RESUMEN
Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (â¼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that â¼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.
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Pruebas Genéticas , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Pruebas Genéticas/métodos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Glucosilceramidasa/genética , alfa-Sinucleína/genética , Predisposición Genética a la Enfermedad , Ubiquitina-Proteína Ligasas/genética , Estudios de Cohortes , Proteínas Quinasas/genética , Mutación , AdultoRESUMEN
Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.
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Predisposición Genética a la Enfermedad/genética , Miastenia Gravis/genética , Polimorfismo Genético/genética , Transducción de Señal/genética , Adulto , Femenino , Expresión Génica/genética , Frecuencia de los Genes/genética , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Músculo Esquelético/patología , Receptores Colinérgicos/genética , Receptores Nicotínicos/genéticaRESUMEN
The association of hypogonadism and cerebellar ataxia was first recognized in 1908 by Gordon Holmes. Since the seminal description, several heterogeneous phenotypes have been reported, differing for age at onset, associated features, and gonadotropins levels. In the last decade, the genetic bases of these disorders are being progressively uncovered. Here, we review the diseases associating ataxia and hypogonadism and the corresponding causative genes. In the first part of this study, we focus on clinical syndromes and genes (RNF216, STUB1, PNPLA6, AARS2, SIL1, SETX) predominantly associated with ataxia and hypogonadism as cardinal features. In the second part, we mention clinical syndromes and genes (POLR3A, CLPP, ERAL1, HARS, HSD17B4, LARS2, TWNK, POLG, ATM, WFS1, PMM2, FMR1) linked to complex phenotypes that include, among other features, ataxia and hypogonadism. We propose a diagnostic algorithm for patients with ataxia and hypogonadism, and we discuss the possible common etiopathogenetic mechanisms.
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Aminoacil-ARNt Sintetasas , Ataxia Cerebelosa , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Hipogonadismo , ARN Polimerasa III , Humanos , Ataxia Cerebelosa/genética , Ataxia/genética , Fenotipo , Hipogonadismo/genética , Hipogonadismo/patología , Mutación , Factores de Intercambio de Guanina Nucleótido/genética , Ubiquitina-Proteína Ligasas/genética , ADN Helicasas/genética , ARN Helicasas/genética , Enzimas Multifuncionales/genéticaRESUMEN
OBJECTIVE: Personality changes have often been reported among people with Parkinson's disease (PD); however, no studies have investigated the associations between personality traits, cognitive function, and specific motor symptoms. In this study, the investigators assessed whether particular personality traits were associated with specific motor subtypes of PD (e.g., tremor-dominant and akinetic-rigid phenotypes) and whether frontal-executive functions were associated with personality traits among patients with a specific motor phenotype. METHODS: Forty-one people with PD and 40 healthy control participants were enrolled in the study. All participants underwent assessments of cognitive and psychological function and personality traits. The study was conducted in Italy. RESULTS: Tremor-dominant symptoms occurred among 20 (48.8%) people with PD, whereas 21 (51.2%) patients exhibited akinetic-rigid symptoms. Multivariate analyses of variance revealed that participants with akinetic-rigid PD demonstrated significantly poorer performance on frontal-executive tests compared with those with tremor-dominant PD. Moreover, those with akinetic-rigid PD exhibited more psychopathological symptoms and higher neuroticism and introversion compared with those with tremor-dominant PD. Correlations revealed that among participants with akinetic-rigid PD, psychopathological symptoms and neuroticism and introversion personality traits were associated with frontal-executive dysfunction, whereas among those with tremor-dominant PD, no significant associations were found between personality traits and cognitive abilities. CONCLUSIONS: These findings suggest that specific personality and frontal-executive profiles are associated with the akinetic-rigid motor subtype of PD, thus helping to refine the different clinical manifestations of PD. A better understanding of the psychological, personality, and cognitive mechanisms in PD could also help to develop more targeted treatments.
