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

Patients with a recessively inherited “pure” hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 α 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. Patients with a recessively inherited “pure” hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 α 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. “Pure” hereditary spastic paraplegias (HSP) are a clinically and genetically heterogenous group of rare neurodegenerative diseases. Patients with syndromic HSP may also have mental retardation, cerebellar ataxia, and optic and peripheral neuropathy. The spasticity occurs due to axonal degeneration of corticospinal motor neurons forming the corticospinal tracts. In addition, there is a degeneration of dorsal columns with relative preservation of the dorsal root ganglia neuron. About 40 loci have been mapped in this heterogenous disease and causative mutations in several genes have been found in the different subgroups of the disease. These genes have diverse functions including axonal transport, mitochondrial functions, and myelin sheet formation. A specific subgroup of HSP inherited as an autosomal recessive trait has been defined, called SPG5 (1Hentati A. Pericakce M.A. Hung W.Y. Balal S. Laing N. Boustany R.M. Hentati F. Ben Hamida M. Siddique T. Link age of pure autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity.Hum. Mol. Genet. 1994; 3: 1263-1267Crossref PubMed Scopus (117) Google Scholar). Very recently patients in this subgroup were shown to have mutations in the gene coding for the steroid-metabolizing enzyme, cytochrome P-4507B1 (2Tsaousidou M.K. Ouahchi K. Warner T.T. Yang Y. Simpson M.A. Ling N.G. Wilkinson P.A. Madrid R.E. Patel H. Hentati F. et al.Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration.Am. J. Hum. Genet. 2008; 82: 510-515Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 3Schule R. Brandt E. Karle K.N. Tsaousidou M. Klebe S. Klimpe S. Auer-Grumbach M. Crosby A.H. Hübner C.A. Schöls L. et al.Aalysis of CYP7B1 in non-consangious cases of hereditary spastic paraplegia.Neurogenetics. 2009; 10: 97-104Crossref PubMed Scopus (45) Google Scholar, 4Goizet C. Boukhris A. Durr A. Beetz C. Truchetto J. Tesson C. Tsaousidou M. Forlani S. Guyant-Maréchal L. Fontaine B. et al.CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5.Brain. 2009; 132: 1589-1600.Crossref PubMed Scopus (88) Google Scholar). Clinically 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 (1Hentati A. Pericakce M.A. Hung W.Y. Balal S. Laing N. Boustany R.M. Hentati F. Ben Hamida M. Siddique T. Link age of pure autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity.Hum. Mol. Genet. 1994; 3: 1263-1267Crossref PubMed Scopus (117) Google Scholar, 2Tsaousidou M.K. Ouahchi K. Warner T.T. Yang Y. Simpson M.A. Ling N.G. Wilkinson P.A. Madrid R.E. Patel H. Hentati F. et al.Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration.Am. J. Hum. Genet. 2008; 82: 510-515Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 3Schule R. Brandt E. Karle K.N. Tsaousidou M. Klebe S. Klimpe S. Auer-Grumbach M. Crosby A.H. Hübner C.A. Schöls L. et al.Aalysis of CYP7B1 in non-consangious cases of hereditary spastic paraplegia.Neurogenetics. 2009; 10: 97-104Crossref PubMed Scopus (45) Google Scholar, 4Goizet C. Boukhris A. Durr A. Beetz C. Truchetto J. Tesson C. Tsaousidou M. Forlani S. Guyant-Maréchal L. Fontaine B. et al.CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5.Brain. 2009; 132: 1589-1600.Crossref PubMed Scopus (88) Google Scholar). Cytochrome P-4507B1 (CYP7B1) is responsible for a specific step in bile acid biosynthesis, 7α-hydroxylation of the oxysterol 27-hydroxycholesterol. This is an important reaction in the alternative pathway of bile acid synthesis from cholesterol in the liver (for a review, see ref. 5Russell D.W. The enzymes, regulation and geneics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1406) Google Scholar). A knockout of this gene in mice causes accumulation of the oxysterols 27-hydroxycholesterol and 25-hydroxy cholesterol, but otherwise the mice have no obvious phenotype (6Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. Disruption of the oxysterol 7α-hydroxylase gene in mice.J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). In contrast to the situation in humans, mice with a knockout of cyp7b1 thus do not