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  1. Propionyl coenzyme A (CoA)—formed in the catabolism of several essential amino acids (isoleucine, valine, methionine, threonine), odd-chain fatty acids, and cholesterol—is metabolized primarily by enzymatic conversion to methylmalonyl CoA, which is subsequently isomerized to succinyl CoA. This sequence depends on the activity of several enzymes (see Fig. 94-2): propionyl CoA carboxylase, methylmalonyl CoA racemase, and methylmalonyl CoA mutase. Propionyl CoA carboxylase requires biotin as a cofactor, whereas methylmalonyl CoA mutase requires adenosylcobalamin (AdoCbl), a cobalamin (Cbl; vitamin B12) coenzyme.

  2. Propionyl CoA carboxylase and methylmalonyl CoA mutase are oligomeric enzymes. Propionyl CoA carboxylase is composed of nonidentical subunits (α and β); biotin binds to the α subunit. The holocarboxylase contains six α and six β subunits (α6β6). The α subunit is encoded by a gene on chromosome 13 (NM_000282) in humans, the β subunit by a gene on chromosome 3 (NM_000532). Methylmalonyl CoA mutase is a dimer of identical subunits (α2), encoded by a gene on chromosome 6 (NM_000255).

  3. Inherited deficiency of propionyl CoA carboxylase activity in humans results from genetically distinct defects at four loci. Isolated deficiency is caused by mutations at the α and β loci coding for the carboxylase subunits. Deficiency of multiple biotin-dependent carboxylases occurs in two forms: one resulting from deficiency of holocarboxylase synthase (the enzyme that attaches biotin to apocarboxylase subunits), the other from deficiency of biotinidase (the enzyme that cleaves biotin from the lysine residue in the carboxylase to which the biotin is attached). Multiple carboxylase deficiency is discussed in detail in Chapter 156.

  4. Isolated deficiency of propionyl CoA carboxylase, a major cause of the ketotic hyperglycinemia syndrome, results in the accumulation of propionate in blood and of 3-hydroxypropionate, methylcitrate, tiglylglycine, and unusual ketone bodies in urine. Two complementation groups, pccA (MIM 232000) and pccBC (MIM 232050) have been defined among propionyl CoA carboxylase–deficient patients. These groups correspond to mutations affecting genes coding for the α subunit and the β subunit, respectively, of the carboxylase apoprotein. Clinically, the disorder is characterized by severe metabolic ketoacidosis, which often appears in the neonatal period and requires vigorous alkali therapy and protein restriction. Oral antibiotic therapy to reduce gut propionate production also may prove useful.

  5. Multiple carboxylase deficiency (MIM 253270) leads to impaired activity of four biotin-dependent enzymes: acetyl CoA carboxylase, propionyl CoA carboxylase, 3-methylcrotonyl CoA carboxylase, and pyruvate carboxylase. The clinical hallmarks of this disorder include ketoacidosis, a diffuse erythematous rash, alopecia, seizures, hypotonia, and developmental retardation (see Chapter 156).

  6. Inherited deficiency of methylmalonyl CoA mutase activity in humans is caused by mutations at many different loci. Isolated deficiency results from mutations at the apomutase locus (MIM 251000) and at two loci coding for gene products required, specifically for the biosynthesis of AdoCbl. Combined deficiency of mutase and of the other major Cbl-dependent enzyme in mammalian cells, methionine synthase (formally, N 5-methyltetrahydrofolate:homocysteine methyltransferase), results from inherited defects in Cbl transport and from three distinct defects in the intracellular pathway of Cbl coenzyme synthesis affecting the synthesis of both AdoCbl and methylcobalamin (MeCbl), the coenzyme required by methionine synthase. These several defects in intracellular Cbl metabolism are discussed in detail in Chapter 155.

  7. Neonatal or infantile metabolic ketoacidosis is the clinical hallmark of isolated methylmalonyl CoA mutase deficiency. Cells from some apomutase-deficient children have no functional mutase (designated 0); cells from others contain a structurally altered mutase with reduced affinity for AdoCbl and with reduced stability (mut ). Such children exhibit methylmalonic acidemia and methylmalonic aciduria that do not respond to Cbl supplementation but can sometimes be treated with dietary protein restriction. Carnitine, as well as oral antibiotic therapy to reduce gut flora, may be effective as well.

  8. Two abnormalities in AdoCbl synthesis only, designated CblA (MIM 251100) and CblB (MIM 251110), lead to impaired methylmalonyl CoA mutase activity and are characterized by a clinical and chemical picture virtually identical to that seen in apomutase-deficient children. In most CblA patients and some CblB patients, pharmacologic supplements of CN-Cbl or hydroxocobalamin (OH-Cbl) produce distinct reductions in methylmalonate accumulation and offer a valuable therapeutic adjunct to dietary protein limitation.

  9. Three other distinct defects—CblC (MIM 277400), CblD (MIM 277410), and CblF (MIM 277380)—lead to impaired synthesis of both AdoCbl and MeCbl and, accordingly, to deficient activity of both methylmalonyl CoA mutase and methionine synthase. Such children have methylmalonic aciduria and homocystinuria. Most children with a CblC mutation appear to be more severely affected clinically than the two known sibs in the CblD group, although a number of CblC patients have had an onset of disease in adult life. Major clinical problems in CblC patients include failure to thrive, developmental retardation, and such hematologic abnormalities as megaloblastic anemia and macrocytosis. The precise defect in the CblC and CblD patients is not yet known, but it involves an early step in the intracellular metabolism of cobalamins. The defect in CblF cells involves impaired efflux of free Cbl from lysosomes. Therapy includes protein restriction, pharmacologic doses of OH-Cbl, and betaine supplementation.

  10. The discriminating biochemical features of the known forms of inherited methylmalonic acidemia are shown in Table 94-4.

  11. All of the disorders of propionate and methylmalonate metabolism for which there are adequate data are inherited as autosomal-recessive traits. Heterozygotes for the following defects can be detected biochemically: , 0, mut , and . Genetic complementation analyses with somatic cell heterokaryons have been particularly useful in demonstrating genetic heterogeneity and in confirming the existence of autosomal-recessive inheritance among the propionic acidemias and the methylmalonic acidemias. Precise molecular defects have been described for pccA, pccBC, mut 0, and mut patients.

  12. Prenatal detection of fetuses with propionyl CoA carboxylase deficiency, methylmalonyl CoA apomutase deficiency, and defective synthesis of AdoCbl or of both coenzymes is best done using assays in cultured amniotic cells and gas chromatographic/mass spectroscopic determinations on amniotic fluid or maternal urine.

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