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.

Interaction between sex and neurofilament light chain on brain structure and clinical severity in Huntington's disease.

Female Huntington's disease (HD) patients have consistently shown a faster clinical worsening than male, but the underlying mechanisms responsible for this observation remain unknown. Here, we describe how sex modifies the impact of neurodegeneration on brain atrophy and clinical severity in HD. Cerebrospinal fluid neurofilament light chain (NfL) levels were used as a biological measure of neurodegeneration, and brain atrophy was assessed by structural magnetic resonance imaging. We found that larger NfL values in women reflect higher brain atrophy and clinical severity than in men (p < 0.05 for an interaction model). This differential vulnerability could have important implications in clinical trials.

Alterations in cerebral white matter and neuropsychology in patients with cirrhosis and falls.

BACKGROUND & AIM: Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls. PATIENTS AND METHODS: Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson's Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson's Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients. RESULTS: The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson's Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05). CONCLUSIONS: With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment.

[Dopaminergic treatment in Parkinson's disease: what has each therapeutic family got to offer?]. / Tratamiento dopaminérgico en la enfermedad de Parkinson: ¿qué puede ofrecer cada familia terapéutica?

Different families of dopaminergic agents have allowed to increase the availability of dopamine within the central nervous system by different mechanisms of action. Each drug family has specific efficacious properties, as well as a different profile of adverse events. The knowledge in detail of these specificities is mandatory to avoid severe systemic or neuropsychiatric complications. Despite these limitations, the development of new drugs within the past 20 years has prolonged survival in Parkinson's disease, increasing the time with preserved daily day functionality compared with the levodopa era, when this drug was the only dopaminergic drug available. The correct combination of dopaminergic drugs with different mechanisms of action allows the management of Parkinson's disease motor symptoms within safety dose ranges, and up to day, this appears as the best algorithm to maintain functionality for longer periods of time.

TITLE: Tratamiento dopaminergico en la enfermedad de Parkinson: que puede ofrecer cada familia terapeutica?Diferentes familias de farmacos dopaminergicos han permitido aumentar el suministro de dopamina en el estriado por diferentes mecanismos. Cada familia de farmacos posee un grado de eficacia determinado, asi como un perfil de efectos secundarios especifico que debe conocerse en detalle para evitar complicaciones sistemicas y neuropsiquiatricas graves. A pesar de estas limitaciones, la disponibilidad de multiples farmacos ha permitido aumentar la supervivencia media en la enfermedad de Parkinson, con un periodo de funcionalidad en el dia a dia significativamente mas largo al que se conseguia cuando la levodopa era practicamente el unico farmaco disponible. La correcta adicion de farmacos dopaminergicos con diferentes mecanismos de accion permite tratar la enfermedad de Parkinson sin tener que llegar a dosis excesivamente altas de ninguno de ellos, lo que parece, en el momento actual, el mejor algoritmo para el control de los sintomas motores durante un periodo lo mas duradero posible.

[Candidate patient for treatment with continuous apomorphine infusion]. / Paciente candidato a tratamiento con apomorfina en infusión continua.

Subcutaneous apomorphine infusion has been shown to be effective in reducing motor fluctuations and, to a lesser extent, also the levodopa induced dyskinesias in patients with advanced Parkinson's disease (PD). Based on the literature data, the following article reviews the clinical features of PD patients in order to be considered candidates for this therapy. In general, the vast majority of patients with advanced PD can benefit from this therapy and the authors' experience suggests that it should be considered as soon as the conventional pharmacological therapy fails to significantly reduce the number of daily off hours.

[Descriptive analysis of the activity in a movement disorder unit in a tertiary hospital in Catalonia]. / Análisis descriptivo de la actividad de una unidad de trastornos del movimiento en un hospital terciario de Cataluña.

INTRODUCTION: Movement disorders are an important part of the activity of a Neurology service, but there are few studies examining their health care demand. AIMS: To analyze the first visits of the Movement Disorders Unit of the Hospital de la Santa Creu i Sant Pau in Barcelona and to compare the results with those of previous studies. PATIENTS AND METHODS: Prospective study of the first neurological assessments carried out during 2010. Demographic variables of patients were collected and diagnoses were reviewed 12 months later. RESULTS: 423 first visits were done (application rate of 1.41 per 1000 inhabitants-year): 54% females, median age 68.8 ± 14.2 years-old. 74.3% of referrals came from the family doctor. The most frequent reasons for consultation were tremor (40%) and parkinsonism-motor clumsiness (26%). The most prevalent diagnoses were Parkinson's disease (36%) and essential tremor (19%). After the first assessment, 84% of patients continued controls in the Unit. One year later, in the 8% of cases there was a change in the initial diagnosis. Taking into account the incidence of each disorder, the number of patients seen was fewer compared to the estimated (19.5 times lower), especially marked in cases of restless legs syndrome, essential tremor and Tourette syndrome. CONCLUSIONS: In our Unit the most frequent reason for consultation is tremor and the most prevalent diagnosis is Parkinson's disease. The number of patients treated is clearly lower than the estimated according to the incidence of the diseases in the population.

