Propionyl-CoA carboxylase deficiency: case report, effect of low-protein diet and identification of 3-oxo-2-methylvaleric acid 3-hydroxy-2-methylvaleric acid, and maleic acid in urine

Abstract

Vomiting, lethargy and metabolic acidosis were the main initial symptoms of metabolic disease in a 1 month old girl. Her older sister had died from a similar disease, considered to be Reye's syndrome, at an age of 15 months. The urine of the present case contained 2-methylcitric acid, 3-hydroxypropionic acid, N-propionylglycine, 2-hydroxy-3-methylbutyric acid, N-tiglylglycine, 3-hydroxyvaleric acid and glutaric acid. These metabolites are all known to be associated with propionyl-CoA accumulation. Free propionic acid was not detected in the urine. In addition, the urine contained 3-oxo-2-methylvaleric acid and 3-hydroxy-2-methylvaleric acid, probably formed by condensation of two molecules of propionyl-CoA. The identity of these metabolites was confirmed by synthesis. An elevated urinary concentration of maleic acid and fumaric acid was another constant abnormality. The activity of propionyl-CoA carboxylase in leucocytes was about 20% of the normal activity. The girl was teated with a low-protein diet since the diagnosis was made at an age of 1 month, and her psychomotor development was satisfactory at an age of 2 1/2 years. She had a few episodes of acidosis during infections.

Pantothenate kinase activation relieves coenzyme A sequestration and improves mitochondrial function in mice with propionic acidemia

“…Instead, these intermediates diffuse out of tissues into the plasma and accumulate in urine. Elevated TCA cycle intermediates in PA mouse urine provide direct evidence for a dysfunctional TCA cycle and corroborate the similar observations in human PA ( 7 , 8 ). TCA cycle intermediates are not routinely assessed in plasma or urine of patients with PA, but future work will determine whether they may serve as biomarkers for the severity of mitochondrial impairment or to assess treatment efficacy.…”

“…The profiling of liver metabolites after propionate stress shows that when C3-CoA becomes the dominant CoA species, malate increases 6.6-fold along with other TCA cycle metabolites ( 64 ). Urinary TCA intermediates are not used as human PA biomarkers, but there is evidence for elevation of TCA cycle intermediates in PA urine ( 7 , 8 ). We used a metabolomics screen to identify changes in TCA cycle metabolites, selected amino acids, and other metabolites in the PA mouse.…”

“…6.4.1.3) genes (PCCA or PCCB) that produce proteins with diminished catalytic activity, resulting in compromised catabolism of propionyl-CoA (C3-CoA) and disrupted metabolism (2)(3)(4)(5)(6). The CoA-dependent tricarboxylic acid (TCA) cycle activity is dysfunctional in patients with PA, leading to TCA cycle intermediates being excreted in urine (7,8). Reduced PCC activity is thought to lead to the accumulation of intracellular C3-CoA, which is converted to propionyl-carnitine (C3-carnitine) that is released into the plasma and urine (2).…”

Pancytopenia in Propionic Acidemia: Hematologic Evaluation and Studies of Hematopoiesis in Vitro

“…Serum levels of PA as high as 5.4 mM (13) and glycine as high as 1.6 mM (14) have been observed in acutely ill infants. Urinary levels of tiglic acid and 3-0H PA greater than one hundred times normal have been reported, although tissue and serum levels are significantly less elevated due to the rapid renal clearance of these compounds (14,15). Infants with propionic acidemia frequently develop neutropenia, thrombocytopenia, and, occasionally, anemia (16).…”

Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

“…Mitochondrial dysfunction is also indicated in PA based on the inhibition of pyruvate oxidation, 18,19 fatty acid oxidation, 19,20 ureagenesis, 21,22 and gluconeogenesis 21–23 in cell cultures treated with propionate. Compromised TCA cycle activity in human PA patients is indicated by the elimination of TCA cycle intermediates in urine 11,24 …”