Jacqueline Medrano Montero

Progression of early features of spinocerebellar ataxia type 2 in individuals at risk: a longitudinal study

BACKGROUND The effects of ATXN2 expansion on the nervous system arise before the cerebellar syndrome can be diagnosed; however, progression of the underlying early clinical manifestations is unknown. We aimed to assess progression of the main clinical features in early stages of the spinocerebellar ataxia type 2 (SCA2). METHODS We did this longitudinal study between Aug 12, 1986, and Sept 3, 2013, in carriers and non-carriers of the SCA2 mutation. We enrolled participants aged 6-60 years who were asymptomatic offspring or siblings of patients with SCA2. Participants were repeatedly assessed (two to seven times) until they presented definite cerebellar syndrome. All participants underwent standardised neurological examinations and electrophysiological (nerve conduction tests and somatosensory evoked potentials) and genetic assessments. FINDINGS We enrolled 40 (73%) of 55 eligible participants to the baseline assessment, of whom 21 (13 women and eight men) were carriers of the SCA2 mutation, and 19 (14 women and five men) were non-carriers. Muscle cramps and sensory abnormalities were the most common clinical features in carriers (n=17 [81%] for both features) compared with controls (n=3 [16%] and n=4 [21%], respectively; χ(2)=84·58; p<0.0001, and χ(2)=72·03; p<0·0001, respectively) Both features showed a notable worsening over time and, in 17 (81%) carriers, age at onset was inversely correlated to CAG repeats (cramps: r -0·76, p=0·0004; sensory abnormalities: r -0·77, p=0·0004). Hyper-reflexia was associated with long time to ataxia onset (mean 5·71 years [SD 5·03]), whereas hyporeflexia was associated with short time (median 1·29 years [range 1-3]). Electrophysiological recordings obtained between 5 and 8 years before ataxia in 11 (52%) carriers showed reduced sensory amplitudes for median nerve (10·34 uV [SD 5·07]) and prolonged mean P40 latency (39·31 ms [2·40]) compared with age-matched and sex-matched controls (20·72 uV [9·08 uV]; p=0·0085, and 35·60 ms [2·05]; p=0·0023, respectively). INTERPRETATION Early features of SCA2 are detectable before the onset of the cerebellar syndrome, and are associated with expanded CAG repeats and the time to onset of cerebellar syndrome. These findings could aid early diagnosis and genetic counselling, and also offer physiopathological insights that could help in the implementation of clinical trials in early stages of the disease. FUNDING Cuban Ministry of Public Health.

Progression markers of Spinocerebellar Ataxia 2. A twenty years neurophysiological follow up study

Nerve conduction is profoundly affected in Spinocerebellar ataxia 2 (SCA2) even before the onset of the disease, but there is no information regarding its progression to the final stage of SCA2. In order to study the progression patterns of nerve conduction abnormalities in SCA2 we performed a prospective follow up evaluation of sensory and motor conduction in 21 SCA2 mutation carriers-initially presymptomatics- and 19 non-SCA2 mutation carriers during 20years. The earliest electrophysiological alterations were the reduction of sensory amplitudes in median and sural nerves, which could be found 8 to 5years prior disease onset and in the last 4years of the preclinical stage respectively. These abnormalities were followed by the increase of sensory latencies and decrease of conduction velocities. Sensory amplitudes progressively decreased during the follow-up clinical stage, rendering almost all patients with abnormal amplitudes and lack of sensory potentials, with faster progression rates in patients with larger CAG repeat lengths. Peripheral motor nerves showed the later involvement. These findings were used to define three distinct stages that describe the progression of the peripheral neuropathy. We suggest that sensory amplitudes could be useful biomarkers to assess the progression of peripheral nerve involvement and therefore to evaluate future clinical trials of therapeutic agents.

