Fused in Sarcoma (FUS) gene mutations are not a frequent cause of essential tremor in Europeans.

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population.

Lack of association of LINGO1 rs9652490 and rs11856808 SNPs with familial essential tremor.

BACKGROUND: Essential tremor (ET) is a frequent movement disorder with a substantial family aggregation. A genome-wide association study has recently shown that LINGO1 gene variants are associated with increased risk of ET. METHODS: We intended to replicate these findings by genotyping rs9652490 and rs11856808 in a series of 226 familial ET subjects and 1117 healthy controls from referral movement disorder clinics in Spain. RESULTS: We were unable to replicate the association between LINGO1 variants and familial ET. CONCLUSIONS: Our results indicate that the LINGO1 variants analyzed are not a major risk factor for developing familial ET in our population, which suggests the existence of other unknown genetic risk factors responsible for familial ET in the Spanish population.

Posturas de manos seudotónicas contralaterales a una metástasis de la corteza de asociación parietal / Pseudodystonic hand posturing contralateral to a metastasis of the parietal association cortex

Se comunica el caso de una paciente de 56 años de edad, con historia previa de cáncer de mama intervenido y tratado 3 años antes, que desarrolló un trastorno de la coordinación motora mientras tocaba el piano. La exploración neurológica reveló una apraxia cinética y una leve disminución de la sensibilidad posicional en la porción distal de la extremidad superior derecha. Sin embargo, el signo neurológico más sobresaliente fue una postura distónica de la mano derecha, desencadenada únicamente cuando la paciente mantenía sus extremidades superiores extendidas hacia delante con los ojos cerrados. La RM demostró una lesión metastásica en la corteza parietal posterior izquierda. La asociación de posturas distónicas en casos de lesiones de la corteza de asociación parietal indica que la distonía puede deberse al daño de estructuras cerebrales corticales alejadas de los ganglios basales. Además, proporciona elementos de apoyo a la hipótesis de que los sistemas sensoriales pueden desempeñar un papel en el origen de ciertos estados hipercinéticos, como las distonías y las atetosis (AU)

Alzheimer's risk associated with human apolipoprotein E, alpha-2 macroglobulin and lipoprotein receptor related protein polymorphisms: absence of genetic interactions, and modulation by gender.

Apolipoprotein E (apoE), the lipoprotein receptor related protein (LRP) and alpha-2 macroglobulin (alpha2M) have been proposed as a functional complex involved in amyloid clearance, a crucial event for Alzheimer's disease development. In this work, we present an epidemiological approach aimed to study the interactions among these genes, age and gender. This approach did not reveal significant associations between the genes; however, the present study indicated that the risk associated with APOE promoter and LRP gene polymorphisms is modulated by gender.

Late-onset isolated gelastic epilepsy secondary to entrapment of the right temporal horn.

The case is reported of a 70 year-old woman with isolated gelastic seizures (GS) secondary to a rare form of focal obstructive hydrocephalus, called entrapment of the lateral horn. Laughing attacks started five years after conservative intracranial surgery for a giant basilar aneurysm. Serial neuro-imaging studies revealed a progressive cystic enlargement of the right temporal horn, damaging the baso-lateral temporal cortex. An ictal EEG recording confirmed the epileptic nature of laughing attacks, and showed that the epileptiform activity originated in the right temporal lobe. Complete seizure control was achieved with current doses of diphenilhydantoin. Analysis of this and other previously reported cases, indicate that symptomatic GS may originate in multiple sites of both cerebral hemispheres, although related to the limbic system. The fact that this case exhibited isolated GS stresses the importance of the baso-lateral temporal cortex in the genesis of this type of seizures.

Whipple's disease with isolated central nervous system symptomatology diagnosed by molecular identification of Tropheryma whippelii in peripheral blood.

We report a new case of Whipple's disease (WD) confined to the central nervous system. The patient presented with ataxia, ophthalmoplegia, hypersomnia, hemiparesis and generalized myorhythmia. The diagnosis was confirmed by identification of specific sequences of the causal agent of WD, the actinobacteria Tropheryma whippelii (TW), by PCR of DNA extracted from peripheral blood. An epidemiological survey of TW in patients with dementia suggests that WD is an uncommon cause of dementia in our population. Molecular methods may allow rapid identification of TW in peripheral fluids, and non-invasive diagnosis of this disorder.

