Advertisement

Treatment with chenodeoxycholic acid in cerebrotendinous xanthomatosis: clinical, neurophysiological, and quantitative brain structural outcomes

  • Maria del Mar Amador
  • Marion Masingue
  • Rabab Debs
  • Foudil Lamari
  • Vincent Perlbarg
  • Emmanuel Roze
  • Bertrand Degos
  • Fanny Mochel
Original Article

Abstract

Background

Cerebrotendinous xanthomatosis (CTX) is a rare neurodegenerative disease related to sterols metabolism. It affects both central and peripheral nervous systems but treatment with chenodeoxycholic acid (CDCA) has been reported to stabilize clinical scores and improve nerve conduction parameters. Few quantitative brain structural studies have been conducted to assess the effect of CDCA in CTX.

Methods and results

We collected retrospectively clinical, neurophysiological, and quantitative brain structural data in a cohort of 14 patients with CTX treated by CDCA over a mean period of 5 years. Plasma cholestanol levels normalized under treatment with CDCA within a few months. We observed a significant clinical improvement in patients up to 25 years old, whose treatment was initiated less than 15 years after the onset of neurological symptoms. Conversely, patients whose treatment was initiated more than 25 years after neurological disease onset continued their clinical deterioration. Eleven patients presented with a length-dependent peripheral neuropathy, whose electrophysiological parameters improved significantly under CDCA. Volumetric analyses in a subset of patients showed no overt volume loss under CDCA. Moreover, diffusion weighted imaging showed improved fiber integrity of the ponto-cerebellar and the internal capsule with CDCA. CDCA was well tolerated in all patients with CTX.

Conclusion

CDCA may reverse the pathophysiological process in patients with CTX, especially if treatment is initiated early in the disease process. Besides tendon xanthoma, this study stresses the need to consider plasma cholestanol measurement in any patient with infantile chronic diarrhea and/or jaundice, juvenile cataract, learning disability and/or autism spectrum disorder, pyramidal signs, cerebellar syndrome or peripheral neuropathy.

Notes

Acknowledgements

We are very grateful to the patients who participated in this study. We would also like to thank Damien Galanaud for MRI methods development, Isaac Adanyeguh for technical assistance, Philippe Couvert for molecular analyses, Frédéric Sedel and Yann Nadjar for patients referral. This study was supported the Investissements d’Avenir (Paris Institute of Neurosciences – IHU) grant number ANR-10-IAIHU-06.

Compliance with ethical standards

Conflict of interest

Maria del Mar Amador, Marion Masingue, Rabab Debs, Foudil Lamari, Vincent Perlbarg, Emmanuel Roze, Bertrand Degos declare that they have no conflict of interest.

Fanny Mochel has received an education grant from Sigma Tau pharmaceuticals.

Animal rights

This article does not contain any studies with animal subjects performed by the any of the authors.

Supplementary material

10545_2018_162_MOESM1_ESM.xlsx (56 kb)
ESM 1 (XLSX 56 kb)
10545_2018_162_MOESM2_ESM.docx (28 kb)
ESM 2 (DOCX 27 kb)