develop spastic paraplegia in spite of elevated level of 27-hydroxycholesterol. A transgenic mouse model overexpressing the gene for human CYP27A1 has been developed and characterized (7Meir K. Kitsberg D. Alkalay I. Szafer F. Rosen H. Shpitzen S. Avi L.B. Staels B. Fievet C. Meiner V. Björkhem I. Leitersdorf E. Human sterol 27-hydroxylase (CYP27) overexpressor transgenc mouse model.J. Biol. Chem. 2002; 277: 34036-34041Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). Also these mice have levels of 27-hydroxycholesterol about 6-fold higher than normal without any obvious phenotype. It may be concluded from the characterization of cyp7b1 deficient and CYP27A1 overexpressing mice that increasing the levels of 27-hydroxycholesterol by a factor of 6–7 is not sufficient to cause obvious neurological deficits in mice. The situation may be different in humans, because normal levels of 27-hydroxycholesterol are considerably higher in humans than in mouse, possibly as a consequence of a less efficient metabolism. Another factor that may be of relevance is the small corticospinal tract and its redundancy in rodents. Lack of Alsin resulting from loss of function mutations of the ALS2 gene results in severe disorder of human corticospinal and corticobulbar tract degeneration with primary lateral sclerosis. However, in mouse models, Alsin deletion has minimal effect on ambulation and muscle tone (8Yang Y. Hentati A. Deng H.X. Dabbagh O. Sasaki T. Hirano M. Hung W.Y. Ouahchi K. Yan J. Azim A.C. et al.The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.Nat. Genet. 2001; 29: 160-165Crossref PubMed Scopus (662) Google Scholar, 9Deng H.X. Zhai H. Fu R. Shi Y. Gorrie G.H. Yang Y. Liu E. Dal Canto M.C. Mugnaini E. Siddique T. Distal axonopathy in an alsin-deficient mouse model.Hum. Mol. Genet. 2007; 16: 2911-2920Crossref PubMed Scopus (41) Google Scholar). A fatal case with mutations in the CYP7B1 gene has been reported: an infant who died in the neonatal stage with liver failure (10Setchell K.D.R. Schwarz M. O’Connell N.C. Lund E.G. Davis D.L. Lathe R. Thompson H.R. Weslie Tyson R. Sokol R.J. Russell D.W. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7 alpha-hydroxylase gene causes severe neonatal liver disease.J. Clin. Invest. 1998; 102: 1690-1703Crossref PubMed Scopus (294) Google Scholar, 11Stiles A.R. McDonald J.G. Bauman D.R. Russell D.W. CYP7B1: One cytochrome P-450, two human genetic disease, and multiple physiological functions.J. Biol. Chem. 2009; (In press.)Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Plasma levels of 27-hydroxy cholesterol were increased more than 1,000 times those of normal controls. This 10-wk-old boy presented with severe cholestasis, cirrhosis, and liver failure, which may have affected the 27-hydroxycholesterol levels. Another metabolite, 24-hydroxycholesterol, was also increased in this infant by a similar magnitude. This oxysterol is metabolized by CYP39A1 (5Russell D.W. The enzymes, regulation and geneics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1406) Google Scholar) and is not a substrate for CYP7B1 (12Norlin M. Toll A. Björkhem I. Wikvall K. 24-Hydroxycholesterol is a substrate for hepatic cholesterol 7α-hydroxylase.J. Lipid Res. 2000; 41: 1629-1639Abstract Full Text Full Text PDF PubMed Google Scholar). More recently, another fatal neonatal case with a mutation in the CYP7B1 gene and development of cholestasis was described (13Ueki I. Kimura A. Nishiyori A. Chen H.L. Takei H. Nittono H. Kurosawa T. Neonatal cholestatic liver disease in an Asian patient with a homozygous mutation in the oxysterol 7 alpha hydroxylase gene.J. Pediatr. Gastroenterol. Nutr. 2008; 46: 465-469Crossref PubMed Scopus (53) Google Scholar). The oxysterol levels in this patients were not reported. Whether or not the mutation was causative or a contributing factor in the death of the above two infants is not known with certainty. The possibility has been discussed that an infection and a concomitant elevation of 25-hydroxycholesterol may be a precipitating condition of liver failure in infants with CYP7B1 deficiency (11Stiles A.R. McDonald J.G. Bauman D.R. Russell D.W. CYP7B1: One cytochrome P-450, two human genetic disease, and multiple physiological functions.J. Biol. Chem. 2009; (In press.)Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). In the present work, 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. Case 1 (2Tsaousidou M.K. Ouahchi K. Warner T.T. Yang Y. Simpson M.A. Ling N.G. Wilkinson P.A. Madrid R.E. Patel H. Hentati F. et al.Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration.Am. J. Hum. Genet. 2008; 82: 510-515Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar) is a 26-year-old woman of Italian origin, the child of first cousins, affected with gait difficulties since childhood. The family denies anyone else being similarly affected. She exhibits a spastic gait with left greater than right weakness of the iliopsoas and glutei, which requires the use of a motorized wheelchair, flexor spasm in the legs to noxious stimuli, transient bilateral convergent spasm of extraocular muscles, and urinary retention, as well as extensive decreased superficial and proprioceptive atrophy and mild cerebellar and She has a homozygous Case R. Brandt E. Karle K.N. Tsaousidou M. Klebe S. Klimpe S. Auer-Grumbach M. Crosby A.H. Hübner C.A. Schöls L. et al.Aalysis of CYP7B1 in non-consangious cases of hereditary spastic paraplegia.Neurogenetics. 2009; 10: 97-104Crossref PubMed Scopus (45) Google Scholar) is a of with a of complicated In to spastic severe dorsal and optic atrophy are She from that a She a homozygous and are of Italian R. Brandt E. Karle K.N. Tsaousidou M. Klebe S. Klimpe S. Auer-Grumbach M. Crosby A.H. Hübner C.A. Schöls L. et al.Aalysis of CYP7B1 in non-consangious cases of hereditary spastic paraplegia.Neurogenetics. 2009; 10: 97-104Crossref PubMed Scopus (45) Google Scholar). Case is a who has from pure HSP since the age of developed pure HSP at the age of are for a and a R. Brandt E. Karle K.N. Tsaousidou M. Klebe S. Klimpe S. Auer-Grumbach M. Crosby A.H. Hübner C.A. Schöls L. et al.Aalysis of CYP7B1 in non-consangious cases of hereditary spastic paraplegia.Neurogenetics. 2009; 10: 97-104Crossref PubMed Scopus (45) Google Scholar). patients to this the of the patients and the of serum and cerebrospinal were by of the oxidized acid as well as bile acids were by with use of as described S. O. of cholesterol in human plasma by Biochem. PubMed Scopus Google Scholar, I. O. of the bile acids in serum by J. Clin. Invest. PubMed Google Scholar, A. S. B. N. J. K. M. Björkhem I. Patients with may have increased levels of 27-hydroxycholesterol and J. Clin. Invest. PubMed Scopus Google Scholar). was a to normal and K. A. H. C. J. E. protein in cerebrospinal a for axonal degeneration in Chem. PubMed Scopus Google Scholar). was a with forms of as and to as a E. H. E. B. M. N. K. of at in human cerebrospinal a with a for 2000; PubMed Scopus Google Scholar). The of CYP7B1 to a metabolic of the alternative pathway for of bile the of the alternative pathway in bile acid synthesis is acid (5Russell D.W. The enzymes, regulation and geneics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1406) Google a relative in the level of this bile acid be shown in there was a to decreased levels of acid and increased levels of The pattern of bile acids in serum with and acid as bile acids was normal, and no bile acids be levels of bile acids in SPG5 acid acid acid acid levels were from and The levels were from (13Ueki I. Kimura A. Nishiyori A. Chen H.L. Takei H. Nittono H. Kurosawa T. Neonatal cholestatic liver disease in an Asian patient with a homozygous mutation in the oxysterol 7 alpha hydroxylase gene.J. Pediatr. Gastroenterol. Nutr. 2008; 46: 465-469Crossref PubMed Scopus (53) Google Scholar) and S. B. K. K. Björkhem I. of acid in and of humans as by Full Text PDF PubMed Scopus Google Scholar). in a new shown in the serum levels of 27-hydroxycholesterol were 6- to 9-fold higher than in the four patients. The levels of which is also a substrate for were increased about 100-fold. The levels of which is not a substrate for the enzyme, were oxysterols were present at normal levels be expected to have serum levels of 27-hydroxycholesterol than the patients but higher than those of the controls. In accordance with this, the of patient 1 a serum level of above the level of the and about of those of the levels of cholesterol and oxysterols in the SPG5 to patient to patient levels of the oxysterols were from ref. and the levels of acid from not The levels of the oxysterols were from ref. and the levels of acid from S. O. of cholesterol in human plasma by Biochem. PubMed Scopus Google