#606054
ICD+
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| PROPIONIC ACIDEMIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| PROPIONYL-CoA CARBOXYLASE DEFICIENCY PCC DEFICIENCY GLYCINEMIA, KETOTIC HYPERGLYCINEMIA WITH KETOACIDOSIS AND LEUKOPENIA KETOTIC HYPERGLYCINEMIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because propionic acidemia is caused by mutation in the genes encoding propionyl-CoA carboxylase, PCCA (232000) or PCCB (232050). Cells from patients with mutations in the PCCA gene fall into complementation group pccA. Cells from patients with mutations in the PCCB gene fall into complementation group pccBC. Mutations in the pccB subgroup occur in the N terminus of the PCCB gene, which includes the biotin-binding site, whereas mutations in the pccC subgroup occur in the C terminus of the PCCB gene (Fenton et al., 2001). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The features of propionic acidemia are episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein. Outstanding chemical features are hyperglycinemia and hyperglycinuria. This disorder is not to be confused with hereditary glycinuria (138500), which is presumably transmitted as a dominant. Soriano et al. (1967) suggested that in the disorder first described by Childs et al. (1961), a generalized defect in utilization of amino acids results in excessive deamination of certain amino acids in muscle, with consequent hyperammonemia and ketoacidosis. In a second group of patients whose disorder is also termed hyperglycinemia, ketoacidosis, neutropenia, and thrombocytopenia have not been observed and glycine is the only amino acid present in excess in serum and urine; see glycine encephalopathy (605899). Hsia et al. (1969) studied fibroblasts from a sister of the boy described by Childs et al. (1961) and demonstrated deficient propionate carboxylation as the basic defect in ketotic hyperglycinemia. Hsia et al. (1971) also showed that 'ketotic hyperglycinemia' is the same as propionic acidemia and is the result of a defect in PCC. In further studies on this patient, Brandt et al. (1974) demonstrated that with low protein diet, growth and intelligence developed normally to age 9 years; indeed, intelligence was superior. The family originally reported by Childs et al. (1961) had the pccA type of propionic acidemia (Wolf, 1986). In a male Pakistani offspring of first-cousin parents, Gompertz et al. (1970) described acidosis and ketosis due to propionic acidemia, leading to death at 8 days of age. A sib had died at 2 weeks of age with metabolic acidosis and ketonuria. The defect was found to involve mitochondrial propionyl-CoA carboxylase. The same condition was described by Hommes et al. (1968). Al Essa et al. (1998) pointed out that not only do acute intercurrent infections precipitate acidosis in propionic acidemia, but such infections are unusually frequent in propionic acidemia in Saudi Arabia. Propionic acidemia is unusually frequent in Saudi Arabia, with a frequency of 1 in 2,000 to 1 in 5,000, depending on the region. The disorder has a severe phenotype in Saudi Arabia. Al Essa et al. (1998) had information on approximately 90 patients; certain tribes accounted for almost 80% of these cases, suggesting a founder effect. The number of other cases of organic acidemias observed during the same period was 656. Longitudinal data, in some instances up to 8 years, were available for 38 patients with propionic acidemia. A high frequency of infections was observed in 80% of the patients. Most microorganisms implicated were unusual, suggesting an underlying immune deficiency. The infections occurred despite aggressive treatment with appropriate diets, carnitine, and, during acute episodes of the disease, with metronidazole, which suggested a global effect of the disease on T and B lymphocytes as well as on the bone marrow cells. In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with branched-chain organic aciduria, including isovaleric aciduria (243500), propionic aciduria, and methylmalonic aciduria (251000) can rarely have strokes. Cerebellar hemorrhage has been described in all 3 disorders, and basal ganglia ischemic stroke has been described in propionic aciduria and methylmalonic aciduria. These events may occur in the absence of metabolic decompensation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biochemical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hillman et al. (1978) observed biotin-responsive propionic acidemia. Wolf and Hsia (1978) suggested that biotin-responsiveness can be tested by measuring propionyl-CoA carboxylase and beta-methylcrotonyl CoA