Neonatal-onset PA largely resembles hyperammonemic encephalopathy that manifests within the first few days of life. Parents may claim feeding difficulties, note their children to become increasingly somnolent or lethargic. Vomiting and hyperventilation are frequently observed; seizures may be reported. While hyperventilation may provoke respiratory alkalosis, most patients present with metabolic acidosis due to further metabolic disturbances. Eventually, neonates may fall into a coma and die.

Patients suffering from late-onset PA may have a history of cognitive and motor deficits as well as mental retardation (55%); language acquisition may be impaired (55%) [9]. Muscular hypotonia (51%), ataxia (9%), hearing or visual impairment (13% and 7%, respectively), and an aversion to or intolerance of protein-rich food may be reported. Symptoms, as described for neonatal-onset PA, may be experienced chronically or recurrently. An exacerbation of symptoms may be triggered by situations inducing a catabolic state, e.g., by infectious disease, surgery or other forms of stress. Most frequently, affected individuals suffer from vomiting, but an acute metabolic decompensation may also provoke complications as mentioned above.

Cardiomyopathy is common in PA patients (9%), and may occasionally be the only symptom of PA [10]. A considerable share of patients also present with long QT syndrome (22%). Less frequently, pancreatitis, renal failure, premature ovarian failure, and an altered mental status have been described.

Laboratory analyses of blood and urine samples usually yield results that prompt a strong suspicion of organic acidemia in general and PA in particular:

• Anemia is very common (82%), while only about a third of PA patients presents with neutropenia or thrombocytopenia; pancytopenia is diagnosed in 11% of PA patients [9]
• Hyperammonemia
• Hypoglycemia
• Hyperglycinemia
• Acylcarnitine profile with an elevation of C3 (propionyl carnitine) [11]
• Metabolic acidosis with high anion gap (pH as low as 6.8)
• Ketosis with ketonemia and ketonuria
• Enhanced concentrations of 3-hydroxypropionate, propionyl carnitine, propionyl glycine, and methyl citrate in urine samples

Patients presenting with neonatal-onset PA show most of the aforementioned metabolic anomalies, while the diagnosis of late-onset PA strongly relies on the detection of propionyl-CoA metabolites in blood and urine specimens [12].

For confirmation of a tentative diagnosis of PA, the activity of propionyl-CoA carboxylase may be determined in peripheral blood leukocytes or cultured skin fibroblasts. Molecular biological techniques may be applied to identify mutations of PCCA and/or PCCB.

PA patients are required to maintain a diet with a low content of proteins, although fasting should be discouraged. Such a diet diminishes the formation of propionyl-CoA and its metabolites. In periods of stress, patients should augment their daily caloric intake to prevent protein catabolism. A detailed table of protein requirements and maximum daily protein intake dependent on the age of the patient is provided elsewhere [13]. Some experts recommend the supplementation of precursor free amino acids. Further medication may comprise intermittent application of metronidazole (10–20 mg/kg/day in up to 3 doses) or other antimicrobials to decrease propionic acid production by anaerobic bacteria in the gastrointestinal tract, L-carnitine to promote the elimination of propionyl groups (100-200 mg/kg/d in up to 4 doses), and N-carbamoyl glutamate to compensate for the inhibition of N-acetyl-glutamate synthase. Ammonia scavengers like sodium benzoate (150-250 mg/kg per day) have occasionally been used for the long-term therapy of PA.

Acute metabolic decompensation is a medical emergency and requires immediate attention. There is a negative correlation between the duration of coma and maximum ammonia levels, and the neurological outcome. Briefly, protein intake should be stopped entirely for up to 36 hours. Patients are to be infused with dextrose, possibly plus insulin, to slow down catabolic processes. L-carnitine and ammonia scavengers are to be administered. For a detailed description of the treatment of hyperammonemia, the reader is referred to the article treating with urea cycle disorder. With regards to decompensated PA patients, disturbances of acid-base and electrolyte balance have to be corrected. Besides fluid therapy and dextrose application, bicarbonate and potassium may become necessary.

Patients who frequently present with metabolic decompensation may be considered for liver transplantation.

