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A disorder of branch-chain amino acid metabolism characterized by the build-up of propionic acid resulting in episodes of vomiting, dehydration, and severe metabolic acidosis.

Propionic acidemia was first described in 1961 by Childs et al. (1961). The patient presented with dehydration, lethargy, and coma on the first day of life. He was found to be severely ketoacidotic and responded slowly to massive alkali replacement. The clinical course was characterized by recurrent attacks of ketoacidosis, precipitated by infections or protein ingestion, and by developmental retardation, EEG abnormalities, and osteoporosis. The patient had episodic neutropenia and thrombocytopenia prior to death at age 7. Wolf et al. (1981) reported that the clinical course of symptomatic patients is characterized by repeated relapses — usually precipitated by excessive protein intake, constipation, or intercurrent infection. Treatment of these children has been quite difficult, and neurologic sequelae have been common. The most common neurologic complications that have been observed include developmental delay, focal and general seizures, cerebral atrophy, and EEG abnormalities (Fenton and Rosenberg 1995). Surtees et al. (1992) have also reported a high prevalence of neurologic sequelae, including dystonia, severe chorea, and pyramidal signs, particularly in patients who survive longer. Leukopenia and thrombocytopenia, perhaps due to marrow suppression by one or more of the toxic metabolites produced, is also not uncommon. Recently, magnetic resonance imaging of the brain in three PCC patients revealed delayed myelination and some cerebral atrophy. Proton magnetic resonance spectroscopy from a voxel located in basal ganglia revealed a decrease in N-acetylaspartate and myo-inositol peaks and an elevation of GLN/GLU. The presence of spectroscopic abnormalities indicates that the metabolic balance on cerebral parenchymal level is less optimal than estimated from biochemical analysis of urine, plasma, or cerebrospinal fluid (Bergman et al. 1996). 

Biochemically, patients with this disorder present with elevated levels of propionic acid, methylcitrate, b-hydroxy-propionate, propionylglycine, and tiglic acid. Ketones such as butanone may also be found in the urine (Menkes 1966). Hyperammonemia originates secondarily from carbamoyl phosphate synthetase inhibition (Coude et al. 1979; Stewart and Walser 1980). Ketoacidotic episodes are frequently life threatening and many neonates die within the first few weeks of life (Fenton and Rosenberg 1995). The condition can be treated by severely restricting protein intake; however, management of such patients is often difficult (Wolf et al. 1981). Under normal circumstances, bacteria synthesize as much as 20% of the odd-chain-length fatty acids (Thompson et al. 1990). Conditions such as constipation or bacterial infections can dramatically increase the propionate load, precipitating a ketoacidotic crisis (Fenton and Rosenberg 1995).

While many PCC deficient children exhibit the symptoms described above, there is considerable heterogeneity in the severity of the disease. Some individuals who are PCC deficient may be clinically normal while others can die within a day of birth (Wolf et al. 1979). The metabolic rationale for this heterogeneity has yet to be established, though prognosis may be assessed by determining 13C-propionate metabolism in the patient (Thompson et al. 1990). Clearly, the observed heterogeneity between the phenotype and genotype of propionic acidemia due to PCC deficiency, complicates the rational development of improved treatment strategies and illustrates the pressing need for a better understanding of the structure, function and regulation of PCC.

Propionyl-CoA carboxylase deficiency causes propionic acidemia

Propionic acid is liberated from the beta-oxidation of odd-chain fatty acids or from catabolism of methionine, isoleucine, valine, threonine, thymine, uracil or cholesterol (Fenton and Rosenberg 1995). Propionate metabolism is normally anaplerotic. Several groups have shown that the carboxylation of propionyl-CoA is a two-step reaction. In the first step, which requires ATP and Mg2+, bicarbonate is attached to the ureido nitrogen of the apoenzyme-biotin complex, forming a carboxybiotin-apoenzyme intermediate. This complex, in turn, reacts with propionyl-CoA and transfers the carboxyl group from biotin to the second carbon of propionyl-CoA, forming D-methylmalonyl-CoA (Fig. 1).

