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BACKGROUND: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. OBJECTIVES: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. METHODS: The STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains. RESULTS: Of the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented. CONCLUSION: DBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Parálisis Cerebral , Estimulación Encefálica Profunda , Discinesias , Trastornos del Movimiento , Humanos , Niño , Adolescente , Parálisis Cerebral/terapia , Estudios de Seguimiento , Estudios Prospectivos , Discinesias/etiología , Discinesias/terapia , Globo Pálido , Trastornos del Movimiento/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: Mucopolysaccharidosis type III (Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in the heparan-N-sulfatase enzyme involved in the catabolism of the glycosaminoglycan heparan sulfate. It is characterized by early nonspecific neuropsychiatric symptoms, followed by progressive neurocognitive impairment in combination with only mild somatic features. In this patient group with a broad clinical spectrum a significant genotype-phenotype correlation with some mutations leading to a slower progressive, attenuated course has been demonstrated. CASE PRESENTATION: Our patient had complications in the neonatal period and was diagnosed with Mucopolysaccharidosis IIIa only at the age of 28 years. He was compound heterozygous for the variants p.R245H and p.S298P, the latter having been shown to lead to a significantly milder phenotype. CONCLUSIONS: The diagnostic delay is even more prolonged in this patient population with comorbidities and a slowly progressive course of the disease.
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Mucopolisacaridosis III , Diagnóstico Tardío , Estudios de Asociación Genética , Humanos , Masculino , Mucopolisacaridosis III/complicaciones , Mucopolisacaridosis III/diagnóstico , Mucopolisacaridosis III/genética , Mutación , FenotipoRESUMEN
Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective: To identify common genetic factors associated with risk of ET. Design, Setting, and Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485â¯250 individuals, data for 483â¯054 passed data quality control and were used. Main Outcomes and Measures: Genotypes of common variants associated with risk of ET. Results: Of the 483â¯054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475â¯877 control individuals (253â¯785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. Conclusions and Relevance: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.
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Temblor Esencial/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , TranscriptomaRESUMEN
BACKGROUND: The spondylodysplastic Ehlers-Danlos subtype (OMIM #130070) is a rare connective tissue disorder characterized by a combination of connective tissue symptoms, skeletal features and short stature. It is caused by variants in genes encoding for enzymes involved in the proteoglycan biosynthesis or for a zinc transporter. PRESENTATION OF CASES: We report two brothers with a similar phenotype of short stature, joint hypermobility, distinct craniofacial features, developmental delay and severe hypermetropia indicative for a spondylodysplastic Ehlers-Danlos subtype. One also suffered from a recurrent pneumothorax. Gene panel analysis identified two compound heterozygous variants in the B4GALT7 gene: c.641G > A and c.723 + 4A > G. B4GALT7 encodes for galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans. CONCLUSIONS: This is a first full report on two cases with spondylodysplastic Ehlers-Danlos syndrome and the c.723 + 4A > G variant of B4GALT7. The recurrent pneumothoraces observed in one case expand the variable phenotype of the syndrome.
