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Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5

Cecilia Marelli 1, 2 Foudil Lamari 3, 4 Dominique Rainteau 5 Alexandre Lafourcade 6 Guillaume Banneau 7 Lydie Humbert 8 Marie-Lorraine Monin 9 Elodie Petit 9 Rabab Debs 10 Giovanni Castelnovo 11 Elisabeth Ollagnon 12 Julie Lavie 13 Julie Pilliod 13 Isabelle Coupry 13 Patrick Babin 13 Claire Guissart 14 Imen Benyounes 3 Urielle Ullmann 14 Gaetan Lesca Christel Thauvin-Robinet 15 Pierre Labauge 16 Sylvie Odent 17 Claire Ewenczyk 10, 9 Claude Wolf 18 Giovanni Stevanin 10, 9, 19 David Hajage 20, 21 Alexandra Durr 20, 9 Cyril Goizet 13 Fanny Mochel 22, 20, * 
* Auteur correspondant
Abstract : The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7α-hydroxylase implicated in cholesterol and bile acids metabolism. We developed a method based on ultra-performance liquid chromatography electrospray tandem mass spectrometry to validate two plasma 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) as diagnostic biomarkers in a cohort of 21 patients with SPG5. For 14 patients, SPG5 was initially suspected on the basis of genetic analysis, and then confirmed by increased plasma 25-OHC, 27-OHC and their ratio to total cholesterol. For seven patients, the diagnosis was initially based on elevated plasma oxysterol levels and confirmed by the identification of two causal CYP7B1 mutations. The receiver operating characteristic curves analysis showed that 25-OHC, 27-OHC and their ratio to total cholesterol discriminated between SPG5 patients and healthy controls with 100% sensitivity and specificity. Taking advantage of the robustness of these plasma oxysterols, we then conducted a phase II therapeutic trial in 12 patients and tested whether candidate molecules (atorvastatin, chenodeoxycholic acid and resveratrol) can lower plasma oxysterols and improve bile acids profile. The trial consisted of a three-period, three-treatment crossover study and the six different sequences of three treatments were randomized. Using a linear mixed effect regression model with a random intercept, we observed that atorvastatin decreased moderately plasma 27-OHC (∼30%, P < 0.001) but did not change 27-OHC to total cholesterol ratio or 25-OHC levels. We also found an abnormal bile acids profile in SPG5 patients, with significantly decreased total serum bile acids associated with a relative decrease of ursodeoxycholic and lithocholic acids compared to deoxycholic acid. Treatment with chenodeoxycholic acid restored bile acids profile in SPG5 patients. Therefore, the combination of atorvastatin and chenodeoxycholic acid may be worth considering for the treatment of SPG5 patients but the neurological benefit of these metabolic interventions remains to be evaluated in phase III therapeutic trials using clinical, imaging and/or electrophysiological outcome measures with sufficient effect sizes. Overall, our study indicates that plasma 25-OHC and 27-OHC are robust diagnostic biomarkers of SPG5 and shall be used as first-line investigations in any patient with unexplained spastic paraplegia.
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Contributeur : LNC - université de Bourgogne Connectez-vous pour contacter le contributeur
Soumis le : lundi 19 mars 2018 - 15:43:17
Dernière modification le : mercredi 28 septembre 2022 - 16:20:11

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Cecilia Marelli, Foudil Lamari, Dominique Rainteau, Alexandre Lafourcade, Guillaume Banneau, et al.. Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain - A Journal of Neurology , 2018, 141 (1), pp.72 - 84. ⟨10.1093/brain/awx297⟩. ⟨hal-01737580⟩



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