Skip to main content
Springer Nature Link
Log in

The Latest Developments for the Treatment of Ataxia Telangiectasia: A Narrative Review

  • Review
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

See More

Ataxia telangiectasia (AT), Louis-Bar syndrome, is a rare neurodegenerative disorder caused by autosomal recessive biallelic mutations within the ataxia telangiectasia mutated (ATM) gene. Currently, there are no curative therapies available for this disorder. This review provides an overview of the latest advances in treatment methods including 1- Acetyl-DL-leucine, 2- Bone Marrow Transplantation, 3- Gene Therapy, 4- Dexamethasone, and finally 5- Red Blood Cells (RBCs) as a carrier for dexamethasone (encapsulation of dexamethasone sodium phosphate into autologous erythrocytes, known as EryDex). Most of the treatments under investigation are in the early stages, except for the EryDex System. It appears that the EryDex system and N-Acetyl-DL-Leucine may hold promise as potential treatment options.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

Data Availability

No datasets were generated or analysed during the current study.

References

  1. Levy A, Lang AE. Ataxia-telangiectasia: a review of movement disorders, clinical features, and genotype correlations. Mov Disord. 2018;33(8):1238–47.

    Article  PubMed  Google Scholar 

  2. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016;11(1):1–21.

    Article  Google Scholar 

  3. Sedgwick RP, Boder E. In: Vinken PJ, Bruyn GW, Klawans H, editors. Handbook of clinical neurology. New York, NY: Elsevier; 1991. p. 347–93.

    Google Scholar 

  4. Chun HH, Gatti RA. AtaxiATelangiectasia, an evolving phenotype. DNA Repair (Amst). 2004;3:1187–96.

    Article  CAS  PubMed  Google Scholar 

  5. Krauthammer A, Lahad A, Goldberg L, Sarouk I, Weiss B, Somech R, et al. Elevated IgM levels as a marker for a unique phenotype in patients with Ataxia telangiectasia. BMC Pediatr. 2018;18(1):185.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Verhagen MM, Last JI, Hogervorst FB, Smeets DF, Roeleveld N, Verheijen F, Catsman-Berrevoets CE, Wulffraat NM, Cobben JM, Hiel J, Brunt ER. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia‐telangiectasia: a genotype–phenotype study. Hum Mutat. 2012;33(3):561–71.

    Article  CAS  PubMed  Google Scholar 

  7. Lockman JL, Iskander AJ, Bembea M, Crawford TO, Lederman HM, McGrath-Morrow S, Easley RB. The critically ill patient with ataxia–telangiectasia: a case series. Pediatr Crit Care Med. 2012;13(2):e84-90.

    Article  PubMed  Google Scholar 

  8. Van Os NJH, Jansen AFM, Van Deuren M, Haraldsson A, Van Driel NTM, Etzioni A, et al. Ataxia-telangiectasia: immunodeficiency and survival. Clin Immunol. 2017;178:45–55. https://doi.org/10.1016/j.clim.2017.01.009.

  9. Habek M, Brinar VV, Rados M, Zadro I, Zarkovic K. Brain MRI abnormalities in ataxia-telangiectasia. Neurologist. 2008;14(3):192–5. https://doi.org/10.1097/NRL.0b013e31815fa5a7.

  10. Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004;104(8):2263–8.

    Article  CAS  PubMed  Google Scholar 

  11. Weiss B, Krauthammer A, Soudack M, Lahad A, Sarouk I, Somech R, Heimer G, Ben-Zeev B, Nissenkorn A. Liver disease in pediatric patients with ataxia telangiectasia: a novel report. J Pediatr Gastroenterol Nutr. 2016;62(4):550–5.

    Article  CAS  PubMed  Google Scholar 

  12. Moslemi M, Vafaei M, Khani P, Soheili M, Nedaeinia R, Manian M, Moradi Y, Sohrabi E. The prevalence of ataxia telangiectasia mutated (ATM) variants in patients with breast cancer patients: a systematic review and meta-analysis. Cancer Cell Int. 2021;21:1–9.

    Article  Google Scholar 

  13. Fields T, Patterson M, Bremova-Ertl T, Belcher G, Billington I, Churchill GC, et al. A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: niemann-pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. Trials. 2021;22(1):84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Strupp M, Teufel J, Habs M, Feuerecker R, Muth C, van de Warrenburg BP, et al. Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J Neurol. 2013;260(10):2556–61.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Brueggemann A, Bicvic A, Goeldlin M, Kalla R, Kerkeni H, Mantokoudis G, Abegg M, Kolníková M, Mohaupt M, Bremova-Ertl T. Effects of acetyl-DL-leucine on ataxia and downbeat-nystagmus in six patients with ataxia telangiectasia. J Child Neurol. 2022;37(1):20–7.

