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Inborn error of metabolism affecting the mitochondrial
catabolism of valine and isoleucine untreated resulting in ketoacidosis,
lethargy, coma, and, finally, death.
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Propionic Aciduria; Ketotic Hyperglycinemia;
Hyperglycinemia with Ketoacidosis and Leukopenia; Propionyl-CoA Carboxylase
Deficiency.
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First described in 1961 by B. Childs, an American pediatrician.
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Approximately 1:100,000 live births with both genders
equally affected. Incidences as high as 1:2000 to 1:5000 live births have been
reported from Saudi Arabia.
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Autosomal recessive. The enzyme is composed of
two independently encoded enzyme subunits, an α subunit encoded on
chromosome 13 and a β subunit encoded on chromosome 3. Biotin is a
cofactor and binds to the α subunit. Two distinct genotypes can be
identified by cell complementation: PCCA (propionyl-CoA carboxylase A)
resulting in a defect of the α subunit and PCCB (propionyl-CoA
carboxylase B) in a defect of the β subunit. A defect in the
synthesis or function of biotin (deficiency of biotinidase, which is
responsible for the cleaving of biotin from biocytin), or a deficiency of
holocarboxylase synthetase (biotin-methylcrotonyl-CoA-carboxylase ligase),
which catalyzes the incorporation of biotin into apo-carboxylases) can,
however, lead to a similar clinical picture.
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The mutation results in a defect in the
mitochondrial enzyme propionyl-CoA carboxylase. This enzyme is responsible
for the generation of methylmalonyl-CoA from propionyl-CoA, which derives
from the catabolism of essential amino acids such as isoleucine, valine,
methionine, and threonine, as well as from odd-chain fatty acids and
cholesterol. Accumulation of propionyl-CoA results in inhibitory effects on
various pathways of intermediary mitochondrial metabolism and secondary
carnitine deficiency. The appearance of increased levels of long, odd-chain
fatty acids may be related to the increased concentration of propionyl-CoA,
which is a primer for these compounds. Ketoacidosis develops secondary to
inhibition of the citric acid cycle enzymes by propionic acid. Propionyl-CoA
is split in coenzyme-A and propionic acid, which contributes to the
metabolic acidosis. Decreased ureagenesis and hyperammonemia seem to be
secondary to inhibition of mitochondrial carbamyl phosphate synthetase (CPS)
by intramitochondrial accumulation of organic acids and CoA-esters caused by
the defect in propionyl-CoA carboxylase. Furthermore, increased
concentration of propionate results in decreased levels of hepatic
N-acetyl-glutamate, which is an allosteric effector for CPS. In contrast,
hyperglycinemia may be nonspecific because it can also be found in other
conditions in children with negative nitrogen balance. Moreover, anaerobic
fermentation of odd-chain fatty acids in the GI tract also yields propionic
acid.
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Made by clinical presentation and organic aciduria with
high levels of propionic acid, methylcitrate, and tiglylglycine. Tiglylglycine is an
intermediate product of the catabolism of isoleucine. It is a potential marker of
disorders of the respiratory chains. Cultured fibroblasts are used to analyze the enzyme
activity. However, propionyl-CoA carboxylase activity does not necessarily
correlate with the clinical picture, because there are (unexplained) case reports with
almost absent enzyme activity but no clinical symptoms. Measuring propionyl-CoA
carboxylase activity in cultured amniotic cells or chorionic villous biopsies allows for
prenatal ...