex parkinsonian phenotypes, and the identification of additional patients carrying "old" SNCA mutations (p.A53T, p.A30P, p.E46K and whole gene multiplications), which has allowed to further expand their phenotypic spectrum. This review aims at providing a clinical and functional update on the most recent findings in alpha-syn genetics, at the same time discussing novel avenues of SNCA research such as those on somatic mutations and epigenetic mechanisms.

Background Mutations in the PINK1 gene are the second most frequent cause of autosomal recessive early-onset parkinsonism. Methods We evaluated five affected PINK1 homozygous and 14 heterozygous mutation carriers from two large Italian families over a 12-year follow-up period. Motor, nonmotor, cognitive, psychiatric, and behavioral profiles were systematically assessed. Four homozygotes and eight heterozygotes underwent magnetic resonance imaging. Results All homozygotes showed a mild progression of motor signs and a persistent excellent response to levodopa. All but one patient complained of nonmotor symptoms and sleep impairment. Three presented impulse control disorders and two anxiety and apathy. All obtained abnormal scores at Montreal Cognitive Assessment (MoCA) and in tests sensitive to frontal functions; one presented a global cognitive impairment. Three heterozygotes showed motor signs and were diagnosed as possibly affected. They had nonmotor symptoms and cognitive impairment, and two of them showed mild bilateral temporal atrophy. Five unaffected heterozygotes reported abnormal scores at MoCA and low performances at tests sensitive to frontal functions. Conclusion We expanded the phenotypic profile of PINK1-related parkinsonism, including psychiatric and cognitive features as part of clinical presentation. © 2014 International Parkinson and Movement Disorder Society

BackgroundVariants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. ConclusionsEstablishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. (c) 2013 International Parkinson and Movement Disorder Society (Less)

Background Multiplications of the SNCA gene that encodes alpha-synuclein are a rare cause of autosomal dominant Parkinson's disease (PD). Methods Here, we describe 2 novel families in which there is autosomal dominant PD associated with SNCA duplication, and we compare the clinical features of all known patients carrying 3 or 4 SNCA copies. Results Affected members in family A presented with early onset PD that was variably associated with nonmotor features, such as dysautonomia, cognitive deficits, and psychiatric disturbances. In family B, the clinical presentation ranged from early onset PD-dementia with psychiatric disturbances to late onset PD with mild cognitive impairment. Conclusions The presence of 4 SNCA copies is associated with a rich phenotype, characterized by earlier onset of motor and nonmotor features compared with patients who bear 3 SNCA copies. The clinical spectrum associated with SNCA duplications is wide, even within a single family, suggesting a role for as yet unidentified genetic or environmental modifiers. © 2013 Movement Disorder Society

To study prevalence, specific patterns and response to treatment of tremor in dementia with Lewy bodies (DLB), in comparison with other tremulous disorders prevalence, qualitative and quantitative features of tremor were studied in an incident cohort of 67 dopaminergic treatment naive DLB, 111 Parkinson’s Disease (PD) and 34 Essential Tremor (ET) patients. Tremulous DLB patients (tDLB) were compared with tremulous PD (tPD) and ET patients and followed for 2 years. Double blind placebo-controlled acute drug challenge with l-Dopa and alcohol was performed in all ET, 24 tDLB and 27 tPD. Effects of dopaminergic chronic treatment in all tDLB and tPD patients and primidone in 8 tDLB were also assessed. Tremor occurred in 44.76 % of DLB patients. The tDLB patients presented a complex pattern of mixed tremors, characterized by rest and postural/action tremor, including walking tremor and standing overflow in 50 % tDLB. Standing tremor with overflow was characteristic of tDLB (p

Objective: The aim of this multicenter, case-control study was to investigate the prevalence and severity of impulsive-compulsive behaviors (ICBs) in a cohort of patients with parkin -associated Parkinson disease (PD) compared to a group of patients without the mutation. Methods: We compared 22 patients with biallelic parkin mutations (parkin-PD) and 26 patients negative for parkin , PINK1 , DJ-1 , and GBA mutations (PD-NM), matched for age at onset, disease duration, levodopa, and dopamine agonist equivalent daily dose. A semistructured interview was used to diagnose each of the following ICBs: compulsive sexual behavior, compulsive buying, binge eating, punding, hobbyism, and compulsive medication use. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson9s Disease–Rating Scale (QUIP-RS) was adopted to rate ICB severity. Results: Frequency of patients with at least one ICB was comparable between parkin-PD and PD-NM. Nevertheless, when analyzing the distribution of specific ICBs, a higher frequency of compulsive shopping, binge eating, and punding/hobbyism was found in the parkin-PD group. Compared to PD-NM, parkin-PD patients with ICB had younger onset age and higher frequency of smokers; in 5 patients, ICB had predated PD onset. Total and partial (compulsive buying, compulsive sexual behavior, binge eating, hobbyism/punding) QUIP-RS scores were higher in patients with parkin-PD compared to patients with PD-NM. Logistic regression analysis showed that the presence of parkin mutations was associated with smoking status and higher QUIP-RS total score. Conclusions: Our data expand the parkin -associated phenotypic spectrum demonstrating higher frequency and severity of specific ICBs, and suggesting an association between the parkin genotype, smoking status, and ICB severity.

