Lemming, cholesterol

Fig. 5.1.2 Cholesterol biosynthesis branch of the isoprenoid biosynthetic pathway. Enzymes are numbered as follows 1 squalene synthase 2 squalene epoxidase 3 2,3-oxidosqua-lene sterol cyclase 4 sterol A24-reductase (desmosterolosis) 5 sterol C-14 demethylase 6 sterol A14-reductase (hydrops-ectopic calcification-moth-eaten, HEM, dysplasia) 7 sterol C-4 demethylase complex (including a 3/ -hydroxysteroid dehydrogenase defective in congenital hemidyspla-sia with ichthyosiform nevus and limb defects, CHILD, syndrome) 8 sterol A8-A7 isomerase (Conradi-Hunermann syndrome CDPX2) 9 sterol A5-desaturase (lathosterolosis) 10 sterol A7-reductase (Smith-Lemli-Opitz syndrome). Enzyme deficiencies are indicated by solid bars across the arrows...

Fig. 5.1.3 Sterol analysis in patients with defective cholesterol biosynthesis. Gas chromatography-mass spectrometry analysis of trimethylsilyl derivatives of sterols extracted from primary skin fibroblasts of a control subject, a Smith-Lemli-Opitz syndrome (SLOS) patient, and a Con-radi-Hunermann syndrome (CDPX2) patient, and lymphoblasts of a desmosterolosis patient cultured in lipoprotein-deficient medium reveals the accumulation of sterol intermediates indicative of a defect in cholesterol biosynthesis. Similar spectra can be obtained by sterol analysis of the plasma of such patients...

As an alternative, primary skin fibroblasts or lymphoblasts of patients suspected to be affected with a cholesterol biosynthesis defect can be cultured for 3-7 days in medium supplemented with fetal calf serum depleted of lipoproteins to induce cholesterol biosynthesis, whereupon the specific defect can be determined by sterol analysis using GC-MS as described above. This procedure will readily identify patients affected with Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, hydrops-ectopic calcification-motheaten (HEM) skeletal dysplasia and most patients with Conradi-Hunermann syndrome (CDPX2). Patients with congenital hemidys-plasia with ichthyosiform nevus and limb defects (CHILD) syndrome may not be identified with this assay, but they can be readily diagnosed on the basis of their typical clinical presentation. 

Fig. 5.3.6 Diagnose of Smith-Lemli-Opitz syndromesyndrome (SLOS). Urinary dehydropreg-nanetriols (DHPT 5/ -pregn-7-ene-3a,17a,20a-triol and 5j3-pregn-8-ene-3a,17a,20a-triol) partially replace PT in 7-dehydrocholesterol reductase deficiency and can be used to diagnose SLOS. The ratio of DHPT/PT correlates with dehydrocholesterol (DHC)/cholesterol (C) in affected patients (n = 34) and also correlates with clinical severity...

Irons M, Elias ER, Salen G, Tint GS, Batta AK (1993) Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet 341 1414... 

Abetalipoproteinemia is a rare lEM involving lipid dysfunction. Also called Bassen-Komzweig syndrome, it is characterized by extremely low cholesterol due to deficient or absent beta lipoproteins, which are an important component of the cholesterol molecular complex. Symptoms include growth retardation, neurological dysfunction, retinal pigment degeneration, and upper intestinal malabsorption. 

Sterol-A -isomerase deficiency, known as Conradi-HUnermann syndrome (CDPX2), is an X-linked dominant disorder. Clinical manifestations of this disorder include skeletal abnormalities, chondrodysplasia punctata, craniofacial anomalies, cataracts, and skin abnormalities. The 7-dehydrocholesterol reductase deficiency, known as Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder occurring in about 1 in 20,000 births. Clinical manifestations of affected individuals include craniofacial abnormalities, microcephaly, congenital heart disease, malformation of the limbs, psychomotor retardation, cerebral maldevelopment, and urogenital anomalies. Measurement of 7-dehydrocholesterol in amniotic fluid during second trimester or in neonatal blood specimen has been useful in the identification of the disorder. The sterol-A " -reductase deficiency causes a developmental phenotype similar to SLO syndrome and is associated with accumulation of desmosterol. The inability of de novo fetal synthesis of cholesterol combined with its inadequate transport from the mother to the fetus appears... 

C. Cunniff, L. E. Kratz, A. Mosher, et al. Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. American Journal of Medical Genetics 68,263 (1997). 

The wide differences in the mutation rate inherent in these disorders govern the efforts of national associations of patients affected by lipidoses and that of enzyme replacement therapeutic industries. In turn, the clinical everyday practice triggers campaigns for the detection by genotyping combined with biochemical lipidomic methods which establish the screening efficiency in neonates. The history of cholesterol deficits such as the Smith-Lemli-Opitz... 