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Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Temblor/etiología , Neuroticismo , Introversión Psicológica , Disfunción Cognitiva/complicacionesRESUMEN
BACKGROUND: So far, mutations in genes encoding lysosomal enzymes have been associated with Parkinson's disease (PD). Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A (α-GAL) deficiency, leading to deposition of globotriaosylceramide in the nervous system and other organs. We aimed to screen for FD a case series of PD patients from Southern Italy and to review the literature. METHODS: One hundred and forty-four consecutive unrelated PD subjects were enrolled. The α-GAL activity was measured in all men and, in case of pathological values, subsequent determination of globotriaosylsphingosine (lyso-Gb3) and GLA gene sequencing were also performed. All the women underwent GLA gene sequencing. RESULTS: α-GAL levels resulted low in fifteen men, whereas lyso-Gb3 testing showed values within the reference range in all of them. GLA gene variants were not detected in any tested subjects. One pathological study, six case series, and five case reports are currently reported in literature. CONCLUSIONS: The few studies reviewed are heterogeneous, and the results are controversial. An unknown significance variant in GLA gene was detected in PD patients in one large study, whereas decreased α-GAL activity was observed in PD subjects in two other researches, but without confirmation by lyso-Gb3 assessment or genetic analysis. Vascular parkinsonism was associated to FD in five case reports. We found no association between PD and FD in our population. However, it is not possible to draw definitive conclusions due to limited sample size. Furthermore, controls would have been missing in case of a positive finding.
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Enfermedad de Fabry , Enfermedad de Parkinson Secundaria , Enfermedad de Parkinson , Masculino , Humanos , Femenino , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , alfa-Galactosidasa/genética , Mutación/genéticaRESUMEN
BACKGROUND: Huntington's disease (HD) patients often present with abnormal modulation of blood pressure and heart rate. We investigated whether cardiac autonomic innervation assessed by 123I-metaiodobenzylguanidine (MIBG) imaging is impaired in HD patients, in comparison with controls (Ctrl). METHODS: Fifteen patients (6 F and 9 M) were assessed by the motor section of the Unified HD Rating Scale, the Total Function Capacity, and the scale for outcomes in Parkinson's disease-autonomic (SCOPA-AUT) questionnaire. All patients and 10 Ctrl (5 F and 5 M) underwent 123I-MIBG imaging. From planar images, the early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR) were calculated. RESULTS: We did not find significant differences in early and late H/M ratios and WR between the two groups. At individual level, three patients showed reduced early and/or late H/M ratios. The most common autonomic complaints were gastrointestinal and genitourinary disorders. SCOPA-AUT questionnaire score results positively correlated with the disease duration and WR. CONCLUSIONS: Our study indicates that myocardial postganglionic sympathetic innervation is essentially preserved or only minimally involved in HD. These findings suggest that the cardiovascular dysfunction might be mainly due to the impairment of brain areas associated with the regulation and modulation of the heart function.
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Enfermedades del Sistema Nervioso Autónomo , Enfermedad de Huntington , Imagen de Perfusión Miocárdica , 3-Yodobencilguanidina , Enfermedades del Sistema Nervioso Autónomo/diagnóstico por imagen , Corazón/inervación , Humanos , Enfermedad de Huntington/diagnóstico por imagen , Radioisótopos de Yodo , RadiofármacosRESUMEN
INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research.
