Journal of Neurology

, Volume 266, Issue 2, pp 378–385 | Cite as

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 MariottiEmail author
  • Franco Taroni
Original Communication


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.


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



This work was supported in part by research grants from the Italian Ministry of Health: RF-2011-02351165 (to F.T.), RF-2011-02347420 (to C.M.)


Research Grant RF-2011-02351165 from the Italian Ministry of Health to F.T., and RF-2011-02347420 to C.M.

Compliance with ethical standards

Conflicts of interest

All authors declare that they have no conflict of interest.

Ethical standard

All patients gave written informed consent for the clinical and genetic tests in agreement with the procedures approved by the Local Ethic Committee. The consent forms routinely used in our Hospital specifically enquire the patient consent for diagnostic and research purposes. Ethics committee approval is not required for retrospective anonymized observational studies.

Supplementary material

415_2018_9141_MOESM1_ESM.docx (24 kb)
Table S1. ANO10 gene mutations identified in this study. (DOCX 24 KB)
415_2018_9141_MOESM2_ESM.pdf (85 kb)
Table S2. Review of the literature summarizing genetic and clinical features in ARCA3 patients. (PDF 84 KB)


  1. 1.
    Parodi L, Coarelli G, Stevanin G, Brice A, Durr A (2018) Hereditary ataxias and paraparesias: clinical and genetic update. Curr Opin Neurol 31:462–471Google Scholar
  2. 2.
    Beaudin M, Klein CJ, Rouleau GA, Dupré N (2017) Systematic review of autosomal recessive ataxias and proposal for a classification. Cerebellum Ataxias 4:3CrossRefGoogle Scholar
  3. 3.
    Vermeer S, Hoischen A, Meijer RP et al (2010) Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia. Am J Hum Genet 87:813–819CrossRefGoogle Scholar
  4. 4.
    Renaud M, Anheim M, Kamsteeg EJ et al (2014) Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. JAMA Neurol 71:1305–1310CrossRefGoogle Scholar
  5. 5.
    Balreira A, Boczonadi V, Barca E et al (2014) ANO10 mutations cause ataxia and coenzyme Q10 deficiency. J Neurol 261:2192–2198CrossRefGoogle Scholar
  6. 6.
    Fogel BL, Lee H, Deignan JL et al (2014) Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol 71:1237–1246CrossRefGoogle Scholar
  7. 7.
    Chamova T, Florez L, Guergueltcheva V et al (2012) ANO10 c.1150_1151del is a founder mutation causing autosomal recessive cerebellar ataxia in Roma/Gypsies. J Neurol 259:906–911CrossRefGoogle Scholar
  8. 8.
    Maruyama H, Morino H, Miyamoto R, Murakami N, Hamano T, Kawakami H (2014) Exome sequencing reveals a novel ANO10 mutation in a Japanese patient with autosomal recessive spinocerebellar ataxia. Clin Genet 85:296–297CrossRefGoogle Scholar
  9. 9.
    Yoshida K, Miyatake S, Kinoshita T et al (2014) ‘Cortical cerebellar atrophy’ dwindles away in the era of next-generation sequencing. J Hum Genet 59:589–590CrossRefGoogle Scholar
  10. 10.
    Minnerop M, Bauer P (2015) Autosomal recessive cerebellar ataxia 3 due to homozygote c.132dupA mutation within the ANO10 gene. JAMA Neurol 72:238–239CrossRefGoogle Scholar
  11. 11.
    Chamard L, Sylvestre G, Koenig M, Magnin E (2016) Executive and attentional disorders, epilepsy and porencephalic cyst in autosomal recessive cerebellar ataxia type 3 due to ANO10 mutation. Eur Neurol 75:186–190CrossRefGoogle Scholar
  12. 12.
    Mišković ND, Domingo A, Dobričić V et al (2016) Seemingly dominant inheritance of a recessive ANO10 mutation in romani families with cerebellar ataxia. Mov Disord 31:1929–1931CrossRefGoogle Scholar
  13. 13.
