Current and Future Neuropharmacological Options for the Treatment of Essential Tremor.

BACKGROUND: Essential Tremor (ET) is likely the most frequent movement disorder. In this review, we have summarized the current pharmacological options for the treatment of this disorder and discussed several future options derived from drugs tested in experimental models of ET or from neuropathological data. METHODS: A literature search was performed on the pharmacology of essential tremors using PubMed Database from 1966 to July 31, 2019. RESULTS: To date, the beta-blocker propranolol and the antiepileptic drug primidone are the drugs that have shown higher efficacy in the treatment of ET. Other drugs tested in ET patients have shown different degrees of efficacy or have not been useful. CONCLUSION: Injections of botulinum toxin A could be useful in the treatment of some patients with ET refractory to pharmacotherapy. According to recent neurochemical data, drugs acting on the extrasynaptic GABAA receptors, the glutamatergic system or LINGO-1 could be interesting therapeutic options in the future.

Missense Gamma-Aminobutyric Acid Receptor Polymorphisms Are Associated with Reaction Time, Motor Time, and Ethanol Effects in Vivo.

Background: The Gamma-aminobutyric acid type A receptor (GABA-A receptor) is affected by ethanol concentrations equivalent to those reached during social drinking. At these concentrations, ethanol usually causes impairment in reaction and motor times in most, but not all, individuals. Objectives: To study the effect of GABA-A receptor variability in motor and reaction times, and the effect of low ethanol doses. Methods: Two hundred and fifty healthy subjects received one single dose of 0.5 g/Kg ethanol per os. Reaction and motor times were determined before ethanol challenge (basal), and when participants reached peak ethanol concentrations. We analyzed all common missense polymorphisms described in the 19 genes coding for the GABA-A receptor subunits by using TaqMan probes. Results: The GABRA6 rs4454083 T/C polymorphisms were related to motor times, with individuals carrying the C/C genotype having faster motor times, both, at basal and at peak ethanol concentrations. The GABRA4 rs2229940 T/T genotype was associated to faster reaction times and with lower ethanol effects, determined as the difference between basal reaction time and reaction time at peak concentrations. All these associations remained significant after correction for multiple comparisons. No significant associations were observed for the common missense SNPs GABRB3 rs12910925, GABRG2 rs211035, GABRE rs1139916, GABRP rs1063310, GABRQ rs3810651, GABRR1 rs12200969 or rs1186902, GABRR2 rs282129, and GABRR3 rs832032. Conclusions: This study provides novel information supporting a role of missense GABA-A receptor polymorphisms in reaction time, motor time and effects of low ethanol doses in vivo.

Genetics of restless legs syndrome: An update.

A major role of genetic factors in the risk of developing restless legs syndrome (RLS) is supported by the high frequency of positive family history of RLS in patients affected with this disease, and the higher concordance rates in monozygotic twins compared with dizygotic ones in twin studies. In this review we have focused on those reports describing inheritance patterns of RLS, genetic anticipation, the results of studies performed on positivity of family history of RLS, twin studies, linkage studies in familial RLS, genome-wide association studies (GWAS), exome sequencing studies, and case-control association studies on candidate genes in RLS. Although to date the causative gene(s) has(ve) not been definitively identified, a number of variants of several genes, most of them through GWAS, have been associated with RLS risk, the strongest candidates being variants of PTPRD, BTBD9, and MEIS1 genes. Despite results of several recent case-control association studies which have suggested a possible contribution of heme-oxygenase 1 (HMOX1) rs2071746 and vitamin D3 receptor (VDR) rs731236 variants, or the presence of allele 2 of the complex microsatellite repeat Rep1 within the alpha-synuclein (SNCA) gene promoter in modifying the risk for RLS, these studies need to be replicated in further studies involving different populations.

