Cholesterol and SPG5 HSP

If the accumulation of cholesterol is an important disease-causing factor in SPG5 HSP, then a reduction of its levels may reduce or prevent symptoms.

Collaboration between German, Swedish and American scientists lead to key finding regarding the cause of a recessively inherited variety of HSP.

The study found marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. A reduction of its levels may reduce or prevent the neurological symptoms.

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 6-9 fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30-50 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-hydroxycholesterol 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.

SOURCE: Full article can be downloaded from

27-Hydroxycholesterol and 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

*Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tubingen, Tubingen, Germany

** Davee Department of Neurology and Clinical Neurosciences,

Northwestern University Feinberg School of Medicine, Chicago, USA

# Division of Clinical Chemistry, Karolinska University Hospital Huddinge, Karolinska Institutet, Sweden

## Jervis Clinic Institute for BasicResearch, Staten Island, NY, USA.