title: Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis.
abstract: Patients with a recessively inherited "pure" hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 alpha hydroxylase (CYP7B1). One of the expected metabolic consequences of such mutations is accumulation of oxysterol substrates due to decreased enzyme activity. In accordance with this, we demonstrate here that four patients with the SPG5 disease have 6- to 9-fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30- to 50-fold, was found in cerebrospinal fluid. The plasma levels of 25-hydroxycholesterol were increased about 100-fold. There were no measurable levels of this oxysterol in cerebrospinal fluid. The pattern of bile acids in serum was normal, suggesting a normal bile acid synthesis. The findings are discussed in relation to two transgenic mouse models with increased levels of 27-hydroxy cholesterol in the circulation but without neurological symptoms: the cyp27a1 transgenic mouse and the cyp7b1 knockout mouse. The absolute plasma levels of 27-hydroxycholesterol in the latter models are, however, only about 20% of those in the SPG5 patients. If the accumulation of 27-hydroxycholesterol is an important pathogenetic factor, a reduction of its levels may reduce or prevent the neurological symptoms. A possible strategy to achieve this is discussed.
authors.affiliation: Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tubingen, Tubingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.forename: Magnus
authors.initials: M
authors.lastname: Hansson
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Madrid
authors.forename: Nailah
authors.initials: N
authors.lastname: Siddique
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood; D000072474:Cytochrome P450 Family 7; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood* / Q000134:cerebrospinal fluid*; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000097:blood / Q000134:cerebrospinal fluid / Q000209:etiology; D010290:Parents; D010766:Phosphorylation; D015419:Spastic Paraplegia, Hereditary / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000150:complications / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics*; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D001647:Bile Acids and Salts; D006888:Hydroxycholesterols; D016875:tau Proteins; C076996:27-hydroxycholesterol; C007997:25-hydroxycholesterol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human