Epilepsia gelástica aislada de inicio tardío secundaria a atrapamiento del asta temporal derecha / Late-onset isolated gelastic epilepsy secondary to entrapment of the right temporal horn

Se comunica el caso de una paciente de 70 años con crisis gelásticas (CG) aisladas secundarias a una forma rara de hidrocefalia focal obstructiva, denominada atrapamiento del asta temporal. Las crisis de risa aparecieron cinco años después de una intervención quirúrgica conservadora sobre un aneurisma basilar gigante. Los estudios seriados de neuroimagen revelaron un ensanchamiento quístico progresivo del asta temporal derecha, que dañaba la región inferolateral de la corteza temporal. El registro EEG durante una crisis confirmó su carácter epiléptico y mostró que las descargas se originaban en el lóbulo temporal derecho. Las crisis se controlaron completamente con dosis habituales de difenilhidantoína. El análisis de este y otros casos de CG sintomáticas indica que estas pueden originarse en lugares distintos de ambos hemisferios cerebrales, aunque relacionados con el sistema límbico. El hecho de que este caso presentase CG aisladas destaca la importancia de la corteza temporal infero-lateral en la génesis de este tipo de crisis epilépticas (AU)

La enfermedad de whipple con sintomatología aislada del sistema nervioso central diagnosticada por identificación molecular de tropheryma whippelii en sangre periférica / Whipple's disease with isolated central nervous system symptomatology diagnosed by molecular identification of Tropheryma whippelii in peripheral blood

Se comunica un nuevo caso de enfermedad de Whipple (EW), limitada al sistema nervioso central, en un paciente de 65 años de edad, cuyo proceso se inició con un cuadro de ataxia, oftalmoplejía, hipersomnia, hemiparesia y miorritmia. El diagnóstico se confirmó gracias a la identificación de las secuencias genómicas específicas del agente causal de la EW, la actinobacteria Tropheryma whippelii, mediante amplificación en cadena del ADN total extraído de la sangre periférica. La aplicación de este método al análisis de una muestra epidemiológica de pacientes con demencia de evolución rápida sugiere que la EW es una causa rara de demencia en nuestra población. Los métodos moleculares pueden permitir la identificación rápida del bacilo responsable de la EW en fluidos periféricos y el diagnóstico no invasivo de esta enfermedad. (AU)

A polymorphism in the tau gene associated with risk for Alzheimer's disease.

Searching for tau genetic variations which could be associated with risk for Alzheimer's disease (AD), we have performed a mutational analysis of a region containing the whole exon 11 of the tau gene, which encodes a microtubule binding region critical for tau self-assembly, and we have found a biallelic polymorphism at position +34 of intron 11 (IVS11 + 34G/A). We have analyzed the allelic frequencies of this polymorphism in a case-control sample (167 clinically diagnosed AD and 194 controls) and found that the presence of any G allele (genotypes AG + GG) is associated with a five-fold AD risk in individuals carrying the apolipoprotein E4 allele, strongly suggesting that the combined effect of tau and apoE is relevant in relation with AD pathogenesis.

Pseudodystonic hand posturing contralateral to a metastasis of the parietal association cortex.

A 56 year-old patient, with a history of surgically removed breast cancer three years earlier, presented with incoordination of hand movements while playing piano. Neurological examination disclosed mild position sensory loss and limb-kinetic apraxia of the distal part of the right upper extremity. The most conspicuous neurological sign was a dystonic posturing of the right hand, which was only elicited when the patient outstretched her arms with the eyes closed. MRI revealed a metastatic lesion involving the left parietal cortex. The association of focal dystonic postures with lesions of the parietal association cortex indicates that dystonia may feature damage of brain cortical areas far from the basal ganglia. In addition, this provides support to the hypothesis that impairment of sensory pathways may play a role in the origin of some hyperkinetic movement disorders, such as dystonia and athetosis.

Slow allotypic variants of the NAT2 gene and susceptibility to early-onset Parkinson's disease.

OBJECTIVE: To determine the frequency and the linkage distribution of seven mutations at the polymorphic gene coding for the arylamine N-acetyl transferase (NAT2; EC 2.3.1.5) in 121 unrelated patients with sporadic PD and in 121 unrelated healthy volunteers. METHODS: The study was performed with mutation-specific PCR using genomic DNA obtained from blood of the probands. RESULTS: Comparison of the NAT2 genotypes of the overall PD patients and control subjects did not indicate statistically significant differences. However, patients with early-onset PD (onset before the age of 50 years, n=37) showed a higher frequency of slow-acetylation genotypes (78.4% patients) compared with both healthy control subjects (55.4%) and with late-onset (onset after 51 years of age, n=84) PD patients (54.8%). Such a difference was statistically significant (p < 0.015) and was the result of a homogeneous increase in the frequency of slow-acetylation alleles. All subgroups analyzed in the study were in Hardy-Weinberg equilibrium for mutations at the NAT2 gene. CONCLUSIONS: Slow-acetylation-mutated alleles may be considered low-penetrance genes in early-onset PD pathogenesis, with a relative risk ratio for individuals with slow-acetylation genotype of 2.92 (95% CI, 1.26 to 6.78). This study provides evidence for the interaction of genetic and environmental factors in the etiology of sporadic PD.