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Enanismo , Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Humanos , Inestabilidad de la Articulación/genética , Masculino , Fenotipo , HermanosRESUMEN
We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
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Temblor Esencial/genética , Estudio de Asociación del Genoma Completo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Proteínas Serina-Treonina Quinasas/genética , alfa Catenina/genética , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: Essential tremor is a very common disease defined by sparse clinical criteria. It is unlikely that essential tremor is an etiologically homogeneous disease. Stratifying broadly defined diseases using clinical characteristics has often aided the etiopathological understanding. Most studies of essential tremor show 2 distinct age at onset peaks: early and late. This study investigates phenotypical differences between early- and late-onset essential tremor patients. METHODS: We studied a sample of 1137 tremor patients. Of these patients, 978 suffered from definite or probable essential tremor. All of the patients underwent the same standardized examination encompassing, among other items, drawing of the Archimedes spiral and assessment of the Fahn-Tolosa-Marin scale. RESULTS: Two subgroups of early-onset (≤ 24 years of age, n = 317) and late-onset (≥ 46 years of age, n = 356) patients were selected based on the visual and mathematical analysis of the age-at-onset distribution. Tremor severity in both groups was comparable. Tremor progression measured as Archimedes spiral score and the Fahn-Tolosa-Marin subscales divided by the disease duration in 10-year bins was significantly faster in late-onset patients when compared with early-onset patients. Early-onset patients more frequently reported a positive family history and alcohol sensitivity of the tremor. CONCLUSIONS: The age-at-onset distribution suggests a distinction between early- and late-onset tremor. Early-onset and late-onset essential tremor differ in the progression rates and the frequencies of a positive family history and history of a positive effect of alcohol on tremor. © 2016 International Parkinson and Movement Disorder Society.
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Progresión de la Enfermedad , Temblor Esencial/fisiopatología , Adolescente , Adulto , Edad de Inicio , Anciano , Temblor Esencial/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Isolated tremor in the elderly is commonly diagnosed as essential tremor (ET). The prevalence of tremor increases steeply with increasing age, whereas hereditary tremor is becoming less common. Moreover, late-manifesting tremor seems to be associated with dementia and earlier mortality. We hypothesize that different entities underlie tremor in the elderly. METHODS: Two thousand four hundred forty-eight subjects from the Longitudinal Study of Aging Danish Twins older than 70 y answered screening questions for ET in 2001. Two thousand fifty-six (84%) participants drew Archimedes spirals to measure their tremor severity, and classical aging phenotypes were assessed. A subgroup of 276 individuals fulfilling either screening criteria for ET or being controls were personally assessed. Medications and mortality data are available. RESULTS: The spiral score increased with age. The spiral score correlated with tremor severity. For the whole cohort, mortality was significantly correlated with the spiral score, and higher spiral scores were associated with lower physical and cognitive functioning. Multivariate analysis identified higher spiral scores as an independent risk factor for mortality. In contrast, the ET patients did not show an increased but rather a lower mortality rate although it was not statistically significant. Consistent with a slower than normal aging, they were also physically and cognitively better functioning than controls. CONCLUSIONS: Because incident tremors beyond 70 y of age show worse aging parameters and mortality than controls and ET, we propose to label it 'aging-related tremor' (ART). This tremor starts later in life and is accompanied by subtle signs of aging both cognitively and physically. More detailed clinical features and pathogenesis warrant further assessment.
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Envejecimiento/fisiología , Enfermedades en Gemelos/epidemiología , Temblor Esencial/fisiopatología , Índice de Severidad de la Enfermedad , Temblor/fisiopatología , Anciano , Anciano de 80 o más Años , Dinamarca/epidemiología , Temblor Esencial/epidemiología , Temblor Esencial/mortalidad , Femenino , Humanos , Masculino , Temblor/epidemiología , Temblor/mortalidadAsunto(s)
Temblor Esencial/genética , Proteínas Mitocondriales/genética , Serina Endopeptidasas/genética , Edad de Inicio , Anciano , Progresión de la Enfermedad , Femenino , Alemania , Serina Peptidasa A2 que Requiere Temperaturas Altas , Humanos , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Improvement of essential tremor (ET) amplitude after alcohol ingestion is usually based on patient reports but a quantitative test for large numbers of patients is lacking and the percentage of ET patients with a detectable alcohol effect is therefore unknown. METHODS: A validated and published alcohol home test was used in 104 ET patients. The Archimedes spiral was drawn before alcohol ingestion and at 4 time points after alcohol consumption and rated on a 10-point rating scale according to Bain and Findley. A second identical test without alcohol ingestion was performed by the same patients and evaluated by the same two raters to analyze the total variability of the spiral ratings. RESULTS: Alcohol reduces tremor in ET patients as a group and a rebound effect with an increase in tremor intensity was found the next morning. Sex, family history of ET, diagnosis (definite vs. probable) and medical history of alcohol responsiveness do not predict the alcohol response. The minimal detectable difference in the spiral score was 2 due to spontaneous tremor fluctuations and inter-rater differences. The test demonstrated alcohol sensitivity of the tremor in 46% of the patients. Responsivity to alcohol could only be seen in patients with spiral scores above 3. CONCLUSIONS: Alcohol sensitivity is a feature of ET in at least 46% of the patients. We could not find predictors for alcohol sensitivity. The minimal detectable change is 2 scores and alcohol responsivity was only detected in patients with baseline Archimedes spiral rating of ≥3.
