Research Notes: Propionic Acidemia

From Pediatrix:

Background: Propionic acidemia (PA) is characterized by the accumulation of propionic acid due to a deficiency in propionyl CoA carboxylase, a biotin dependent enzyme involved in amino acid catabolism. Propionic acid may also accumulate in multiple carboxylase deficiency and methylmalonic acidemia. Multiple mutations for propionic acidemia have been identified.

Clinical: Patients with propionic acidemia typically present in the first days of life with dehydration, lethargy, hypotonia, vomiting, ketoacidosis, and hyperammonemia. Seizures, neutropenia, thrombocytopenia, and hepatomegaly may be present. Untreated patients can progress to coma and die. Most patients who survive the neonatal period have episodes of metabolic acidosis precipitated by infection, fasting, or a high protein diet. In some cases, episodic hyperammonemia seems to predominate over the metabolic acidosis. Psychomotor retardation is a life-long complication. Some patients have first presented later in infancy with encephalopathy and associated ketoacidosis, or developmental delay.

Testing: Newborns can be screened for propionic acidemia using tandem mass spectrometry analysis of a heel-stick dried blood spot. The finding of elevated three-carbon acylcarnitine (C3) indicates a possible metabolic defect, either propionic acidemia, methylmalonic acidemia, or less likely a defect in biotin metabolism. With methylmalonic acidemia, C4-dicarboxylic acylcarnitine may also be found, helping distinguish this disorder from propionic acidemia. To make a diagnosis, further testing is required. Urine organic acid analysis of a patient with propionic acidemia will demonstrate massive elevations of propionic acid and related compounds such as methylcitrate, propionylglycine, beta-hydroxypropionate, and tiglic acid. In propionic acidemia, carnitine deficiency due to increased renal excretion of propionyl carnitine is often seen.

Treatment: Treatment of propionic acidemia involves reducing protein intake, particularly the amino acids valine, isoleucine, methionine and threonine that feed into the defective pathway. This requires placing the infant on a special metabolic formula depleted in these amino acids. Until the diagnosis of propionic acidemia is clearly established, all patients should be given a trial of cobalamin and biotin to evaluate a response. Carnitine supplementation has proven beneficial. Oral antibiotics help control infections and hypothetically reduce intestinal bacteria, which produce propionic acid that can be absorbed through the gut and contribute to metabolic stress. Prevention of constipation is important. Strict control is most crucial throughout childhood. Rarely, older patients with mild forms of propionic acidemia are reported to function untreated.

Because the diagnosis and therapy of metabolic disorders like propionic acidemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

Inheritance: This disorder most often follows an autosomal recessive inheritance pattern.

Clin Chim Acta. 2000 May.
Identification of undescribed medium-chain acylcarnitines present in urine of patients with propionic and methylmalonic acidemias.
Libert R, Van Hoof F, Thillaye M, Vincent MF, Nassogne MC, de Hoffmann E, Schanck A.
Laboratoire des Maladies Metaboliques, Departement de Biologie Clinique, Cliniques Universitaires St Luc, 10 Avenue Hippocrate, B-1200, Brussels, Belgium.

In urine of patients with propionyl-CoA carboxylase deficiency or with methylmalonic acidemia, carnitine esters of 2-methyl-branched fatty acids of all chain lengths between 4 and 9 atoms of carbon were identified during the acute phase of the diseases. The chemical structure of these compounds was obtained by gas chromatography-mass spectrometry analysis of their fatty acid moieties in their free and picolinyl ester forms. We suggest mechanisms for the biosynthesis of these branched fatty acids, and their accumulation in urine during episodes of caloric imbalance.

Pediatr Res. 1984 Dec.
Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine.
Chalmers RA, Roe CR, Stacey TE, Hoppel CL.

Concentrations of l-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic acid metabolism associated with an intramitochondrial accumulation of acyl-CoA intermediates. These included propionic acidemia, methylmalonic aciduria, isovaleric acidemia, multicarboxylase deficiency, 3-hydroxy-3-methylglutaric aciduria, methylacetoacetyl-CoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria, medium-chain acyl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values. The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1. l-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be propionylcarnitine in methylmalonic aciduria and propionic acidemia, isovalerylcarnitine in isovaleric acidemia, and hexanoylcarnitine and octanoylcarnitine in medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding acyl-CoA esters in these diseases. In this group of disorders, the increased acylcarnitine/carnitine ratio in urine and plasma indicates an imbalance of mitochondrial mass action homeostasis and, hence, of acyl-CoA/CoA ratios. Despite naturally occurring attempts to increase endogeneous l-carnitine biosynthesis, there is insufficient carnitine available to restore the mass action ratio as demonstrated by the further increase in acylcarnitine excretion when patients were given oral l-carnitine.

J Clin Invest. 1984 Jun.
L-carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia.
Roe CR, Millington DS, Maltby DA, Bohan TP, Hoppel CL.
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Treatment with L-carnitine greatly enhanced the formation and excretion of short-chain acylcarnitines in three patients with propionic acidemia and in three normal controls. The use of fast atom bombardment mass spectrometry and linked scanning at constant magnetic (B) to electric (E) field ratio identified the acylcarnitine as propionylcarnitine in patients with propionic acidemia. The normal children excreted mostly acetylcarnitine. Propionic acidemia and other organic acidurias are characterized by the intramitochondrial accumulation of short-chain acyl-Coenzyme A (CoA) compounds. The substrate specificity of the carnitine acetyltransferase enzyme and its steady state nature appears to facilitate elimination of propionyl groups while restoring the acyl-CoA:free CoA ratio in the mitochondrion. We suggest that L-carnitine may be a useful therapeutic approach for elimination of toxic acyl CoA compounds in several of these disorders.

Arch Dis Child. 1983 Nov.
Metabolic response to carnitine in methylmalonic aciduria. An effective strategy for elimination of propionyl groups.
Roe CR, Hoppel CL, Stacey TE, Chalmers RA, Tracey BM, Millington DS.

Patients with methylmalonic aciduria have an excessive intramitochondrial accumulation of acyl-coenzyme A compounds that may reduce the availability of free coenzyme A (CoA) for normal metabolic requirements, producing profound metabolic disturbances. Giving carnitine to a patient with methylmalonic aciduria produced an increase in hippurate excretion (an index of intramitochondrial adenosine triphosphate (ATP) and CoA availability), a large increase in short chain urinary acylcarnitines, and a reduction in excretion of methylmalonate and methylcitrate. These acylcarnitines were shown by fast atom bombardment and B/E linked scan mass spectrometry to be propionylcarnitine and acetylcarnitine. Carnitine acts by removing (detoxifying) propionyl groups, thereby releasing CoA and restoring ATP biosynthesis and concentrations towards normal. L-carnitine may play a central role in maintenance of mitochondrial and cellular homoeostasis in methylmalonic aciduria and propionic acidaemia. These principles may provide an approach to the treatment of this and other disorders, inherited and acquired, in which accumulation of acyl CoA metabolites results in sequestration of free CoA, thereby perturbing metabolic homoeostasis.