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Distonía , Trastornos Distónicos , Temblor Esencial , Distonía/complicaciones , Humanos , Italia/epidemiología , Estudios Prospectivos , Síndrome , Temblor/complicaciones , Temblor/diagnóstico , Temblor/epidemiologíaRESUMEN
BACKGROUND: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease that is characterized by a wide range of neurologic and neuropsychological impairments. Constructional impairments have been reported in some cases but have never been assessed systematically. OBJECTIVE: To evaluate constructional abilities and their cognitive and neural correlates in nondemented individuals with CADASIL. METHOD: Thirty individuals with CADASIL who were not affected by clinically relevant cognitive deterioration and 30 healthy controls (HC) underwent an extensive cognitive assessment and paper-and-pencil visuoconstructional tasks in order to detect constructional impairments. Performance on the visuoconstructional tasks was correlated with the cognitive assessment scores and with quantitative indices of regional gray matter atrophy (obtained via FreeSurfer image analysis) and white matter involvement. RESULTS: The individuals with CADASIL achieved significantly lower scores on the cognitive assessment compared with the HC. Poor visuoconstructional abilities were observed in seven (23.3%) of the individuals with CADASIL when performing the copy drawing task and in nine (30%) when performing the Rey Complex Figure Test. Logistic regression revealed that visuoconstructional impairments were significantly associated with scores on the Frontal Assessment Battery and the Attentional Matrices Test. Morphometric results revealed that scores on the visuoconstructional tasks were related to gray matter atrophy of the left frontal lobe and right parietal lobe. CONCLUSION: Impairments on visuoconstructional tasks are quite common in individuals with CADASIL, even in the lack of clinically relevant cognitive deterioration, and are critically related to frontal and parietal atrophy.
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CADASIL , Leucoencefalopatías , Adulto , Humanos , CADASIL/diagnóstico por imagen , CADASIL/patología , Infarto Cerebral , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/patología , Lóbulo Frontal , Atrofia/patología , Imagen por Resonancia MagnéticaRESUMEN
AIM: Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative tauopathy characterised by motor, behavioural and cognitive dysfunction. While in the last decade, sensory and autonomic disturbances as well as peripheral nerve involvement are well-recognised in Parkinson's Disease (PD), little is known in this regard for PSP. Herein, we aim to assess peripheral sensory and autonomic nerve involvement in PSP and to characterise possible differences in morpho-functional pattern compared to PD patients. METHODS: We studied 27 PSP and 33 PD patients without electrophysiological signs of neuropathy, and 33 healthy controls (HC). In addition to motor impairment, evaluated by means of UPDRS-III and the PSP rating scale, all patients underwent clinical, functional and morphological assessment of sensory-autonomic nerves through dedicated questionnaires, sympathetic skin response, dynamic sweat test and skin biopsies. The analysis of cutaneous sensory and autonomic innervation was performed using indirect immunofluorescence and confocal microscopy. RESULTS: PSP patients displayed a length-dependent loss of sensory and autonomic nerve fibres associated with functional impairment compared to HC and, overall, a more severe picture than in PD patients. The disease severity correlated with the loss of intraepidermal nerve fibre density in the leg of PSP patients (p < 0.05). CONCLUSION: We demonstrated a length-dependent small fibre pathology in PSP, more severe compared to PD, and paralleling disease severity. Our findings suggest the morphological and functional study of cutaneous nerves as possible biomarkers to monitor disease progression and response to new treatments.
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Desnervación Autonómica , Vías Autónomas/patología , Disfunción Cognitiva/patología , Parálisis Supranuclear Progresiva/patología , Anciano , Desnervación Autonómica/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Índice de Severidad de la EnfermedadRESUMEN
RESEARCH QUESTION: Wilson's disease (WD) is a disorder of copper metabolism that can cause hormonal alterations. The impact of WD and its therapies on fertility is not well defined. The aim of this study was to evaluate ovarian reserve and sperm parameters in long-term treated WD patients with hepatic onset. DESIGN: WD patients with hepatic onset treated for at least 5 years were compared with healthy controls. Men underwent spermiogram and sperm DNA fragmentation (SDF) analysis. Women were tested for serum FSH, anti-Müllerian hormone (AMH) and sonographic antral follicle count (AFC) in the early follicular phase. Ovulation was monitored with ultrasound and progesterone serum concentrations in the luteal phase. RESULTS: The WD group included 26 patients (12 males), the control group 19 subjects (9 males). All patients apart from four (one male) were responders to WD treatment. Sperm count and morphology were comparable between cases and controls. Sperm motility (total and after 1 h) was significantly lower in cases (44.78 ± 21.65%; 47.85 ± 21.52%) than controls (61.88 ± 11.03; 69.44 ± 11.02%, P = 0.03 and 0.01, respectively). The only non-responder had severe oligo-astheno-teratozoospermia. SDF values were normal in cases and controls. AMH, AFC and FSH did not differ between cases and controls. LH was significantly lower in cases (3.36 ± 1.65 mIU/ml) than controls (6.25 ± 1.03 mIU/ml, P < 0.0001). A non-responder woman who developed neurological signs had a 7-year history of infertility. CONCLUSIONS: WD patients with hepatic onset, diagnosed early and treated, have no impairment in fertility potential even if males show reduced sperm motility and females lower LH values. Only patients with poor disease control have some evidence of impaired fertility.
