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Sulfur-containing amino acids have various roles: They mediate
the transfer of methyl groups for virtually all transmethylation
reactions; they provide reactive thiol groups that are needed for
detoxification of endogenous and exogenous substances; they help
maintain the intracellular redox potential; and they are a source
of sulphate. Thirteen disorders of sulphur amino acid metabolism
have been consistently described, 11 of them potentially leading
to disease.
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Severe hyperhomocysteinemia, defined as plasma total homocysteine
(tHcy) concentrations above 100 μmol/L,
is generally caused by single-enzyme deficiencies of homocysteine
metabolism. When concentrations of free homocysteine exceed the
plasma protein binding capacity, the disulfide homocystine forms
nonenzymatically and is excreted in urine, hence causing homocystinuria.
The term homocystinuria is sometimes used to indicate
the most common form of the disease, which is caused by defective
activity of the enzyme cystathionine β-synthase (CBS).1 Homocystinuria,
however, results from a defect in CBS and from defects in the folate-
and cobalamin-dependent remethylation cycle (see Chapter 147). Severe
deficiency of cobalamin or folate can also cause homocystinuria
and should always be ruled out.
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Homocystinuria should not be confused with mild (tHcy 15 to 30 μmol/l)
or moderate (tHcy 30 to 100 μmol/l) hyperhomocysteinemia, which
is much more common and is usually caused by nutritional deficiency
of folates or cobalamin. It can also occur secondary to systemic or
liver and kidney disease, or from medication, often in combination
with homozygosity for a common polymorphism in the enzyme.
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Classical homocystinuria presents as multisystemic disease with
a dysplasia of connective tissue, with a predisposition to arterial
and venous thromboembolism, and with mental retardation. Clinical
variability is wide,2but presentation is usually
in the first decade with the exception of embolism, which occurs
later. Homocystinuria is one of the few disorders of amino acid
metabolism in which clinical manifestations tend to be progressive
in adulthood, because many clinical manifestations result from arteriosclerosis
and thrombotic complications.
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The most characteristic feature of this disorder is subluxation
of the ocular lens, which occurs in almost all untreated individuals
until adulthood. Most patients have osteoporosis and skeletal abnormalities
similar to those seen in Marfan syndrome, such as tall stature, scoliosis,
genu valgum, pes cavus, arachnodactyly, and pectus carinatum or
excavatum.3 In homocystinuria, however, the joints
tend to be limited in mobility rather than hypermobile. Mental retardation
is common, although it is often mild, and many individuals have psychiatric
disturbances.4
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Metabolic Derangement, Pathophysiology
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The disturbance in metabolism resulting in homocystinuria is
shown in Figure 138-1. CBS initiates the
first step of homocysteine elimination. As a consequence of CBS
deficiency, homocysteine, SAH, SAM, and methionine accumulate when
methionine intake exceeds the residual transsulfuration and total
remethylation activity. Moreover, high SAH inhibits many transmethylases,
which increases accumulation of SAM and methionine. Increased homocysteine
facilitates remethylation, which leads to further accumulation of
methionine. The intermediate metabolites ...