Propionic Acidemia 

Propionic acidemia is a metabolic disorder in which a defective form of the enzyme propionyl-coenzyme A (CoA) carboxylase results in the 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.

Patients whose disease is diagnosed before birth (from the family history or sibling history) or soon after birth have the best prognosis.^[1] 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 age 6 weeks. The early onset group was characterized by mental retardation and early death, with the median survival period being 3 years. The late-onset group was characterized by severe movement disorders and dystonias.^[2] Patients with late-onset disease usually have permanent neurologic damage.

Patient education

To improve patient outcome, educate the patient's family to recognize early signs of dehydration, poor feeding, seizures, and respiratory distress. This education is important because metabolic decompensation plays a major role in the neurologic problems and sequelae observed in patients with propionic acidemia. For patient education information, see the Brain and Nervous System Center, as well as Stroke.

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.^{[3, 4, 5, 6, 7, 8, 9]}

Metabolic pathway

The 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 enzyme propionyl-CoA carboxylase, which requires biotin as a cofactor, catalyzes conversion of propionyl-CoA to methylmalonyl-CoA.

Basal ganglia damage

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.^[10]

Defects in the metabolic pathway produce several potentially toxic metabolites. Numerous theories regarding basal ganglia infarction resulting from the effects of these metabolites have been suggested.^[11] 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.^[12] Endothelial damage is the presumed basis for strokes. The authors confirmed that basal ganglia 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 lacking the PCCA gene has been developed. Experiments with this model may improve our understanding of the pathophysiology of this disease.^[13]

Antisense morpholino oligonucleotides directed at intronic pseudoexons have been shown to increase propionyl-CoA carboxylase activity to normal levels in fibroblast cell lines derived from patients suffering from propionic acidemia.^[14]

The prevalence of propionic acidemia in the United States 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.

Mild forms of the disease due to differences in the mutations of PCCA or PCCB may exist in different parts of the world. The true incidence of propionic acidemia may be as high as 1 case in 18,000 people.^[15]

Patients with propionic acidemia present in the neonatal period or during early infancy. Patients with mild forms of the disease may present later in life.^{[16, 17]} In a study of 65 patients, a slight female predominance was found, with a female-to-male ratio of 1.4:1.

Patient history

Patients with propionic acidemia 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 examination

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 ganglia 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.

The low incidence of propionic acidemia, coupled with the condition's nonspecific presenting symptoms, make the diagnosis difficult. The patient's family history and sibling history must be obtained and carefully investigated when one deals with any inherited disease. Prenatal and neonatal diagnosis must be pursued aggressively. The differential diagnosis of propionic acidemia includes the following disorders:

• Brainstem syndromes
• Cyanotic heart disease
• Ehlers-Danlos syndrome
• Marfan syndrome
• Mitochondrial cytopathies
• Organic acidurias
• Patent foramen ovale
• Sickle cell disease
• Thrombocytopenia
• Anterior circulation stroke
• Aseptic meningitis
• Basilar artery thrombosis
• Cardioembolic stroke
• Disorders of carbohydrate metabolism
• Fabry Disease
• Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome
• Posterior cerebral artery stroke

Laboratory studies

When acidosis is suspected on the basis of electrolyte and arterial blood gas abnormalities, eliminate the common causes of ketoacidosis and lactic acidosis first. Seizures, diabetes, alcoholic ketoacidosis, liver disease, shock, and anoxic and/or ischemic injury of tissues are often present with acidosis.

If the clinical picture suggests a metabolic disorder, a presumptive diagnosis may be made on the basis of blood analysis for ammonia levels, amino acids, and organic acids. Serum levels of ammonia, glycine, B-hydroxybutyrate, and acetoacetate should be elevated. A complete blood count (CBC) may reveal neutropenia and thrombocytopenia.

Perform a urinalysis for amino acids and organic acids. Methyl citrate, 3-hydroxy propionate, propionyl glycine, tiglate, and tiglyl glycine should be increased in the urine.

Make a definitive diagnosis after an enzyme analysis of fibroblasts is done. The results may show a severely depressed level of propionyl-CoA carboxylase. Genetic mutation analysis can also be undertaken. During the workup of a young patient with suspected stroke, exclude other causes of stroke by obtaining blood, brain, vascular, and cardiac studies.^[18]

Imaging studies

Acute changes in neurologic status (eg, stroke, seizure, encephalopathy) warrant a neuroimaging study. Several reports confirm that patients with propionic acidemia and movement disorders most likely have lesions in the bilateral lenticular and caudate nuclei. By convention, computed tomography (CT) scanning and magnetic resonance imaging (MRI) were used in these reports to identify these lesions. However, positron emission tomography (PET) scanning has subsequently been used in patient evaluation, to show decreased glucose uptake in the basal ganglia.^{[19, 20, 21, 22]}

A protein-restricted diet is the cornerstone of treatment. A low-protein diet (1.5-2mg/kg/day), L-carnitine supplementation (100mg/kg/day), and biotin supplementation (10mg/day) are required.^[23] Carnitine, an enzyme involved in the metabolism of long-chain fatty acids, buffers the acyl-CoA metabolites that accumulate with protein-restricted diets. The acyl-carnitine that is produced by the buffering action is excreted in the urine.

Biotin is a cofactor for propionyl-CoA carboxylase (and for 3 other carboxylases). Therefore, propionic acidemia may be present in a patient suffering from the broader metabolic problem of multiple carboxylase deficiency. Biotin responsiveness may depend on the genetic heterogeneity of isolated propionic acidemia versus propionic acidemia existing as a subset of multiple carboxylase deficiency. In patients with biotin-unresponsive disease, restricting their intake of isoleucine, valine, threonine, and methionine is the only solution.

Prompt dietary modification and supplementation may reverse clinical symptoms and normalize laboratory findings. The success of therapy can be measured as changes in propionic acid level in the serum. In-home testing of urine for ketones, especially during suspected infections, has been advocated.

In the acute phase, identify and treat intercurrent infections that have triggered an acidotic episode. Dietary modifications must be made in a hospital setting.

Because gastrointestinal bacteria produce propionic acid, neomycin and metronidazole have been proposed as treatments. Clinical data about this treatment regimen are limited. Dialysis may be required for life-threatening acute phases of illnesses that are triggered by infections or other stresses.

Organ transplantation of the liver or of the liver and kidney has been attempted. However, perioperative and postoperative complications are apparently high, and the long-term benefits are unclear.^{[24, 25]}

Transfer

The incidence of propionic acidemia is low, and the expertise to deal with this disease may be available only in tertiary medical centers. Life-threatening issues (eg, acidosis, dehydration, seizures) can possibly be addressed locally. However, when acidemia is suspected, the patient may need to be transferred to a facility with a high level of expertise in this area.

Consultations

Consultation with a pediatric neurologist is necessary when a patient presents with stroke, seizure, or encephalopathy. Dietary and/or nutritional specialists may help in modifying the patient's diet, and a physical therapist and/or an occupational therapist should also be consulted, for functional assessment and therapeutic recommendations. After the diagnosis of propionic acidemia is confirmed, a geneticist should be consulted.