Buchanan et al. (1980) pointed out that propionic acidemia can be diagnosed either by an elevated quantity of the metabolite methylcitrate in amniotic fluid or by deficient activity of propionyl-CoA carboxylase in amniocytes. Contamination ...- Prenatal Diagnosis Buchanan et al. (1980) pointed out that propionic acidemia can be diagnosed either by an elevated quantity of the metabolite methylcitrate in amniotic fluid or by deficient activity of propionyl-CoA carboxylase in amniocytes. Contamination by maternal cells can give a normal value for the latter determination; methylcitrate assay may be the most reliable approach. Perez-Cerda et al. (1989) successfully diagnosed PCC deficiency in the first trimester of pregnancy by direct enzyme assay in uncultured chorionic villi. Muro et al. (1999) reported prenatal diagnosis of an affected fetus based on DNA analysis in chorionic villus tissue in a family where the proband had previously been shown to carry the 1170insT mutation (232050.0004) and a private leu519-to-pro (L519P) mutation in the PCCB gene. Muro et al. (1999) also assessed carrier status in this family by DNA analysis
The features of propionic acidemia are episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein. Outstanding chemical features are hyperglycinemia and hyperglycinuria. This disorder is not to be confused with hereditary glycinuria (138500), ...The features of propionic acidemia are episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein. Outstanding chemical features are hyperglycinemia and hyperglycinuria. This disorder is not to be confused with hereditary glycinuria (138500), which is presumably transmitted as a dominant. Soriano et al. (1967) suggested that in the disorder first described by Childs et al. (1961), a generalized defect in utilization of amino acids results in excessive deamination of certain amino acids in muscle, with consequent hyperammonemia and ketoacidosis. In a second group of patients whose disorder is also termed hyperglycinemia, ketoacidosis, neutropenia, and thrombocytopenia have not been observed and glycine is the only amino acid present in excess in serum and urine; see glycine encephalopathy (605899). Hsia et al. (1969) studied fibroblasts from a sister of the boy described by Childs et al. (1961) and demonstrated deficient propionate carboxylation as the basic defect in ketotic hyperglycinemia. Hsia et al. (1971) also showed that 'ketotic hyperglycinemia' is the same as propionic acidemia and is the result of a defect in PCC. In further studies on this patient, Brandt et al. (1974) demonstrated that with low protein diet, growth and intelligence developed normally to age 9 years; indeed, intelligence was superior. The family originally reported by Childs et al. (1961) had the pccA type of propionic acidemia (Wolf, 1986). In a male Pakistani offspring of first-cousin parents, Gompertz et al. (1970) described acidosis and ketosis due to propionic acidemia, leading to death at 8 days of age. A sib had died at 2 weeks of age with metabolic acidosis and ketonuria. The defect was found to involve mitochondrial propionyl-CoA carboxylase. The same condition was described by Hommes et al. (1968). Al Essa et al. (1998) pointed out that not only do acute intercurrent infections precipitate acidosis in propionic acidemia, but such infections are unusually frequent in propionic acidemia in Saudi Arabia. Propionic acidemia is unusually frequent in Saudi Arabia, with a frequency of 1 in 2,000 to 1 in 5,000, depending on the region. The disorder has a severe phenotype in Saudi Arabia. Al Essa et al. (1998) had information on approximately 90 patients; certain tribes accounted for almost 80% of these cases, suggesting a founder effect. The number of other cases of organic acidemias observed during the same period was 656. Longitudinal data, in some instances up to 8 years, were available for 38 patients with propionic acidemia. A high frequency of infections was observed in 80% of the patients. Most microorganisms implicated were unusual, suggesting an underlying immune deficiency. The infections occurred despite aggressive treatment with appropriate diets, carnitine, and, during acute episodes of the disease, with metronidazole, which suggested a global effect of the disease on T and B lymphocytes as well as on the bone marrow cells. In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with branched-chain organic aciduria, including isovaleric aciduria (243500), propionic aciduria, and methylmalonic aciduria (251000) can rarely have strokes. Cerebellar hemorrhage has been described in all 3 disorders, and basal ganglia ischemic stroke has been described in propionic aciduria and methylmalonic aciduria. These events may occur in the absence of metabolic decompensation
Ugarte et al. (1999) reviewed mutations in the PCCA and PCCB genes. A total of 24 PCCA mutations had been reported, mostly missense point mutations and a variety of splicing defects. No mutation was predominant in the Caucasian or ...Ugarte et al. (1999) reviewed mutations in the PCCA and PCCB genes. A total of 24 PCCA mutations had been reported, mostly missense point mutations and a variety of splicing defects. No mutation was predominant in the Caucasian or Oriental populations studied. Among 10 patients with propionic acidemia, Desviat et al. (2006) identified 4 different PCCA splice site mutations and 3 different PCCB splice site mutations. The authors emphasized the different molecular effects of splicing mutations and the possible phenotypic consequences
Neonatal-onset propionic acidemia (PA), the most frequently recognized form of PA, manifests in the neonatal period as EITHER:...