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Temblor Esencial/inducido químicamente , Temblor Esencial/tratamiento farmacológico , Etanol/efectos adversos , Etanol/farmacología , Anciano , Temblor Esencial/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: We analyzed the coding region of the Fused in Sarcoma (FUS) gene in familial essential tremor (ET) and reviewed previous studies assessing FUS variants in ET. BACKGROUND: ET is often a familial disorder with an autosomal dominant inheritance pattern. A potentially causative variant in FUS has been identified in one ET family. Subsequent studies described further putatively causal variants. METHODS: We performed DNA sequencing of FUS in 85 unrelated, familial German and French definite ET patients. RESULTS: We did not find novel variants affecting the protein sequence. Seven previously published studies and data from the exome variant server (EVS) showed that rare exonic variants in FUS are not more frequent in ET than in the general population. CONCLUSIONS: Our findings provide no evidence for a role of rare genetic variants in the pathogenesis of ET, apart from the initially published FUS mutation segregating in a large ET family.
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Temblor Esencial/genética , Mutación/genética , Proteína FUS de Unión a ARN/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Bases de Datos Bibliográficas/estadística & datos numéricos , Femenino , Francia , Alemania , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Essential tremor (ET) follows an autosomal dominant type of inheritance in the majority of patients, yet its genetic basis has not been identified. Its exact origin is still elusive, but coherence measurements between electromyography tremor bursts and electroencephalography unequivocally demonstrate a correlation. METHODS: We tested these measurements in 37 healthy first-degree relatives (children) of patients with essential tremor (ET) and a group of 37 age-matched and sex-matched controls. Pooled coherence spectra of the maximally coherent electroencephalogram electrodes were computed for ET relatives and controls. RESULTS: The maximal coherence and its frequency were significantly higher in ET relatives than in controls during the pinch grip task and during slow hand movements. Electromyography amplitude (root-mean-square) was slightly but significantly greater in ET relatives, whereas 2-Hz to 40-Hz power and spectral peak frequency were not different. CONCLUSIONS: The presymptomatic alteration in corticomuscular interaction may reflect a role of genetic factors.
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Temblor Esencial/genética , Salud de la Familia , Corteza Motora/fisiopatología , Músculo Esquelético/fisiopatología , Adulto , Electroencefalografía , Electromiografía , Temblor Esencial/patología , Temblor Esencial/fisiopatología , Femenino , Lateralidad Funcional , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
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Catecol O-Metiltransferasa/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Edad de Inicio , Anciano , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
OBJECTIVE: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET. METHODS: Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET. RESULTS: We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 × 10(-5), odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10(-3), OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 10(-10), OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087. CONCLUSIONS: We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.