fig1.JPG (30264 bytes)
Both of these steps are catalyzed by propionyl-CoA carboxylase (PCC) (Halenz et al. 1962)
. D-methylmalonyl-CoA is subsequently racemized to L-methylmalonyl-CoA, then converted to succinyl-CoA by methylmalonyl-CoA racemase and methylmalonyl-CoA mutase, respectively. Deficiencies in any of these enzymes lead to corresponding organic acidemias and more specifically, defects in PCC lead to propionic acidemia (Hsia et al. 1971). The incidence of propionic acidemia may be only a little lower than the incidence of methylmalonic acidemia, in the range of 1:35,000-1:70,000 (Saudubray et al. 1989).

Biotin, which is covalently attached to the a subunit by holocarboxylase synthetase (Achuta Murthy and Mistry 1974; Leon-Del-Rio et al. 1995; Moss and Lane 1971) shuttles CO2 to the propionyl-CoA moiety (Fig. 2) (Fenton and Rosenberg 1995). fig2.JPG (18202 bytes)Impaired biotinylation suppresses the function of PCC, pyruvate carboxylase, acetyl-CoA carboxylase, and b-methylcrotonyl-CoA carboxylase thus causing mixed organic acidemia (Fenton and Rosenberg 1995). Biotin malnutrition is extremely rare, owing to biotin synthesis by intestinal flora. Genetic defects in biotin metabolism, including holocarboxylase synthetase and biotinidase, do occur, and account for most cases of mixed carboxylase deficiency (Wolf and Heard 1989).


PCC is a complex mitochondrial protein

Human PCC was initially reported to be a 540 kDa octamer, composed of pairs of nonidentical subunits (Gravel et al. 1980; Kalousek et al. 1980). Since both sheep and Mycobacterium PCC are 700-800 kDa, a6b6 dodecamers, it is more likely that the human enzyme is also a dodecamer (Goodall et al. 1985; Haase et al. 1984). The 72 kDa a subunit and the 56 kDa b subunit (Gravel et al. 1980; Kalousek et al. 1980) are encoded by separate genes designated, PCCA, found on chromosome 13 (Lamhonwah et al. 1986), and PCCB, found on chromosome 3 (Kraus et al. 1986b), respectively. Both corresponding cDNAs have been sequenced (Kraus et al. 1986a; Lamhonwah et al. 1989;1994 Ohura et al. 1993a). The subunits are synthesized as longer precursors, imported into the mitochondrion, cleaved and assembled (Fig. 3) (Browner et al. 1989; Kraus et al. 1986a). fig3.JPG (8387 bytes)Exactly where in the cell PCC biotinylation occurs is uncertain as holocarboxylase synthetase exists both in the cytoplasm and the mitochondrion (Achuta Murthy and Mistry 1974; Moss and Lane 1971). The a subunit contains the sequence that accepts biotin (Kalousek et al. 1980; Lamhonwah et al. 1987; Leon-Del-Rio and Gravel 1994); it also binds CO2, Mg2+, ATP, and can be up regulated by binding K+ (Kalousek et al. 1980). The b subunit binds propionyl-CoA (Fenton and Rosenberg 1995). None of the binding sites for these PCC ligands have been identified.

PCC mutations can be classified into complementation groups

Initial investigations into the genetics of PCC deficiency were performed on fused fibroblast lines (Gravel et al. 1977; Wolf 1980; Wolf et al. 1980). Two main complementation groups were discovered: pccA and pccBC. The pccBC group was further divided into subgroups designated pccB, pccC, and pccBC. Intergenic complementation was observed for pccA X pccBC groups; intragenic complementation was found for pccB X pccC. a subunit abnormalities were found in pccA patients; b subunit abnormalities, in group pccBC patients (Lam Hon Wah et al. 1983; Ohura et al. 1989). Transfection of pccA-deficient cultured fibroblasts with expression plasmids containing aPCC cDNA under the control of the CMV promoter restored PCC activity (Stankovics and Ledley 1993). Similar experiments using microinjection of ▀PCC cDNA into the nucleus or RNA transcript into the cytoplasm restored PCC functional activity in bPCC-deficient cell lines (Loyer et al. 1995). These results confirmed the completeness of the ▀PCC cDNA clone and the capacity for b subunits derived from its expression to be transported into mitochondria and assembled with endogenously derived a subunits to form functional PCC (Lamhonwah et al. 1994).