Scholar). not in a new acid is an important of present in the circulation A. S. B. N. J. K. M. Björkhem I. Patients with may have increased levels of 27-hydroxycholesterol and J. Clin. Invest. PubMed Scopus Google Scholar). The level of this acid was normal or only was also increased in cerebrospinal with levels 30- to higher than in controls. levels of 25-hydroxycholesterol were found in this The levels of which are known to be increased in neurodegenerative V. T. B. J. Björkhem I. use of and Chem. PubMed Scopus Google were not of protein and protein in cerebrospinal from three of the SPG5 The oxysterol levels were from K. A. H. C. J. E. protein in cerebrospinal a for axonal degeneration in Chem. PubMed Scopus Google Scholar). The levels for the levels of and were those of the of the I. O. of the bile acids in serum by J. Clin. Invest. PubMed Google Scholar, A. S. B. N. J. K. M. Björkhem I. Patients with may have increased levels of 27-hydroxycholesterol and J. Clin. Invest. PubMed Scopus Google Scholar). in a new The oxysterol levels were from K. A. H. C. J. E. protein in cerebrospinal a for axonal degeneration in Chem. PubMed Scopus Google Scholar). The levels for the levels of and were those of the of the I. O. of the bile acids in serum by J. Clin. Invest. PubMed Google Scholar, A. S. B. N. J. K. M. Björkhem I. Patients with may have increased levels of 27-hydroxycholesterol and J. Clin. Invest. PubMed Scopus Google Scholar). In of a possible neurodegenerative effect of the levels of protein and protein in cerebrospinal markers of were also The levels of these markers were normal The of the alternative pathway in bile acid synthesis is CYP7B1 (5Russell D.W. The enzymes, regulation and geneics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1406) Google Scholar) and as a a of acid be shown in 1 acid about of the bile acids in serum as with about in the controls. The is to the relative of the alternative pathway but because of the small of patients and the no can be Another was that acid about of the bile acids in serum of the SPG5 patients as with less than of the controls. A as a consequence of a neurological be expected to such an no can be because of the small of patients. the plasma levels of the substrates for the CYP7B1 enzyme, 27-hydroxycholesterol and 25-hydroxy cholesterol, were increased in the four SPG5 patients. The of this increase, 6- to 9-fold in case of 27-hydroxycholesterol and about in the case of is similar to the in mice with a knockout of the cyp7b1 gene (6Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. Disruption of the oxysterol 7α-hydroxylase gene in mice.J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar) and higher than the of 27-hydroxycholesterol in mice with an of CYP27A1 (7Meir K. Kitsberg D. Alkalay I. Szafer F. Rosen H. Shpitzen S. Avi L.B. Staels B. Fievet C. Meiner V. Björkhem I. Leitersdorf E. Human sterol 27-hydroxylase (CYP27) overexpressor transgenc mouse model.J. Biol. Chem. 2002; 277: 34036-34041Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). There is an important The plasma levels of the side-chain oxidized oxysterols are considerably in mice than in The absolute plasma levels of the two side-chain oxidized oxysterols were thus about to in the patients in this but only about in the mice (6Li-Hawkins J. Lund E.G. Turley S.D. Russell D.W. Disruption of the oxysterol 7α-hydroxylase gene in mice.J. Biol. Chem. 2000; 275: 16536-16542Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar) and in the CYP27A1 mice (7Meir K. Kitsberg D. Alkalay I. Szafer F. Rosen H. Shpitzen S. Avi L.B. Staels B. Fievet C. Meiner V. Björkhem I. Leitersdorf E. Human sterol 27-hydroxylase (CYP27) overexpressor transgenc mouse model.J. Biol. Chem. 2002; 277: 34036-34041Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). is that the of the patients are to considerably higher levels of the two side-chain oxidized oxysterols than the in the two mouse the other the levels of the side-chain oxidized oxysterols were considerably than those in the first case with CYP7B1 the levels of oxysterols in that were to the cholestasis and the liver The liver failure may have been the of other than the CYP7B1 this mutation have been an important contributing there are no of cholestasis the neonatal of adult patients with the SPG5 disease. may be metabolized by a and possibly also by or a of