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Fertilidad , Degeneración Hepatolenticular/fisiopatología , Reserva Ovárica , Motilidad Espermática , Adulto , Femenino , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/terapia , Hormonas/sangre , Humanos , Masculino , Estudios Prospectivos , Salud Reproductiva , Adulto JovenRESUMEN
PURPOSE: Cerebellar ataxias are a large and heterogeneous group of disorders. The evaluation of brain parenchyma via MRI plays a central role in the diagnostic assessment of these conditions, being mandatory to exclude the presence of other underlying causes in determining the clinical phenotype. Once these possible causes are ruled out, the diagnosis is usually researched in the wide range of hereditary or sporadic ataxias. METHODS: We here propose a review of the main clinical and conventional imaging findings of the most common hereditary degenerative ataxias, to help neuroradiologists in the evaluation of these patients. RESULTS: Hereditary degenerative ataxias are all usually characterized from a neuroimaging standpoint by the presence, in almost all cases, of cerebellar atrophy. Nevertheless, a proper assessment of imaging data, extending beyond the mere evaluation of cerebellar atrophy, evaluating also the pattern of volume loss as well as concomitant MRI signs, is crucial to achieve a proper diagnosis. CONCLUSION: The integration of typical neuroradiological characteristics, along with patient's clinical history and laboratory data, could allow the neuroradiologist to identify some conditions and exclude others, addressing the neurologist to the more appropriate genetic testing.
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Ataxia Cerebelosa , Ataxia/diagnóstico por imagen , Ataxia/genética , Encéfalo , Ataxia Cerebelosa/diagnóstico por imagen , Ataxia Cerebelosa/genética , Humanos , Imagen por Resonancia Magnética , NeuroimagenRESUMEN
INTRODUCTION: Psychosis in Parkinson's disease (PD) is common and consists of hallucinations, illusions, and delusions. Among the latter, delusional jealousy, also named Othello syndrome (OS), might impair the quality of life of both patients and their partners. We aimed to perform a systematic review and report a series of PD patients presenting with OS. METHODS: A systematic review research was performed in PubMed database, excluding non-English articles, single case reports, reviews and neuropathology articles, comments, and articles concerning OS associated with deep brain stimulation (DBS) and levodopa-carbidopa intestinal gel infusion. We also described eleven PD patients (9 M and 2 F) with OS, identified in a cohort of consecutive 153 patients, comparing them with eleven matched no OS (nOS) PD subjects taken from the same cohort. RESULTS: We included eight articles (four case series and four cross-sectional studies). OS resulted more common among males than females. We did not find higher levodopa dose and levodopa equivalent dose for dopamine agonists and for all anti-parkinsonian drugs in our OS group. In our case series, OS patients showed visual hallucinations (p=0.001) and a trend to have depression (p=0.080) more frequently than nOS ones. CONCLUSIONS: OS is not a rare disorder in PD, probably due not only to abnormal dopaminergic stimulation but also to serotonergic dysfunction in biologically predisposed subjects. Visual hallucinations and other concomitant psychiatric diseases, in particular depression, might represent a risk factor for the OS development.
