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Mutations inLRRK2represent the most common causes of Parkinson's disease (PD) identified to date, but their penetrance is incomplete and probably due to the presence of other genetic or environmental factors required for development of the disease. We analyzed the presence ofparkinsequence variants (mutations or polymorphisms) and exon rearrangements inLRRK2mutations carriers (both PD patients and unaffected relatives) in order to detect a possible modifier effect on penetrance. Eight familiesdoi:10.4061/2010/537698 pmid:20976090 pmcid:PMC2957242 fatcat:am4bv6ucevbxvkyvldxssm5oae
more »... ith nine PD patients with heterozygousLRRK2mutations (identified within 380 Sardinian PD patients screened for the presence of the five most commonLRRK2mutations) and sixteen additional relatives were genetically investigated for the presence ofLRRK2andparkinmutations. No evidence was found for the presence of pathologicalparkinmutations or exon rearrangements in patients or not affected family members. Three single-nucleotide polymorphisms (SNPs) were identified both in patients and unaffected relatives but did not significantly differ between the two groups. These data provide no support to the hypothesis whereby suchparkingene mutations may be commonly implicated in possible effect on penetrance inLRRK2mutation carriers.
Cat scratch disease (CSD) is a world-wide, diffuse, non-epidemic infection caused by the Gram-negative bacillus Bartonella henselae. The occurrence of encephalopathy represents an infrequent and atypical complication, whose manifestations include ischemic strokes, transverse myelitis and epileptic seizures. Status epilepticus has been described as the most frequent emergency in CSD encephalopathy. In this report, we describe a case of CSD complicated by an epilepsia partialis continua (EPC)doi:10.1016/s1059-1311(03)00159-6 pmid:15010059 fatcat:fwdvkh6jgjc6hmk5yqyaqlhkvy
more »... fested as rhythmic movements of the flexor muscles of the left hand. Although CSD is a benign, self-limited disease and a complete neurological recovery usually occurs, in the present case the EPC resulted in a partial epilepsy. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and back-averaged EEG data recorded during myoclonic activity document this CSD complication.
Recent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-a-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride (FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose-and time-dependentlydoi:10.1038/npp.2008.39 pmid:18354385 fatcat:cwwzc3gxkvekfigxpuklzefqbi
more »... ized prepulse inhibition (PPI) deficits induced by apomorphine (APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine (AMPH, 5 mg/kg, s.c.), in a manner analogous to haloperidol (HAL, 0.1 mg/kg, i.p.) and clozapine (CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride (DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 (30 mg/kg, i.p.). FIN (60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH (1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO (0.25 mg/kg, s.c.). Nevertheless, FIN (100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine (0.1 mg/kg, s.c.). FIN (60-300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.
Purpose: Drug resistance is a critical issue in the treatment of epilepsy, contributing to clinical emergencies and increasing both serious social and economic burdens on the health system. The wide variety of potential drug combinations followed by often failed consecutive attempts to match drugs to an individual patient may mean that this treatment stage may last for years with suboptimal benefit to the patient. Given these challenges, it is valuable to explore the availability of newdoi:10.3389/fneur.2017.00459 pmid:28928712 pmcid:PMC5591409 fatcat:b5uhm5wisvfytdlbmuixgbsdcq
more »... ogies able to shorten the period of determining a rationale pharmacologic treatment. Metabolomics could provide such a tool to investigate possible markers of drug resistance in subjects with epilepsy. Methods: Blood samples were collected from (1) controls (C) (n = 35), (2) patients with epilepsy "responder" (R) (n = 18), and (3) patients with epilepsy "non-responder" (NR) (n = 17) to the drug therapy. The samples were analyzed using nuclear magnetic resonance spectroscopy, followed by multivariate statistical analysis. Key findings: A different metabolic profile based on metabolomics analysis of the serum was observed between C and patients with epilepsy and also between R and NR patients. It was possible to identify the discriminant metabolites for the three classes under investigation. Serum from patients with epilepsy were characterized by increased levels of 3-OH-butyrate, 2-OH-valerate, 2-OH-butyrate, acetoacetate, acetone, acetate, choline, alanine, glutamate, scyllo-inositol (C < R < NR), and decreased concentration of glucose, lactate, and citrate compared to C (C > R > NR). significance: In conclusion, metabolomics may represent an important tool for discovery of differences between subjects affected by epilepsy responding or resistant to therapies and for the study of its pathophysiology, optimizing the therapeutic resources and the quality of life of patients.