DiagnosisClinical Diagnosis Neonatal-onset propionic acidemia (PA), the most frequently recognized form of PA, manifests in the neonatal period as EITHER:An abnormal newborn screening (NBS): elevated propionylcarnitine (C3) Note: Symptoms may be evident before NBS results are available. ORAcute clinical deterioration of unexplained origin, in which an infant who appeared healthy at birth develops nonspecific symptoms including vomiting, refusal to feed, and hypotonia in the first few days of life. If untreated, encephalopathy, coma, seizures, and cardiorespiratory failure can ensue. Late-onset PA includes developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and movement disorders (i.e. dystonia, choreoathetosis) [Delgado et al 2007]. These children can have an acute decompensation that resembles the neonatal presentation and is precipitated by a catabolic stress such as infection, injury, or surgery.Isolated cardiomyopathy is a recently recognized presentation [Lee et al 2009].TestingPA is caused by deficiency of propionyl-CoA carboxylase (PCC) (EC 6.4.1.3), the mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC enzymatic activity deficiency results in accumulation of propionic acid and other metabolites in plasma and urine (see Molecular Genetic Pathogenesis and Figure 1).FigureFigure 1. Metabolic pathway. Propionyl-CoA carboxylase (PCC) catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, which enters the Krebs cycle via succinyl-CoA. Sources of propionate include: valine, isoleucine, threonine, methionine, odd-chain (more...)Abnormalities frequently (but not universally) seen during acute decompensation common to other organic acidemias: Mild to severe high-anion gap metabolic acidosisElevated ketones in blood or urine (normally absent in healthy newborns)Low to normal blood glucose concentrationHyperammonemia (frequent)Neutropenia and occasionally thrombocytopenia Specialized biochemical evaluations for the diagnosis of propionic acidemia:Urine organic acids: Elevated 3-hydroxypropionate (normal value: 3-10 mmol/mol Cr)Methylcitrate (normally absent)Tiglylglycine (normally absent)Propionylglycine (normally absent)Occasionally lactatePlasma amino acids: Elevated glycine Acylcarnitine profile: Elevated C3 (propionylcarnitine)Note: The elevation of 3-hydroxypropionate is also seen in holocarboxylase synthetase deficiency and biotinidase deficiency; however, these disorders also have elevated 3-hydroxyisovalerate and 3-methylcrotonylglycine because of defective activity of pyruvate carboxylase, propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase.Newborn screening. Acylcarnitine profile performed by tandem mass spectrometry (MS/MS) on dried blood spots shows an elevation of C3 in newborns with PA, usually above 5 μM (C3: normal range <0.33 μM). Note: Some children with a benign variant of propionic acidemia are detected by NBS [Yorifuji et al 2002, Dionisi-Vici et al 2006]. (See also Differential Diagnosis of elevated C3.)Propionyl-CoA carboxylase (PCC) enzyme activity can be determined in peripheral blood leukocytes or cultured skin fibroblasts by assaying the substrate-dependent fixation of 14C from NaH14CO3 or 1-14C-propionate. Molecular Genetic TestingGenes. PCCA and PCCB are the two genes in which biallelic mutations are known to cause PA. The enzyme propionyl-CoA carboxylase (PCC) comprises alpha and beta subunits encoded by PCCA and PCCB, respectively [Huang et al 2010]. Biallelic mutation of either PCCA or PCCB results in PA.Table 1. Summary of Molecular Genetic Testing Used in Propionic AcidemiaView in own windowGene SymbolProportion of PA Attributed to Mutations in This Gene 1Test MethodMutations DetectedMutation Detection Frequency by Test Method 2Test AvailabilityPCCA~35%-50%Sequence analysisSequence variants 3~80%ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions~20% 5PCCB~50%-65% Sequence