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Enfermedad de Parkinson , Antiparkinsonianos/efectos adversos , Estudios Transversales , Deluciones/etiología , Agonistas de Dopamina , Femenino , Humanos , Levodopa/uso terapéutico , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Calidad de VidaRESUMEN
BACKGROUND: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear. OBJECTIVES: We determined the frequency of GBA-related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time. METHODS: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. ß-glucocerebrosidase activity was measured. The Kaplan-Meier method and Cox proportional hazard regression models were performed. RESULTS: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA-PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA-PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA-PD had the lowest ß-glucocerebrosidase activity. CONCLUSIONS: GBA-PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles. © 2020 International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Disección , Genotipo , Glucosilceramidasa/genética , Humanos , Italia/epidemiología , Mutación/genética , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , FenotipoRESUMEN
BACKGROUND: Mutations in TGM6 gene, encoding for transglutaminase 6 (TG6), have been implicated in the pathogenesis of spinocerebellar ataxia type 35 (SCA35), a rare autosomal dominant disease marked by cerebellar degeneration and characterized by postural instability, incoordination of gait, features of cerebellar dysfunction and pyramidal signs. CASE PRESENTATION: Here we report the case of an Italian patient with late-onset, slowly progressive cerebellar features, including gait ataxia, scanning speech and ocular dysmetria and pyramidal tract signs. Whole exome sequencing revealed the rare heterozygous c.1024C > T (p.R342W) variant of TGM6, located at a highly evolutionary conserved position and predicted as pathogenic by in silico tools. Expression of TG6-R342W mutant in HEK293T cells led to a significant reduction of transamidase activity compared to wild-type TG6. CONCLUSION: This finding extends SCA35 genetic landscape, highlighting the importance of TGM6 screening in undiagnosed late-onset and slowly progressive cerebellar ataxias.
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Ataxias Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/diagnóstico , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Mutación , Transglutaminasas/genética , Transglutaminasas/metabolismoRESUMEN
OBJECTIVE: Timed neuropsychological tests do not take into account physical impairment during scoring procedures. Dysarthria and upper limb impairment can be easily measured with the PATA rate test (PRT) and the nine-hole pegboard test (9HPT). We recently validated a normalization method for timed neuropsychological tests using the PRT and 9HPT (p9NORM). We now validate the p9NORM in Parkinson's disease (Yarnall et al. Neurology 82(4):308-316; 2014) and multiple system atrophy (MSA). METHODS: We enrolled twenty-six patients with PD, eighteen patients with MSA, and fifteen healthy controls (HC). p9NORM was applied to patients with abnormal PRT and/or 9HPT. All subjects were tested with a comprehensive neuropsychological battery. RESULTS: No differences emerged in demographics across groups: (PD: mean age ± SD 66 ± 8; education 9 ± 4 years; MSA: age 60 ± 8; education 10 ± 4 years; HC: age 61 ± 12; education 9 ± 4 years). In MSA patients, the scores on the trail making test (TMT-A p = 0.003; TMT-B p = 0.018), attentional matrices (AM; p = 0.042), and symbol digit modalities test (SDMT p = 0.027) significantly differed following application of p9NORM. In PD patients, the TMT-A (p < 0.001), TMT-B (p = 0.001), and AM (p = 0.001) differed after correction. PD and MSA showed cognitive impairment relative to HC performance. When comparing MSA with PD, the SDMT, AM, and fluencies were similar. TMT-A and -B raw scores were different between groups (p = 0.006; p = 0.034), but these differences lost significance after p9NORM corrections (p = 0.100; p = 0.186). CONCLUSIONS: We confirm that the p9NORM can be successfully used in both PD and MSA patients, as it mitigates the impact of disability on timed tests, resulting in a more accurate analysis of cognitive domains.