Journal of Neurology
From 2006, a locus on chromosome 9p21 has been associated with a large proportion of ALS and FTD    . Recently, two independent groups have identified a hexanucleotide repeat expansion in noncoding region of the C9ORF72 gene as the cause of chromosome 9p21-linked ALS-FTD [4, 5] . We report the case of a 64-year-old man who presented with a 3-year history of delusional mystic thoughts, auditive, visual, and olfactory hallucinations, and hyperreligiosity. The patient later developeddoi:10.1007/s00415-012-6444-3 pmid:22323211 pmcid:PMC4164047 fatcat:qkq3bha7zrdlbkavwckshyudiq
more »... essive apathy, dysphoric mood, hyperphagia, self-care reduction, and progressive cognitive decline with motor retardation. The man's father had died at age 68 after committing suicide, and his older brother developed parkinsonism associated with behavioral disturbances at age 60 and died 2 years later. Neuropsychological assessment of this patient, performed 3 years after the onset of neurological symptoms, demonstrated bradyphrenia, marked impairment of attention and executive functions, marked constructional apraxia, mild visual and verbal long-term memory deficit, mild anomia, emotional lability, fatuity, and mild utilization behavior. Blood exams, thyroid antibodies and hormones, vitamin B12, folic acid, and TPHA were all normal. Neurological examination revealed symmetric akinetic-rigid syndrome characterized by hypomimia, dysarthria, camptocormia with anterocollis, and diffuse bradykinesia. Brain MRI documented atrophy mainly frontotemporal but with consistent posterior region involvement (Fig. 1 ). Perfusion SPECT with 99 Tc-ethylene cystine dimer (ECD) showed a marked reduction of the uptake in the frontotemporal and parietal regions bilaterally (Fig. 1) . A few months after the first neurological assessment, the patient had a rapid progression to a severe dementia and developed marked pyramidal involvement of upper and lower limbs with an inability to walk. The patient became anarthric, dysphagic, and developed constipation. The nature of the dysarthria was both pseudobulbar and extrapyramidal. Lower motor neuron signs or symptoms were not present. Later the patient was admitted to a surgical department for intestinal sub-occlusion; during the hospitalization, a pulmonary embolism (PE) occurred. The patient died 4 years after the first neurological manifestations. Mutations of TARDBP, MAPT, and PGRN genes were excluded. The patient has been found positive for a GGGGCC hexanucleotide repeat expansion in the first intron of C9ORF72 gene (>50). Our patient developed a dementia with prominent behavioral disturbances at presentation, characterized mostly by psychosis with mystic themes. The neuropsychological evaluation Floris et al.
Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases.doi:10.1016/j.neurobiolaging.2015.06.013 pmid:26208502 pmcid:PMC5193218 fatcat:u3icmtjvxzalvnck5gi2laxvqy
more »... e frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival.