analysisSequence variants 399%ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletionsUnknown, none reported1. A higher proportion of PA may be caused by mutations in PCCB than PCCA. In published reports approximately two thirds of cases of PA of European origin resulted from mutations in PCCB [Pérez et al 2003], whereas individuals of Japanese origin had an equal proportion of mutations in PCCA and PCCB [Yang et al 2004].2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Exonic deletions may comprise ~20% of PCCA disease-causing alleles [Desviat et al 2009]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. Clinical suspicion of PA may be based on abnormal newborn screening, clinical presentation, and/or family history. Any individual thought to have PA should be evaluated and managed immediately by a metabolic team at an institution with expertise in caring for individuals with inborn errors of metabolism (see Management).1.Routine initial laboratory studies: blood gases, electrolytes, glucose, serum ammonia concentration, and complete blood count; renal function tests; liver function tests; and urine ketones 2.Specialized biochemical evaluations: urine organic acids, plasma amino acids, and acylcarnitine profile3.Confirmatory testing: either determination of PCC enzymatic activity or molecular genetic testing of PCCA and PCCBSee Figure 2.FigureFigure 2. Immediate management and testing algorithm to be pursued simultaneously after the clinical or laboratory suspicion of PA Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in PCCA or PCCB.
See Table 2 for a summary of major clinical findings in propionic academia (PA). ...
Natural History See Table 2 for a summary of major clinical findings in propionic academia (PA). Neonatal onset. The typical presentation involves a healthy newborn who develops poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Unless diagnosed correctly and managed promptly, neonates develop progressive encephalopathy, seizures, and coma that result in death. Late onset. The onset of symptoms in PA varies depending on several factors including residual enzymatic activity, the intake of propiogenic precursors, and the occurrence of catabolic stressors. Isolated cardiomyopathy in the absence of clinical metabolic decompensation or neurocognitive deficits has been reported on rare occasion [Lee et al 2009].Table 2. Clinical Phenotypes View in own windowOnsetClinical featuresFindingsNeonatal onsetPoor feeding Vomiting Irritability Lethargy Progressive encephalopathy Seizures Coma Respiratory failureHigh anion-gap metabolic acidosis Ketonuria Hyperammonemia (~80%) Hypoglycemia Elevated 3-OH propionic acid and methylcitric acid Hyperglycinemia Elevated propionylcarnitine Neutropenia ThrombocytopeniaLate onsetAcute, intermittent: Encephalopathy, coma, and/or seizures precipitated by catabolic stressors (e.g., intercurrent illness, surgery) Chronic progressive:Vomiting, protein intolerance, failure to thrive, hypotonia, developmental regression, movement disorders Isolated cardiomyopathy 1+/- Metabolic acidosis or hyperammonemia Elevated 3-OH propionic acid and methylcitric acid Hyperglycinemia MRI abnormalities including basal ganglia lesions 21. Lee et al [2009]2. Broomfield et al [2010]Early detection by newborn screening (NBS) and optimized management strategies offer the potential to improve the survival and long-term outcome of individuals with PA: A study of 49 patients with PA treated at European centers showed a lower mortality rate (~30%) in the first year of life than previously reported [Sass et al 2004]. A more recent study showed that although mortality was decreased in patients with PA diagnosed through NBS, their neurologic outcome did not improve [Grünert et al 2012]. In this study, 63% of those detected through NBS were symptomatic at the time of diagnosis. Metabolic decompensations. Children