Biomarker discovery for SPG5 HSP

Posted - February 2018 in Research Highlights

Two cholesterol derivatives identified

 

Confirmation of two blood biomarkers for SPG5 HSP, together with genetic testing, helps establish a definitive diagnosis.

 

SPG5 HSP is characterised by impaired cholesterol metabolism leading to toxic levels of buildup of cholesterol byproducts in the brain. This study confirms that increased levels of two of these byproducts in the blood, compounds known as oxysterols, and their ratio to total cholesterol levels, is a reliable indicator of SPG5 HSP.

 

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 plasma25-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.

 

SOURCE: Brain. 2018 Jan 1;141(1):72-84. doi: 10.1093/brain/awx297. PMID: 29228183

 

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

 

Marelli C1,2, Lamari F3,4,5, Rainteau D6, Lafourcade A7, Banneau G8, Humbert L6, Monin ML9,10, Petit E10, Debs R11, Castelnovo G12, Ollagnon E13, Lavie J14, Pilliod J14, Coupry I14, Babin PJ14, Guissart C15, Benyounes I3, Ullmann U16, Lesca G17, Thauvin-Robinet C18, Labauge P1,19, Odent S20, Ewenczyk C9,10, Wolf C6, Stevanin G9,10,21, Hajage D7,22, Durr A9,10,23, Goizet C14,24,25, Mochel F5,9,10.

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.

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