Cerebellar Cognitive Affective Syndrome in Costa da Morte Ataxia (SCA36).

SCA36 is an autosomal dominant spinocerebellar ataxia (SCA) affecting many families from Costa da Morte, a northwestern region of Spain. It is caused by an intronic GGCCTG repeat expansion in NOP56. In order to characterize the cognitive and affective manifestations of this cerebellar disease, a group of 30 SCA36 mutation carriers (11 preataxic and 19 ataxic patients) were assessed with a comprehensive battery of standardized tests. Phonological verbal fluency - but not semantic fluency - was already mildly impaired in preataxic subjects. In ataxic patients, both phonological and semantic fluencies were significantly below normal. Depression, while more frequent and prominent in ataxic patients, was also often present in the preataxic stage. This is the first systematic study supporting the presence of a mild cerebellar cognitive and affective syndrome in SCA36. Routine evaluation of cognitive and emotional spheres in SCA36 patients as well as asymptomatic mutation carriers should allow early detection and timely therapeutic intervention.

La ataxia espinocerebelosa 36 (SCA36): «Ataxia da Costa da Morte» / Spinocerebellar ataxia 36 (SCA36): «Costa da Morte ataxia»

Introducción-objetivos: Describir la historia del descubrimiento de la SCA36 y revisar los conocimientos actuales sobre esta entidad que, por un efecto fundador, ha pasado a ser la SCA más prevalente en Galicia (España). Desarrollo: La SCA36 es una enfermedad heredodegenerativa autosómica dominante, de inicio tardío y lenta progresión, que cursa con ataxia cerebelosa, hipoacusia neurosensorial y discreta afectación de neuronas motoras (atrofia y fasciculaciones linguales y signos piramidales leves). Ha sido descrita inicialmente en Japón (ataxia del río Asida) y en Galicia (ataxia da Costa da Morte). Se produce por una mutación (expansión intrónica de hexanucleótido) en el gen NOP56, localizado en 20p13. En los estudios de resonancia magnética se observa inicialmente atrofia vermiana superior, que se extenderá al resto del cerebelo y finalmente a la porción bulboprotuberancial del tronco cerebral, sin lesiones de sustancia blanca. Las velocidades de conducción nerviosa periférica son normales y en los estudios de potenciales evocados somatosensoriales se detecta retraso de la conducción al estimular en miembros inferiores. En los pacientes con hipoacusia, suele encontrarse en la audiometría una caída > 40dB a partir de 2.400Hz; también se observa ausencia de ondas I y II en los estudios de potenciales evocados auditivos. Conclusiones: La ataxia da Costa da Morte-SCA36 es la SCA más prevalente en Galicia (España). Dada la alta tasa de emigración de nuestra comunidad autónoma, se espera que se diagnostiquen nuevos casos en diversas latitudes, sobre todo en América Latina. Ahora está disponible el diagnóstico genético para pacientes con clínica y portadores asintomáticos. Dado el alto número de pacientes en riesgo de sufrir la enfermedad, continuamos con las investigaciones para aclarar los mecanismos moleculares patogénicos y poder encontrar una terapéutica (AU)

Introduction-objective: To describe the history of the discovery of SCA36 and review knowledge of this entity, which is currently the most prevalent hereditary ataxia in Galicia (Spain) owing to a founder effect. Development: SCA36 is an autosomal dominant hereditary ataxia with late onset and slow progression. It presents with cerebellar ataxia, sensorineural hearing loss, and discrete motor neuron impairment (tongue atrophy with denervation, discrete pyramidal signs). SCA36 was first described in Japan (Asida River ataxia) and in Galicia (Costa da Morte ataxia). The condition is caused by a genetic mutation (intronic hexanucleotide repeat expansion) in the NOP56 gene on the short arm of chromosome 20 (20p13). Magnetic resonance image study initially shows cerebellar vermian atrophy that subsequently extends to the rest of the cerebellum and finally to the pontomedullary region of the brainstem without producing white matter lesions. Peripheral nerve conduction velocities are normal, and sensorimotor evoked potential studies show delayed conduction of stimuli to lower limbs. In patients with hearing loss, audiometric studies show a drop of > 40dB in frequencies exceeding 2,500Hz. Auditory evoked potential studies may also show lack of waves I and II. Conclusions: Costa da Morte ataxia or SCA36 is the most prevalent SCA in the Spanish region of Galicia. Given the region's history of high rates of emigration, new cases may be diagnosed in numerous countries, especially in Latin America. Genetic studies are now available to patients and asymptomatic carriers. Since many people are at risk for this disease, we will continue our investigations aimed at elucidating the underlying pathogenic molecular mechanisms and discovering effective treatment (AU)

PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia.

