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

Schüle, Rebecca; Siddique, Teepu; Deng, Han Xiang; Yang, Yi; Donkervoort, Sandra; Hansson, Magnus; Madrid, R. E.; Siddique, Nailah; Schöls, Lüdger; Björkhem, Ingemar

doi:10.1194/jlr.m002543

Cited by 102 publications

(95 citation statements)

References 35 publications

(30 reference statements)

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“…In our patients, long-term administration of cholesterollowering drugs reduced serum levels of 27OHC by about 50 %, in line with what was expected [2]. Although 27OHC never normalized, we achieved a marked decrease, without loss of biochemical effectiveness over time.…”

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confidence: 67%

“…Spastic paraplegia type 5 (SPG5) is an autosomal recessive hereditary spastic paraparesis (HSP) associated with pure or complicated phenotypes and mutations in CYP7B1 [1] causing an impairment of the alternative pathway of bile acid synthesis with marked accumulation of 27-hydroxycholesterol (27OHC) in plasma and cerebrospinal fluid [2]. Since brain 27OHC has an extracerebral origin [3], cholesterol-lowering drugs might prevent neurological impairment in SPG5 by reducing circulating 27OHC, which is derived from cholesterol.…”

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confidence: 99%

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Treatment of SPG5 with cholesterol-lowering drugs

et al. 2015

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Spastic paraplegia type 5 (SPG5) is an autosomal recessive hereditary spastic paraparesis (HSP) associated with pure or complicated phenotypes and mutations in CYP7B1 [1] causing an impairment of the alternative pathway of bile acid synthesis with marked accumulation of 27-hydroxycholesterol (27OHC) in plasma and cerebrospinal fluid [2]. Since brain 27OHC has an extracerebral origin [3], cholesterol-lowering drugs might prevent neurological impairment in SPG5 by reducing circulating 27OHC, which is derived from cholesterol.We previously reported a nine-month follow-up in two ambulant siblings harboring mutations in SPG5/CYP7B1 [4]. At that time, we evaluated the effects of statin therapy in one of the two cases (patient 1) and observed moderate serum 27OHC reduction. Here, we present a 24-month follow-up in patient 1, treated with simvastatin and ezetimibe, and a 12-month follow-up in patient 2, treated with ezetimibe alone.Clinical details, laboratory and instrumental findings, and molecular data in the two patients have been described elsewhere [4]. In the present study, both subjects underwent neurological evaluation including Spastic Paraplegia Rating Scale (SPRS) and Modified Rankin Scale (MRS) clinical scoring, routine blood tests, cholesterol and 27OHC determinations every 3 months, and instrumental follow-up including motor evoked potentials (MEPs), conventional brain magnetic resonance imaging (MRI), and MR spectroscopy every 6 months. Patient 1 received different oral doses of simvastatin (from 20 to 60 mg/day) during the first 12 months, and then oral ezetimibe 10 mg/day was added to simvastatin 40 mg/day for 12 months. Treatments were well tolerated. Serum 27OHC concentration progressively decreased under treatment with simvastatin either alone (reduction ranged from 10 to 45 % compared to baseline) or when in combination with ezetimibe (55 % decrease compared to baseline), and cholesterol tended to decrease in parallel with 27OHC (Fig. 1a). Association of simvastatin and ezetimibe was more effective in reducing 27OHC than the increase of simvastatin dosage up to 60 mg/day. No changes of neurological disability as well as brain MRI and spectroscopic pattern were observed. MEPs revealed a trend toward improvement or stabilization of central motor conduction times (CMCTs).Patient 2, who had not tolerated simvastatin because of cramps and marked hyperCKemia [4], received ezetimibe 10 mg/day for 12 months, and tolerated well this therapy. We observed a persistent decrease of serum 27OHC values (38-50 % reduction compared to baseline), whereas cholesterol levels initially decreased and then returned to baseline (Fig. 1b). Alike his sister, SPRS and MRS scores as well as brain MRI and spectroscopy were unchanged. MEPs showed substantially stable CMCTs values over time.Since chenodeoxycholic acid (CDCA) has been reported to be beneficial in a child with liver disease associated with a missense variant in CYP7B1 [5], we added oral CDCA