A second metabolic defect in cholesterol synthesis leads to Smith-Lemli-Opitz syndrome (SLOS) (B.U. Fitzkey, 1999) [11]. SLOS is one of the most common autosomal D cessive disorders, with estimates of incidence ranging from 1 in 10,000 to 1 in 60,000 of live births [12]. Individuals with SLOS have markedly elevated levels of plasma 7-DHC and low plasma cholesterol levels. 7-DHC A7-reductase activity is deficient in SLOS patients samples, and cloning of the 7-DHC A7-reductase gene led to identification of over 100 missense and many null mutations in SLOS patients (RE. lira, 2003). 

P450 7A1 has also been demonstrated to convert lathosterol to 7-ketolathosterol (the immediate precursor of cholesterol in the normal pathway) to 7-ketoeholesterol and a trace of the 7,8-epoxide [1777]. The reaction with A -dehydrocholesterol is proposed to be responsible for the high level of the oxysterol 7-ketocho-lesterol in individuals with Smith-Lemli-Opitz syndrome [1777], and the ketone is formed in a direct reaction (carbocationic intermediate, with hydride transfer) rather than via rearrangement of the epoxide [1777], The relevance of this reaction has been demonstrated in Smith-Lemli-Optiz syndrome and cerebrotendinous xanthomatosis patients [1778],... 

Bjorkhem I, Diczfalusy U, Lovgren-Sandblom A, Starck L, Jonsson M, Tallman K, Schirmer H, Ousager LB, Crick PJ, Wang Y, GrilEths WJ, Guengerich FP (2014) On the formation of 7-keto-cholesterol from 7-dehydrocholesterol in patients with cerebrotendinous xanthomatosis and Smith-Lemli-Opitz syndrome. J Lipid Res 35 1165-1172... 

Mast N, Norcross R, Andersson U, Shou M, Na-kayama K, Bjorkhem I, Pikuleva lA (2003) Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry 42 14284-14292 Bjorkhem I, Starck L, Andersson U, Lutjohann D, von Bahr S, Pikuleva I, Babiker A, Diczfalusy U (2001) Oxysterols in the circulation of patients with the Smith-Lemli-Opitz syndrome abnormal levels of 24S- and 27-hydroxycholesterol. J Lipid Res 42 366-371... 

Cholesterol 4 3-Methylglutaconic acidurai, other types Mevalonic aciduria Abetalipoproteinemia Hypobetalipoproteinemia 3 -Hydroxy-A -C27-steroid dehydrogenase (3/ -HSDH) def 3reductase def (5 -reductase def) Smith-Lemli-Opilz syndrome Barth syndrome Glucosyltransferase I def CDG-Ic... 

Defects of the biosynthesis of cholesterol were not included in the previous edition of this book, because they were practically non-existing . Since the mid-nineties it has been recognized that patients with the Smith-Lemli-Opitz syndrome lack the final enzyme of cholesterol biosynthesis, i.e. 7-de-hydrocholesterol reductase. Consequently the patients have hypocholestero-lemia and accumulate 7-dehydrocholesterol and 8-dehydrocholesterol in their plasma [12]. 

Tint, G.S., M. Irons, E.R. Elias, A.K. Batta, R. Frieden, T.S. Chen, and G. Salen (1994) Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N. Engl /. Med. 330 107-113. 

The most common disorder of cholesterol biosynthesis, with an estimated incidence of 1 in 40,000 births, is Smith-Lemli-Opitz (RSH) syndrome [18, 19]. This autosomal recessive disorder is characterized clinically by distinctive facial anomalies, limb and genital malformations, and mental retarda-... 

In disorders which affect cholesterol synthesis (e.g, mevalonic aciduria, 7-dehydrocholesterol reductase deficiency [Smith-Lemli-Opitz syndrome]) there may be markedly reduced bile acid synthesis - these disorders are beyond the scope of his chapter. As indicated in section 3, the synthesis of bile acids involves conversion of C27 bile acids (cholestanoic acids) to their C24 analogues (cholanic acids) and this occurs by a process of )5-oxidation in the peroxisomes. Thus defective bile acid synthesis occurs in disorders of peroxisomal yff-oxidation and in disorders of peroxisome biogenesis. These disorders affect pathways other than the bile acid synthesis pathway and are discussed in Chap. 23. 

Patti, G.J., Shriver, L.P., Wassif, C.A., Woo, H.K., Uritboonthai, W., Apon, J., Manchester, M., Porter, F.D. and Siuzdak, G. (2010) Nanostructure-initiator mass spectrometry (NIMS) imaging of brain cholesterol metabolites in Smith-Lemli-Opitz syndrome. Neuroscience 170, 858-864. 

Smith-Lemli Opitz syndrome (defect of cholesterol biosynthesis). 

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