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Disfunción Cognitiva , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Anciano , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Humanos , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/diagnóstico , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Prueba de Secuencia AlfanuméricaRESUMEN
BACKGROUND: Huntington disease (HD) and spinocerebellar ataxia type 1-2-17 (SCA1-2-17) are adult-onset autosomal dominant diseases, caused by triplet repeat expansions in the HTT, ATXN1, ATXN2, and TBP genes. Alleles with a repeat number just below the pathological threshold are associated with reduced penetrance and meiotic instability and are defined as intermediate alleles (IAs). OBJECTIVES: We aimed to determine the frequencies of IAs in healthy Italian subjects and to compare the proportion of the IAs with the prevalence of the respective diseases. METHODS: We analyzed the triplet repeat size in HTT, ATXN1, ATXN2, and TBP genes in the DNA samples from 729 consecutive adult healthy Italian subjects. RESULTS: IAs associated with reduced penetrance were found in ATXN2 gene (1 subject, 0.1%) and TBP gene (0.82%). IAs at risk for meiotic instability were found in HTT (5.3%) and ATXN2 genes (2.7%). In ATXN1, we found a low percentage of IAs (0.4%). Alleles lacking the common CAT interruption within the CAG sequence were also rare (0.3%). CONCLUSIONS: The high frequencies of IAs in HTT and ATXN2 genes suggest a correlation with the prevalence of the diseases in our population and support the hypothesis that IAs could represent a reservoir of new pathological expansions. On the opposite, ATXN1-IA were very rare in respect to the prevalence of SCA1 in our country, and TBP- IA were more frequent than expected, suggesting that other mechanisms could influence the occurrence of novel pathological expansions.
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Frecuencia de los Genes/genética , Enfermedad de Huntington/genética , Péptidos/genética , Ataxias Espinocerebelosas/genética , Repeticiones de Trinucleótidos/genética , Adulto , Anciano , Alelos , Ataxina-1/genética , Ataxina-2/genética , Femenino , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/epidemiología , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Ataxias Espinocerebelosas/epidemiología , Proteína de Unión a TATA-Box/genéticaRESUMEN
Gustatory perception has been poorly explored in Parkinson's disease (PD). Aim of this study was to assess the flavor ability in PD patients, using the "flavor test" (FT), a new standardized and validated tool to examine the flavor perception. Thirty-eight patients (17 F and 21 M) and 36 control subjects (15 F and 21 M) comparable for age and gender were enrolled. All the subjects underwent the flavor test (FT), the Sniffin' Sticks test (SST), and the gustometry test (GT), based on the basic four tastants ("salty," "sour," "sweet," and "bitter"). PD patients presented a FT score significantly lower than controls (p < 0.001). Olfaction (SST) was impaired in PD in comparison with controls (p < 0.001), and the patients also showed a mild reduction of basic tastant identification at the GT (p = 0.08), with a trend toward statistical significance. There was no correlation between SST, FT, and GT. GT performance was negatively correlated with disease severity (p = 0.004) and stage (p = 0.024). The SST and FT resulted abnormal in PD in comparison with controls, independently of disease duration and severity. The ability to identify the basic four tastants was correlated with the disease severity and stage in PD patients suggesting that it might occur later in the course of the disease. FT might be a sensitive tool in identifying the sensorineural perception dysfunction in PD, even in the early stage and regardless of the disease severity.
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Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Trastornos del Gusto/diagnóstico , Trastornos del Gusto/etiología , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Índice de Severidad de la Enfermedad , Trastornos del Gusto/fisiopatología , Percepción del Gusto/fisiologíaRESUMEN
BACKGROUND: Progressive supranuclear palsy (PSP) is a rare rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. The use of health-related quality of life (HR-QoL) measures allows assessing changes in health status induced by therapeutic interventions or disease progress in neurodegenerative diseases. The PSP-QoL is a 45-item, self-administered questionnaire designed to evaluate HR-QoL in PSP. METHODS AND RESULTS: Here, the PSP-QoL was translated into Italian and validated in 190 PSP (96 women and 94 men; mean age ± standard deviation, 72 ± 6.5; mean disease duration, 4.2 ± 2.3) patients diagnosed according to the Movement Disorder Society criteria and recruited in 16 third level movement disorders centers participating in the Neurecanet project. The mean PSP-QoL total score was 77.8 ± 37 (physical subscore, 46.5 ± 18.7; mental subscore, 33.6 ± 19.2). The internal consistency was high (Cronbach's alpha = 0.954); corrected item-total correlation was > 0.40 for the majority of items. The significant and moderate correlation of the PSP-QoL with other HR-QoL measures as well as with motor and disability assessments indicated adequate convergent validity of the scale. Gender and geographic location presented a significant impact on the PSP-QoL in our sample with women and patients from the South of Italy scoring higher than their counterparts. CONCLUSION: In conclusion, the Italian version of the PSP-QoL is an easy, reliable and valid tool for assessment of HR-QoL in PSP.