[Rasagiline: effectiveness and protection in Parkinson's disease]. / Rasagilina: eficacia y proteccion en la enfermedad de Parkinson.

INTRODUCTION: Parkinson's disease (PD) is the second most frequent neurodegenerative disease in the general population after Alzheimer's disease. Its diagnosis is based on the presence of characteristic motor symptoms due to the striatal dopaminergic depletion caused by progressive neuronal death in the pars compacta substantiae nigrae. Thus, not only is it necessary to restore the neurochemical deficits that are present from the initial phases of the disease onwards, but therapeutic strategies also need to be developed to stop the degenerative process. DEVELOPMENT: Rasagiline is a monoamine oxidase-B inhibitor whose dopaminergic stimulation has proved to be effective in monotherapy or in combined therapy for improving the motor symptoms in patients with PD in the initial and advanced phases. Likewise, it is also effective in diminishing motor fluctuations. CONCLUSIONS: Comparatively, rasagiline has proved to be at least as effective as entacapone in the control of motor fluctuations. With regard to the possible effect and the neuroprotective properties of rasagiline in vitro and in vivo, it is the first pharmaceutical to have displayed a change in the developmental course of PD after 72 weeks' treatment.

Cardiac (123)I-metaiodobenzylguanidine imaging allows early identification of dementia with Lewy bodies during life.

PURPOSE: Differential diagnosis between dementia with Lewy bodies (DLB) and other neurodegenerative diseases with cognitive impairment represents a clinical challenge. Due to the overlapping of symptoms, the clinical diagnosis can be modified during the prolonged follow-up of these diseases. The purpose of this study was to assess the ability of cardiac metaiodobenzylguanidine (MIBG) imaging for early identification of DLB. MATERIALS AND METHODS: Since January 2003, all patients with neurodegenerative diseases with cognitive impairment at their first visit at the Memory Unit and clinical criteria of DLB were consecutively recruited and underwent a cardiac (123)I-MIBG study. The heart-to-mediastinum ratio (HMR) and the washout rate (WR) of cardiac MIBG uptake were obtained. RESULTS: Sixty-five patients were included. After a clinical follow-up of 4 years, the progress of the disease procured a definite diagnosis in 44 (68%) patients: 19 DLB, 12 Alzheimer disease (AD), and 13 other neurodegenerative diseases with cognitive impairment. HMR was significantly decreased in DLB with respect to the other neurodegenerative diseases. WR was only significantly different between DLB and AD. The HMR cut off point of 1.36 differentiated DLB from the other dementias with a sensitivity of 94% and a specificity of 96% with an accuracy of 95%. CONCLUSIONS: Cardiac MIBG imaging performed at the time of the first clinical diagnosis of DLB can help early clinical identification or exclusion of this disease.

Usefulness of an intraoperative electrophysiological navigator system for subthalamic nucleus surgery in Parkinson's disease.

OBJECTS: The characteristics and benefits are presented of an intraoperative neurophysiological navigator computerized system developed in our center (Columbus-Track 1.0) that helps the surgical team in neuronal identification and in strategy processes in subthalamic nucleus surgery for Parkinson's disease (PD). METHODS: The navigator consists of three assembled parts: (1) neuronal identification, based on wavelet processing, filtering and gaussian characteristics of the signal; (2) track identification, based on anatomical coincidence, somatomotor response and microstimulation quotient, and (3) strategy, coordinating correction for the next track. A retrospective comparative study was performed with 15 consecutive PD patients (30 targets) operated without the system and the next 15 consecutive patients operated with the aid of the system. With the aid of the computerized navigation system, a significant reduction in the number of tracks was observed (t = -2.503, p = 0.0015), with a mean difference of 1.2 tracks per hemisphere. A non-significant reduction in the total intervention time was also observed, with a mean difference of 20 min per hemisphere (t = -1.418, p = 0.161). CONCLUSIONS: The intraoperative computerized navigation system can aid the surgical team in better identifying the neuronal signal and in defining the optimal track to achieve the target.