Synthesis and degradation rates for a and b subunits are different

There is currently no data available concerning the transcriptional regulation of either of the PCC subunits and the structure and location of the PCC promoters is unknown. Observations regarding the relative levels of PCCA and PCCB encoded mRNA in human fibroblasts have indicated that these genes are probably regulated independently of each other. Free a subunits are inherently more resistant to mitochondrial degradation than b subunits (Ohura et al. 1989). b subunits are normally synthesized in excess of a subunits; however, only those b subunits assembled into complete enzyme escape degradation. Consequently, it is the lack of available a subunits that leads to the depletion of b subunits by mitochondrial degradation in pccA type patients (Lam Hon Wah et al. 1983; Ohura et al. 1989). The differential rates of synthesis of a and b chains account for the previously reported finding that individuals heterozygous for pccBC mutations have normal carboxylase activity in their cells (Ohura et al. 1989; Wolf et al. 1978). This work is a good example of how an understanding of the genetics of PCC expression can be used to clarify the observed variability in propionic acidemia.

71 mutations found in propionic acidemia patients

To date, 34 mutations and 2 polymorphisms and 37 mutations and 1 polymorphism have been identified in the a and subunits of PCC, respectively (Campeau et al. 1999; Lamhonwah et al. 1990; Ohura et al. 1993b,1995; Richard et al. 1997,1999; Rodriguez-Pombo et al. 1998; Tahara et al. 1990,1993, Ugarte et al. 1999). Although numerous PCC mutations have been reported, detailed functional and mechanistic analysis of their effects is lacking. Only recently some PCCB mutations have been expressed in E. coli (Kelson et al. 1996, Chloupkova et al. 2000, 2002) and in PCC deficient fibroblasts (Perez-Cerda et al. 2001).

Four mutations account for nearly half of the defective ▀PCC alleles

Roughly 30% of the Caucasian alleles studied to date exhibit a deletion/insertion mutation which eliminates an Msp I restriction site (Lamhonwah et al. 1990; Tahara et al. 1990,1993). A frequent C>T transition has also been found in Japanese propionic acidemia patients which substitutes tryptophan for arginine at position 410 on the polypeptide chain (R410W) and also abolishes the same Msp I site (Gravel et al. 1994; Ohura et al. 1991; Tahara et al. 1993). An ATC deletion eliminates isoleucine 408 from the same exon (Lamhonwah et al. 1990; Tahara et al. 1993). Lastly, a C>T transition at 1283 of the cDNA sequence encodes a T428I change (Ohura et al. 1993a). This region is highly conserved  (83%) between bPCC and the 12S subunit of transcarboxylase from Propionibacterium shermanii and comprises a helix with three basic amino acids (R, H, K), a phenolic ring (Y), and an acidic residue (E) arranged on one side (Samols et al. 1988). We showed that the four different mutations were all found in exon 12 and within the same 14 nucleotides in 21 out of 50 affected alleles (Tahara et al. 1993). Although mutations in only a small portion of the coding sequence of the PCCB gene account for almost 1/2 of the defective alleles, it is becoming clear that the remaining mutations are scattered throughout the amino-terminal and carboxyl-terminal thirds of the coding region.

Many mutations in the aPCC subunit reduce mRNA stability

Mutations in aPCC are in many cases, deletions or splicing defects leading to premature stop codons and result in an aPCC mRNA negative phenotype. A recent report has demonstrated the possible use of RT-PCR to measure relative levels of an mRNA species containing an 84-bp intronic insert, as a marker for RNA destabilizing mutations in the a PCC subunit (Campeau et al. 1999).



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