Propionic Acidemia

Propionic acidemia is classified as an inherited, autosomal recessive, organic acid disorder. 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. 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. ^[4]  

Defects in the metabolic pathway produce several potentially toxic metabolites. Toxic buildup of propionic acid can be found in the brain and other parts of the nervous system. 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. ^{[5, 6, 7, 8, 9, 10, 11, 12]}  

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 of these clinical characteristics. Numerous theories regarding basal ganglia infarction resulting from the effects of these metabolites have been suggested. ^[13] 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. ^[14] 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. ^[15]

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. ^[16]

The estimated incidence of propionic acidemia in the United States is 1:105,000–130,000 people, highest amongst the Amish populations. ^{[17, 18, 19]} The incidence is highest in the Inuit of Greenland—1:1,000 ^{[17, 20]} and next highest is in some Saudi Arabian populations—1:2,000- 28,000. ^{[17, 21, 22]}  The true prevalence may be higher, because many neonatal deaths may be caused by undocumented acidopathies.

Mild forms of the disease may exist due to differences in the mutations of PCCA or PCCB in different parts of the world. The true incidence of propionic acidemia may be as high as 1 case in 18,000 people. ^[23]

Patients with propionic acidemia often present in the neonatal period or during early infancy. Patients with mild forms of the disease may present later in life. ^{[24, 25, 26]} 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 an acidopathy.

Physical examination

Neonates may present in the first few days of life with decreased feeding, vomiting, lethargy, and seizures. Hepatomegaly may be present. Patients with infantile or late-onset forms may have failure-to-thrive, developmental delay, seizures, and spasticity.

In patients in whom propionic acidemia was previously diagnosed, the acute onset of abnormal movements may be a presenting sign of an infarction of the basal ganglia. Such abnomal movements can include dystonia, rigidity, and choreoathetosis. 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.

Rarely, optic atrophy, hearing loss, premature ovarian failure, and chronic renal failure has been reported. ^[17]  Isolated cases of cardiomyopathy have been reported as the sole clinical presentation of propionic acidemia. ^{[17, 27, 28]}  There are some incomplete reports of co-morbidities such as attention-deficit disorder, autism, anxiety, and acute psychosis seen in patients with propionic acidemia. ^{[17, 29, 30, 31, 32]}

The low incidence of propionic acidemia, coupled with the condition's nonspecific presenting symptoms, ^[33]  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

Initial laboratory studies may reveal metabolic acidosis with anion gap, hypoglycemia, hyperammonia, and ketonuria. One should 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. ^[34]  C3 propionylcarnitine will be elevated as well. 

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.

Diagnosis is confirmed when molecular genetic testing reveals a pathogenic variant in PCCA or PCCB or when there is deficient propionyl-CoA carboxylase enzyme activity. If molecular testing is equivocal, a combination of enzymatic and molecular testing may be necessary. ^[35]

During the workup of a young patient with suspected stroke, exclude other causes of stroke by obtaining blood, brain, vascular, and cardiac studies. ^[36]

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. ^{[37, 38, 39, 40]}  MR spectroscopy can reveal increased myoinositol, N-acetylaspartate and elevated glutamine, glutamate, and gamma-aminobutyric acid peaks in the basal ganglia. ^[38]

Consider EEG if patient is lethargic/comatose if suspicious for subclinical seizures/non-convulsive status epilepticus.

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. ^[41] 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.

Acute management

In the acute setting, all protein intake should be held. Treatment should be aimed at treating metabolic acidosis, hypoglycemia, and hyperammonemia.  

• Dextrose-containing IV fluid and lipid management are essential to treat dehydration and for high caloric supplementation. Dextrose boluses should be given when indicated.

• Use of Lactated Ringer's solution should be avoided in patients with propionic acidemia.

• IV carnitine should be given at 100 mg/kg/day divided every 8 hours (max of 5 g/day) as well as biotin (10mg/day).

• Consider hemodialysis for refractory metabolic acidosis or extremely high ammonia levels.  

• Monitor for signs/symptoms of increased intracranial pressure and treat appropriately.

• If there are any signs/symptoms of stroke, neuro-imaging (such as CT, MRI) is warranted.

• Monitor amylase and lipase as pancreatitis can occur during an acute crisis as well.

• Close monitoring of cardiac status is important as there is risk for cardiomyopathy as well.

• Appropriate antibiotics should be given for treatment of infection.

• Treat hyperammonemia due to PA accordingly (eg, stop or restrict protein intake). Carglumic acid was approved as adjunctive therapy to standard-of-care for the treatment of acute hyperammonemia due to PA.

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 and/or biochemical geneticist 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. 

Other treatment

Because gastrointestinal bacteria produce propionic acid, neomycin and metronidazole have been proposed as treatments. Clinical data about this treatment regimen are limited. ^[42]

Hemodialysis 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. ^{[43, 44, 45, 46, 47]}  One study analyzed the survival probability of 94 patients with PA that underwent liver transplantation. The study reported at 33 years old the survival probability was 62% compared to 98% in the general population. ^[48]

If a patient with propionic acidemia requires surgery, it is important to provide adequate hydration and caloric supplementation before surgery and post-operatively. One should try to limit fasting/NPO status as much as possible. 

NG tube or G-tube placement should be considered if the patient is not alert enough to feed by mouth during a crisis or if the patient remains encephalopathic.

Messenger RNA (mRNA) therapeutics are under investigation for the treatment of a number of metabolic diseases caused by protein deficiency, including PA. Preclinical murine model studies of mRNA-3927, an investigational dual mRNA therapy encoding PCCA and PCCB and delivered via lipid nanoparticles, have shown promising results with reduced biomarkers for disease with minimal toxicity, inflammatory, or immune responses. ^{[49, 50]}

Interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927 reported no dose-limiting toxicities in the 16 participants. Clinical efficacy was evaluated based on the occurrence of metabolic decompensation events (MDEs). Overall, 50% of participants experienced one or more MDEs during the pretreatment period, 12.5% during the dose-optimization study, and 18.8% during the combined dose-optimization study and the extension study. Participants had an overall relative risk of MDEs of 0.30 (95% confidence interval (CI), 0.066–1.315) during the treatment period compared to the pretreatment period (P = 0.0927). The study is ongoing. ^[51]