To date, causative treatment for PA is not available. During the last decades, survival times could be improved considerably, but the neurological outcome is still poor [9]. An individual patient's prognosis largely depends on complications present at the time of diagnosis: Irreversible cardiac or brain damage may severely shorten a patient's life expectancy and reduce their life quality. Indeed, heart failure is the leading cause of death in PA patients [4]. On the other hand, if treatment is started before such lesions occur, the risk of developmental delays and premature death can be reduced significantly. In this context, patients are to be advised as to the chronic nature of their disease, and to the necessity to strictly adhere to dietary recommendations. Residual activity of propionyl-CoA carboxylase is a favorable prognostic factor, although it cannot be deducted from the patient's genotype but requires an assessment in cell culture.

Metabolic disturbances characteristic of PA is caused by a functional defect of propionyl-CoA carboxylase. This enzyme is composed of six α and β subunits, respectively, and these are encoded by genes PCCA and PCCB, respectively. While PCCA is located on the long arm of chromosome 13, PCCB is part of the long arm of chromosome 3. Of note, elder literature may refer to PCCC mutations. This designation has been chosen for mutations of those sequence segments of PCCB that encode for the carboxy-terminus of the β subunit.

To date, more than 100 mutations of either gene have been associated with PA, and the genetic heterogeneity of PA patients is a major obstacle for the identification of genotype-phenotype relationships. Moreover, individual patients may present with more than one mutation of PCCA and PCCB. With regards to the nature of gene mutations, insertions, and deletions, missense mutations, as well as anomalies provoking alternative splicing, have been reported. Sequence anomalies may lead to the assembly of an unstable protein, may interfere with ATP binding or conformational changes upon ATP binding [1]. The majority of mutations diminishes the activity of propionyl-CoA carboxylase to less than 5%, but occasionally, residual activities of >25% have been described [2].

Although PA is a hereditary disorder, patients don't necessarily have a family history of the disease. This may be the result of underdiagnosing, of phenotypic changes due to the influence of additional genetic and non-genetic factors, or of de novo mutations of PCCA and PCCB. Reliable data cannot be provided to this end, but the heterogeneity of PA-associated mutations in some populations argues for a considerable share of sporadic cases, while homogeneity, likely due to the inheritance of gene defects, is observed in other ethnicities. In detail, no prevalent mutations have been identified in Caucasians, while the total allelic frequency of three mutations of PCCA was 56% in Japanese patients [3].

Some authors estimated the overall incidence of PA to be in the range of 1 in 165,000 to 1 in 300,000 persons [4], while an incidence of 1 in 100,000 people was reported elsewhere. In fact, it has been proposed that the true incidence of the disease is as high as 1 in 18,000 inhabitants, with the majority of cases remaining undiagnosed due to the disease following a mild course [5]. Furthermore, there are considerable geographic differences, and highest incidence rates have been calculated for the Arabian Peninsula. Here, more than 1 in 5,000 people may be affected. Consanguineous marriage has been identified as a risk factor for PA and is very common among the Arabian population [6].

Propionyl-CoA carboxylase is a mitochondrial enzyme that catalyzes the conversion of propionyl-CoA, ATP, and bicarbonate to (S)-methylmalonyl-CoA, ADP, and pyrophosphate.

Propionyl-CoA is an intermediate metabolite of amino acid and fatty acid metabolism and is primarily produced during the breakdown of isoleucine, methionine, valine, and threonine, of odd-chain fatty acids and methyl-branched fatty acids. Minor quantities originate from bile acid synthesis and nucleic acid metabolism. Under physiological conditions, conversion of propionyl-CoA to (S)-methylmalonyl-CoA is followed by racemization and isomerization to succinyl-CoA. These reactions are mediated by methylmalonyl-CoA epimerase and methylmalonyl-CoA mutase, respectively, and depend on the availability of vitamin B12. In contrast, propionyl-CoA carboxylase deficiency results in the accumulation of propionyl-CoA, propionic acid, 3-hydroxypropionate, propionyl carnitine, and methyl citrate, primarily in mitochondria of hepatocytes. Here, these compounds interfere with important metabolic pathways like the Krebs cycle and electron transport chain, proximal reactions of the urea cycle and the glycine cleavage system [7]. Direct results are lactic acidosis, hyperammonemia, and ketotic hyperglycinemia. The underlying pathophysiological mechanisms are complex. For instance, propionyl-CoA acts as a competitive inhibitor of N-acetyl-glutamate synthase reduces the production of N-acetyl-glutamate and thus the activity of carbamoyl phosphate synthase I, which catalyzes the initial reaction of ammonia detoxification in the urea cycle. Thus, PA may present clinically similar to hyperammonemia type 3 or carbamoyl phosphate synthase deficiency. These diseases differ, however, in blood and urine levels of metabolites like methyl citrate. Also, dysfunction of the Krebs cycle seems to contribute to hyperammonemia [8].

