ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype

Lorenzo Nanetti, Elisa Sarto, Anna Castaldo, Stefania Magri, Alessia Mongelli, Davide Rossi Sebastiano, Laura Canafoglia, Marina Grisoli, Chiara Malaguti, Francesca Rivieri, Maria Chiara D’Amico, Daniela Di Bella, Silvana Franceschetti, Caterina Mariotti, Franco Taroni

Research output: Contribution to journalArticle

Abstract

Autosomal recessive cerebellar ataxia type 3 (ARCA3) is a rare inherited disorder caused by mutations in the ANO10 gene. The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline. We performed mutational screening in 80 patients with sporadic or autosomal recessive adult-onset ataxia. We identified 11 ANO10 gene variants in 10 patients from 8 families (10%): 4 mutations were previously described and 7 were novel. Age at onset ranged between 27 and 53 years. All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI. Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10). Six patients, with normal MMSE score, failed several neuropsychological tests rating executive functions. Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures. Our observational study indicates a high frequency of ARCA3 disease in sporadic patients with adult-onset cerebellar ataxia. We extended the ANO10 mutational spectrum with the identification of novel gene variants, and further defined the clinical, cognitive, and neurophysiological features in a new cohort of patients. These findings may contribute to the refinement of the complex ARCA3 phenotype and be valuable in clinical management and natural history studies.

Original languageEnglish
JournalJournal of Neurology
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Ataxia
Cerebellar Ataxia
Phenotype
Genes
Hypokinesia
Mutation
Somatosensory Evoked Potentials
Neuropsychological Tests
Executive Function
Motor Neurons
Paresis
Natural History
Age of Onset
Atrophy
Observational Studies
Electroencephalography
Epilepsy
Seizures
Brain

Keywords

  • ARCA3
  • Dysexecutive cognitive syndrome
  • SCAR10, recessive ataxia
  • Somatosensory evoked potentials
  • Spastic ataxia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

ANO10 mutational screening in recessive ataxia : genetic findings and refinement of the clinical phenotype. / Nanetti, Lorenzo; Sarto, Elisa; Castaldo, Anna; Magri, Stefania; Mongelli, Alessia; Rossi Sebastiano, Davide; Canafoglia, Laura; Grisoli, Marina; Malaguti, Chiara; Rivieri, Francesca; D’Amico, Maria Chiara; Di Bella, Daniela; Franceschetti, Silvana; Mariotti, Caterina; Taroni, Franco.

In: Journal of Neurology, 01.01.2018.

Research output: Contribution to journalArticle

Nanetti, Lorenzo ; Sarto, Elisa ; Castaldo, Anna ; Magri, Stefania ; Mongelli, Alessia ; Rossi Sebastiano, Davide ; Canafoglia, Laura ; Grisoli, Marina ; Malaguti, Chiara ; Rivieri, Francesca ; D’Amico, Maria Chiara ; Di Bella, Daniela ; Franceschetti, Silvana ; Mariotti, Caterina ; Taroni, Franco. / ANO10 mutational screening in recessive ataxia : genetic findings and refinement of the clinical phenotype. In: Journal of Neurology. 2018.
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AU - Nanetti, Lorenzo

AU - Sarto, Elisa

AU - Castaldo, Anna

AU - Magri, Stefania

AU - Mongelli, Alessia

AU - Rossi Sebastiano, Davide

AU - Canafoglia, Laura

AU - Grisoli, Marina

AU - Malaguti, Chiara

AU - Rivieri, Francesca

AU - D’Amico, Maria Chiara

AU - Di Bella, Daniela

AU - Franceschetti, Silvana

AU - Mariotti, Caterina

AU - Taroni, Franco

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N2 - Autosomal recessive cerebellar ataxia type 3 (ARCA3) is a rare inherited disorder caused by mutations in the ANO10 gene. The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline. We performed mutational screening in 80 patients with sporadic or autosomal recessive adult-onset ataxia. We identified 11 ANO10 gene variants in 10 patients from 8 families (10%): 4 mutations were previously described and 7 were novel. Age at onset ranged between 27 and 53 years. All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI. Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10). Six patients, with normal MMSE score, failed several neuropsychological tests rating executive functions. Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures. Our observational study indicates a high frequency of ARCA3 disease in sporadic patients with adult-onset cerebellar ataxia. We extended the ANO10 mutational spectrum with the identification of novel gene variants, and further defined the clinical, cognitive, and neurophysiological features in a new cohort of patients. These findings may contribute to the refinement of the complex ARCA3 phenotype and be valuable in clinical management and natural history studies.

AB - Autosomal recessive cerebellar ataxia type 3 (ARCA3) is a rare inherited disorder caused by mutations in the ANO10 gene. The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline. We performed mutational screening in 80 patients with sporadic or autosomal recessive adult-onset ataxia. We identified 11 ANO10 gene variants in 10 patients from 8 families (10%): 4 mutations were previously described and 7 were novel. Age at onset ranged between 27 and 53 years. All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI. Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10). Six patients, with normal MMSE score, failed several neuropsychological tests rating executive functions. Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures. Our observational study indicates a high frequency of ARCA3 disease in sporadic patients with adult-onset cerebellar ataxia. We extended the ANO10 mutational spectrum with the identification of novel gene variants, and further defined the clinical, cognitive, and neurophysiological features in a new cohort of patients. These findings may contribute to the refinement of the complex ARCA3 phenotype and be valuable in clinical management and natural history studies.

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