Cerebrovascular diseases are considered among possible causes of acute/subacute parkinsonism, representing up to 22% of secondary movement disorders. In cases of suspected vascular parkinsonism (VP), dopamine transporter SPECT has been highly recommended to exclude nigrostriatal dopaminergic degeneration. We report the case of a hemiparkinsonism related to a left midbrain infarct with focal lateralized putaminal abnormalities at123I-FP-CIT SPECT imaging. The asymmetric uptake at dopaminedoi:10.1155/2015/642764 pmid:26550502 pmcid:PMC4624914 fatcat:utht4dovqrfqjpydm2bgzea7ay
more »... rter SPECT was different to findings commonly observed in typical PD pattern, because the ipsilateral striatum, in opposite to idiopathic PD, showed normal tracer binding. However, this selective parkinsonism after infarction of the midbrain was responsive to levodopa. In conclusion, we retain that there is a need of more functional imaging studies in VP addressed to a more consistent classification of its different clinical forms and to a better understanding of the adequate pharmacological management.
Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic ALS provide unique information on the genetics of the disease. Our aim was to describe the genetic profile of a consecutive series of ALS patients of Sardinian ancestry. All ALS patients of Sardinian ancestry, identified between 2008 and 2013 through the ITALSGEN consortium, were eligible to be included in the study. Patients and controls underwent the analysis of TARDBP, C9ORF72, SOD1, and FUS genes.doi:10.1016/j.neurobiolaging.2014.07.012 pmid:25123918 pmcid:PMC4252367 fatcat:oibsuz4fkzcchctk3uohkybcme
more »... netic mutations were identified in 155 out of 375 Sardinian ALS cases (41.3%), more commonly the p.A382T and p.G295S mutations of TARDBP, and the GGGGCC hexanucleotide repeat expansion of C9ORF72. One patient had both p.G295S and p.A382T mutation of TARDBP and eight carried both the heterozygous p.A382T mutation of TARDBP and a repeat expansion of C9ORF72. Patients carrying the p.A382T and the p.G295S mutations of TARDBP and the C9ORF72 repeat expansion shared distinct haplotypes across these loci. Patients with co-occurrence of C9ORF72 and TARDBP p.A382T missense mutation had a significantly lower age at onset and shorter survival. More than 40% of all cases on the island of Sardinia carry a mutation of an ALS-related gene, representing the highest percentage of ALS cases genetically explained outside of Scandinavia. Clinical phenotypes associated with different genetic mutations show some distinctive characteristics, but the heterogeneity between and among families carrying the same mutations implies that ALS manifestation is influenced by other genetic and non-genetic factors.
The past decade has seen extraordinary increase in worldwide availability of and access to several large multiple sclerosis (MS) databases and registries. MS registries represent powerful tools to provide meaningful information on the burden, natural history, and long-term safety and effectiveness of treatments. Moreover, patients, physicians, industry, and policy makers have an active interest in real-world observational studies based on register data, as they have the potential to answer thedoi:10.1007/s10072-018-3610-0 pmid:30426289 fatcat:pmcocohjefaxzkxi3qrwznxlga
more »... uestions that are most relevant to daily treatment decision-making. In 2014, the Italian MS Foundation, in collaboration with the Italian MS clinical centers, promoted and funded the creation of the Italian MS Register, a project in continuity with the existing Italian MS Database Network set up from 2001. Main objective of the Italian MS Register is to create an organized multicenter structure to collect data of all MS patients for better defining the disease epidemiology, improving quality of care, and promoting research projects in high-priority areas. The aim of this article is to present the current framework and network of the Italian MS register, including the methodology used to improve the quality of data collection and to facilitate the exchange of data and the collaboration among national and international groups.