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Treatment of SPG5 with cholesterol-lowering drugs

et al. 2015

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“…3 In GBA2, mutated in autosomal recessive HSP SPG46, the conversion of glucosylceramide to free glucose and ceramide by the non-lysosomal glucosylceramidase is deficient. 6 In SPG5 mutations in the 7a-hydroxylase gene CYP7B1 not only lead to accumulation of oxysterols in SPG5 patients 26 but may also influence neurosteroid metabolism. 27 During preparation of this manuscript Schuurs-Hoeijmakers et al 28 reported mutations in DDHD2 in four families with autosomal recessive HSP.…”

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confidence: 99%

Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)

et al. 2013

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Hereditary spastic paraplegias (HSP) are a genetically heterogeneous group of disorders characterized by a distal axonopathy of the corticospinal tract motor neurons leading to progressive lower limb spasticity and weakness. Intracellular membrane trafficking, mitochondrial dysfunction and myelin formation are key functions involved in HSP pathogenesis. Only recently defects in metabolism of complex lipids have been implicated in a number of HSP subtypes. Mutations in the 23 known autosomal recessive HSP genes explain less than half of autosomal recessive HSP cases. To identify novel autosomal recessive HSP disease genes, exome sequencing was performed in 79 index cases with autosomal recessive forms of HSP. Resulting variants were filtered and intersected between families to allow identification of new disease genes. We identified two deleterious mutations in the phospholipase DDHD2 gene in two families with complicated HSP. The phenotype is characterized by early onset of spastic paraplegia, mental retardation, short stature and dysgenesis of the corpus callosum. Phospholipase DDHD2 is involved in intracellular membrane trafficking at the golgi/ endoplasmic reticulum interface and has been shown to possess phospholipase A1 activity in vitro. Discovery of DDHD2 mutations in HSP might therefore provide a link between two key pathogenic themes in HSP: membrane trafficking and lipid metabolism.

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“…The importance of CYP7B1 in connection with the turnover of the neurosteroids dehydroepiandrosterone and pregnenolone is less well defi ned. As anticipated, SPG5 patients have increased plasma levels of 27-OHC (6-to 9-fold) and 25-OHC (100-fold) ( 50 ). A 30-to 50-fold increase in 27-OHC was found in cerebrospinal fl uid.…”

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confidence: 59%

“…It has been reported that 25-OHC induces production of interleukin-1 ␤ and interleukin-8 from human macrophages ( 54,55 ) as well as altering the production of IgA ( 56 ). We have discussed the possibility that a local interleukin release as a consequence of the high levels of 25-OHC may be a pathogenetic factor in the SPG5 patients ( 50 ).…”

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Genetic connections between neurological disorders and cholesterol metabolism

Björkhem

Leoni²,

Meaney³

2010

Journal of Lipid Research

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and store such a large amount of cholesterol indicates that there is a close link between the evolution of the nervous system and a specifi c role for cholesterol. Within the brain, some 70% of cholesterol is present in myelin, where it fulfi lls a critical insulating role. It is likely that the requirement for effi cient signaling despite a small transverse diameter of axons was a key selective pressure driving the accretion of cholesterol in the mammalian brain ( 1, 2 ). The requirement for large amounts of cholesterol is further underscored by the long half-life of brain cholesterol; overall brain cholesterol turns over some 250-300 times slower than that in the circulation ( 3 ).At a cellular level, the myelin sheath consists of sections of plasma membrane repeatedly wrapped around an axon, with the extrusion of virtually all of the cytoplasm. Myelin is formed by 2 very specialized cells: the oligodendrocyte in the central nervous system (CNS) and the Schwann cell in the peripheral nervous system (PNS). Because an individual axon may be ensheathed by myelin from several oligodendrocytes, periodic gaps are present in the sheath. These are called the "nodes of Ranvier" and are the site of propagation of the action potential. Myelin can thus be regarded as a discontinuous insulation that enables the saltatory conduction of the action potential ( 1, 2 ). In addition Abstract Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defi ned defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders. -Björkhem, I., V. Leoni, and S. Meaney. The mammalian nervous system contains a disproportionate amount of cholesterol. In the brain, the cholesterol content is about 10-fold greater than in any other organ ( 1 ). The development of the capacity to synthesize

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

Cited by 102 publications

References 35 publications

Treatment of SPG5 with cholesterol-lowering drugs

Treatment of SPG5 with cholesterol-lowering drugs

Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)

Genetic connections between neurological disorders and cholesterol metabolism

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