Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5.
Brain. 2017-12-08; 141(1): 72-84
DOI: 10.1093/brain/awx297
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1. Brain. 2018 Jan 1;141(1):72-84. doi: 10.1093/brain/awx297.
Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia
type 5.
Marelli C(1)(2), Lamari F(3)(4)(5), Rainteau D(6), Lafourcade A(7), Banneau G(8),
Humbert L(6), Monin ML(9)(10), Petit E(10), Debs R(11), Castelnovo G(12),
Ollagnon E(13), Lavie J(14), Pilliod J(14), Coupry I(14), Babin PJ(14), Guissart
C(15), Benyounes I(3), Ullmann U(16), Lesca G(17), Thauvin-Robinet C(18), Labauge
P(1)(19), Odent S(20), Ewenczyk C(9)(10), Wolf C(6), Stevanin G(9)(10)(21),
Hajage D(7)(22), Durr A(9)(10)(23), Goizet C(14)(24)(25), Mochel F(5)(9)(10).
Author information:
(1)Gui de Chauliac University Hospital, Department of Neurology, Montpellier,
France.
(2)Gui de Chauliac University Hospital, Expert Center for Neurogenetic Diseases
and Adult Mitochondrial and Metabolic Diseases, Montpellier, France.
(3)APHP, La Pitié-Salpêtrière University Hospital, Department of Biochemistry,
Paris, France.
(4)University Pierre and Marie Curie, Neurometabolic Research Group, Paris,
France.
(5)APHP, La Pitié-Salpêtrière University Hospital, Reference Center for Adult
Neurometabolic Diseases, Paris, France.
(6)APHP, Hôpital Saint Antoine, Département PM2 Plateforme de Métabolomique,
Peptidomique et dosage de Médicaments, Paris, France.
(7)APHP, Hôpital La Pitié-Salpêtrière, Département de Biostatistiques, Santé
publique et Information médicale, Centre de Pharmacoépidémiologie (Cephepi),
F-75013, Paris, France.
(8)APHP, La Pitié-Salpêtrière University Hospital, Department of Genetics,
Functional Unit of Molecular and Cellular Neurogenetics, Paris, France.
(9)APHP, La Pitié-Salpêtrière University Hospital, Department of Genetics, Paris,
France.
(10)Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S
1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
(11)APHP, La Pitié-Salpêtrière University Hospital, Department of Neurology,
Paris, France.
(12)Caremeau University Hospital, Department of Neurology, Nimes, France.
(13)La Croix-Rousse University Hospital, Department of Genetics, Lyon, France.
(14)Laboratoire MRGM, INSERM U1211, Univ Bordeaux, Bordeaux, France.
(15)Institut Universitaire de Recherche Clinique, Laboratoire de Génétique
Moléculaire, Montpellier, France.
(16)Institut de Pathologie et Génétique, Centre de Génétique Humaine, Gosselies,
Belgium.
(17)Lyon University Hospital, Department of Medical Genetics, Lyon, France.
(18)Dijon University Hospital, Department of Genetics, Dijon, France.
(19)Gui de Chauliac University Hospital, Reference Center for Adult
Leukodystrophy, Montpellier, France.
(20)Rennes University Hospital, Department of Clinical Genetics, Rennes, France.
(21)Ecole Pratique des Hautes Etudes, PSL Research University, Neurogenetic lab,
Paris, France.
(22)Paris Diderot University, Sorbonne Paris Cité, UMR 1123 ECEVE, Paris, France.
(23)APHP, La Pitié-Salpêtrière University Hospital, Neurogenetic Reference
Center, Paris, France.
(24)Bordeaux University Hospital, Department of Medical Genetics, Bordeaux,
France.
(25)Bordeaux University Hospital, Neurogenetic Reference Center, Bordeaux,
France.
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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DOI: 10.1093/brain/awx297
PMID: 29228183 [Indexed for MEDLINE]