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Psicometría/normas , Calidad de Vida , Parálisis Supranuclear Progresiva/diagnóstico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Italia , Masculino , Psicometría/instrumentación , Reproducibilidad de los Resultados , AutoinformeRESUMEN
Progressive supranuclear palsy (PSP) is a rare, rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. Caring for a partner or relative who suffers from PSP entails a strenuous and demanding task, usually lasting for years that affects carers' everyday life routines and emotional and social well-being. The 26-item Parkinsonism Carers QoL (PQoL Carer) is a self-administered, concise instrument evaluating the quality of life of caregivers of patients with atypical parkinsonism (both PSP and multiple system atrophy). Here, the PQoL Carer was translated into Italian and validated in 162 carers of PSP patients (54.3% women; mean age (standard deviation), 62.4 (15.4)) diagnosed according to the Movement Disorder Society criteria and recruited in 16 third-level movement disorders centers participating in the Neurecanet project. The mean PQoL total score was 40.66 ± 19.46. The internal consistency was excellent (Cronbach's alpha = 0.941); corrected item-total correlation was > 0.40 for all the items. A correlation with other health-related quality of life measures as well as with behavioral assessments was shown suggesting adequate convergent validity of the scale. PQoL also correlated with patients' severity of disease. The discriminant validity of the scale was evidenced by its capacity to differentiate between carers with varying levels of self-reported health (p < 0.001). In conclusion, the Italian version of the PQoL Carer is an easy, consistent, and valid tool for the assessment of the quality of life in carers of PSP patients.
Asunto(s)
Cuidadores/psicología , Psicometría/instrumentación , Calidad de Vida/psicología , Encuestas y Cuestionarios , Adulto , Anciano , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/etiología , Parálisis Supranuclear Progresiva/complicaciones , TraducciónRESUMEN
Friedreich's ataxia (FRDA) is an autosomal recessive disease presenting with ataxia, corticospinal signs, peripheral neuropathy, and cardiac abnormalities. Little effort has been made to understand the psychological and emotional burden of the disease. The aim of our study was to measure patients' ability to recognize emotions using visual and non-verbal auditory hints, and to correlate this ability with psychological, neuropsychological, and neurological variables. We included 20 patients with FRDA, and 20 age, sex, and education matched healthy controls (HC). We measured emotion recognition using the Geneva Emotion Recognition Test (GERT). Neuropsychological status was assessed measuring memory, executive functions, and prosopagnosia. Psychological tests were Patient Health Questionnaire-9 (PHQ-9), State Trait Anxiety Inventory-state/-trait (STAI-S/-T), and Structured Clinical Interview for DSM Disorders II. FRDA patients scored worse at the global assessment and showed impaired immediate visuospatial memory and executive functions. Patients presented lower STAI-S scores, and similar scores at the STAI-T, and PHQ-9 as compared to HC. Three patients were identified with personality disorders. Emotion recognition was impaired in FRDA with 29% reduction at the total GERT score (95% CI - 44.8%, - 12.6%; p < 0.001; Cohen's d = 1.2). Variables associated with poor GERT scores were the 10/36 spatial recall test, the Ray Auditory Verbal Learning Test, the Montreal Cognitive Assessment, and the STAI-T (R2 = 0.906; p < 0.001). FRDA patients have impaired emotion recognition that may be secondary to neuropsychological impairment. Depression and anxiety were not higher in FRDA as compared to HC and should not be considered as part of the disease.