SLC1A2 rs3794087 variant and risk for essential tremor: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVE: Recently, a genome-wide association study showed a statistically significant association between the rs3794087 single nucleotide polymorphism (SNP) in the solute carrier family 1--glial affinity glutamate transporter, member 2 (SLC1A2) and the risk for essential tremor (ET). However, four further association studies showed controversial results.We carried out a systematic review and a meta-analysis including all the studies published on the risk of ET related to this SNP. MATERIALS AND METHODS: The systematic review was performed using several databases, the meta-analysis was carried out using the software Meta-DiSc 1.1.1, and heterogeneity between studies was tested using the Q statistic. RESULTS: The meta-analysis included five association studies for the SLC1A2 rs3794087 SNP (1925 ET patients, 4914 controls) and the risk for ET. The global diagnostic odds ratio (95% confidence intervals) was 1.08 (0.79-1.48) for the total group. After excluding data from the discovery series (which was responsible for a high degree of heterogeneity), the global diagnostic odds ratio (95% confidence intervals) was 0.96 (0.74-1.23). The separate analysis in White and Asiatic individuals on the frequency of the minor allele of rs3794087 did not show significant differences between ET patients and controls in both subgroups after excluding the discovery series. CONCLUSION: The results of the meta-analysis suggest that rs3794087 is not associated with the risk for ET.

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor.

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

Heme Oxygenase 1 and 2 Common Genetic Variants and Risk for Essential Tremor.

Several reports suggested a role of heme oxygenase genes 1 and 2 (HMOX1 and HMOX2) in modifying the risk to develop Parkinson disease (PD). Because essential tremor (ET) and PD share phenotypical and, probably, etiologic factors of the similarities, we analyzed whether such genes are related with the risk to develop ET. We analyzed the distribution of allelic and genotype frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 single nucleotide polymorphisms, as well as the presence of copy number variations of these genes in 202 subjects with familial ET and 747 healthy controls. Allelic frequencies of rs2071746T and rs1051308G were significantly lower in ET patients than in controls. None of the studied polymorphisms influenced the disease onset. The present study suggests a weak association between HMOX1 rs2071746 and HMOX2 rs1051308 polymorphisms and the risk to develop ET in the Spanish population.

Actividad asistencial neurológica en un hospital comarcal de reciente creación: modelo de alta eficiencia / Neurological health care activity in a recently created district hospital: model of high efficiency

Objetivo. Analizar la actividad asistencial de un hospital comarcal de reciente creación, con especial énfasis en los indicadores asistenciales en consultas externas y en actos médicos de pacientes ingresados. Pacientes y métodos. Describimos la actividad asistencial realizada por nuestra sección de neurología durante los años 2008-2013. Se comparan nuestros indicadores asistenciales de los años 2012 y 2013 (quinto y sexto año de actividad), tanto en consultas externas como en pacientes ingresados, con los de otros dos hospitales de características similares, otros tres de nivel secundario y otros cuatro de nivel terciario. Resultados. La sección de neurología de nuestro hospital fue la que realizó mayor número de primeras consultas por facultativo, tuvo el mejor índice de consultas sucesivas/primeras y el mayor porcentaje de consultas de alta resolución, tuvola menor estancia media en los dos grupos relacionados por el diagnóstico (GRD) más frecuentes en nuestra especialidad, y fue la segunda en ingresos por facultativo del GRD ‘ictus con infarto’ y la tercera en ingresos por facultativo del GRD ‘otros trastornos del sistema nervioso’. Conclusiones. Los indicadores asistenciales de la sección de neurología de nuestro hospital muestran un modelo de muy alta eficiencia, al cual sólo se aproximan los de otros dos de características y desarrollo similares al nuestro. La implantación gradual de modelos similares al de estos tres hospitales en los niveles secundario y terciario podría ser de utilidad en la mejora de su eficiencia asistencial (AU)