CYP2D6 polymorphism is not associated with essential tremor.

Recent reports have shown an association between cytochrome P450IID6 (CYP2D6) polymorphism and Parkinson's disease. We investigated the association between this polymorphism and the risk for developing essential tremor (ET). Leukocytic DNA from 91 unrelated ET patients and a control group of 258 unrelated healthy individuals was studied for the occurrence of eight different CYP2D6 allelic variants by using allele-specific PCR amplification Xbal and EcoRI-RFLP's analyses. The prevalence for these allelic variants in the ET and control groups were, respectively: CYP2D6*1 76.9 and 78.7%, CYP2D6*2 0.5 and 0.2%, CYP2D6*3 0 and 1%, CYP2D6*4 12.1 and 12.2%, CYP2D6*5 1.6 and 1.7%, CYP2D6*9 4.4 and 2.9%, CYP2D6*2x2 4.4 and 3.2%. The prevalence of subjects with absent CYP2D6 activity (those carrying two defect genes) was 1.1 and 3.1% in ET and control groups, respectively. Both groups studied were in Hardy-Weinberg equilibrium. These results indicate that mutations at the CYP2D6 gene do not seem to be a major factor in determining susceptibility to ET, and reinforces the view that ET and parkinsonism are distinct conditions.

Cerebral amyloid angiopathies.

The cerebral amyloid angiopathies comprise a heterogeneous group of disorders that are characterized clinically by ischaemic and/or haemorrhagic strokes, and histologically by deposition of amyloid in the wall of leptomeningeal and cerebral cortical blood vessels. On the basis of the molecular composition of the amyloid, two forms can be distinguished. Cystatin C amyloid angiopathy is a rare autosomal dominant disorder confined to several families from Iceland. beta-amyloid cerebral amyloid angiopathies may be hereditary or sporadic, and share clinical, pathological and biochemical features with Alzheimer's disease. Both types of vascular amyloid derive from precursor proteins synthesized in situ by astrocytes (cystatin C) or smooth muscle cells (beta-amyloid), and induce progressive degeneration of smooth muscle cells, blood vessel rupture and haemodynamic changes. In recent years, it has been reported that mutations underlying both types of hereditary cerebral amyloid angiopathy directly involve the gene encoding the precursor protein. These findings have increased our understanding of the amyloidogenic mechanisms and allowed preclinical diagnosis. Nevertheless, the aetiopathogenetic factors involved in the more frequent sporadic form of amyloid angiopathy remain unknown.

[Genetic neuroepidemiology]. / Neuroepidemiología genética.

Many human diseases result from the combined effect of several genetic and non genetic factors. Thanks to the development of powerful tools for molecular analysis, researchers in recent years have begun to uncover the genes behind such multifactorial neurologic and systemic disorders as Alzheimer's and Parkinson's diseases and diabetes. Likewise investigators have been able to confirm that the course of these diseases and their clinical manifestations depend on the concurrence in the same individual of specific genetic variations. Because each gene confers a certain degree of predisposition to a specific disease, they are therefore called susceptibility genes. The search for and analysis of susceptibility genes in defined populations is termed genetic epidemiology. This multidisciplinary science is providing valuable data that further our understanding and ability to diagnose of disorders of the nervous system. It also enables us to predict the clinical course of disease in a given patient with a high degree of reliability, even when no clinical signs are yet evident.

Screening Parkinson's disease: a validated questionnaire of high specificity and sensitivity.

A questionnaire designed to screen Parkinson's disease (PD) in literate populations has been developed. It consists of nine questions, self-administered at medical facilities or by mail, and a scale of weights for ascribing scores to specific questions when the answer is positive. The questions were chosen to be symptom specific for PD and the weights were determined from answers provided by 37 PD patients in a neurological outpatient clinic. The questionnaire sensitivity was tested on a different PD population from the same outpatient clinic--50 individuals--and the specificity on a group of 100 ophthalmological patients. The sensitivity was 100% and the specificity was 100%. Three individuals who screened positive among the 100 ophthalmological patients were assessed and given a new diagnosis of PD. This questionnaire therefore constitutes an instrument that should prove valuable as the first stage of a door-to-door survey. It has high sensitivity and specificity.