Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Rebecca Schüle,Teepu Siddique,Han-Xiang Deng,Yi Yang,Sandra Donkervoort,Magnus Hansson,Ricardo E Madrid,Nailah Siddique,Ludger Schöls,Ingemar Björkhem

doi:10.1194/jlr.m002543

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.

Highlights

Patients with a recessively inherited “pure” hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 ␣ hydroxylase (CYP7B1)
SPG5 is characterized by a progressive spastic paraplegia with variable age at onset, which is pure in most cases, but can be complicated by mild cerebellar ataxia and optic atrophy [1,2,3,4]
The activity of the alternative pathway in bile acid synthesis is dependent upon Cytochrome P-4507B1 (CYP7B1) [5] and as a consequence, a reduced formation of chenodeoxycholic acid would be expected

Summary

Introduction

Patients with a recessively inherited “pure” hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 ␣ hydroxylase (CYP7B1). We measured levels of 27-hydroxycholesterol and other side-chain oxidized oxysterols as well as bile acids in the circulation of four adult patients with the SPG5 disease and defined mutations in the CYP7B1 gene. The serum levels of 27-hydroxycholesterol were 6- to 9-fold higher than controls in the four patients.

Results

Conclusion