with PA can develop episodic metabolic decompensations, especially in the first years of life. Acidosis, hyperammonemia, pancreatitis, metabolic stroke, cardiomyopathy, bone marrow suppression, seizures, and encephalopathy can accompany acutely deranged metabolism. These episodes, which typically require hospitalization and can be life threatening, are usually precipitated by illnesses, infections, surgery, or any stress augmenting catabolism. The long-term cognitive outcome of individuals with PA is negatively correlated to the number of metabolic decompensations [Grünert et al 2012]. Therefore, metabolic decompensations should be recognized and treated promptly (see Management, Treatment of Manifestations, Neonatal/Acute Decompensation). Of note, normal cognitive development has been described in several individuals with late-onset (mild) forms of PA. Growth impairment may become evident with age. Failure to thrive may be exacerbated by malnutrition secondary to poor feeding and excessive protein restriction.Neurologic manifestations include hypotonia, developmental regression, neurocognitive deficits, stroke-like episodes [Scholl-Bürgi et al 2009], seizures, and movement disorders. Seizures are frequent in early-onset PA and include tonic-clonic, myoclonic, focal, or absence seizures. EEG abnormalities may precede the onset of seizures. In a study of 17 individuals with PA, all who had clinical seizures had abnormal MRI findings and a history of more than ten metabolic decompensations [Haberlandt et al 2009]. Individuals with PA are predisposed to basal ganglia lesions, especially during episodes of acute encephalopathy or metabolic instability [Broomfield et al 2010, Davison et al 2011]. Basal ganglia infarction may be preceded by an acute “stroke-like” episode and manifest as altered mental status, dystonia, choreoathetosis, and/or hemiplegia. Brain MRI shows delayed myelination, symmetric basal ganglia disease, and cerebral atrophy. Cardiomyopathy has recently been recognized as a common complication of PA. Romano et al [2010] reported cardiomyopathy in six of 26 children from a retrospective study; mean age of detection was age seven years. The age of diagnosis of PA, amount of metabolic control, or amount of residual enzymatic activity do not seem to modify the risk for cardiomyopathy [Romano et al 2010]. Most individuals with cardiomyopathy have mild to moderate forms of PA that are well controlled. Cardiomyopathy may resolve or progress to cardiac failure and has been associated with sudden death in a child with PA [Dionisi-Vici et al 2006]. Cardiac rhythm abnormalities include prolonged QTc interval associated with syncope [Kakavand et al 2006, Baumgartner et al 2007] and cardiac arrest [Jameson & Walter 2008].Pancreatitis, a well-known complication of PA and other organic acidemias, may be recurrent and should be suspected in those with anorexia, nausea, and/or abdominal pain. Hematologic abnormalities. Neutropenia, thrombocytopenia, and rarely pancytopenia are seen during acute decompensations. Affected persons are predisposed to infections. Myelodysplasia has also been reported [Sipahi et al 2004].Dermatologic manifestations resembling acrodermatitis enteropathica are frequently associated with deficiency of essential amino acids, particularly isoleucine, which is excessively restricted in the diet of persons with PA [Domínguez-Cruz et al 2011]. Other rare complicationsOptic atrophy with acute visual loss [Williams et al 2009]Hearing loss [Williams et al 2009, Lam et al 2011]Premature ovarian insufficiency (POI), described in some long-term survivors [Lam et al 2011] Chronic renal failure [Lam et al 2011]
Elevated C3 on newborn screening (NBS) can be caused by methylmalonic acidemias (resulting from methylmalonyl-CoA mutase deficiency, intracellular cobalamin metabolism) and severe maternal B12 deficiency....