    Bodranghien F, Oulad Ben Taib N, Van Maldergem L, Manto M (2017) A postural tremor highly responsive to transcranial cerebello-cerebral DCS in ARCA3. Front Neurol 8:71CrossRefGoogle Scholar
  14. 14.
    Sun M, Johnson AK, Nelakuditi V et al (2018) Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. Genet Med. Google Scholar
  15. 15.
    Coutelier M, Hammer MB, Stevanin G et al (2018) Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol 75:591–599CrossRefGoogle Scholar
  16. 16.
    Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424CrossRefGoogle Scholar
  17. 17.
    Halliday DM, Rosenberg JR, Amjad AM, Breeze P, Conway BA, Farmer SF (1995) A framework for the analysis of mixed time series/point process data—theory and application to the study of physiological tremor, single motor unit discharges and electromyograms. Prog Biophys Mol Biol 64:237–278CrossRefGoogle Scholar
  18. 18.
    Panzica F, Canafoglia L, Franceschetti S et al (2003) Movement-activated myoclonus in genetically defined progressive myoclonic epilepsies: EEG-EMG relationship estimated using autoregressive models. Clin Neurophysiol 114:1041–1052CrossRefGoogle Scholar
  19. 19.
    Mochizuki H, Hanajima R, Kowa H et al (2001) Somatosensory evoked potential recovery in myotonic dystrophy. Clin Neurophysiol 112:793–799CrossRefGoogle Scholar
  20. 20.
    Visani E, Canafoglia L, Rossi Sebastiano D et al (2013) Giant SEPs and SEP-recovery function in Unverricht–Lundborg disease. Clin Neurophysiol 124:1013–1018CrossRefGoogle Scholar
  21. 21.
    Synofzik M, Smets K, Mallaret M et al (2016) SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study. Brain 139:1378–1393CrossRefGoogle Scholar
  22. 22.
    Slapik M, Kronemer SI, Morgan O et al (2018) Visuospatial organization and recall in cerebellar ataxia. Cerebellum. Google Scholar
  23. 23.
    Schmahmann JD, Sherman JC (1998) The cerebellar cognitive affective syndrome. Brain 121:561–579CrossRefGoogle Scholar
  24. 24.
    Saccà F, Costabile T, Abate F et al (2017) Normalization of timed neuropsychological tests with the PATA rate and nine-hole pegboard tests. J Neuropsychol 12:471–483CrossRefGoogle Scholar
  25. 25.
    Martín-Palomeque G, Castro-Ortiz A, Pamplona-Valenzuela P, Saiz-Sepúlveda M, Cabañes-Martínez L, López JR (2017) Large amplitude cortical evoked potentials in nonepileptic patients. Reviving an old neurophysiologic tool to help detect CNS pathology. J Clin Neurophysiol 34:84–91CrossRefGoogle Scholar
  26. 26.
    Miwa H, Mizuno Y (2002) Enlargements of somatosensory-evoked potentials in progressive supranuclear palsy. Acta Neurol Scand 106:209–212CrossRefGoogle Scholar
  27. 27.
    Shimizu T, Bokuda K, Kimura H et al (2018) Sensory cortex hyperexcitability predicts short survival in amyotrophic lateral sclerosis. Neurology 90:1578–1587CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Lorenzo Nanetti
    • 1
  • Elisa Sarto
    • 1
  • Anna Castaldo
    • 1
  • Stefania Magri
    • 1
  • Alessia Mongelli
    • 1
  • Davide Rossi Sebastiano
    • 2
  • Laura Canafoglia
    • 2
  • Marina Grisoli
    • 3
  • Chiara Malaguti
    • 4
  • Francesca Rivieri
    • 5
  • Maria Chiara D’Amico
    • 1
  • Daniela Di Bella
    • 1
  • Silvana Franceschetti
    • 2
  • Caterina Mariotti
    • 1
    Email author
  • Franco Taroni
    • 1
  1. 1.Unit of Medical Genetics and NeurogeneticsFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
  2. 2.Unit of NeurophysiopathologyFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
  3. 3.Unit of NeuroradiologyFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
  4. 4.Unit of NeurologySanta Chiara HospitalTrentoItaly
  5. 5.Medical Genetic ServiceSanta Chiara HospitalTrentoItaly

Personalised recommendations