carboxylase (see 609010 and 609014) in peripheral blood leukocytes before and after biotin. From kinetic analysis of complementations in heterokaryons of propionyl CoA carboxylase-deficient fibroblasts, Wolf et al. (1980) concluded that the 'bio' and 'pcc' mutations affect different genes; that complementation between pccA and pccB, pccC or pccBC lines is intergenic with subunit exchange and synthesis of new carboxylase molecules and that complementation between pccB and pccC mutants is interallelic. Wolf and Feldman (1982) considered it likely that the pccBC complementation group reflects mutations of the alpha subunit and the pccA group mutations of the beta subunit. Using cDNA clones coding for the alpha and beta chains as probes, Lamhonwah and Gravel (1987) found absence of alpha mRNA in 4 of 6 pccA strains and the presence of beta mRNA in all pccA mutants studied. They also found the presence of both alpha and beta mRNAs in 3 pccBC, 2 pccB, and 3 pccC mutants. Ohura et al. (1989) presented evidence from which they concluded that beta-chain subunits of propionyl-CoA carboxylase are normally synthesized and imported into the mitochondria in excess of alpha-chain subunits, but only that portion assembled with alpha subunits escapes degradation. In pccA patients, the primary defect in alpha-chain synthesis leads secondarily to degradation of normally synthesized beta chains. The differential rates of synthesis of alpha and beta chains appear to account for the finding that persons heterozygous for pccBC mutations have normal carboxylase activity in their cells. Among 15 Japanese patients with propionic acidemia, Ohura et al. (1991) found that both the alpha and beta subunits were absent in 3 and low in 3 others; according to their previous data, they concluded that these 6 patients had an alpha-subunit defect. In 8 other patients, alpha subunits were normal, but the beta subunits were aberrant; these patients were considered to have beta-subunit defects. One of the 15 patients had apparently normal alpha and beta subunits. An altered MspI restriction pattern for PCCB cDNA, consisting of a unique 2.7-kb band, was found in 3 patients with beta-subunit deficiency. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prenatal Diagnosis Buchanan et al. (1980) pointed out that propionic acidemia can be diagnosed either by an elevated quantity of the metabolite methylcitrate in amniotic fluid or by deficient activity of propionyl-CoA carboxylase in amniocytes. Contamination by maternal cells can give a normal value for the latter determination; methylcitrate assay may be the most reliable approach. Perez-Cerda et al. (1989) successfully diagnosed PCC deficiency in the first trimester of pregnancy by direct enzyme assay in uncultured chorionic villi. Muro et al. (1999) reported prenatal diagnosis of an affected fetus based on DNA analysis in chorionic villus tissue in a family where the proband had previously been shown to carry the 1170insT mutation (232050.0004) and a private leu519-to-pro (L519P) mutation in the PCCB gene. Muro et al. (1999) also assessed carrier status in this family by DNA analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The severe metabolic ketoacidosis in this disorder requires vigorous alkali therapy and protein restriction. Oral antibiotic therapy to reduce gut propionate production may also prove useful (Fenton et al., 2001). Van Calcar et al. (1992) described a 22-year-old woman whose first episode of acute acidosis occurred at age 6 months following an upper respiratory infection; diagnosis of propionic acidemia was delayed until the age of 6.5 years. They gave detailed information on her pregnancy, which resulted in the birth of a healthy infant. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ugarte et al. (1999) reviewed mutations in the PCCA and PCCB genes. A total of 24 PCCA mutations had been reported, mostly missense point mutations and a variety of splicing defects. No mutation was predominant in the Caucasian or Oriental populations studied. Among 10 patients with propionic acidemia, Desviat et al. (2006) identified 4 different PCCA splice site mutations and 3 different PCCB splice site mutations. The authors emphasized the different molecular effects of splicing mutations and the possible phenotypic consequences. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ando et al. (1971); Barnes et al. (1970); Gompertz et al. (1975); Nyhan et al. (1961); Nyhan et al. (1963); Ravn et al. (2000); Steinman et al. (1983); Wolf et al. (1979) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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