ABSTRACT
The characterization of prodromal stages in neurodegenerative disorders is becoming increasingly important because of the need for early neuroprotective therapies. Research during the past 3 decades in spinocerebellar ataxia type 2 has revealed a large body of evidence suggesting that many disease features precede the manifest cerebellar syndrome, which delineates the prodromal stage of this disorder. This stage is defined by clinical, imaging, and functional criteria, which are supported by early molecular events demonstrated in animal models. Knowledge regarding prodromal spinocerebellar ataxia type 2 provides insight into the mechanisms underlying neurodegeneration from the early stages, which enables the design of promising disease-modifying clinical trials through the identification of the optimum moment to begin the therapies, the appropriate selection of individuals, and the identification of sensitive outcome measures. The management of patients in prodromal spinocerebellar ataxia type 2 may raise ethical dilemmas related to predictive diagnosis and early interventions, which impose new challenges to clinical and therapeutic research (AU)
Subject(s)
Humans , Early Diagnosis , Evoked Potentials, Auditory, Brain Stem , Evoked Potentials, Somatosensory , Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/genetics , Spinocerebellar Ataxias/physiopathology , Spinocerebellar Ataxias/therapy , Ataxin-2/genetics , Early Medical Intervention/ethics , Early Medical Intervention/methods , Prodromal SymptomsABSTRACT
Studies on prodromal stage in spinocerebellar ataxias (SCAs) have become high priority approaches in view of their usefulness to detect biomarkers that herald the onset of permanent ataxia and assess the efficacy of future therapeutical trials [1]. The most comprehensive evaluation of prodromal SCA2 comes from the large and homogeneous population of Cuban preclinical carriers, which derives from a 13 years presymptomatic diagnostic program and the nationwide molecular epidemiological survey (AU)
Subject(s)
Humans , Adolescent , Young Adult , Adult , Middle Aged , Ataxin-2/genetics , Postural Balance , Prodromal Symptoms , Spinocerebellar Ataxias/genetics , Spinocerebellar Ataxias/physiopathology , Gait , Trinucleotide Repeat ExpansionABSTRACT
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder characterized by progressive cerebellar ataxia associated with macular degeneration. We recently described one of the largest series of patients with SCA7 that originated from a founder effect in a Mexican population, which allowed us to perform herein the first comprehensive clinical, neurophysiological, and genetic characterization of Mexican patients with SCA7. In this study, 50 patients, categorized into adult or early phenotype, were clinically assessed using standard neurological exams and genotyped using fluorescent PCR and capillary electrophoresis. Patients with SCA7 exhibited the classical phenotype of the disease characterized by cerebellar ataxia and visual loss; however, we reported, for the first time, frontal-executive disorders and altered sensory-motor peripheral neuropathy in these patients. Semiquantitative analysis of ataxia-associated symptoms was performed using Scale for the Assessment and Rating of Ataxia (SARA) and the Brief Ataxia Rating Scale (BARS) scores, while extracerebellar features were measured employing the Inventory of Non-ataxia Symptoms (INAS) scale. Ataxia rating scales confirmed the critical role size of cytosine-adenine-guanine (CAG) repeat size on age at onset and disease severity, while analysis of CAG repeat instability showed that paternal rather than maternal transmission led to greater instability.