Affected families may benefit from genetic counseling. Molecular biological techniques allow for the identification of carriers and for prenatal screens. Moreover, increased levels of 3-hydroxypropionate, propionyl carnitine, or methyl citrate in amniotic fluid may indicate PA. If parents decide against the prenatal test, neonates may be tested for PA. A positive result allows for the initiation of therapy before metabolic disturbances result in permanent organ damage.

Propionic acidemia (PA) is a hereditary metabolic disorder; affected individuals carry a mutated gene encoding for a non-functional propionyl-CoA carboxylase. This enzyme is required for the carboxylation of propionyl-CoA, and this reaction yields (S)-methylmalonyl-CoA and finally succinyl-CoA, a compound that can be utilized as a substrate in the Krebs cycle. Propionyl-CoA, in turn, is an intermediate metabolite produced in amino acid, odd-chain and methyl-branched fatty acid catabolism. In the case of insufficient carboxylation, propionyl-CoA, and alternative metabolites, mainly propionic acid, accumulate. They interfere with a variety of metabolic processes in the whole organism, trigger life-threatening ketoacidosis, cardiomyopathy, and encephalopathy. The disease is inherited as an autosomal recessive trait [1].

Age at symptom onset and clinical presentation vary largely. On the one hand, PA may manifest shortly after birth, and this form of the disease is referred to as neonatal-onset PA. On the other hand, symptoms may not be experienced in childhood. This late-onset form of the disease may follow an intermittent course with recurrent bouts of metabolic decompensation, or a chronic course characterized by progressive worsening of the patient's condition. To date, it is not possible to predict the course of the disease in an individual patient.

PA patients may be identified prenatally, by means of analyses of chorionic villi or amniotic fluid samples, and this approach is recommended for families with a known history of PA. Moreover, PA may be diagnosed in a patient presenting with clinical symptoms. Because the outcome largely depends on an early diagnosis and a timely initiation of therapy, the former is preferred over the later. This way, the disease can be identified before vital organs sustain permanent damage. Diagnosis is based on the identification of metabolic disturbances and on molecular biological techniques to demonstrate gene defects. Long-term therapy consists of dietary adjustments, low protein intake, and symptomatic treatment during metabolic crises.

Propionic acidemia (PA) is a hereditary metabolic disorder characterized by the accumulation of propionyl-CoA and metabolites like propionic acid and methyl citrate in hepatocytes. Propionyl-CoA arises from the breakdown of determined amino acids, fatty acids, cholesterol, and thymine. Under physiological conditions, propionyl-CoA is carboxylated and utilized in other metabolic processes. Carboxylation of propionyl-CoA is mediated by an enzyme named propionyl-CoA carboxylase, but PA patients carry a gene defect that impairs the assembly of functional propionyl-CoA carboxylase. In detail, there are two genes encoding for this enzyme, and PA patients may present mutations in either one of both.

The accumulation of propionyl-CoA and its metabolites interferes with a myriad of biochemical reactions and pathways, e.g., with the Krebs cycle and electron transport chain, as well as proximal reactions of the urea cycle. Consequently, toxic compounds like ketone bodies and ammonia accumulate in the patient's body and provoke life-threatening ketoacidosis, cardiomyopathy, and encephalopathy. While there is no causative treatment for PA, strict adherence to a diet low in proteins and adequate medication may diminish the individual risk of such severe complications. Still, every PA patient remains at risk of acute metabolic decompensation, and this condition constitutes a medical emergency that requires immediate attention. Symptoms associated with metabolic decompensation are vomiting, seizures, and reduced consciousness or coma.

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