INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Propionic acidemia is a metabolic disorder in which a defective enzyme, propionyl-coenzyme A (CoA) carboxylase, results in an accumulation of propionic acid. Patients may present with vomiting, dehydration, lethargy, and encephalopathy. Clinical and imaging evidence suggests that propionic acidemia predisposes patients to bilateral infarcts of the basal ganglia involving the caudate, putamen, and globus pallidus. Milder forms may be characterized by the absence of some these clinical characteristics.

Pathophysiology: Metabolism of isoleucine, valine, threonine, and methionine produces propionyl-CoA. To a lesser degree, cholesterol and odd-chain fatty acids also contribute to propionyl-CoA levels. The defective enzyme propionyl-CoA carboxylase, which requires biotin as a cofactor, catalyzes conversion of propionyl-CoA to methylmalonyl-CoA. Several genetic mutations broadly categorized as defects in 2 subunits of the propionyl-CoA carboxylase gene (PCCA and PCCB) may give rise to varying levels of functioning propionyl-CoA carboxylase.

Defects in the metabolic pathway produce several potentially toxic metabolites. Numerous theories regarding basal ganglial infarction (resulting from effects of toxic metabolites) have been suggested. Hamilton et al suggested that metabolites of the dysfunctional propionic acid and methylmalonic acid pathways may be selectively toxic to the endothelial cells in the basal ganglia. Endothelial damage is the presumed basis for strokes. The authors confirmed that basal ganglial lesions were not due to hypoxemia because the hippocampus, which is relatively more sensitive to hypoxemia, was spared.

An alternative hypothesis implicates direct basal ganglia damage due to dysfunction of cytochrome-c oxidase. Accumulation of propionic acid apparently results in an abnormal cytochrome-c oxidase. Another competing hypothesis states that hyperammonemia, which is often associated with propionic acidemia, leads to an accumulation of glutamine and/or glutamate in astrocytes. This excess glutamate may be excitotoxic to neuronal cells in the basal ganglia.

A mouse model that lacks the PCCA gene has been developed. Experiments with this model may improve our understanding of the pathophysiology of this disease.

Frequency:

• In the US: The prevalence is reportedly 1 case per 35,000-75,000 population. The true prevalence may be higher because many neonatal deaths may be caused by undocumented acidopathies.

• Internationally: Mild forms of the disease due to differences in the mutations of PCCA or PCCB may exist in different parts of the world, and the true incidence may be as high as 1 case in 18,000 people.

Mortality/Morbidity: Surtees et al divided patients with propionic acidemia into 2 subgroups: Those with early-onset disease presenting in the first week of life and those with late-onset disease presenting after 6 weeks of age.

• The early-onset group was characterized by mental retardation and early death. The median survival of the early-onset group was 3 years.

• The late-onset group was characterized by severe movement disorders and dystonias.

Sex: In a study of 65 patients, a slight female predominance was found, with a female-to-male ratio of 1.4:1.

Age: Patients present in the neonatal period or during early infancy. Patients with mild forms of the disease may present later in life.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History:

• Patients may present with vomiting, seizures, lethargy, hypotonia, and encephalopathy. These symptoms may be recurrent, with episodes triggered by the onset of feeding, a change in feeding, or an infection.

• The patient may have a family history of the disease, especially a history of unexplained neonatal death or a sibling with acidopathy.

Physical:

• In patients in whom propionic acidemia was previously diagnosed, the acute onset of movement disorders caused by an infarction of the basal ganglia may be a presenting feature. Dystonia, rigidity, choreoathetosis, and dementia in a child with a previous diagnosis of propionic acidemia suggest a basal ganglial infarction.

• Case reports suggest that propionic acidemia should be considered in patients with new choreoathetoid movements, even if the traditional symptoms of metabolic decompensation are absent.

Causes:

• Propionic acidemia is an inherited disease (autosomal recessive).

• Although most children have neurologic damage during a metabolic crisis, rare cases without an identifiable precipitating factor have been reported. The metabolic crisis may result from changes in feeding, or they may be secondary to an infection.