Propionic Acidemia (PA) is a very rare hereditary metabolic disorder that is characterized by an inherited deficiency in propionyl-Coenzyme A carboxylase. This enzyme plays a role in the degradation of specific amino acids such as valine, isoleucine, methionine, and threonine as well as odd-chain fatty acids and cholesterol. The deficiency results to the build-up of toxic organic acids, chiefly propionic acid which has an adverse effect on most vital organs but particularly the central nervous system, heart, and liver.

PA is primarily caused by mutations in two genes:

PCCA (propionyl-CoA carboxylase, alpha subunit)

PCCB (propionyl coenzyme A carboxylase beta chain)

These genes contain information for synthesis of the subunits of the enzyme propionyl-CoA carboxylase. They also found that either the presence of a lower amount of one or the other of two subunits of the enzyme caused it to become nonfunctional.

Propionic acidemia is known to occur with an estimated prevalence of 1 in 105,000 to 130,000 of the population in the United States; however, this disease is more common in people of Amish origin. It is even higher in the Inuit of Greenland at 1 in 1000 and certain Saudi Arabian populations at 1 in 2000 to 28000. These estimates may be lower than the true incidence because many cases remain undiagnosed, resulting in neonatal mortality. Regional genetic variations could lead to milder forms of the disease which could increase the global prevalence to one in every 18,000. They are often manifested early in infancy but can be less severe and manifest in later stages, and there is a relatively higher prevalence in females observed in the studies.

When the enzyme is deficient, propionyl-CoA and related metabolites accumulate in the blood and tissues. This builds up results in metabolic acidosis, hyper ammonaemia and diminishes essential cellular functions including energy production. Altered pathways are gluconeogenesis, urea cycle, increasing the toxic impact on the liver and brain.

Propionic acidemia is an autosomal recessive disease, the result of which is the deficiency of both the PCCA and PCCB genes that codes for the enzyme propionyl-CoA carboxylase. This enzyme abnormality leads to a failure to metabolise some amino acids and fats hence the build-up of toxic substances such as propionic acid. The condition follows autosomal recessive inheritance pattern and both parents are almost always carriers of the mutated gene.

Genotype and Enzyme Activity: There are different degrees of PCCA and PCCB genes and if these genes are severely mutated, symptoms tend to appear earlier and are also more severe. Inactivity of some part of the enzyme also helps in producing a less severe form of the disease.
Age at Diagnosis: Correction of the disease at its infancy through screening during early infancy is beneficial as opposed to when diagnosis is made later in childhood and adulthood as the results are adverse because of neurological impairment.
Metabolic Crises: Further, persistent metabolic decompensations especially during stress or infection decrease the survival prognosis due to the likelihood of irreversible organ damage; the brain inclusive.
Neurological Involvement: Some of the neurological manifestations such as developmental delay, seizures, and movement disorders indicate that the patients are likely to have poor prognosis.
Cardiac Complications: Cardiomyopathy and arrhythmias are severe and life threatening when left without proper management leading to early mortality.

Age Group

Infancy: Usually identified in the first month of life, screening at birth is usually effective in identifying this condition. Mild signs that may be presented may include poor feeds, vomiting, lack of energy and failure to gain weight as expected.

Childhood: May develop later undiagnosed, though grow with chronic metabolic decompensation, developmental impairment, and neurological features becoming more manifest.

Adulthood: However, some other cases may present in early adolescence or adulthood depending on the severity of the case, or inadequate treatment.

Propionic acidemia’s signs and symptoms in neonates include poor feeding, vomiting, poor activity, seizures, and giant liver size. The later-onset forms may manifest with growth failure, developmental disability, epilepsy, and spasms.

New onset of focal neurological deficits in patients previously known to have basal ganglia or thalamic disease might be caused by basal ganglia infarction manifested as dystonia or choreoathetosis. Propionic acidemia should be suspected even if there are no features pointed in a typical metabolic crisis.

The potential but rare sequels are the optic atrophy, hearing impairment, premature ovarian failure, chronic renal failure, and sometimes cardiomyopathy. It is also compounded by other conditions like attention-deficit disorder, autism, and anxiety.

Neurological: Delayed development, having low intelligence, movement disorder which include dystonia, and seizure disorders.

Cardiac: Cardiomyopathy and arrhythmias.

Hepatic: Dysfunction of liver, huge size of liver and fibrosis of liver tissue.

Renal: Renal insufficiency because of metabolic demand that has continued for a long time.

Acute: Normally, they present chronically with severe overlapping metabolic dysfunction in conditions such as infection, stress or starvation. Vomiting, lethargy, and metabolic acidosis are some of the signs that are associated with the disease.

Chronic: Child development concerns include developmental delay, chronic neurological signs, and failure to thrive. Patient self-monitoring is requisite to avoid frequent crisis points and long-term consequences.

Acute Management

Dialysis: In cases of an acute metabolic decompensation, the kidney by either haemodialysis or peritoneal dialysis eliminates the excess propionic acid and any other toxic metabolites.

Fluid and Electrolyte Replacement: Give intravenous fluids and electrolytes to normalize the patient by providing stability.

Nutritional Support: Offer immediate nourishment in predetermined amounts of intravenous glucose and amino acids to allow for the preservation of the patients’ metabolism.

Medications: Give carnitine to help in the regulation of fatty acid metabolism and decrease toxic byproducts.