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Temblor Esencial/genética , Proteínas de Transporte de Glutamato en la Membrana Plasmática/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Intervalos de Confianza , Transportador 2 de Aminoácidos Excitadores , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Alemania , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Control de Calidad , Población Blanca , Adulto JovenRESUMEN
BACKGROUND: The objective of the study was to develop a simple diagnostic test for alcohol sensitivity of essential tremor patients. Here we describe the controlled measurements of tremor severity after alcohol ingestion and the practicability of using it as a home test. METHODS: Ten patients were tested for alcohol sensitivity under controlled conditions in the laboratory (blood alcohol, quantitative tremor recordings, modified Fahn scale, visual analog scale, Archimedes spirals), and 15 patients were instructed to perform an alcohol test at home (visual analog scale, Archimedes spirals) following an adapted dosage of alcohol. RESULTS: The time course of the antitremor effect showed significant improvement of up to 50% in both groups for all the outcome parameters. Tremor deteriorated after 3 hours. A quarter of the patients noticed the alcohol effect for the first time during the test. CONCLUSIONS: Alcohol is an effective drug for essential tremor. Its effect is only short-lived and exhibits a rebound after > 3 hours and the next morning. We propose this essential tremor home test as a diagnostic tool to confirm the alcohol sensitivity of essential tremor.
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Alcoholes/uso terapéutico , Temblor Esencial/tratamiento farmacológico , Temblor Esencial/fisiopatología , Adulto , Anciano , Análisis de Varianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Índice de Severidad de la EnfermedadRESUMEN
Essential tremor (ET) and Parkinson's disease (PD) are the most common movement disorders and show clinical, genetic, and pathophysiological overlap. Single-nucleotide polymorphisms (SNPs) in the leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing, Nogo receptor-interacting protein gene (LINGO1) are associated with ET. LINGO1 is overexpressed in the substantia nigra (SN) of PD patients and inhibition of LINGO1 confers neuroprotection in a rodent model of PD. In this study we test the hypothesis whether SNPs in the LINGO1 gene that are associated with ET are also associated with PD. Three large German case-control samples from Kiel, Lübeck, and Tübingen (total: 1,798 cases and 1,482 controls) were genotyped for the three LINGO1 SNPs associated with ET. Association was assessed using allele- and genotype-based tests in each of the three samples separately, in the combined sample, and in subsets of patients with early-onset PD (<50 years) and of patients with a positive family history of PD. Neither of the three samples alone nor the combined sample showed evidence for association between LINGO1 SNPs and PD. The allele-based test showed a trend toward nominal association for all three SNPs in the Kiel sample. The subsets with early-onset PD or a positive family history did also not reveal evidence for association. SNPs in the LINGO1 gene associated with ET could not be shown to be associated with PD in our study population, despite a postulated overlap between both diseases.
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Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Alemania , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/etnología , Adulto JovenRESUMEN
Essential tremor (ET) is one of the most common movement disorders. Former association studies focussing on candidate genes in ET found a number of risk variants but most of them were not replicated. Recently, a genome-wide association study revealed two intronic sequence variants in the LINGO1 gene associated with ET. Here, we have confirmed association between sequence variants in the LINGO1 gene and the ET phenotype in independent German and French ET samples. The odds ratios for the identified intronic markers rs8030859 (P = 1.0x10(-4)), rs9652490 (P = 9.1x10(-4)), and rs11856808 (P = 3.6x10(-2)) were 1.72 (CI 1.31-2.26), 1.61 (CI 1.21-2.14), and 1.30 (CI 1.02-1.66), respectively, in our German sample. LINGO1 is an interesting candidate gene because it plays a key role in central nervous system biology, is selectively expressed in the nervous system, and is an inhibitor of oligodendrocyte differentiation and neuronal myelination. Our study gives further evidence that LINGO1 acts as a susceptibility gene for ET.