Subject(s)
Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Genotype , Humans , Male , Mexico , Middle Aged , Neuropsychological Tests , Severity of Illness Index , Spinocerebellar Ataxias/physiopathology , Spinocerebellar Ataxias/psychology , Young AdultABSTRACT
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Subject(s)
Humans , Cranial Nerves , Spinocerebellar Ataxias/diagnosis , Electrodiagnosis/methods , Neurologic Examination/methodsABSTRACT
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Subject(s)
Humans , Electromyography , Spinocerebellar Ataxias/diagnosis , Dysarthria/etiology , Gait Ataxia/etiology , SaccadesABSTRACT
Las ataxias cerebelosas autosómicas dominantesautosomal dominant cerebellar ataxias(ADCA)constituyen un grupo heterogéneode enfermedades, caracterizadas clínicamentepor Harding en 1983, quien las dividióen los tipos I, II, III y IV. En la tipo I, laataxia de la marcha es el signo clínico primario,relacionado con oftalmoplejía supranuclear,signos piramidales, extrapiramidales, demenciamoderada y neuropatía periférica. Estegrupo incluye la ataxia espinocerebelosa tipo2 (SCA 2) [1,2], que es una de las 29 formasmoleculares descritas actualmente, en laque se ha comprobado una mutación dinámica[3,4] caracterizada por una expansión intergeneracionaldel triplete CAG (cromosoma 12),que explica el incremento en la gravedad delcuadro clínico y el inicio del cuadro a edadesmás tempranas en generaciones sucesivas...(AU)
Subject(s)
Humans , Spinocerebellar Ataxias/epidemiology , Electromyography , Spinocerebellar AtaxiasABSTRACT
OBJECTIVE: A characteristic feature of spinocerebellar ataxia type 2 (SCA2) is saccadic slowing at early disease stages. We sought to determine whether this sign is detectable before clinical manifestation and quantifies the disease progression throughout life in linear fashion. METHODS: In a specialized ataxia clinic, 54 presymptomatic carriers of SCA2 polyglutamine expansions and 56 relatives without mutation were documented with regard to their maximal saccade velocity (MSV). RESULTS: Among the control individuals, a significant effect of aging on MSV was observed. After elimination of this age influence through a matched-pair approach, a presymptomatic decrease of MSV could be shown. The MSV reduction was stronger in carriers of large expansions. In the years before calculated disease manifestation, the MSV impairment advanced insidiously. CONCLUSION: Saccade velocity is a sensitive SCA2 endophenotype that reflects early pontine degeneration and may be a useful diagnostic parameter before the onset of ataxia. SIGNIFICANCE: Future neuroprotective therapies of polyglutamine neurodegeneration may be assessed by MSV from earliest to prefinal disease stages.
Subject(s)
Ocular Motility Disorders/etiology , Ocular Motility Disorders/physiopathology , Oculomotor Muscles/physiopathology , Saccades/physiology , Spinocerebellar Ataxias/complications , Spinocerebellar Ataxias/physiopathology , Adolescent , Adult , Aged , Ataxins , Cerebellum/physiopathology , Disease Progression , Early Diagnosis , Female , Heterozygote , Humans , Male , Middle Aged , Nerve Tissue Proteins/genetics , Neural Pathways/physiopathology , Ocular Motility Disorders/diagnosis , Oculomotor Muscles/innervation , Predictive Value of Tests , Prognosis , Spinocerebellar Ataxias/diagnosis , Young AdultABSTRACT
La ataxia espinocerebelosa tipo 2 (SCA2) es una enfermedad neurodegenerativa producidapor expansiones del número de repeticiones del trinucleótido CAG en el gen SCA2. Ésta secaracteriza por el síndrome cerebeloso progresivo, el enlentecimiento sacádico y la neuropatíaperiférica, así como por alteracionescognitivas y del sueño [1]. Cuba posee el mayor número de familias afectadas por la SCA2, específicamente en la provincia de Holguín, donde la tasa de prevalencia supera los 40 casospor cada 100.000 habitantes y existen más de 2.000 descendientes directos con riesgo de padecer la enfermedad [2,3]. Hasta el momento,no existe tratamiento farmacológico efectivo contra las ataxias hereditarias, aunque se han descrito numerosos blancos terapéuticos,así como biomarcadores neuroquímicos [4] y electrofisiológicos...(AU)
Subject(s)
Humans , Spinocerebellar Ataxias/epidemiology , Spinocerebellar Ataxias/genetics , ElectromyographyABSTRACT
A characteristic feature of spinocerebellar ataxia type 2 (SCA2) is saccadic slowing at early disease stages. We sought to determine whether this sign is detectable before clinical manifestation and quantifies the disease progression throughout life in linear fashion. In a specialized ataxia clinic, 54 presymptomatic carriers of SCA2 polyglutamine expansions and 56 relatives without mutation were documented with regard to their maximal saccade velocit Spinocerebellar ataxia type 2 Among the control individuals, a significant effect of aging on MSV was observed. After elimination of this age influence through a matched-pair approach, a presymptomatic decrease of MSV could be shown. The MSV reduction was stronger in carriers of large expansions. In the years before calculated disease manifestation, the MSV impairment advanced insidiously.Saccade velocity is a sensitive SCA2 endophenotype that reflects early pontine degenerationPolyglutamine expansion and may be a useful diagnostic parameter before the onset of ataxia. Significance: Future neuroprotective therapies of polyglutamine neurodegeneration may be assessed by MSV from earliest to prefinal disease stages...(AU)