MARIA GIOVANNA MARROSU,1 MARIA RITA MURRU,1 GIANNA COSTA,1 FRANCESCO CUCCA,2 STEFANO SOTGIU,3 GIULIO RoSATI,3 AND FRANCESCO MUNTONIl.* 'Clinic of Child Neuropsychiatry, Department of Neuroscience, University ... The present study, performed with a group of MS patients totally different from those studied elsewhere (Marrosu et al. 1988) , confirms the previously reported MS-DR4 association in Sardinians (Marrosu ...doi:10.1086/524852 pmid:9311753 pmcid:PMC1715886 fatcat:jubb2pxigjglnfrleja2bfv3q4
The identification of noninvasive biomarkers to monitor the disease progression in spinal muscular atrophy (SMA) is becoming increasingly important. MicroRNAs (miRNAs) regulate gene expression and are implicated in the pathogenesis of neuromuscular diseases, including motor neuron degeneration. In this study, we selectively characterized the expression of miR-9, miR-206, and miR-132 in spinal cord, skeletal muscle, and serum from SMA transgenic mice, and in serum from SMA patients. A systematicdoi:10.1038/mtna.2016.47 pmid:27377135 pmcid:PMC5014531 fatcat:u2ie57hannesvhyzuzvqv4scbi
more »... analysis of miRNA expression was conducted in SMA mice with different disease severities (severe type I-like and mild type IIIlike) at different disease stages (pre-, mid-, and late-symptomatic stages), and in morpholino antisense oligonucleotide-treated mice. There was differential expression of all three miRNAs in spinal cord, skeletal muscle and serum samples in SMA mice. Serum miRNAs were altered prior to the changes in spinal cord and skeletal muscle at the presymptomatic stage. The altered miR-132 levels in spinal cord, muscle, and serum transiently reversed to normal level after a single-dose morpholino antisense oligomer PMO25 treatment in SMA mice. We also confirmed a significant alteration of miR-9 and miR-132 level in serum samples from SMA patients. Our study indicates the potential of developing miRNAs as noninvasive biomarkers in SMA.
Paraphilias are intense urges or behaviors involving non-normative sexual interests. The newly approved diagnostic criteria in the DSM-5 have established that, while paraphilias should not be regarded as inherently pathological, they ought to be qualified as paraphilic disorders if resulting in distress, impairment or harm to the affected individual or others. Recent evidence documents that both phenomena can emerge as relatively uncommon iatrogenic consequences in Parkinson's disease (PD)doi:10.1002/mds.26157 pmid:25759330 pmcid:PMC4428164 fatcat:vgjc6mmbnzf3bjnguusig46t44
more »... nts. To outline the clinical characteristics of paraphilias and paraphilic disorders in PD patients, we summarized the available evidence on these phenomena. The review encompasses all studies on paraphilias in PD patients identified by a search on the Pubmed and Scopus online databases through May 2014. Twenty-two case reports on a total of 31 PD patients with paraphilias and/or paraphilic disorders were identified. These phenomena were typically associated with dopaminomimetic treatment (with a mean levodopa-equivalent daily dose of 1303±823 mg/day) in male patients with motor complications, young age at PD onset and long disease duration. Paraphilias were highly concomitant with impulse-control disorders and/or dopamine dysregulation syndrome. Although evidence on paraphilias and paraphilic disorders in PD patients remains anecdotal, available data point to these phenomena as likely sequelae of highdose dopaminomimetic treatment. Accordingly, the intensity of paraphilic urges is typically attenuated by the reduction of dopaminomimetic doses, sometimes in association with atypical antipsychotics. Failure to recognize paraphilic disorders may significantly impair the relational
Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigateddoi:10.1371/journal.pone.0155032 pmid:27163330 pmcid:PMC4862622 fatcat:g7lk74knjrh5zesxm4gjaqoohu
more »... the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.
the northern et al. 1988), confirms the previously reported MS-DR4 association in Sardinians (Marrosu et al. 1988 ) and or central part of the island. ... Hum Hered 31:312-321 genes involved in immune mechanisms -in particular, Lathrop GM, Lalouel JM (1984) Easy calculations of LOD on HLA genes (Haegert and Marrosu 1994). ... Haegert DG, Marrosu MG (1994) Clinic of Child Neuropsychiatry, Department of Ebers GC, Johnson KP, et al (1983) University of Sassari, Sassari in Europe in the 1980s: a critical overview. ...doi:10.1016/s0002-9297(07)64074-9 pmid:9311753 pmcid:PMC1715886 fatcat:prfy65qrnnblvpmz3rv5jr5npa
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