Differential DiagnosisElevated C3 on newborn screening (NBS) can be caused by methylmalonic acidemias (resulting from methylmalonyl-CoA mutase deficiency, intracellular cobalamin metabolism) and severe maternal B12 deficiency.The differential diagnosis of propionic acidemia (PA) as suspected by the elevation of 3-hydroxypropionate and methylcitrate on urine organic acids includes the following:Biotin disorders, which also show elevation of 3-hydroxyvalerate and 3-methyl-crotonylglycine. Biotinidase and holocarboxylase synthetase activities differentiate between biotinidase deficiency and multiple carboxylase deficiency.Methylmalonic acidemias, which have elevations of 2-methylcitric acid and 3-hydroxypropionate, and additionally show massive elevations of methylmalonic acid3-hydroxyisobutyric aciduria, which also has elevation of 3-hydroxyisobutyric acidBacterial contamination (including Propionibacterium)Propionic acidemia should also be included in the differential diagnosis of many common pediatric conditions:Increased anion-gap metabolic acidosis. Possible causes are numerous and may include the following:Those conditions included in the commonly used mnemonic MUDPILES: methanol, uremia (chronic renal failure), diabetic ketoacidosis, propylene glycol, infection, iron, isoniazid, lactic acidosis, ethylene glycol, salicylatesOrganic acidemiasNeonatal “sepsis” of unclear etiology in the newborn period should always prompt a metabolic evaluation.Pyloric stenosis. Infants with PA or other organic acidemias presenting with vomiting and refusal to feed may be given the diagnosis of pyloric stenosis which may lead to unnecessary surgery that provokes acute metabolic decompensation. Blood gas analysis of infants with pyloric stenosis usually shows hypochloremic alkalosis.Failure to thrive or recurrent vomiting of unclear etiology may be the only manifestation of PA and other inborn errors of metabolism.Child abuse or intoxication. PA should always be considered in the differential diagnosis of intoxications. In at least one individual with an organic acidemia the laboratory misidentified propionic acid as ethylene glycol.Diabetic ketoacidosis. Persons with PA usually have ketoacidosis associated with hypoglycemia; however, hyperglycemia has also been reported and confused initially with diabetic ketoacidosis [Dweikat et al 2011, Joshi & Phatarpekar 2011].Cardiomyopathy. An evaluation for PA and other inborn errors of metabolism is warranted in the evaluation of children with cardiomyopathy of unknown origin.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Neonatal onsetLate onset:Acute, intermittentChronic progressiveIsolated cardiomyopathy
The management of patients with propionic acidemia (PA) is ideally performed at a center with expertise in inborn errors of metabolism. The metabolic team comprises a metabolic physician, nutritionist, and genetic counselor....
ManagementThe management of patients with propionic acidemia (PA) is ideally performed at a center with expertise in inborn errors of metabolism. The metabolic team comprises a metabolic physician, nutritionist, and genetic counselor.Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with PA the following evaluations are recommended (see Figure 2):Serial metabolic evaluations of blood gases, electrolytes, glucose, serum ammonia concentration; plasma amino acids, carnitine and acylcarnitines; urine ketones and urine organic acids to guide acute management until the patient stabilizesComplete blood count to evaluate for cytopeniasMolecular genetic testing of PCCA and PCCB if not previously performed to aid in genetic counseling and prediction of disease severityOnce the patient becomes stable, evaluations may include:Clinical assessment of growth parameters, ability to feed, developmental status, and neurologic statusLaboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias.ECG and echocardiogramEEG and brain MRI in symptomatic individualsAge-appropriate developmental evaluationEye examinationHearing evaluation Treatment of ManifestationsNeonatal/Acute DecompensationInjuries, illness, infections, birth, surgery, other forms of stress and hormonal changes can produce a catabolic response that leads, among other things, to protein breakdown with massive release of amino acids which may include propiogenic precursors that cannot be metabolized in PA. The stress response may be perpetuated by release of hormones. The goal of the acute management of persons with decompensated PA is to reverse this process and to remove accumulated