Propionic Acidemia

Overview

Plain-Language Overview

Propionic acidemia is a rare genetic disorder that affects the body's ability to break down certain parts of proteins and fats. This condition occurs when the body lacks enough of an important enzyme called propionyl-CoA carboxylase. Without this enzyme, harmful substances build up in the blood, which can cause serious health problems. Symptoms often appear in early infancy and may include poor feeding, vomiting, and developmental delays. People with propionic acidemia need ongoing medical care to manage their condition and prevent complications.

Clinical Definition

Propionic acidemia is an autosomal recessive metabolic disorder caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase, which catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA. This enzyme deficiency leads to accumulation of propionic acid and other toxic metabolites in the blood and tissues, resulting in metabolic acidosis, hyperammonemia, and secondary mitochondrial dysfunction. Clinically, affected individuals present in the neonatal period or early infancy with poor feeding, vomiting, lethargy, hypotonia, and developmental delay. Laboratory findings include elevated plasma propionylcarnitine, increased urine organic acids such as 3-hydroxypropionate, and metabolic acidosis with an increased anion gap. If untreated, propionic acidemia can cause severe neurological damage, cardiomyopathy, and multi-organ failure. Diagnosis is confirmed by enzymatic assay or molecular genetic testing identifying mutations in the PCCA or PCCB genes. Management involves dietary protein restriction, carnitine supplementation, and prompt treatment of metabolic crises. Long-term prognosis varies depending on severity and treatment adherence.

Inciting Event

Metabolic stress such as infection, fasting, or high protein intake can trigger acute decompensation.
Neonatal period with initiation of protein feeding often precipitates symptoms.
Catabolic states increase production of propionyl-CoA, exacerbating metabolite accumulation.

Latency Period

Symptoms typically appear within the first 1 to 2 weeks of life after protein feeding begins.

Diagnostic Delay

Nonspecific early symptoms such as poor feeding and lethargy can mimic sepsis, delaying diagnosis.
Lack of newborn screening in some regions contributes to delayed recognition.
Variable severity and intermittent symptoms may obscure clinical suspicion.

Clinical Presentation

Signs & Symptoms

Poor feeding and vomiting in the neonatal period.
Lethargy and hypotonia progressing to coma in severe cases.
Recurrent episodes of metabolic acidosis and hyperammonemia.
Developmental delay and failure to thrive.

History of Present Illness

Neonate presents with poor feeding, vomiting, and lethargy progressing to hypotonia.
Episodes of metabolic acidosis with rapid breathing and dehydration are common.
Neurologic symptoms such as seizures or developmental delay may be noted.

Past Medical History

Previous episodes of unexplained metabolic acidosis or hyperammonemia may be present.
History of neonatal intensive care admission for metabolic disturbances.
No prior chronic illnesses typically, as this is a congenital metabolic disorder.

Family History

Siblings with similar neonatal deaths or metabolic crises suggest autosomal recessive inheritance.
Consanguineous parents increase risk of affected offspring.
Family history of other inborn errors of metabolism may be relevant.

Physical Exam Findings

Patients may present with hypotonia and poor muscle tone.
There can be signs of dehydration such as dry mucous membranes and decreased skin turgor.
Neurologic exam may reveal lethargy or altered mental status.
Hepatomegaly may be present due to liver involvement.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of propionic acidemia is based on clinical presentation of metabolic acidosis and hyperammonemia in infancy, combined with biochemical evidence of elevated plasma propionylcarnitine and increased urinary organic acids such as 3-hydroxypropionate. Confirmatory testing includes enzymatic assay demonstrating deficient propionyl-CoA carboxylase activity or molecular genetic testing identifying pathogenic variants in the PCCA or PCCB genes.

Pathophysiology

Key Mechanisms

Propionic acidemia results from a deficiency of the mitochondrial enzyme propionyl-CoA carboxylase, leading to accumulation of propionic acid and toxic metabolites.
The buildup of propionic acid causes metabolic acidosis and inhibits the urea cycle, resulting in hyperammonemia.
Toxic metabolites interfere with normal cellular metabolism, causing multisystemic effects including neurologic dysfunction.

