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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.
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++
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.
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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.
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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).
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Clinical Presentation
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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 ...