Sleep Disorders in Spinocerebellar Ataxia Type 2 Patients

Background: Sleep disturbances are common features in spinocerebellar ataxias (SCAs). Nevertheless, sleep data on SCA2 come from scarce studies including few patients, limiting the evaluation of the prevalence and determinants of sleep disorders. Objective: To assess the frequency and possible determinants of sleep disorders in the large and homogeneous SCA2 Cuban population. Methods: Thirty-two SCA2 patients and their age- and sex-matched controls were studied by video-polysomnography and sleep interviews. Results: The most striking video-polysomnography features were rapid eye movement (REM) sleep pathology and periodic leg movements (PLMs). REM sleep abnormalities included a consistent reduction of the REM sleep percentage and REM density as well as an increase in REM sleep without atonia (RWA). REM sleep and REM density decreases were closely related to the increase in ataxia scores, whereas the RWA percentage was influenced by the cytosine-adenine-guanine (CAG) repeats. PLMs were observed in 37.5% of cases. The PLM index showed a significant association with the ataxia score and disease duration but not with CAG repeats. Conclusions: REM sleep pathology and PLMs are closely related to SCA2 severity, suggesting their usefulness as disease progression markers. The RWA percentage is influenced by the CAG repeats and might thus be a sensitive parameter for reflecting polyglutamine toxicity. Finally, as PLMs are sensible to drug treatment, they represents a new therapeutic target for the symptomatic treatment of SCA2.

Subtle rapid eye movement sleep abnormalities in presymptomatic spinocerebellar ataxia type 2 gene carriers.

Rapid eye movement (REM) sleep disorders are commonly associated to patients with spinocerebellar ataxia type 2 (SCA2); however, these abnormalities have not been studied in presymptomatic gene carriers. To determine whether the REM sleep pathology is detectable before clinical manifestation of SCA2 and evaluate it as a preclinical biomarker, we studied 36 presymptomatic SCA2 individuals and 36 controls by video‐polysomnography (VPSG) and sleep questionnaires. Presymptomatic subjects showed significant decrease of REM sleep percentage, REMs density, total sleep time, and sleep efficiency. Aging effect on REM sleep percentage was significant in both groups. There was no correlation between cytosine‐adenine‐guanine (CAG) repeat length and REM sleep. Our findings identified the REM sleep pathology as a prominent herald sign of SCA2, conferring a special importance to VPSG as a sensitive neurophysiological tool to detect early changes associated with SCA2, which contributes to the understanding of disease pathophysiology and the development of therapeutic trials focused on the preclinical disease stage.

Abnormal corticospinal tract function and motor cortex excitability in non-ataxic SCA2 mutation carriers: A TMS study.

OBJECTIVE To evaluate if the corticospinal tract is affected in the prodromal stage of spinocerebellar ataxia type 2 (SCA2), prior to development of the cerebellar syndrome. METHODS A cross-sectional study was conducted in 37 non-ataxic SCA2 mutation carriers and in age- and sex-matched healthy controls. All subjects underwent clinical assessment and transcranial magnetic stimulation to determine corticospinal tract integrity to the right abductor pollicis brevis and tibialis anterior muscles. RESULTS Non-ataxic SCA2 mutation carriers showed significantly higher resting and active motor thresholds for both muscles, and prolonged cortical silent periods and central motor conduction times (CMCT), compared to controls. CMCT to the tibialis anterior correlated directly with CAG repeat size, and inversely with predicted time to ataxia onset. CONCLUSION Findings provide novel electrophysiological evidence for affection of the corticospinal tract and motor cortex in prodromal SCA2. Slowed conduction in the corticospinal tract to the lower limbs reflects polyglutamine neurotoxicity, and predicts time to ataxia onset. SIGNIFICANCE Identification of corticospinal tract damage and decreases motor cortical excitability in the prodromal stage of SCA2 allows early disease monitoring. This will become important as soon as effective neuroprotective treatment will be available.

Central motor conduction time as prodromal biomarker in spinocerebellar ataxia type 2.

