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The isoprenoid synthesis pathway (Fig. 164-1) 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).1 Prenylation of proteins is important in many signaling cascades in the cell.

Figure 164-1.

Pathway for synthesis of isoprenoids and cholesterol. Abbreviations: 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 (deficient in Greenberg dysplasia); 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.1,2 When cholesterol levels in the cell are low, the 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 sterol regulatory element binding proteins (particularly SREBP-2). High levels of sterols reduce the activity of the cholesterol-synthesizing enzymes by reducing SREBP-2 activity. High levels of sterols in the cell also lead to increased production of oxysterols, which act on the liver X receptor (LXR); this, in turn, drives the disposal of the excess cholesterol. LXR may also reduce cholesterol synthesis by downregulating SREBP-2.

Cholesterol is an important constituent of cell membranes and has important interactions with signaling proteins that are involved in embryogenesis and development (eg, the hedgehog proteins). Disorders of the pathway from lanosterol to cholesterol lead to dysmorphic features and to malformations of internal organs. In all but one of these disorders, psychomotor delay is prominent.

The first-line test for diagnosing an inborn error in the pathway from lanosterol to cholesterol is the analysis of sterols (from a plasma or tissue sample) by gas chromatography–mass spectrometry (GC-MS). Mevalonic acid can be detected by urine organic acid analysis (see below).

Clinical Presentation

Mevalonic aciduria (MA) is the severe form of mevalonate kinase deficiency; the hyper-IgD periodic fever syndrome (HIDS) is more benign. Both present in the first year of life with episodes of pyrexia for 3 to 5 days every 4 to 6 weeks; symptoms include diarrhea and vomiting, abdominal pain, cervical ...

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