toxins. The treatment of persons with acutely decompensated PA is a medical emergency and requires care in a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present.Inpatient ManagementManage ventilation and circulation as necessary.Treat precipitating factors (fever, infection, dehydration, pain, vomiting, and other sources of stress). Aggressively stop catabolism by giving fluids and calories approximately 1.5 times above the estimated baseline requirement in a glucose infusion rate of 10 mg/kg/min, and more than 40% of calories with a parenteral lipid suspension. The use of anabolic hormones (i.e., intravenous insulin drip) that may be needed to stop catabolism is preferably undertaken in an intensive care setting. Restrict intake of propiogenic precursors by avoidance of protein transiently (< 24-36 hours), or ideally, by the use of propiogenic-free parenteral amino acids, if available. Transition to enteral feedings as soon as they are tolerated (see Prevention of Primary Manifestations, Individualized dietary management).Detoxify to reduce hyperammonemia.Pharmacologic detoxification: Scavenger medications, such as those used in urea cycle disorders to help control ammonia levels during acute decompensations, should be used with caution in the treatment of hyperammonemia associated with PA as they lower glutamine levels, which may in turn contribute to hyperammonemia [Al-Hassnan et al 2003, Filipowicz et al 2006]. Scavenger medications include intravenous sodium benzoate (250 mg/kg) and sodium phenylacetate (250 mg/kg) alone or in combination (Ammunol®). Note: To date, no studies have examined the efficacy of scavenger medications in the management of hyperammonemia associated with propionic acidemia. Oral N-carbamoylglutamate (carglumic acid; 100-250 mg/kg) has also been reported to aid in the detoxification of ammonia during neonatal and acute decompensations [Filippi et al 2010, Schwahn et al 2010]. Extracorporeal detoxification (hemodialysis or extracorporeal membrane oxygenation [ECMO]) is frequently required in the acute infantile presentation of PA to control severe metabolic acidosis and/or hyperammonemia. Peritoneal dialysis is not recommended in this setting.Carnitine supplementation (100 mg/kg/day IV) may increase the detoxification of propionic acid by conjugating into propionylcarnitine, which is excreted by the kidneys. Alternatively, it may relieve intracellular coenzyme A accretion and provide a benefit through this mechanism.Home Management of Metabolic StatusThe detection and management of metabolic decompensations at home are a critical part of the chronic management of PA. Strategies to achieve home management should be tailored for the conditions of each patient and family and may include the following: At-home detection and monitoring of ketonesUse of anti-emetics such as ondansetron Close monitoring of clinical status Control of fluid-balance statusModification of the diet under the direction of the metabolic teamOtherAny injury, illness, hospitalization, or surgical procedure should involve consultation with the metabolic team.The diagnosis and management of pancreatitis is the same as for pancreatitis of other causes.Neutropenia and other cytopenias usually improve with metabolic control of PA.The management of cardiomyopathy and arrhythmias is similar to that from other causes. Cardiomyopathy may resolve after liver transplantation [Romano et al 2010]. Dermatologic manifestations are usually secondary to nutritional deficiencies of essential amino acids; these should be corrected.The management of chronic renal failure does not differ from that for other causes of renal failure; renal transplantation may be required.Prevention of Primary ManifestationsThe long-term management of PA includes the following:Individualized dietary management in order to restrict propiogenic substrates (valine, methionine, isoleucine, threonine, and odd chain fatty acids), while ensuring normal protein synthesis and preventing protein catabolism, amino acid deficiencies, and growth restrictionAvoiding fasting and increasing calorie intake during illness to prevent catabolismMetabolic monitoring (see Surveillance)Supportive feeding (nasogastric or gastrostomy) as neededOngoing multidisciplinary care, including caregiver teaching and emergency braceletMedications including:L-carnitine supplementation at a dose of 50-100 mg/kg/dayIntermittent oral metronidazole at a dose of 10-20 mg/kg/day to reduce propionate production by gut bacteriaN-carbamoylglutamate. However, its