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Disorders of Cholesterol Synthesis

INTRODUCTION

Cholesterol is an essential lipid, available through diet but also synthesized endogenously from acetyl-coenzyme A, formed as a byproduct of glucose and fatty acids through glycolysis and β-oxidation pathways, respectively. Cholesterol is a major end product of the isoprenoid and sterol biosynthetic pathway involving numerous enzymatic steps. Enzymatic defects in the pre-squalene cholesterol synthesis pathway are responsible for inherited sterol disorders such as mevalonic aciduria (MVA) and hyper-immunoglobulinemia D and periodic fever syndrome (HIDS). In the descending post-squalene pathway, enzymatic defects are responsible for disorders such as Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, sterol C4 methyl oxidase deficiency (SC4MOL), X-linked dominant chondrodysplasia punctata 2 (CDPX2)/Conradi-Hünermann syndrome, lathosterolosis, desmosterolosis, and the widely known Smith-Lemli-Opitz syndrome (SLOS). Hydrops-ectopic calcification–moth-eaten (HEM)/Greenberg skeletal dysplasia was earlier thought to be a disorder of sterol metabolism but more recently has been shown to be a laminopathy.

PATHOGENESIS AND EPIDEMIOLOGY

Cholesterol has numerous essential functions as a major component of cell membranes and myelin in the nervous system, cellular signal transduction and expression (eg, activation of hedgehog proteins), and as a precursor of bile acid and steroid hormone synthesis; thus, it has perhaps a unique influence on both embryonic and postnatal development.

The isoprenoid synthesis pathway (Fig. 159-1) leads to the synthesis of cholesterol (an important constituent of cell membranes and a precursor of steroid hormones and bile acids), haem A (a component of complex IV of the respiratory chain), ubiquinone (an electron carrier in the respiratory chain), dolichol (which is required for glycosylation of proteins), farnesyl-pyrophosphate, and geranylgeranyl-pyrophosphate (which are important for prenylation of proteins). Prenylation of proteins is important in many signaling cascades in the cell.

Figure 159-1

Pathway for synthesis of isoprenoids and cholesterol. CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl; P, phosphate; PP, pyrophosphate; SREBP, sterol responsive element binding protein. Numbered enzymatic steps (bar across arrow indicates deficiency disorder known): 1, acetyl-CoA acetyl transferase; 2, HMG-CoA synthase; 3, HMG-CoA reductase; 4, mevalonate kinase; 5, mevalonate-P kinase; 6, mevalonate-PP decarboxylase; 7, isopentenyl-PP isomerase; 8, geranyl-PP synthase; 9, farnesyl-PP synthase; 10, squalene synthase; 11, squalene epoxidase; 12, 2,3-oxidosqualene sterol cyclase; 13, sterol Δ24-reductase (deficient in desmosterolosis); 14, sterol C14-demethylase; 15, sterol Δ14-reductase; 16, sterol C4-demethylase complex (3β-hydroxysteroid dehydrogenase component deficient in CHILD syndrome); 17, sterol Δ8Δ7-isomerase (deficient in Conradi-Hünermann syndrome); 18, sterol Δ5-destaurase (deficient in lathosterolosis); 19, sterol Δ7-reductase (deficient in Smith-Lemli-Opitz syndrome).

The cholesterol synthesis pathway is tightly regulated. When cholesterol levels in the cell are low, transcription of the HMG-CoA reductase gene (HMGR), and probably the transcription of every other gene involved in the cholesterol synthesis pathway, is upregulated by ...

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