acid is the most important A. S. B. N. J. K. M. Björkhem I. Patients with may have increased levels of 27-hydroxycholesterol and J. Clin. Invest. PubMed Scopus Google Scholar). In the present we only measured the level of acid in the circulation of the SPG5 patients and this level was found to be normal or only increased In the synthesis of cholesterol in the is higher than in or Turley S.D. in the 2001; PubMed Scopus Google Scholar). In spite of increased the of cholesterol in the is only higher than in these two This that the may have a for of In the the most important for this is of cholesterol which is to the I. D. O. A. of a for of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.W. R. T. enzyme of cholesterol in the Rev. Biochem. 2009; (In PubMed Scopus Google Scholar). The levels of the enzyme cholesterol are in the in relation to the levels in the that there be another for of the cholesterol from the There is a for of 27-hydroxycholesterol from the its the acid acid S. M. L. M. I. J. Björkhem I. for of oxysterols the 7 alpha Lipid Res. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). CYP7B1 is for this It may be that cholesterol is from the by a primary 27-hydroxycholesterol by a 7α-hydroxylation by CYP7B1 and to the above If this specific is of for of cholesterol from the in humans and there is a of the accumulation of 27-hydroxycholesterol in the may be higher than in most other corticospinal tract and dorsal lateral columns and the are the of in have shown that there is a of 27-hydroxycholesterol by the human from the circulation M. S. D. J. Björkhem I. the of 27-hydroxycholesterol the human Lipid Res. 46: Full Text Full Text PDF Scopus Google Scholar) and that most of the 27-hydroxycholesterol present in cerebrospinal from the circulation V. T. Patel S. Björkhem I. oxidized oxysterols in cerebrospinal and the of and Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). There is a levels of cholesterol and 27-hydroxycholesterol in the In contrast to cholesterol not the of this and the effect of 27-hydroxycholesterol on in of in D. S. N. A. Björkhem I. M. of and by of the alpha Res. 2007; PubMed Scopus Google we have that the of 27-hydroxycholesterol from the circulation the may be the and I. the oxysterols as cholesterol and metabolic in the PubMed Scopus Google Scholar, I. A. V. S. and neurodegenerative 2009; PubMed Scopus Google Scholar). The present not the that increased levels of 27-hydroxycholesterol in the cause a that can be by the cerebrospinal There may be and in of the small of the patients is to The of the corticospinal motor neurons and the dorsal root neurons that form the corticospinal and dorsal in the may be more to levels of 27-hydroxycholesterol than most other including and are known to have on of cholesterol and other Rev. 2000; PubMed Scopus Google Scholar, I. or Biol. 2002; PubMed Scopus Google Scholar). The relevance of such for the situation in however, to in the oxysterols are present with a of cholesterol, and this cholesterol may or prevent the of the oxysterol K. N. of oxysterols to human Full Text PDF PubMed Scopus Google Scholar). It has been that 25-hydroxycholesterol of 1 and 8 from human Y. L. O. from human and oxysterols may have a function for Biol. PubMed Scopus Google Scholar, T. O. K. 1 in human J. Clin. Invest. 2002; PubMed Scopus Google Scholar). It be that a as a consequence of the levels of 25-hydroxycholesterol may be of pathogenetic in the SPG5 patients. The absolute levels of 25-hydroxy cholesterol however, considerably than those of and we to demonstrate of 25-hydroxycholesterol in cerebrospinal fluid. If a relation and levels of 27-hydroxycholesterol in the circulation can be in patients with be to reduce the levels of the specific of 27-hydroxycholesterol are but because has been shown that substrate is a factor for CYP27A1 S. D. E. K. D. D. of cholesterol is for bile acid synthesis the alternative pathway in primary Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google a possible strategy be to the patients with have shown that the levels of 27-hydroxycholesterol and cholesterol in It be to reduce the levels of 27-hydroxycholesterol by about which may well have an effect on the of corticospinal tract 27-hydroxycholesterol is a factor in the degeneration of those tracts. The of and is

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