PLA2G6-associated neurodegeneration (PLAN) and hereditary spastic paraplegia (HSP) are 2 groups of heterogeneous neurodegenerative diseases. In this study, we report PLA2G6 gene mutations in 3 families from Turkey, Morocco, and Romania. Two affected Turkish siblings presenting HSP adds the disease to PLAN phenotypes. They were homozygous for the PLA2G6 missense c.2239C>T, p.Arg747Trp variant and the ages of onset were 9 and 21. Parkinsonism, dystonia or cognitive decline were not the clinical elements in these patients contrary to the cases that has been previously reported with the same variant, however, iron accumulation was evident in their cranial magnetic resonance imaging. The Moroccan patient was homozygous for a novel missense c.1786C>T, p.Leu596Phe variant and the Romanian patient had 2 novel mutations; c.1898C>T, p.Ala633Val and c.1765_1768del, p.Ser589ThrfsTer76. Both of these patients conformed better to childhood onset PLAN with the age of onset at 4 and 7 years, respectively. Interestingly, all identified mutations were affecting the highly conserved patatin-like phospholipase domain of the PLA2G6 protein.

Exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia.

Hereditary spastic paraplegias constitute a heterogeneous group of neurodegenerative diseases encompassing pure and complicated forms, for which at least 52 loci and 31 causative genes have been identified. Although mutations in the SPAST gene explain approximately 40% of the pure autosomal dominant forms, molecular diagnosis can be challenging for the sporadic and recessive forms, which are often complicated and clinically overlap with a broad number of movement disorders. The validity of exome sequencing as a routine diagnostic approach in the movement disorder clinic needs to be assessed. The main goal of this study was to explore the usefulness of an exome analysis for the diagnosis of a complicated form of spastic paraplegia. Whole-exome sequencing was performed in two Spanish siblings with a neurodegenerative syndrome including upper and lower motor neuron, ocular and cerebellar signs. Exome sequencing revealed that both patients carry a novel homozygous nonsense mutation in exon 15 of the SPG11 gene (c.2678G>A; p.W893X), which was not found in 584 Spanish control chromosomes. After many years of follow-up and multiple time-consuming genetic testing, we were able to diagnose these patients by making use of whole-exome sequencing, showing that this is a cost-efficient diagnostic tool for the movement disorder specialist.

Tratamiento de los trastornos de la marcha en la enfermedad de Parkinson / Treatment of gait disorders in Parkinson's disease

Se observa un interés creciente por el estudio de los síntomas extranígricos de la enfermedad de Parkinson, como las alteraciones de la marcha, que conllevan una importante disminución de la calidad de vida. La marcha es un proceso complejo cuya afectación puede explicarse por la suma de elementos como hipocinesia, asimetría en el movimiento de ambos hemicuerpos, disfunción ejecutiva, alteraciones en la sensibilidad propioceptiva, factores ambientales y emocionales. En la regulación de la marcha y la postura están implicadas diversas estructuras cerebrales y neurotransmisores que en la enfermedad de Parkinson tienen alterada su activación. En las fases iniciales los trastornos de la marcha son controlados aceptablemente con fármacos dopaminérgicos pero la respuesta a estos medicamentos no es satisfactoria en fases avanzadas, lo cual ha llevado a investigar sustancias con otros mecanismos de acción (metilfenidato, dihidroxifenilserina, anticolinesterásicos, memantina, inhibidores selectivos de los receptores de serotonina, entre otros) y tratamientos no farmacológicos como cirugía (estimulación cerebral profunda del núcleo subtalámico y del pedunculopontino), fisioterapia y acupuntura (AU)

There is currently a growing interest in the study of the extra-nigral symptoms of Parkinson's disease, such as gait disorders, which result in an important reduction in quality of life. Walking is a complex process and the problems affecting it can be explained by the sum of elements like hypokinesia, asymmetry in the movement of the two halves of the body, executive dysfunction, alterations affecting proprioceptive sensitivity, and environmental and emotional factors. The activation of a number of different brain structures and neurotransmitters involved in the regulation of gait and posture is altered in Parkinson's disease. In the early phases gait disorders are controlled to an acceptable extent with dopaminergic drugs, but the response to these agents is not satisfactory in advanced phases. This has led researchers to look for substances with other mechanisms of action (methylphenidate, dihydroxyphenylserine, anticholinesterases, memantine and selective serotonin receptor inhibitors, among others) and non-pharmacological treatments such as surgery (deep brain stimulation of the subthalamic nucleus and of the pedunculopontine), physiotherapy and acupuncture (AU)

Bases anatómicas, fisiopatológicas y neuroquímicas de los síndromes rígido-acinéticos / Anatomical, pathophysiological and neurochemical bases of rigid-akinetic syndrome

Introducción. Los síndromes rígido-acinéticos incluyen un grupo heterogéneo de patologías agrupados por una serie de síntomas comunes en las esferas motora, cognitiva y emocional. Desarrollo. Los ganglios basales están constituidos por un grupo de estructuras anatómicamente dispersas que se conectan entre sí y con diversas estructuras formando un entramado de redes funcionales. Las lesiones en estos circuitos producen síntomas en las esferas motora, cognitiva y emocional. En la enfermedad de Parkinson, el síndrome rígido-acinético más conocido y estudiado, actualmente sólo pueden explicarse del conjunto de sus síntomas el temblor y la bradicinesia. Los síndromes rígido-acinéticos se consideran hoy enfermedades neurodegenerativas que afectan a múltiples estructuras y sistemas del sistema nervioso central y periférico. Una gran parte de estos pueden agruparse dentro de las sinucleinopatías y las taupatías, aunque en ocasiones los hallazgos anatomopatológicos entre ambas se solapan. Conclusiones. Es preciso un mayor conocimiento del funcionamiento del sistema nervioso y los procesos de degeneración neuronal para poder obtener nuevas estrategias terapéuticas más eficaces (AU)

