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

Rodríguez‐Labrada, Roberto; Velázquez‐Pérez, Luis; Ochoa, Nalia Canales; Polo, Lourdes Galicia; Valencia, Reyes Haro; Cruz, Gilberto Sánchez; Montero, Jacqueline Medrano; Laffita-Mesa, José Miguel; Mederos, Luis Enrique Almaguer; Zaldívar, Yanetza González; Parra, Cira Torres; Acosta, Arnoy Peña; Mariño, Tania Cruz

doi:10.1002/mds.23409

Cited by 40 publications

(24 citation statements)

References 22 publications

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“…To our knowledge, this is the first work exploring the association of brain volumes and saccade velocity in SCA2. Besides, the degeneration of the pontine brainstem in SCA2 is in line with the early REM sleep pathology characterizing the disease from prodromal to manifest stage35, 36, 37 since the neural circuit controlling this sleep stage lie mainly in the pontine brainstem 38, 39…”

Section: Discussionmentioning

confidence: 69%

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Reetz

Rodríguez‐Labrada²,

Dogan

et al. 2018

Ann Clin Transl Neurol

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ObjectiveSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease mainly affecting the cerebellum and brainstem. In this Cuban‐German research collaboration, we aimed to characterize atrophy patterns and associations with clinical measures in preclinical and manifest SCA2.MethodsIn this study, 16 nonmanifest SCA2 mutation carriers, 26 manifest patients with SCA2, and 18 healthy control subjects underwent magnetic resonance imaging, as well as genetic and clinical characterization including assessment of ataxia (Scale for the Assessment and Rating of Ataxia) and saccade velocity in Cuba were enrolled. Semiautomated quantitative volumetry of the cerebellum and brainstem, subdivided into the medulla oblongata, the pontine brainstem, and mesencephalon was performed. Additionally, the anteroposterior diameter of the pontine brainstem was measured.ResultsAnalysis of volumetric data revealed degeneration of the cerebellum and brainstem, in particular of pontine volumes and the anteroposterior diameter of the pons, in both manifest SCA2 patients and individuals at risk for SCA2 compared to controls. Comparing patients with nonataxic preclinical SCA2 mutation carriers, we found more pronounced reductions of the pontine brainstem and cerebellum in manifest SCA2. Volumetric data further showed associations with CAG repeat length and predicted age of onset in preclinical SCA2 individuals, and by trend with ataxia signs in patients. Although saccade velocity was associated with reduction in the pontine brainstem in preclinical and manifest SCA2, reduced ability to suppress interfering stimuli measured by the Stroop task was related to cerebellar volume loss in patients.InterpretationPreclinical SCA2 mutation carriers exhibit brain abnormalities, which could be targeted as surrogate parameters for disease progression and in future preventive trials.

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Section: Discussionmentioning

confidence: 69%

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Reetz

Rodríguez‐Labrada²,

Dogan

et al. 2018

Ann Clin Transl Neurol

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“…Besides, there are alterations in the sensory and motor central pathways at intraxial levels and reduced saccade velocity. Imaging studies reveal an early atrophy of the cerebellum and brainstem (Velázquez-Pérez et al 2009a, b, c;Rodríguez-Labrada et al 2011;Velázquez-Pérez et al 2014a).…”

Section: Sca2 Presymptomatic Gene Carrier: a Closer Look To The Conceptmentioning

confidence: 99%

“…The clinical picture of SCA2 includes a progressive cerebellar syndrome accompanied by saccadic slowing, peripheral neuropathy, autonomic dysfunction, sleep disturbances, cognitive abnormalities, and signs of motor neuron involvement. Nonataxic mutation carriers also present somatic, autonomic, cognitive, and oculomotor disturbances (Velázquez-Pérez et al 2009a, b, c;Rodríguez-Labrada et al 2011;Velázquez-Pérez et al 2014a). …”

Section: Introductionmentioning

confidence: 99%

SCA2 predictive testing in Cuba: challenging concepts and protocol evolution

Mariño¹,

Vázquez‐Mojena

Velázquez‐Pérez

et al. 2015

J Community Genet

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Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN2 gene. Cuba has the highest prevalence (6.57 cases/10 5 inhabitants) of SCA2 in the world. The existence of 753 affected individuals and 7173 relatives at risk prompted the development in 2001 of the first predictive testing program in the country. The medical records of over 1193 individuals, who requested the test within a 13-year period, were analyzed retrospectively. The presymptomatic and the prenatal tests had uptake rates of 43.4 and 23.9 %, respectively. Several ethical challenges resulted from this program. These include the following: (1) withdrawal due to the initial protocol's length; (2) the request to participate by 16 at-risk adolescents; (3) the decision made by ten out of 33 couples with a test-positive fetus to carry the pregnancy to term, leading to de facto predictive testing of minors; (4) the elevated frequency of the ATXN2 gene large normal alleles (≥23 to 31 repeats) in the reference population. These issues have led to major changes in the guidelines of the predictive testing protocol: (1) the protocol length was shortened; (2) the inclusion criteria were expanded to reach at-risk adolescents with an interest in prenatal diagnosis; (3) interdisciplinary follow-up was offered to families in which test-positive fetuses were not aborted; (4) prenatal testing was made available to carriers of large normal alleles with ≥27 CAG repeats. The profiles of the participants were similar to those reported for other predictive testing programs for conditions like Huntington disease and familial adenomatous polyposis. The genetic counseling practices at the community level, the ample health education provided to the at-risk population, together with multidisciplinary and specialized attention to the affected families, are lessons from the Cuban experience that can be relevant for other international teams conducting predictive testing for other late-onset neurodegenerative disorders.

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“…Both symptomatic and presymptomatic subjects show a marked decrease in this parameter, which is negatively correlated with the ataxia score in the patients Rodríguez-Labrada et al, 2011b). These findings suggest the usefulness of saccadic density during REM sleep as progression marker of the disease and reflect the extension of the oculomotor brainstem involvement to the sleep.…”

Section: Spinocerebellar Ataxia Type 2 (Sca2)mentioning

confidence: 66%