One important current focus of research in spinocerebellar ataxias (SCAs) is the characterization of the prodromal disease stage that provides novel insight into the SCAs pathogenesis, which might offer early treatment and provides prodromal biomarkers that serve as outcome measures in future interventional trials. In the case of SCA2, the existence of a large and homogeneous population of families in Cuba has allowed us to characterize the prodromal stage comprehensively. Nevertheless, evidence about corticospinal tract involvement before ataxia onset is scarce and has been demonstrated only clinically by the presence of hyperreflexia in 35% to 45% of cases. Here we performed a cross-sectional study of the corticospinal tract in 37 nonataxic SCA2 mutation carriers and their ageand sex-matched healthy controls by employing transcranial magnetic stimulation (TMS) to study corticospinal tract function to the tibialis anterior muscles. Central motor conduction time (CMCT) was determined by using the F-wave method. The study was approved by the ethics committee of the Centre for Research and Rehabilitation of Hereditary Ataxias, and all participants gave their written informed consent. Student’s t-tests revealed a significant prolongation of CMCT in nonataxic SCA2 mutation carriers (20.24 6 7.85 ms) when compared with controls (13.94 6 1.74 ms; P 5 .00001). Of 37 (59.46%) mutation carriers, 22 showed abnormal CMCTs (defined by values above the mean CMCT 1 2 standard deviations in the control group), whereas only 15 (40.54%) cases were detected with hyperreflexia by the neurological examination. Of these, 73.33% had prolonged CMCTs. Correlation analyses revealed that CMCT directly correlated to the cytosine-adenine-guanine (CAG) repeat size (Figure 1A) and inversely correlated to the predicted time to ataxia onset (Figure 1B). This study demonstrates for the first time in SCAs that CMCT measures by TMS has superior sensitivity when compared with a standard neurological examination to detect involvement of the corticospinal tract in the prodromal phase of SCA2. The prolongation of CMCT suggests demyelination or degeneration of the fastest conducting corticospinal tract fibers, a concept that is supported by neuropathological data. The direct correlation between the CMCT and the CAG repeat size suggests an important role of the CAG repeat expansion in corticospinal tract dysfunction, conferring to CMCT a particular value in the search of genetic and/or nongenetic factors modifying polyglutamine toxicity, which could impact future therapeutic approaches and provide new clues on SCA2 physiopathology. The inverse correlation between the CMCT and the predicted time to ataxia onset classifies this TMS measure as a prodromal biomarker with potential utility to track the natural SCA2 progression and its modification in clinical trials. In conclusion, our findings identify novel electrophysiological evidence for early affection of the corticospinal tract in prodromal SCA2 and provide a useful biomarker that predicts time to ataxia onset and reflects polyglutamine neurotoxicity. Longitudinal studies are warranted to further validate CMCT as progression biomarker in SCA2.

Caracterización integral de la ataxia espinocerebelosa 2 en Cuba y su aplicación en proyectos de intervención

Introduccion Cuba es el pais con mayores tasas de prevalencia e incidencia para las ataxias hereditarias, lo que constituye un problema de salud que motivo la creacion del Centro para la Investigacion y Rehabilitacion de Ataxias Hereditarias en Holguin. Objetivos Describir los principales resultados, aportes cientificos, estrategias de intervencion e impactos que durante mas de 10 anos se han obtenido por el citado centro, como modelo para el abordaje integral de las ataxias hereditarias en Cuba. Fuente de datos Se realizo una revision en las bases de datos Pubmed-Medline y Scopus, analizando todos los articulos relevantes, comprendidos en el periodo 1978-2011. Se utilizo el descriptor «ataxia espinocerebelar», de elevada especificidad y sensibilidad para el tema en analisis. Sintesis de los datos La prevalencia de la enfermedad se ha mantenido constante durante 40 anos, extendiendose a toda la isla. La mutacion ataxia espinocerebelosa tipo 2 es responsable del 60 % de la variabilidad fenotipica mientras que el 40 % restante se debe a factores modificadores geneticos y/o ambientales. Se ha descrito la existencia de un dano oxidativo severo, disminucion de neuroprotectores y oligoelementos. Los estudios neurofisiologicos permitieron definir etapas evolutivas desde estadios preclinicos de la enfermedad asi como biomarcadores de progresion y dano genetico. Estos resultados proiciaron el diseno y ejecucion de varios ensayos clinicos controlados en busca de un protocolo de tratamiento contra la enfermedad. Adicionalmente se brinda un servicio de diagnostico prenatal y presintomatico con un impacto positivo sobre las familias afectadas. Conclusiones Las investigaciones sobre la ataxia espinocerebelosa tipo 2 cubana, como problema de salud, han tenido un enfoque integral. Los nuevos descubrimientos sobre la patogenia, la identificacion de biomarcadores, los ensayos clinicos, el diagnostico prenatal y presintomatico permitieron conformar un nuevo modelo cubano para el abordaje de las ataxias hereditarias y el estudio de otras enfermedades neurodegenerativas.