Introduction. The rigid-akinetic syndromes include a heterogeneous collection of pathologies grouped by a series of common symptoms that appear in the motor, cognitive and emotional spheres. Development. The basal ganglia are made up of a group of anatomically dispersed structures that are nonetheless connected to each other and with several other structures to form a cluster of functional networks. Lesions in these circuits produce symptoms in the motor, cognitive and emotional spheres. Of all the syndromes that occur in Parkinson's disease, which is the best-known and most widely studied rigid-akinetic syndrome, only tremor and bradykinesia can presently be explained. Rigid-akinetic syndromes are nowadays considered to be neurodegenerative diseases that affect a number of structures and systems within the central and peripheral nervous system. Many of these can be included within the groups of synucleinopathies and tauopathies, although on occasions the pathological findings overlap between the two. Conclusions. Further knowledge of the functioning of the nervous system and the processes involved in neuronal degeneration is needed to be able to produce new, more effective therapeutic strategies (AU)

Utilidad de los niveles de colestanol en el diagnóstico y seguimiento de los pacientes con xantomatosis cerebrotendinosa / Usefulness of cholestanol levels in the diagnosis and follow-up of patients with cerebrotendinous xanthomatosis

Introducción: la xantomatosis cerebro-tendinosa (XCT) es una enfermedad autosómica recesiva producida por un déficit de la enzima 27-hidroxilasa. Como consecuencia, existe una deficiencia de ácido quenodeoxicólico y una sobreproducción de colestanol que se deposita en los tejidos. Clínicamente cursa con cataratas, diarrea, xantomas y diferentes síntomas neurológicos. A pesar de que los niveles de colestanol se emplean en el diagnóstico de la XCT, se desconoce su correlación con la clínica y el pronóstico. Métodos: se han revisado 14 pacientes afectos de XCT, diagnosticados entre 1995 y 2008 en dos centros de referencia para el diagnóstico genético, en los que se había determinado el colestanol. Se han estudiado los principales datos demográficos, clínicos y terapéuticos y su posible relación con los niveles de colestanol. Resultados: la media de los niveles de colestanol al diagnóstico fue de 106μmol/ l. No se encontró ninguna relación entre el colestanol plasmático y los diferentes síntomas neurológicos, ni con el grado de discapacidad al diagnóstico medido mediante la EDSS. Tras la instauración del tratamiento se obtuvo una reducción significativa del colestanol plasmático en todos los casos (reducción media de 91μmol/ l en una media de 34 meses), a pesar de lo cual sólo un paciente se estabilizó clínicamente. Conclusiones: la presencia de niveles elevados de colestanol es muy útil para el diagnóstico de la XCT, pero no tiene valor pronóstico (no se correlaciona con la situación funcional). Su normalización no siempre se acompaña de una estabilización clínica, pero su monitorización puede ser útil para el ajuste del tratamiento (AU)

Introduction: cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease caused by a deficiency of mitochondrial enzyme sterol 27-hydrolylase. Such a deficiency results in a reduced production of chenodeoxycholic acid and in an increased formation of cholestanol. It is clinically characterized by cataracts, diarrhoea, xanthomas, premature arteriosclerosis and a number of progressive neurological symptoms. Although cholestanol levels are used for the diagnosis of CTX, their correlation with the clinical symptoms and their prognostic usefulness have not been assessed so far. Methods: we reviewed 14 CTX patients diagnosed between 1995 and 2008 in two reference centres for the genetic diagnosis of this disorder, whose cholestanol levels had been recorded. We studied the main demographic, clinical and therapeutical data and their correlation with plasma cholestanol levels. Results: the average cholestanol level at diagnosis was 105.8μmol/l. These levels did not correlate with any neurological symptoms or with disability at diagnosis scored by the EDSS. After treatment, all patients achieved a significant reduction in plasma cholestanol levels (average reduction of 91μmol/l in an average follow-up of 34 months), although only one patient remained clinically stable. Conclusions: high cholestanol levels are very useful for diagnosis of CTX but they do not have a prognostic value (they do not correlate with severity). Normalisation of cholestanol levels is not always associated with clinical stabilisation. However, follow-up of cholestanol levels can be useful for the dose adjustment (AU)

Possible association of the tau H1/H1 genotype with primary progressive aphasia.

The authors screened for tau gene mutations and polymorphisms to determine whether genetic variation at or near the tau locus contributes to the development of primary progressive aphasia (PPA). No mutations were detected in 25 patients with PPA. However, a significant overrepresentation of the tau H1/H1 genotype, also found in progressive supranuclear palsy and corticobasal degeneration, was found in the PPA group. Whether tau haplotypes have a primary causal role or whether they affect the topology of neurodegeneration remains to be determined.