Neurogenetics DOI 10.1007/s10048-014-0424-y
ORIGINAL ARTICLE
A comprehensive clinical and genetic study of a large Mexican population with spinocerebellar ataxia type 7 L. Velázquez-Pérez & C. M. Cerecedo-Zapata & O. Hernández-Hernández & E. Martínez-Cruz & Y. S. Tapia-Guerrero & R. González-Piña & J. Salas-Vargas & R. Rodríguez-Labrada & R. Gurrola-Betancourth & N. Leyva-García & B. Cisneros & J. J. Magaña
Received: 23 April 2014 / Accepted: 8 September 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract 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. Keywords Ataxia rating scales . Autosomal dominant cerebellar ataxia . CAG repeats . Electrophysiological findings . Intergenerational transmission . Spinocerebellar ataxia type 7
Introduction Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant genetic disease characterized by cerebellar dysfunction associated with gait ataxia, dysarthria, dysmetria, dysdiadochokinesia, hyperreflexia, sensory loss, postural
Electronic supplementary material The online version of this article (doi:10.1007/s10048-014-0424-y) contains supplementary material, which is available to authorized users. L. Velázquez-Pérez : C. M. Cerecedo-Zapata : O. Hernández-Hernández : Y. S. Tapia-Guerrero : N. Leyva-García : J. J. Magaña (*) Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute (INR), Mexico City, Mexico e-mail: [email protected] L. Velázquez-Pérez : B. Cisneros (*) Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Av. Instituto Politécnico Nacional No. 2508, Col. San Pedro Zacatenco, 07360 Mexico City, Mexico e-mail: [email protected]
L. Velázquez-Pérez : R. Rodríguez-Labrada Center for Research and Rehabilitation of the Hereditary Ataxias (CIRAH), Holguín, Cuba
C. M. Cerecedo-Zapata : E. Martínez-Cruz : J. Salas-Vargas : R. Gurrola-Betancourth Rehabilitation and Social Inclusion Center of Veracruz (CRIS-DIF), Xalapa, Veracruz, Mexico R. González-Piña Department of Brain Plasticity, INR, Mexico City, Mexico
Neurogenetics
tremor, and visual problems, due to progressive loss of neurons within the cerebellum, retina, and brainstem [1–3]. SCA7 is genetically caused by the expansion of a cytosine-adenineguanine (CAG) trinucleotide repeat located in exon 3 of the ATXN7 gene. The polymorphic tract of CAG repeats ranges from 4 to 18 repeats in normal population and from 36 to up to 460 in affected individuals, which results in the incorporation of a segment of polyglutamines into the mutant protein [4]; longer expansions are associated with earlier onset and more severe disease symptomatology in subsequent generations [5]. SCA7 is considered one of the rarest forms of autosomal dominantly inherited ataxias, with a worldwide prevalence of
ORIGINAL ARTICLE
A comprehensive clinical and genetic study of a large Mexican population with spinocerebellar ataxia type 7 L. Velázquez-Pérez & C. M. Cerecedo-Zapata & O. Hernández-Hernández & E. Martínez-Cruz & Y. S. Tapia-Guerrero & R. González-Piña & J. Salas-Vargas & R. Rodríguez-Labrada & R. Gurrola-Betancourth & N. Leyva-García & B. Cisneros & J. J. Magaña
Received: 23 April 2014 / Accepted: 8 September 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract 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. Keywords Ataxia rating scales . Autosomal dominant cerebellar ataxia . CAG repeats . Electrophysiological findings . Intergenerational transmission . Spinocerebellar ataxia type 7
Introduction Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant genetic disease characterized by cerebellar dysfunction associated with gait ataxia, dysarthria, dysmetria, dysdiadochokinesia, hyperreflexia, sensory loss, postural
Electronic supplementary material The online version of this article (doi:10.1007/s10048-014-0424-y) contains supplementary material, which is available to authorized users. L. Velázquez-Pérez : C. M. Cerecedo-Zapata : O. Hernández-Hernández : Y. S. Tapia-Guerrero : N. Leyva-García : J. J. Magaña (*) Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute (INR), Mexico City, Mexico e-mail: [email protected] L. Velázquez-Pérez : B. Cisneros (*) Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Av. Instituto Politécnico Nacional No. 2508, Col. San Pedro Zacatenco, 07360 Mexico City, Mexico e-mail: [email protected]
L. Velázquez-Pérez : R. Rodríguez-Labrada Center for Research and Rehabilitation of the Hereditary Ataxias (CIRAH), Holguín, Cuba
C. M. Cerecedo-Zapata : E. Martínez-Cruz : J. Salas-Vargas : R. Gurrola-Betancourth Rehabilitation and Social Inclusion Center of Veracruz (CRIS-DIF), Xalapa, Veracruz, Mexico R. González-Piña Department of Brain Plasticity, INR, Mexico City, Mexico
Neurogenetics
tremor, and visual problems, due to progressive loss of neurons within the cerebellum, retina, and brainstem [1–3]. SCA7 is genetically caused by the expansion of a cytosine-adenineguanine (CAG) trinucleotide repeat located in exon 3 of the ATXN7 gene. The polymorphic tract of CAG repeats ranges from 4 to 18 repeats in normal population and from 36 to up to 460 in affected individuals, which results in the incorporation of a segment of polyglutamines into the mutant protein [4]; longer expansions are associated with earlier onset and more severe disease symptomatology in subsequent generations [5]. SCA7 is considered one of the rarest forms of autosomal dominantly inherited ataxias, with a worldwide prevalence of