Involvement	Details
Organs	Liver is the main organ responsible for metabolism of propiogenic substrates and is affected by enzyme deficiency.
Organs	Brain is affected by neurotoxic effects of accumulated metabolites causing neurological dysfunction.
Tissues	Liver tissue is primarily involved as the site of propionyl-CoA carboxylase deficiency and metabolite accumulation.
Tissues	Brain tissue is affected by toxic metabolite-induced injury leading to developmental delay and encephalopathy.
Cells	Hepatocytes are the primary cells affected due to deficient propionyl-CoA carboxylase activity causing toxic metabolite accumulation.
Cells	Neurons are vulnerable to damage from metabolic acidosis and toxic organic acid buildup leading to neurological symptoms.
Chemical Mediators	Propionic acid accumulates due to enzyme deficiency and contributes to metabolic acidosis and toxicity.
Chemical Mediators	Ammonia levels increase secondary to impaired urea cycle function, causing neurotoxicity.

Treatment

Pharmacological Treatments

L-carnitine
- Mechanism: Facilitates the excretion of toxic organic acids by forming acylcarnitine esters
- Side effects: Gastrointestinal upset, fishy body odor
Metronidazole
- Mechanism: Reduces intestinal propionate-producing bacteria to decrease propionic acid load
- Side effects: Nausea, metallic taste, peripheral neuropathy with prolonged use
Sodium bicarbonate
- Mechanism: Corrects metabolic acidosis by buffering excess hydrogen ions
- Side effects: Electrolyte imbalance, alkalosis

Non-pharmacological Treatments

A protein-restricted diet limits intake of propiogenic amino acids to reduce toxic metabolite accumulation.
During metabolic crises, intravenous glucose administration provides calories to suppress catabolism.
In severe cases, liver transplantation may be considered to restore deficient enzyme activity.

Prevention

Pharmacological Prevention

Use of carnitine supplementation to enhance excretion of toxic metabolites.
Administration of metronidazole to reduce propionate-producing gut bacteria.
Use of sodium bicarbonate to correct metabolic acidosis during acute episodes.

Non-pharmacological Prevention

Dietary restriction of protein intake to limit propionate precursor amino acids.
Avoidance of fasting to prevent catabolic states and metabolic decompensation.
Early recognition and treatment of infections to reduce metabolic stress.

Outcome & Complications

Complications

Metabolic stroke due to toxic metabolite accumulation.
Severe hyperammonemic encephalopathy leading to brain injury.
Chronic renal dysfunction from metabolite toxicity.
Cardiac complications such as dilated cardiomyopathy.

Short-term Sequelae	Long-term Sequelae
Acute episodes of metabolic acidosis requiring hospitalization. Transient encephalopathy with altered mental status. Dehydration and electrolyte imbalances.	Chronic developmental delay and intellectual disability. Persistent movement disorders such as dystonia or ataxia. Progressive cardiomyopathy and heart failure. Chronic kidney disease from ongoing metabolite toxicity.

Differential Diagnoses

Propionic Acidemia versus Isovaleric Acidemia

Propionic Acidemia	Isovaleric Acidemia
No sweaty feet odor present in clinical presentation.	Presence of characteristic sweaty feet odor due to isovaleric acid accumulation.
Elevated propionic acid rather than isovaleric acid.	Elevated isovaleryl-CoA dehydrogenase deficiency markers.
Deficiency of propionyl-CoA carboxylase enzyme activity.	Increased levels of isovaleric acid in blood and urine.

Propionic Acidemia versus Maple Syrup Urine Disease (MSUD)

Propionic Acidemia	Maple Syrup Urine Disease (MSUD)
No elevation of branched-chain amino acids in plasma.	Elevated branched-chain amino acids (leucine, isoleucine, valine) in plasma.
No maple syrup odor in urine.	Characteristic sweet, maple syrup odor of urine.
Deficiency of propionyl-CoA carboxylase enzyme activity.	Deficiency of branched-chain alpha-ketoacid dehydrogenase complex.

Propionic Acidemia versus Methylmalonic Acidemia

Propionic Acidemia	Methylmalonic Acidemia
Elevated propionic acid and its metabolites in blood and urine.	Elevated methylmalonic acid levels in blood and urine.
Deficiency of propionyl-CoA carboxylase enzyme activity.	May have vitamin B12 deficiency or responsiveness.
No response to vitamin B12 supplementation.	Normal or mildly elevated propionyl-CoA carboxylase activity.