Dietary Management
Low-Protein Diet: A strict low protein diet must be observed to reduce the synthesis of propionic acid. This frequently entails special preparations, Such preparations may be in form of specialized formulas.
High-Calorie Intake: People especially children and athletes need to take enough calories derived from carbohydrates and fats to enable growth and sustaining of body activities.
Frequent Feedings: These include frequent feeding of patients with more than three meals in a day in order to regulate their blood glucose levels and avoid catabolism.

Long-Term Management
Ongoing Dietary Monitoring: Remind to abide by the diabetic diet and modified for child’s growth, activities, and general health condition as a paediatric.
Carnitine Supplementation: Prolong oral/enteral L-carnitine supplementation at the dosage of 50-100mg/kg/day of body weight for promoting the fatty acid metabolism and avoiding toxicity of its metabolites.
Biotin Supplementation: Give biotin (5-10 mg/day) as it was reported to be coenzyme for propionyl-CoA carboxylase which is involved in propionate metabolism.
Regular Monitoring: Propionic acid concentration and other related metabolite should regularly be measured in the blood. Monitor intellectual, emotional and social achievement progress.

Advanced Management
Liver Transplantation: Indications to undergo liver transplantation include severe or progressive PPA which cannot be controlled by other medical interventions. The recipient gets a new liver that has the possibility to correct the metabolic defect.
Gene Therapy: Consider gene therapy as one of the treatment options to cure the congenital ailments like propionic acidemia by repairing the affected gene. This approach is still under test.
Stem Cell Therapy: Research on stem cell therapy for two reasons: firstly, as a cure to metabolic dysfunction secondly as a source of functional enzyme.

Neurology

Dietary Management: A restrictive protein intake should be maintained along with the use of specialized formulas and multiple feedings per day aimed at controlling both protein and blood glucose intake.
Carnitine Supplementation: Employed in the handling of the fatty acid metabolism.
Metabolic Monitoring: Monitor blood levels of propionic acid occasionally and observe the child’s growth and developmental progress.
Lifestyle Management: It is recommended to not fast, stress and infections should be dealt quickly.

Neurology

Specialty wise: Neurology

Carnitine is required for the transport of long-chain fatty acid inside the mitochondria where they undergo beta oxidation to generate energy. This results in the prevention of accumulation of toxic metabolites which are because of defective fatty acid oxidation. It also ensures that excess propionic acid is eliminated from the body by forming propionylcarnitine which is expelled through the urine.

Oral Carnitine Supplementation: Normally administered in the form of L-carnitine supplements. For instance, a patient might need to be administered L-carnitine 50-100 mg/kg/day, and this may be spread in different doses.

Intravenous Carnitine: It is typically applied in the acute settings for undertaking severe metabolic crises. For instance, carnitine can be given intravenously in higher concentrations to respond to episodes of acute metabolic deterioration.

Neurology

Specialty wise: Neurology

Biotin is a vitamin which belongs to the vitamin B7 class which can help in the management of propionic acidemia by acting as a coenzyme to different carboxylase enzymes among them being propionyl-CoA carboxylase. Biotin is involved with propionyl-CoA carboxylase where it catalyses the conversion of propionyl-CoA to methylmalonyl-CoA. This reaction is specific for the normal metabolism of propionates.
Oral Biotin Supplementation: Biotin is usually available in the form of capsules, with the recommended dosage per day varying between 5 to 10 mg, depending on the patient’s condition and reaction towards the medicine.

Neurology

Specialty wise: Neurology

Metronidazole: Orally administered metronidazole reduces the concentration of compounds that are toxic for the gut in patients with PA due to the decrease of propionic acid producing bacteria. Another related potential mechanism of metronidazole is that it can directly reduce the synthesis of propionic acid in gut to reduce the overall toxicity of this metabolite in body. Metronidazole should be taken only in combination with other methods of treatment including diet modification, supplementation of carnitine, and certain drugs to manage metabolism disorders.

Neurology

Hemodialysis or Peritoneal Dialysis: More seriously affected children in acute states and during metabolic crises may require dialysis to eliminate propionic acid and other toxic intermediates from the bloodstream. This can assist in stabilising the patient and lessen the demands that it places upon the metabolism of the body.

Liver Transplantation: In some patients especially those who have either severe or progressive forms of the disorder which cannot be managed well with conventional treatments, liver transplant may be done. Since propionyl-CoA carboxylase is found in the liver, one might be able to cure the disease by receiving a transplanted liver.

Gene Therapy: Although in its early stage, gene therapy seems to be the only way of treating propionic acidemia by correcting the defective gene. This is done by bringing to the patient’s cells a functional copy of the gene responsible for the synthesis of propionyl-CoA carboxylase. It is a developing approach and there are still some clinical trials conducted to assess the possibility and efficiency of this approach.

Stem Cell Therapy: Another experimental technique that has been practiced involves the use of stem cells with a hope of rectifying the metabolic dysfunction or a new source of functional enzyme. This strategy is also involved in research as well.

Neurology

There are several phases in the management of propionic acidemia. Acute management involves managing the patient on dialysis, fluid and electrolyte replacement, and providing the patient with emergency nutrition, while giving him medications such as carnitine. In the short-term low protein high calories diet is followed strictly while monitoring of the metabolic status is done frequently. The patient must also maintain a proper diet by holding certain food items they once consumed, constant meetings with the dietitian, and taking the medication as prescribed. For advanced treatment, the physician might recommend liver transplant surgery, another choice that can be mentioned is gene or stem cell therapy in clinical trial.