    Article  PubMed  Google Scholar 

  16. Tighilet B, Leonard J, Bernard-Demanze L, Lacour M. Comparative analysis of pharmacological treatments with N-acetyl-DL-leucine (Tanganil) and its two isomers (N-acetyl-L-leucine and N-acetyl-D-leucine) on vestibular compensation: behavioral investigation in the cat. Eur J Pharmacol. 2015;769:342–9.

    Article  CAS  PubMed  Google Scholar 

  17. Sarkar C, Hegdekar N, Lipinski MM. N-acetyl-L-leucine treatment attenuates neuronal cell death and suppresses neuroinflammation after traumatic brain injury in mice. BioRxiv. 2019;759894.

  18. Hegdekar N, Lipinski MM, Sarkar C. N-acetyl-L-leucine improves functional recovery and attenuates cortical cell death and neuroinflammation after traumatic brain injury in mice. Sci Rep. 2021;11(1):9249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Churchill GC, Strupp M, Galione A, Platt FM. Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance. PLoS ONE. 2020;15(2):e0229585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vibert N, Vidal PP. In vitro effects of acetyl-dl‐leucine (tanganil®) on central vestibular neurons and vestibulo‐ocular networks of the guinea‐pig. Eur J Neurosci. 2001;13(4):735–48.

    Article  CAS  PubMed  Google Scholar 

  21. Vanderkam P, Blanchard C, Naudet F, Pouchain D, Vaillant Roussel H, Perault-Pochat MC, et al. Efficacy of acetylleucine in vertigo and dizziness: a systematic review of randomised controlled trials. Eur J Clin Pharmacol. 2019;75(5):603–7.

    Article  CAS  PubMed  Google Scholar 

  22. Saberi-Karimian M, Beyraghi-Tousi M, Mirzadeh M, Gumpricht E, Sahebkar A. The effect of N-acetyl-DL-leucine on neurological symptoms in a patient with ataxiATelangiectasia: a case study. Cerebellum. 2023;22(1):96–101.

    Article  CAS  PubMed  Google Scholar 

  23. Beyraghi-Tousi M, Sahebkar A, Houra M, Sarvghadi P, Jamialahmadi T, Bagheri R, Tavallaie S, Gumpricht E, Saberi-Karimian M. Efficacy and safety of N-acetyl-L-leucine in patients with ataxia telangiectasia: a randomized, double-blind, placebo-controlled, crossover clinical trial. Eur J Pediatr Neurol. 2024;50:57–63.

    Article  CAS  Google Scholar 

  24. O’brien SW, Konsler, Gwen K. Alleviating children’s postoperative pain. MCN: Am J Maternal/Child Nurs. 1988;133:183–6.

    Google Scholar 

  25. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167(6):1469-e14801412. https://doi.org/10.1016/j.cell.2016.11.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. XU, Zhifeng, et al. N-acetyl-L-leucine protects MPTP-treated Parkinson’s disease mouse models by suppressing desulfobacterota via the gut-brain axis. Brain Res Bull. 2023;202:110729.

    Article  CAS  PubMed  Google Scholar 

  27. Sabino P, de Oliveira B, Putti S, Naro F, Pellegrini M. Bone marrow transplantation as therapy for AtaxiATelangiectasia: a systematic review. Cancers (Basel). 2020;12(11).

  28. Díaz D, Del Pilar C, Carretero J, Alonso JR, Weruaga E. Daily bone marrow cell transplantations for the management of fast neurodegenerative processes. J Tissue Eng Regen Med. 2019;13(9):1702–11.

    Article  PubMed  Google Scholar 

  29. Harris VK, Yan QJ, Vyshkina T, et al. Clinical and pathological effects of intrathecal injection of mesenchymal stem cell-derived neural progenitors in an experimental model of multiple sclerosis. J Neurol Sci. 2012;313(1–2):167–77. https://doi.org/10.1016/j.jns.2011.08.036.

    Article  PubMed  Google Scholar 

  30. Harris VK, Faroqui R, Vyshkina T, Sadiq SA. Characterization of autologous mesenchymal stem cell-derived neural progenitors as a feasible source of stem cells for central nervous system applications in multiple sclerosis. Stem Cells Transl Med. 2012;1(7):536–47. https://doi.org/10.5966/sctm.2012-0015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fan Y, Goh EL, Chan JK. Neural cells for neurodegenerative diseases in clinical trials. Stem Cells Transl Med. 2023;12(8):510–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Harris VK, Stark J, Vyshkina T, Blackshear L, Joo G, Stefanova V, Sara G, Sadiq SA. Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis. EBioMedicine. 2018;29:23–30.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ovchinnikov DA, Withey SL, Leeson HC, Lei UW, Sundarrajan A, Junday K, et al. Correction of ATM mutations in iPS cells from two ataxiATelangiectasia patients restores DNA damage and oxidative stress responses. Hum Mol Genet. 2020;29(6):990–1001.

    Article  CAS  PubMed  Google Scholar 

  34. Buoni S, Zannolli R, Sorrentino L, Fois A. Betamethasone and improvement of neurological symptoms in ataxiATelangiectasia. Arch Neurol. 2006;63(10):1479–82.