Fattouch J, Di Bonaventura C, Casciato S, Bonini F, Petrucci S, Lapenta L, Manfredi M, Prencipe M, Giallonardo AT. Intravenous Levtiracetam as first-line treatment of status epilepticus in the elderly. Acta Neurol Scand: 2010: 121: 418–421. © 2010 John Wiley & Sons A/S. Background – Status epilepticus is a condition of prolonged/repetitive seizures that often occurs in the elderly. Treatment in the elderly can be complicated by serious side effects associated with traditional drugs. Objective – The aim of this pilot study was to evaluate the short-term efficacy/safety of intravenously administered LEV (IVLEV) as the treatment of choice for SE in the elderly. Methods – We enrolled nine elderly patients (five female/four male; median age 78 years) with SE. Two patients had a previous diagnosis of epilepsy; in the remaining seven, SE was symptomatic. SE was convulsive in five and non-convulsive in four. All the patients presented concomitant medical conditions (arrhythmias/respiratory distress/hepatic diseases). As the traditional therapy for SE was considered unsafe, IVLEV was used as first-line therapy (loading dose of 1500 mg/100 ml/15 min, mean maintenance daily dose of 2500 mg/24 h) administered during video-EEG monitoring. Results/conclusions – In all the patients but one, IVLEV was effective in the treatment of SE and determined either the disappearance of (7/8), or significant reduction in (1/8), epileptic activity; no patient relapsed in the subsequent 24 h. No adverse events or changes in the ECG/laboratory parameters were observed. These data suggest that IVLEV may be an effective/safe treatment for SE in the elderly.

Summary Purpose: Diffusion-weighted magnetic resonanceimaging(DWI)isusedtodetectchangesinthedis-tribution of water molecules in regions affected byvarious pathologies. Like other conditions, ictalepileptic activity, such as status epilepticus (SE),can cause regional vasogenic/cytotoxic edemathat reflects hemodynamic and metabolicchanges. This study describes the electroclinicaland neuroimaging findings in 10 patients with par-tial SE whose DWI evaluation disclosed periictalchangesrelatedtosustainedepilepticactivity.Patients and Methods: In this retrospective studywe selected 10 patients with partial SE of differentetiologies (six acute symptomatic SE; four withprevious epilepsy and concomitant precipitatingfactors) who underwent video-EEG (electroen-cephalography) monitoring and a DWI studyduring the periictal phase. We analyzed ictal elec-troclinical features and DWI changes in the acutephaseandduringthefollow-upperiod.Results: DWI images revealed significant signalalterations in different brain regions depending onthe location of ictal activity. DWI changes werehighly concordant with the electroclinical findingsin all 10 patients. As the SE resolved and the clini-cal conditions improved, DWI follow-up showedthat the signal alterations gradually disappeared,thereby documenting their close relationship withictalactivity.Conclusions: This study confirms the usefulness ofDWI imaging in clinical practice for a more accu-rate definition of the hemodynamic/metabolicchanges occurring during sustained epilepticactivity.KEY WORDS: DWI, Status epilepticus, Epilepsy,Neuroimaging.Many neuroimaging techniques disclose in vivochangesintheregion involvedbyepilepticactivityduringprolonged seizures or status epilepticus (SE). Thesechangesare caused by factorssuch as increased metabolicactivity, the consequent ictal hyperperfusion (often fol-lowed by postictal hypoperfusion), and some transientultrastructural pathologic alterations, all of which reflectthesustainedelectricalactivityofepilepticneurons.Sinceictalfunctionalchangeswerefirstdocumentedbyangiography(Penfield,1933),theyhavebeeninvestigatedby means of other neuroimaging techniques that explorehemodynamics perfusion computed tomography (CT),perfusion magnetic resonance imaging (PWI), functionalMRI (fMRI), single-proton emission computed tomogra-phy (SPECT)] and brain metabolism [positron emissiontomography(PET)andspectroscopy-MRI].By measuring the apparent diffusion coefficient(ADC), diffusion-weighted MRI (DWI) detects changesin the distribution of water molecules in regions affectedby various forms of epileptic activity, such as partial SE(Cole, 2004). DWI is used to investigate many brain dis-eases (namely, acute ischemic stroke, brain tumors, infec-tions, etc.), as it is sensitive to the molecular motion ofwater,ordiffusivity,anintrinsicpropertyoftissues(Grantet al., 2001). Changes in water diffusion in the epileptic

Parkinson disease (PD) is one of the most common neurodegenerative disorders. Over the past 15 years, several genes have been identified that cause PD in a Mendelian fashion, or act as susceptibility factors. Study of the protein products encoded by these genes and the pathogenetic effect related to specific mutations has greatly improved our understanding of PD, indicating many cellular pathways that, when impaired, lead to neurodegeneration. In particular, mitochondrial dysfunction and alterations in intracellular clearance mechanisms such as autophagy and the ubiquitin-proteasome system result in oxidative stress and accumulation of misfolded proteins/damaged organelles, and represent critical processes in the etiology of both familiar and sporadic PD.

Hypoglycaemia, common in diabetic patients treated with insulin, can induce various neurological disturbances. Of these, seizures are the most common acute symptom, mainly of the generalised tonic-clonic type, with focal events only exceptionally being reported and documented. Hypoglycaemia can modify cortical excitability by determining an imbalance between excitation and inhibition; some brain structures, such as the temporal lobe and hippocampus, appear to be particularly susceptible to this insult. We describe a case of a 61-year-old diabetic patient in whom insulin-induced transient hypoglycaemia triggered a focal seizure of temporal origin that was well documented by EEG during 24-hour ambulatory monitoring. This is, to our knowledge, one of the few, well-documented cases of this type of seizure.