Aim. To analyze the neurological attention of a county hospital of recent creation, with a special emphasis in the health care indicators, both in hospital out-patients consultations and in patients admitted to the hospital. Patients and methods. We have made a descriptive analysis of the neurological attention developed by our Neurology Section between the years 2008 and 2013. We also made a comparative analysis of health care indicators corresponding to the years 2012 and 2013 (5th and 6th years of clinical activity) of our hospital with those of two other hospitals with similar features, other three hospitals of secondary level, and four of tertiary level. Results. The Neurology Section of our hospital was the best in the number of first visits divided by number of physicians, in the follow-up/first visit index, in the percentage of high-resolution visits, and was the best in the mean stay in hospital for the two most frequent diagnostic related groups (DRG) in our speciality, the second in number of hospital admissions divided by number of physicians for the DRG ‘stroke with infarction’ and the third in number of hospital admissions divided by number of physicians for the DRG ‘other nervous system disorders’. Conclusions. The health care indicators of the Neurology Section of our hospital showed a very high efficiency model of medical assistance, which was only followed by other two hospitals with similar features to ours. The gradual implementation of assistance models similar to that used in these hospitals in other of secondary or tertiary levels could be useful in theimprovement of their health care efficiency (AU)

[Neurological health care activity in a recently created district hospital: model of high efficiency]. / Actividad asistencial neurológica en un hospital comarcal de reciente creación: modelo de alta eficiencia.

AIM: To analyze the neurological attention of a county hospital of recent creation, with a special emphasis in the health care indicators, both in hospital out-patients consultations and in patients admitted to the hospital. PATIENTS AND METHODS: We have made a descriptive analysis of the neurological attention developed by our Neurology Section between the years 2008 and 2013. We also made a comparative analysis of health care indicators corresponding to the years 2012 and 2013 (5th and 6th years of clinical activity) of our hospital with those of two other hospitals with similar features, other three hospitals of secondary level, and four of tertiary level. RESULTS: The Neurology Section of our hospital was the best in the number of first visits divided by number of physicians, in the follow-up/first visit index, in the percentage of high-resolution visits, and was the best in the mean stay in hospital for the two most frequent diagnostic related groups (DRG) in our speciality, the second in number of hospital admissions divided by number of physicians for the DRG 'stroke with infarction' and the third in number of hospital admissions divided by number of physicians for the DRG 'other nervous system disorders'. CONCLUSIONS: The health care indicators of the Neurology Section of our hospital showed a very high efficiency model of medical assistance, which was only followed by other two hospitals with similar features to ours. The gradual implementation of assistance models similar to that used in these hospitals in other of secondary or tertiary levels could be useful in the improvement of their health care efficiency.

TITLE: Actividad asistencial neurologica en un hospital comarcal de reciente creacion: modelo de alta eficiencia.Objetivo. Analizar la actividad asistencial de un hospital comarcal de reciente creacion, con especial enfasis en los indicadores asistenciales en consultas externas y en actos medicos de pacientes ingresados. Pacientes y metodos. Describimos la actividad asistencial realizada por nuestra seccion de neurologia durante los años 2008-2013. Se comparan nuestros indicadores asistenciales de los años 2012 y 2013 (quinto y sexto año de actividad), tanto en consultas externas como en pacientes ingresados, con los de otros dos hospitales de caracteristicas similares, otros tres de nivel secundario y otros cuatro de nivel terciario. Resultados. La seccion de neurologia de nuestro hospital fue la que realizo mayor numero de primeras consultas por facultativo, tuvo el mejor indice de consultas sucesivas/primeras y el mayor porcentaje de consultas de alta resolucion, tuvo la menor estancia media en los dos grupos relacionados por el diagnostico (GRD) mas frecuentes en nuestra especialidad, y fue la segunda en ingresos por facultativo del GRD 'ictus con infarto' y la tercera en ingresos por facultativo del GRD 'otros trastornos del sistema nervioso'. Conclusiones. Los indicadores asistenciales de la seccion de neurologia de nuestro hospital muestran un modelo de muy alta eficiencia, al cual solo se aproximan los de otros dos de caracteristicas y desarrollo similares al nuestro. La implantacion gradual de modelos similares al de estos tres hospitales en los niveles secundario y terciario podria ser de utilidad en la mejora de su eficiencia asistencial.

TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study.

INTRODUCTION: Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. METHODS: This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. RESULTS: There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations. CONCLUSIONS: These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed.

Drug and xenobiotic biotransformation in the blood-brain barrier: a neglected issue.

Drug biotransformation is a crucial mechanism for facilitating the elimination of chemicals from the organism and for decreasing their pharmacological activity. Published evidence suggests that brain drug metabolism may play a role in the development of adverse drug reactions and in the clinical response to drugs and xenobiotics. The blood-brain barrier (BBB) has been regarded mainly as a physical barrier for drugs and xenobiotics, and little attention has been paid to the BBB as a drug-metabolizing barrier. The presence of drug-metabolizing enzymes in the BBB is likely to have functional implications because local metabolism may inactivate drugs or may modify the drug's ability to cross the BBB, thus modifying drug response and the risk of developing adverse drug reactions. In this perspective paper, we discuss the expression of relevant xenobiotic metabolizing enzymes in the brain and in the BBB, and we cover current advances and future directions on the potential role of these BBB drug-metabolizing enzymes as modifiers of drug response.

Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential search for biomarkers for this disease.

The blood-brain barrier supplies brain tissues with nutrients and filters certain compounds from the brain back to the bloodstream. In several neurodegenerative diseases, including Parkinson's disease (PD), there are disruptions of the blood-brain barrier. Cerebrospinal fluid (CSF) has been widely investigated in PD and in other parkinsonian syndromes with the aim of establishing useful biomarkers for an accurate differential diagnosis among these syndromes. This review article summarizes the studies reported on CSF levels of many potential biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the progression of the disease; (b) the possible relations of CSF total tau and phosphotau protein with the progression of PD and with the preservation of cognitive function in PD patients; (c) the possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the differential diagnosis between PD and other parkinsonian syndromes. Future multicentric, longitudinal, prospective studies with long-term follow-up and neuropathological confirmation would be useful in establishing appropriate biomarkers for PD.

An association study between Heme oxygenase-1 genetic variants and Parkinson's disease.

The blood-brain barrier (BBB) supplies brain tissues with nutrients, filters harmful compounds from the brain back to the bloodstream, and plays a key role in iron homeostasis in the human brain. Disruptions of the BBB are associated with several neurodegenerative conditions including Parkinson's disease (PD). Oxidative stress, iron deposition and mitochondrial impaired function are considered as risk factors for degeneration of the central nervous system. Heme oxygenase (HMOX) degrades heme ring to biliverdin, free ferrous iron and carbon monoxide being the rate-limiting activity in heme catabolism. The isoform HMOX1 is highly inducible in response to reactive oxygen species, which induce an increase in BBB permeability and impair its pathophysiology. Consequently, an over- expression of this enzyme may contribute to the marked iron deposition found in PD. We analyzed the HMOX1 SNPs rs2071746, rs2071747, and rs9282702, a microsatellite (GT) n polymorphism and copy number variations in 691 patients suffering from PD and 766 healthy control individuals. Copy number variations in the HMOX1 gene exist, but these do not seem to be associated with PD risk. In contrast two polymorphisms that modify the transcriptional activity of the gene, namely a VNTR (GT) n and the SNP rs2071746, are strongly associated with PD risk, particularly with the classic PD phenotype and with early onset of the disease. This study indicates that HMOX1 gene variants are associated to the risk of developing some forms of PD, thus adding new information that supports association of HMOX gene variations with PD risk.

