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Clinical and Molecular Findings of Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay: an Iranian Case Series Expanding the Genetic and Neuroimaging Spectra

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Abstract

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.

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Data Availability

Human variants and pertinent phenotypes have been reported to ClinVar (Submission IDs: SUB9677044, SUB9677045, SUB9677050, SUB9677685, SUB9677710, SUB9677755, SUB9677767, SUB9677775).

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Acknowledgements

The authors thank all participant families and their patients in this research. The authors are especially thankful to Ali Mohebi and Nahid Vafaee from the Growth and Development Research Center, Tehran University of Medical Sciences, for their support in data gathering. The authors thank the Hertie Institute for Clinical Brain Research, Tübingen, Germany, as the international collaborative party of the study.

Funding

This project was supported by the Deutsche Forschungsgemeinschaft (DFG) (German Research Foundation) No. 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575. This study was granted by NIMAD under the proposal No. 971846.

Author information

Authors and Affiliations

  1. Pediatric Neurology Division, Children’s Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran

    Mahmoud Reza Ashrafi, Pouria Mohammadi, Ali Reza Tavasoli, Morteza Heidari, Sareh Hosseinpour, Maryam Rasulinejad, Masoud Ghahvechi Akbari, Reza Shervin Badv, Ali Zare Dehnavi, Ali Rabbani & Zahra Rezaei

  2. Department of Pediatrics Center, Growth and Development Research Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran

    Mahmoud Reza Ashrafi & Ali Rabbani

  3. Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran

    Pouria Mohammadi

  4. Pediatric Neurology Division, Children’s Medical Center, Pediatrics Center of Excellence, Myelin Disorders Clinic, Tehran University of Medical Sciences, Tehran, Iran

    Ali Reza Tavasoli & Morteza Heidari

  5. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, USA

    Ali Reza Tavasoli

  6. Department of Pediatric Neurology, Vali-E-Asr Hospital, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

    Sareh Hosseinpour

  7. Department of Neurology, School of Medicine, Hazrat Rasool-E Akram General Hospital, Iran University of Medical Sciences, Tehran, Iran

    Mohammad Rohani

  8. Physical Medicine and Rehabilitation Department, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Masoud Ghahvechi Akbari

  9. Division of Pediatric Neurology, Department of Pediatrics, Golestan Medical, Educational and Research Center, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran

    Reza Azizi Malamiri

  10. Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

    Davood Fathi

  11. Neurology Department, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Davood Fathi

  12. Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran

    Shahram Savad

  13. Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany

    Matthis Synofzik

  14. Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany

    Matthis Synofzik

  15. Cardiogenetic Research Center, Rajaei Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

    Nejat Mahdieh

Authors
  1. Mahmoud Reza Ashrafi
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  2. Pouria Mohammadi
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  3. Ali Reza Tavasoli
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  4. Morteza Heidari
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  6. Maryam Rasulinejad
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  7. Mohammad Rohani
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  8. Masoud Ghahvechi Akbari
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  12. Ali Zare Dehnavi
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  13. Shahram Savad
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  14. Ali Rabbani
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  15. Matthis Synofzik
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  16. Nejat Mahdieh
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  17. Zahra Rezaei
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Contributions

MRA and MH designed and supervised the study. ZR, ART, PM, and NM had a major contribution in drafting the manuscript. ZR, MH, ART, SH, MR, MR, RAM, RSB, DF, AZD, and AR interpreted clinical data. ART and MS contributed in the final scientific revision. NM, PM, and SS contributed in genetic data analyses. MGA interpreted the electrodiagnostic data. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Nejat Mahdieh or Zahra Rezaei.

Ethics declarations

Ethics Approval

This study was approved by the ethics committee of the National Institute for Medical Research Development of Iran (Ethics ID: IR.NIMAD.REC.1397.508) and has thus been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent to Participate

Informed consent was obtained from all individual participants enrolled in the study.

Consent for Publication

Participant families agreed on anonymous publication of patients’ clinical information and their relevant data.

Competing Interests

The authors declare no competing interests.

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Mahmoud Reza Ashrafi and Pouria Mohammadi have an equal contribution as the first authors.

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Ashrafi, M.R., Mohammadi, P., Tavasoli, A.R. et al. Clinical and Molecular Findings of Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay: an Iranian Case Series Expanding the Genetic and Neuroimaging Spectra. Cerebellum 22, 640–650 (2023). https://doi.org/10.1007/s12311-022-01430-3

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  • DOI: https://doi.org/10.1007/s12311-022-01430-3

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