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Temblor Esencial/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Temblor Esencial/epidemiología , Europa (Continente)/epidemiología , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding alpha-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
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Variación Genética , Enfermedad de Parkinson/genética , Estudios de Cohortes , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Japón , Enfermedad de Parkinson/epidemiología , Factores de RiesgoRESUMEN
The genetic causes of essential tremor (ET) seem to be heterogeneous. Recently, ET has been found associated with a functional variant (Ser9Gly) of the dopamine D(3) receptor (DRD3), located in the ETM1 locus on chromosome 3q13.3 described for the first time in 1997. We examined this variant in three different populations from Germany, Denmark and France. We undertook an association study of the Ser9Gly variant in 202 cases with a familial history from unrelated families with ET, 97 cases with isolated non-familial ET and 528 healthy controls. In addition, linkage and segregation analyses were carried out in 22 ET families. The distribution of genotypes and allele frequencies showed no significant differences in the whole sample and in a subanalysis of familial and sporadic cases. Age at onset of tremor, tremor duration and tremor severity did not show an association with the genotype. In addition, the DRD3 variant was not found linked to the disease in a subset of informative ET families. We did not find a significant association of the DRD3 variant with ET nor linkage to the DRD3 receptor in German, Danish and French ET patients and families, suggesting that it is unlikely to be a causal factor for ET.
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Temblor Esencial/genética , Receptores de Dopamina D3/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dinamarca , Temblor Esencial/etnología , Femenino , Francia , Ligamiento Genético , Variación Genética , Genotipo , Alemania , Humanos , Masculino , Persona de Mediana Edad , Linaje , Población Blanca/genéticaRESUMEN
To evaluate a screening instrument for essential tremor (ET) consisting of a seven-item questionnaire and a spiral drawing. A total of 2,448 Danish twins aged 70 years or more and a second sample aged 60 years or more (n = 1,684) from a population-based northern German cross-sectional study (PopGen ET) were screened for ET. Inclusion criteria were a previous diagnosis of ET, a positive answer to two or more questions of the questionnaire or a spiral rating >4 (range of scale 0-9). Three hundred thirteen of 380 positively screened and 321 negatively screened subjects were clinically examined. Definite or probable ET was diagnosed in 104 patients, possible in 86 and other tremors in 98 patients. The sensitivity of the screening instrument was 70.5%, the positive predictive value was 64.9%, the specificity was 68.2%, and the negative predictive value was 73.5%. Tremor severity correlated significantly with higher spiral scores and more positive items. More patients were identified by spiral drawing in all tremor groups. The interrater and intrarater reliability for spirals ranged from 0.7 to 0.8 using intraclass coefficient. A cluster analysis revealed that the questionnaire can be reduced to three items, about uncontrollable tremor in any body part, tremor while drinking or pouring and other family members with tremor, without loosing efficacy. We present an easy to use and reliable screening instrument that is effective to identify patients with ET but not able to exclude patients with other tremor forms.
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Temblor Esencial , Tamizaje Masivo/métodos , Gemelos/genética , Anciano , Anciano de 80 o más Años , Estudios Transversales , Temblor Esencial/diagnóstico , Temblor Esencial/epidemiología , Temblor Esencial/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodosRESUMEN
PURPOSE OF REVIEW: This review focuses on recent findings on the aetiological, clinical, pathological and genetic heterogeneity of essential tremor and new therapeutic approaches. RECENT FINDINGS: Although essential tremor is one of the most common movement disorders, understanding of the causes and mechanisms of the disease is still very limited. Studies on the clinical presentation of essential tremor have expanded the clinical dimension, now including nontremor manifestations such as cerebellar signs, neuropsychological characteristics, distinct personality traits and behavioural symptoms. Results of neuropathologic and imaging studies are conflicting, with hints of neurodegeneration or a nondegenerative disturbance of functional circuits or receptors. Genetic heterogeneity of essential tremor has been demonstrated by linkage to three different chromosomal loci so far, and several negative genetic studies. New animal models are reinforcing previous hypotheses about gamma-aminobutyrate (GABA)-ergic mechanisms in essential tremor. New therapeutic agents for essential tremor have been tested and demonstrated to be partly effective. SUMMARY: The traditional view of essential tremor as a single disease entity has been replaced with the concept that this disorder is a complex and heterogeneous disease. Heterogeneity of the condition, and lack of diagnostic criteria and objective diagnostic tests add to this problem. Many conflicting results may be due to differences in patient selection.