chronic use in PA needs to be further studied [Ah Mew et al 2010].Antiepileptic drugs, as needed [Haberlandt et al 2009]Therapy of arrhythmias, as needed Note: No persons with PA have been proven to be biotin responsive.Management before, during, and after any surgery by a metabolic team to ensure adequate hydration and caloric intake in order to minimize the risk of decompensationsOrthotopic liver transplantation (OLT). May be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and restricted growth [Barshes et al 2006]. Reported benefits of OLT include decrease in the frequency of metabolic decompensations, improved quality of life [Vara et al 2011], and reversal of dilated cardiomyopathy [Yorifuji et al 2004, Romano et al 2010]. Liver transplantation has been performed successfully from unrelated donors [Romano et al 2010] and from heterozygous related donors [Vara et al 2011]. Continuous hemofiltration, extracorporeal membrane oxygenation (ECMO) [Sato et al 2009], and left ventricular assist devices have been used while waiting for OLT [Ameloot et al 2011]. Prevention of Secondary ComplicationsIt is suggested that protein intake be regularly monitored by a biochemical geneticist and a nutritionist to avoid insufficient or excessive protein restriction. Many factors should be taken into account to guide protein restriction: age, gender, severity of PA, nutritional status, and presence of other factors such as intercurrent illness, surgery, or growth spurts. The effects of excessive protein restriction can include impaired growth, essential amino acid deficiencies, and catabolism-induced metabolic decompensation.SurveillanceMonitor closely patients with a catabolic stressor (fasting, fever, illness, injury, and surgery) to prevent and/or detect and manage metabolic decompensations early.The following evaluations are performed at different intervals depending on factors including age, disease severity, and presence of catabolic stressors.Clinical evaluation should include assessment of the following:GrowthNutritional statusFeeding abilityDevelopmental and neurocognitive progress, as age-appropriateLaboratory evaluation should include:Metabolic studies: urine organic acids (if available, quantitative plasma methylcitric and propionate are preferable), plasma amino acids, serum ammonia concentration, and quantitative acylcarnitine profile;Nutritional studies: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), and trace minerals;Complete blood count to monitor for cytopenias;Renal function tests;Amylase and lipase as needed to evaluate for pancreatitis.Evaluations: Screening for cardiomyopathy and arrhythmias by echocardiogram, ECG, and Holter monitor. The ideal screening frequency has not been defined.Brain MRI and/or EEG as clinically indicatedOphthalmologic evaluations to assess optic nerve changes. Frequency has not been determined.Screening for premature ovarian insufficiency (POI) in females. Frequency and recommended age to begin screening has not been determined. Agents/Circumstances to AvoidAvoid prolonged fasting and catabolic stressors.Evaluation of Relatives at RiskTesting of at-risk sibs is warranted to allow for early diagnosis and treatment. If prenatal testing has not been performed on at-risk sibs, measure urine organic acids, plasma amino acids, and acylcarnitine profile immediately in the newborn period in parallel with newborn screening (NBS). Note: The results of NBS may not be available before symptoms of PA appear. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationTherapies under investigation include:Anaplerotic therapy [Filipowicz et al 2006];Gene therapy. Adeno-associated viral (AAV) gene delivery has been successful in the treatment of Pcca knock-out mice [Chandler et al 2011] and may represent a future treatment option for patients.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Propionic Acidemia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPCCA13q32.3Propionyl-CoA carboxylase alpha chain, mitochondrialPCCA homepage - Mendelian genesPCCAPCCB3q22.3Propionyl-CoA carboxylase beta chain, mitochondrialPCCB homepage - Mendelian genesPCCBData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Propionic Acidemia (View All in OMIM) View in own window 232000PROPIONYL-CoA CARBOXYLASE, ALPHA SUBUNIT; PCCA 232050PROPIONYL-CoA CARBOXYLASE, BETA SUBUNIT; PCCB 606054PROPIONIC ACIDEMIAMolecular Genetic PathogenesisPropionic acidemia (PA) is an organic acidemia (see Organic Acidemias) caused by deficiency of propionyl-CoA carboxylase (PCC), a biotin-dependent