References

  1. Appadurai V, DeBarber A, Chiang PW et al (2015) Apparent underdiagnosis of cerebrotendinous xanthomatosis revealed by analysis of ~60,000 human exomes. Mol Genet Metab 116:298–304Google Scholar
  2. Barkhof F, Verrips A, Wesseling P et al (2000) Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 217:869–876CrossRefPubMedGoogle Scholar
  3. Berginer VM, Salen G, Shefer S (1984) Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med 311:1649–1652CrossRefPubMedGoogle Scholar
  4. Berginer VM, Berginer J, Korczyn AD, Tadmor R (1994) Magnetic resonance imaging in cerebrotendinous xanthomatosis: a prospective clinical and neuroradiological study. J Neurol Sci 122:102–108CrossRefPubMedGoogle Scholar
  5. Chang CC, Lui CC, Wang JJ et al (2010) Multi-parametric neuroimaging evaluation of cerebrotendinous xanthomatosis and its correlation with neuropsychological presentations. BMC Neurol 10:59–66CrossRefPubMedPubMedCentralGoogle Scholar
  6. Degos B, Nadjar Y, Amador Mdel M et al (2016) Natural history of cerebrotendinous xanthomatosis: a paediatric disease diagnosed in adulthood. Orphanet J Rare Dis 11:41–44CrossRefPubMedPubMedCentralGoogle Scholar
  7. Ginanneschi F, Mignarri A, Mondelli M et al (2013) Polyneuropathy in cerebrotendinous xanthomatosis and response to treatment with chenodeoxycholic acid. J Neurol 260:268–274CrossRefPubMedGoogle Scholar
  8. Guerrera S, Stromillo ML, Mignarri A et al (2010) Clinical relevance of brain volume changes in patients with cerebrotendinous xanthomatosis. J Neurol Neurosurg Psychiatry 81:1189–1193CrossRefPubMedGoogle Scholar
  9. Honda A, Yamashita K, Miyazaki H et al (2008) Highly sensitive analysis of sterol profiles in human serum by LC-ESI-MS/MS. J Lipid Res 49:2063–2073CrossRefPubMedGoogle Scholar
  10. Inglese M, De Stefano N, Pagani E et al (2003) Quantification of brain damage in cerebrotendinous xanthomatosis with magnetization transfer MR imaging. Am J Neuroradiol 24:495–500PubMedGoogle Scholar
  11. Inoue K, Kubota S, Seyama Y (1999) Cholestanol induces apoptosis of cerebellar neuronal cells. Biochem Biophys Res Commun 256:198–203CrossRefPubMedGoogle Scholar
  12. Marelli C, Lamari F, Rainteau D et al (2018) Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain 141:72–84CrossRefPubMedGoogle Scholar
  13. Masingue M, Adanyeguh I, Nadjar Y et al (2017) Evolution of structural neuroimaging biomarkers in a series of adult patients with Niemann-pick type C under treatment. Orphanet J Rare Dis 12:22–28CrossRefPubMedPubMedCentralGoogle Scholar
  14. Mignarri A, Rossi S, Ballerini M et al (2011) Clinical relevance and neurophysiological correlates of spasticity in cerebrotendinous xanthomatosis. J Neurol 258:783–790CrossRefPubMedGoogle Scholar
  15. Mignarri A, Gallus GN, Dotti MT, Federico A (2014) A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis 37:421–429CrossRefPubMedGoogle Scholar
  16. Mignarri A, Magni A, Del Puppo M et al (2016) Evaluation of cholesterol metabolism in cerebrotendinous xanthomatosis. J Inherit Metab Dis 39:75–83CrossRefPubMedGoogle Scholar
  17. Mignarri A, Dotti MT, Federico A et al (2017) The spectrum of magnetic resonance findings in cerebrotendinous xanthomatosis: redefinition and evidence of new markers of disease progression. J Neurol 264:862–874CrossRefPubMedGoogle Scholar
  18. Modat M, Ridgway GR, Taylor ZA et al (2010) Fast free-form deformation using graphics processing units. Comput Methods Prog Biomed 98:278–284CrossRefGoogle Scholar
  19. Mondelli M, Sicurelli F, Scarpini C, Dotti MT, Federico A (2001) Cerebrotendinous xanthomatosis: 11-year treatment with chenodeoxycholic acid in five patients. An electrophysiological study. J Neurol Sci 190:29–33CrossRefPubMedGoogle Scholar
  20. Mori S, Oishi K, Jiang H et al (2008) Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template. NeuroImage 40:570–582CrossRefPubMedPubMedCentralGoogle Scholar
  21. Nie S, Chen G, Cao X, Zhang Y (2014) Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 9:179–189CrossRefPubMedPubMedCentralGoogle Scholar
  22. O'Donnell LJ, Westin CF (2011) An introduction to diffusion tensor image analysis. Neurosurg Clin N Am 22(2):185–196CrossRefPubMedPubMedCentralGoogle Scholar
  23. Otsu N (1979) A threshold selection method from gray-level histograms. IEEE Trans Sys Man Cyber 9:62–66CrossRefGoogle Scholar
  24. Pilo-de-la-Fuente B, Jimenez-Escrig A, Lorenzo JR et al (2011) Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and genetic survey. Eur J Neurol 18:1203–1211CrossRefPubMedGoogle Scholar
  25. Reuter M, Schmansky NJ, Rosas HD, Fischl B (2012) Within-subject template estimation for unbiased longitudinal image analysis. NeuroImage 61:1402–1418CrossRefPubMedPubMedCentralGoogle Scholar
  26. Salen G, Shefer S, Berginer V (1991) Biochemical abnormalities in cerebrotendinous xanthomatosis. Dev Neurosci 13:363–370CrossRefPubMedGoogle Scholar
  27. Salen G, Steiner RD (2017) Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inherit Metab Dis 40:771–781CrossRefPubMedGoogle Scholar
  28. Stelten BML, Bonnot O, Huidekoper HH, et al (2017) Autism spectrum disorder: an early and frequent feature in cerebrotendinous xanthomatosis. J Inherit Metab Dis doi:10.1007/s10545-017-0086-7Google Scholar
  29. van Heijst AF, Verrips A, Wevers RA et al (1998) Treatment and follow-up of children with cerebrotendinous xanthomatosis. Eur J Pediatr 157:313–316CrossRefPubMedGoogle Scholar
  30. Yahalom G, Tsabari R, Molshatzki N et al (2013) Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis. Clin Neuropharmacol 36:78–83CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  1. 1.Assistance Publique-Hôpitaux de Paris, Département de NeurologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  2. 2.Assistance Publique-Hôpitaux de Paris, Département de NeurophysiologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  3. 3.Assistance Publique-Hôpitaux de Paris, Laboratoire de Biochimie MétaboliqueGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  4. 4.Centre de Référence Neurométabolique AdulteGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  5. 5.Université Pierre et Marie CurieGroupe de Recherche Clinique NeurométaboliqueParisFrance
  6. 6.Sorbonne Universités, UPMC-Paris 6, UMR S 1127 and Inserm U 1127, and CNRS UMR 7225, and ICMParisFrance
  7. 7.Laboratoire d’imagerie biomédicale (LIB)ParisFrance
  8. 8.Bioinformatics and Biostatistics Core Facility, iCONICS, IHU-A-ICM, ICM, F-75013ParisFrance
  9. 9.CNRS-UMR 7241/INSERM U1050, CIRBCollège de France, UPMCParisFrance
  10. 10.Assistance Publique-Hôpitaux de Paris, Service de NeurologieHôpital Universitaire d’AvicenneBobignyFrance
  11. 11.Assistance Publique-Hôpitaux de Paris, Département de GénétiqueGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  12. 12.Reference Center for Neurometabolic Diseases, Department of GeneticsLa Pitié-Salpêtrière University HospitalParisFrance

Personalised recommendations