    Article  PubMed  Google Scholar 

  35. Platt SR, Abramson CJ, Garosi LS. Administering corticosteroids in neurologic diseases. Compendium. 2005;27(3):210–20.

    Google Scholar 

  36. Zannolli R, Buoni S, Betti G, Salvucci S, Plebani A, Soresina A, et al. A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia. Mov Disord. 2012;27(10):1312–6.

    Article  CAS  PubMed  Google Scholar 

  37. Menotta M, Biagiotti S, Bianchi M, Chessa L, Magnani M. Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity. J Biol Chem. 2012;287(49):41352–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Menotta M, Biagiotti S, Bartolini G, Marzia B, Orazi S, Germani A, et al. Nano-mechanical characterization of Ataxia telangiectasia cells treated with dexamethasone. Cell Biochem Biophys. 2017;75(1):95–102.

    Article  CAS  PubMed  Google Scholar 

  39. Saberi-Karimian M, Beyraghi‐Tousi M, Jamialahmadi T, Sahebkar A. The positive short‐term effect of dexamethasone on ataxia symptoms in a patient with ataxia‐telangiectasia: a case report. Clin Case Rep. 2022;10(5):e05895.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rossi L, Pierige F, Aliano MP, Magnani M. Ongoing developments and clinical progress in drug-loaded red blood cell technologies. BioDrugs. 2020;34(3):265–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chessa L, Leuzzi V, Plebani A, Soresina A, Micheli R, D’Agnano D, et al. Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: results of a phase 2 trial. Orphanet J Rare Dis. 2014;9:5.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Leuzzi V, Micheli R, D’Agnano D, Molinaro A, Venturi T, Plebani A, et al. Positive effect of erythrocyte-delivered dexamethasone in ataxia-telangiectasia. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e98. https://doi.org/10.1212/NXI.0000000000000098.

  43. Menotta M, Biagiotti S, Orazi S, Rossi L, Chessa L, Leuzzi V, et al. In vivo effects of dexamethasone on blood gene expression in ataxia telangiectasia. Mol Cell Biochem. 2018;438(1–2):153–66.

    Article  CAS  PubMed  Google Scholar 

  44. Nguyen PH, Jayasinghe MK, Le AH, Peng B, Le MT. Advances in drug delivery systems based on red blood cells and their membrane-derived nanoparticles. ACS Nano. 2023;17(6):5187–210.

    Article  CAS  PubMed  Google Scholar 

  45. Schubert R, Schmitz N, Pietzner J, Tandi C, Theisen A, Dresel R, Christmann M, Zielen S. Growth hormone supplementation increased latency to tumourigenesis in atm-deficient mice. Growth Factors. 2009;27(5):265–73.

    Article  CAS  PubMed  Google Scholar 

  46. Nissenkorn A, Hassin-Baer S, Lerman SF, Levi YB, Tzadok M, Ben-Zeev B. Movement disorder in ataxiATelangiectasia: treatment with amantadine sulfate. J Child Neurol. 2013;28(2):155–60.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

No/Not applicable.

Funding

No particular funding was provided to the authors for this study.

Author information

Authors and Affiliations

  1. Endoscopic and Minimally Invasive Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Ali Mehri

  2. Department of Pediatric Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Mehran Beiraghi Toosi

  3. Pediatric Neurology Division, Pediatrics Center of Excellence, Myelin Disorders Clinic, Children’s Medical Center, Tehran University of Medical Sciences, No. 61, Gharib Street, Keshavarz Blvd, Tehran, 1419733151, Iran

    Ali Reza Tavasoli

  4. Pediatric Headache Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, USA

    Ali Reza Tavasoli

  5. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Maryam Saberi-Karimian

  6. Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Maryam Saberi-Karimian

  7. International UNESCO center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran

    Maryam Saberi-Karimian

Authors
  1. Ali Mehri
    View author publications

    Search author on:PubMed Google Scholar

  2. Mehran Beiraghi Toosi
    View author publications

    Search author on:PubMed Google Scholar

  3. Ali Reza Tavasoli
    View author publications

    Search author on:PubMed Google Scholar

  4. Maryam Saberi-Karimian
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Author contributionsA.M., M.BT., and M.SK. wrote the main manuscript text.A.M., M.BT., and M.SK. prepared the figure and table. AR.T. reviewed the final version of the manuscript.All authors reviewed the manuscript.

Corresponding author

Correspondence to Maryam Saberi-Karimian.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ali Mehri and Mehran Beiraghi Toosi are equal first author.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehri, A., Toosi, M.B., Tavasoli, A.R. et al. The Latest Developments for the Treatment of Ataxia Telangiectasia: A Narrative Review. Cerebellum 23, 2607–2615 (2024). https://doi.org/10.1007/s12311-024-01746-2

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1007/s12311-024-01746-2

Keywords

Profiles

  1. Ali Mehri View author profile