COMT gene and risk for Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND/AIMS: Several single-nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been associated with the risk of developing Parkinson's disease (PD). We conducted a systematic review and a meta-analysis including all the studies published on PD risk related with COMT SNPs (mainly rs4680). We also reviewed the possible relationship of COMT SNPs with clinical, neuropharmacological, neurochemical, and neuroimaging features of PD. MATERIALS AND METHODS: The systematic review was conducted using several databases. Meta-analysis of the eligible studies was carried out using the software Meta-Disc 1.1.1. Heterogeneity between studies was tested using the Q-statistic. RESULTS: The meta-analysis included 24 association studies for the COMT rs4680 SNP (9719 PD patients, 14 634 controls) and the risk for PD. The frequency of allele positivity showed a significant association between rs4680 and the risk for PD in the total series, as well as homozygosity for the low-activity allele in the Asiatic population (these associations were marginal or disappeared when studies on Hardy-Weinberg disequilibrium were not considered). Global diagnostic odds ratios (95% confidence intervals) for rs4680 were 0.99 (0.94-1.04) for the total group, 0.99 (0.93-1.05) for White, and 1.05 (0.90-1.22) for Asiatic individuals. COMT genotypes could be related with a modest modification in the age at onset of PD, but its possible genotypes in excessive daytime somnolence, impulse control disorders, cognitive impairment, and neuropharmacological or neurochemical variables are unclear. CONCLUSION: The results of the meta-analysis suggest that the COMT rs4680 polymorphism is not a major determinant of either the risk for PD or clinical, neuropharmacological and neurochemical features of PD. Data on other COMT polymorphisms are scarce but do not suggest association with PD.

No association of the SLC1A2 rs3794087 allele with risk for essential tremor in the Spanish population.

BACKGROUND/AIMS: A recent genome-wide association study and other replication studies have suggested that the rs3794087 single nucleotide polymorphism in the solute carrier family 1 - glial affinity glutamate transporter-member 2 (SLC1A2) gene is associated with an increased risk for essential tremor (ET), and a replication study in an Asian cohort has shown a decreased risk for ET associated with the rs3794087T allele. We tried to replicate this association in a White Spanish population. MATERIALS AND METHODS: We analyzed the distribution of allelic and genotypic frequencies of rs3794087 in 202 patients with familial ET and 308 healthy controls using a TaqMan-based quantitative PCR assay. RESULTS: Genotypic and allelic frequencies of rs3794087 did not differ significantly between patients with ET and controls and were unrelated with the age at onset of tremor or sex. CONCLUSION: Our study suggests that SLC1A2 rs3794087 is not associated with the risk for developing familial ET in the Spanish population, thus subtracting relevance to SLC1A2 rs3794087 as a risk biomarker for ET.

Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain.

The development of clinical practice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance with regard to adverse drug reactions. The potential of pharmacogenomic biomarkers has been extensively investigated in recent years. However, several barriers to implementing the use of pharmacogenomics testing exist. We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of major gene/drug pairs. Of 11 potential barriers, the highest importance was attributed to lack of institutional support for pharmacogenomics testing, and to the issues related to the lack of guidelines. Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen. In this perspective article, we compare the relative importance of 29 gene/drug pairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutics study, and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testing.

Puntualizaciones acerca de las unidades de toxina botulínica tipo A. Réplica / No disponible

No disponible

[Treatment of severe bruxism with botulinum toxin type A]. / Tratamiento del bruxismo grave con toxina botulínica tipo A.

INTRODUCTION: The possible usefulness of botulinum toxin type A in the treatment of bruxism has not been studied exhaustively, being limited to some isolated case reports, two short case-series and a double-blind study involving a small number or patients. This article report our long-term experience in the treatment of bruxism with botulinum toxin type A. PATIENTS AND METHODS: The outcome of 19 patients with severe bruxism who underwent periodical treatment with botulinum toxin A infiltrations in both temporal and masseter muscles, using initial doses of 25 IU per muscle, during a follow-up period ranging from 0.5 to 11 years, is described. Doses were adjusted in follow-up visits according the response degree. RESULTS: None of the patients reported side-effects. Final doses ranged from 25 to 40 IU per muscle (mean: 29.7 ± 4.9 UI), and duration of the effect from 13 to 26 weeks (mean: 16.7 ± 5.1 weeks). CONCLUSION: Botulinum toxin A infiltrations are a safe and useful treatment for patients with severe bruxism.