carboxylase located in the mitochondrial inner space. PCC is a heterododecamer (α6β6) composed of six α-subunits encoded by PCCA and six α-subunits encoded by PCCB [Huang et al 2010]. The β-subunits form a central core and each of the α-subunits attaches to a β-subunit (see Figure 1).PCC catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA, which eventually enters the Krebs cycle as succinyl-CoA. Propionyl-CoA is common to the pathway for degradation of some amino acids (isoleucine, valine, threonine, and methionine), odd-chain fatty acids, and cholesterol. Gut bacteria (i.e., Propionibacterium sp.) are also an important source of propionate metabolized through PCC. The deficiency of PCC enzymatic activity profoundly deranges metabolism at several levels. Possible explanations include: The toxic effects of free organic acids and ammonia; The accumulation of propionyl-CoA, which in turn can inhibit other enzyme systems including oxidative phosphorylation [de Keyzer et al 2009], resulting in decreased energy production; Decreased production of Krebs cycle intermediates. PCCANormal allelic variants. PCCA comprises 24 exons. The normal variant, c.1651G>T, results in a change in amino acid residue.Pathologic allelic variants. Nearly 60 mutations in PCCA have been reported. The largest group (~40%) is missense mutations, followed by small insertions/deletions and splicing mutations [Desviat et al 2006]. Table 3. Selected PCCA Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesNormalc.1651G>Tp.Val551Phe 1NM_000282.3 NP_000273.2 NC_000013.10Pathologicc.412G>Ap.Ala138Thr 2c.491T>Cp.Ile164Thr 2c.862A>Gp.Arg288Gly 2c.937C>Tp.Arg313X 2c.1685C>Gp.Ser562X 2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). See cbs.lf1.cuni.cz for an updated list of PCCA mutations and polymorphisms.1. Pérez et al [2003]2. Desviat et al [2004]Normal gene product. The alpha subunit of PCC has ATP, bicarbonate, and biotin-binding domains, and is responsible for transferring bicarbonate to form carboxybiotin, the first step in the PCC reaction [Campeau et al 2001].Abnormal gene product. Most of mutations in PCCA cause protein instability, and two are predicted to impede ATP binding [Desviat et al 2004].PCCBNormal allelic variants. PCCB comprises 15 exons. Table 4 describes two normal variants that result in a change of amino acid residue.Pathologic allelic variants. More than 60 mutations in PCCB have been reported. The largest group (~40%) is missense mutations, followed by small insertions/deletions and splicing mutations [Desviat et al 2006]. The mutation c.1218_1231del14ins12 is reported to comprise roughly 30% of disease-causing alleles in individuals of northern European origin [Desviat et al 2004].The mutation c.1304T>C, associated with a milder form of propionic acidemia, comprises 25% of mutant alleles in Japanese.Table 4. Selected PCCB Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1) Protein Amino Acid Change (Alias 1)Reference SequencesNormalc.862G>Ap.Val288IleNM_000532.4 NP_000523.2 NC_000003.11c.1490C>Tp.Ala497ValPathologicc.280G>Tp.Gly94Xc.335G>Ap.Gly112Aspc.457G>Cp.Ala153Pro 2c.502G>Ap.Glu168Lys 3c.1218del14ins12 4p.Gly407fsc.1228C>Tp.Arg410Trp 2c.1283C>Tp.Thr428Ile 2c.1304A>Gp.Tyr435Cys 5c.1495C>Tp.Arg499Xc.1534C>Tp.Arg512Cysc.1539_1540dupCCC (1540insCCC)p.Arg514Profs*38 6(513insP)c.1556T>Cp.Leu519Proc.1606A>G 7p.Asn536AspSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). See cbs.lf1.cuni.cz for an updated list of PCCB mutations and polymorphisms.1. Variant designation that does not conform to current naming conventions2. Common in Japan [Yang et al 2004]3. Common in Spanish populations [Desviat et al 2004]4. Most frequent mutant allele reported in individuals of northern European origin (~30%)5. Detected in asymptomatic newborns through newborn screening in Japan; long-term effects are yet to be determined [Yorifuji et al 2002].6. Common mutation among Inuits in Greenland with a carrier frequency in that community of ~5% [Ravn et al 2000]7. A less severe form of PA is seen in some Amish communities; a mutation in the PCCB (1606A>G) has been identified in Lancaster County, Pennsylvania. Normal gene product. The beta subunit of PCC has a propionyl-CoA binding site and is responsible for transferring the carboxyl group to propionyl-CoA. Abnormal gene product. Most mutations are predicted to alter the active site and reduce the enzymatic activity. A smaller percent of mutations affect subunit interactions, and, thus, the assembly of the heterododecamer of PCC [Desviat et al 2004].