Clinical characteristics.

The spectrum of propionic acidemia (PA) ranges from neonatal onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis (often through newborn screening) and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.

Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy.

Isolated cardiomyopathy can be observed on rare occasions in the absence of clinical metabolic decompensation or neurocognitive deficits.

Manifestations of neonatal-onset and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, and chronic kidney disease. Other rarely reported complications include optic atrophy, sensorineural hearing loss, and premature ovarian insufficiency.

Diagnosis/testing.

PA is caused by deficiency of propionyl-coenzyme A carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Newborns with PA tested by expanded newborn screening (NBS) have elevated C3 (propionylcarnitine). Testing of urine organic acids in persons who are symptomatic or those detected by NBS reveals elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, propionylglycine, and lactic acid. Testing of plasma amino acids generally reveals elevated glycine. Confirmation of the diagnosis relies on detection of biallelic pathogenic variants in PCCA or PCCB by molecular genetic testing, or detection of deficient PCC enzymatic activity. In individuals with equivocal molecular genetic test results, a combination of enzymatic and molecular diagnostics may be necessary.

Management.

Treatment of manifestations: The treatment of individuals with acutely decompensated PA is a medical emergency: treat precipitating factors such as infection, dehydration, vomiting; reverse catabolism by providing intravenous glucose and lipids; manage protein intake to reduce propiogenic precursors; remove toxic compounds using intravenous carnitine, and when necessary nitrogen scavenger medications and/or extracorporeal detoxification; transfer to a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present.

Prevention of primary manifestations: Individualized dietary management should be directed by an experienced physician and metabolic dietician to control the intake of propiogenic substrates and to guide increased caloric intake during illness to prevent catabolism, typically by using specialized medical food. Gastrostomy tube placement is an effective strategy to facilitate the administration of medications and nutrition during acute decompensations and to improve adherence in chronic management of PA. Medications may include L-carnitine supplementation to enhance excretion of propionic acid and oral metronidazole to reduce propionate production by gut bacteria. Orthotopic liver transplantation may be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and/or poor growth.

Prevention of secondary complications: Consistent evaluation of the protein prescription, depending on age, sex, level of physical activity, severity of disorder, and presence of other factors such as intercurrent illness, surgery, and growth spurts to avoid insufficient or excessive protein intake is necessary. Excessive protein restriction or overreliance on medical foods can result in deficiency of essential amino acids and impaired growth, as well as catabolism-induced metabolic decompensation.

Surveillance: Monitor affected individuals with a catabolic stressor (fasting, fever, illness, injury, and surgery) closely to prevent and/or detect and manage metabolic decompensations early. Regularly assess: (1) growth, nutritional status, feeding ability, and psychomotor development; (2) vision and hearing; (3) cardiac function for signs of cardiomyopathy and prolonged QT interval; (4) metabolic status by monitoring routine chemistries, plasma ammonia, plasma amino acids, and plasma carnitine levels; (5) complete blood count; and (6) kidney function.

Agents/circumstances to avoid: Avoid prolonged fasting, catabolic stressors, and excessive protein intake. Lactated Ringer's solution is not recommended in individuals with organic acidemias. In individuals with QT abnormalities, avoid medications that can prolong the QT interval. Neuroleptic antiemetics (e.g., promethazine) can mask symptoms of progressive encephalopathy and are best avoided.

Evaluation of relatives at risk: Testing of at-risk sibs of an affected individual is warranted to allow for early diagnosis and treatment.

Genetic counseling.

PA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PCCA or PCCB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the PCCA or PCCB pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

NBS for propionic acidemia (PA) is primarily based on the quantification of propionylcarnitine (C3) and calculation of the C3/C2 ratio from the acylcarnitine profile on dried blood spots [Pajares et al 2021]. Other biochemical markers and ratios have been proposed as first-tier assessments to improve the accuracy of NBS, such as C17, C16:1-OH + C17, or C3/Met and C3/C16 ratios [Malvagia et al 2015, Martín-Rivada et al 2022].

Propionylcarnitine (C3) and/or C3/C2 ratio values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see Figure 1 and in Scenario 2, Preliminary laboratory findings). Some laboratories have implemented methylmalonate, 2-methylcitrate, total homocysteine, and 3-hydroxypropionic acid as a second-tier assessment to improve the positive predictive value of the NBS [Monostori et al 2017, Tangeraas et al 2020, Held et al 2022].

Figure 1.

Immediate management and testing algorithm to be pursued simultaneously after abnormal newborn screening concerning for propionic acidemia

If the follow-up biochemical testing supports the diagnosis of PA, confirmatory testing is required (see Establishing the Diagnosis).

The following medical interventions need to begin immediately upon receipt of an abnormal NBS result while additional testing is being performed:

• Clinical evaluation of the newborn
• Education of the caregivers to avoid prolonged fasting and identify concerning symptoms, including poor feeding, hypothermia, difficulty breathing, vomiting, seizures, or lethargy
• Immediate intervention if concerning symptoms are present (see also Management):
  • Admission to the hospital
  • Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
  • Infusion of IV glucose
  • Nutritional evaluation and consideration of dietary protein restriction
  • Carnitine supplementation

Scenario 2: Symptomatic Individual

A symptomatic individual who has either (1) typical findings associated with late-onset PA or (2) untreated infantile-onset PA resulting from NBS not performed, false negative NBS result, symptoms prior to receiving NBS result, or caregivers not adherent to the recommended treatment after a positive NBS result may have the following nonspecific clinical findings, preliminary laboratory findings, and family history.

Clinical findings

• Developmental delay
• Intellectual disability
• Failure to thrive
• Chronic gastrointestinal complaints
• Protein intolerance
• Acute psychosis
• Hypotonia
• Difficulty breathing
• Seizures
• Movement disorders such as dystonia and choreoathetosis
• Apparently isolated dilated or hypertrophic cardiomyopathy without a known history of metabolic decompensation or neurocognitive deficits

Preliminary laboratory findings. Biochemical findings consistent with PA include (see Figure 2):

Figure 2.

Metabolic pathway. Propionyl-coenzyme A 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...)

• Plasma acylcarnitine profile. Elevated propionylcarnitine (C3)
• Urine organic acids
  • Elevated 3-hydroxypropionate
  • Elevated 2-methylcitrate
  • Presence of tiglylglycine and/or propionylglycine
• Plasma amino acids. Elevated glycine and/or low glutamine
• Pertinent negative findings. Individuals with propionic acidemia have normal methylmalonic acid and total plasma homocysteine levels.

Note: Because elevations of PA metabolites individually are not entirely specific to PA, follow-up molecular or enzymatic testing is required to establish or rule out the diagnosis of PA (see Establishing the Diagnosis).

Common laboratory abnormalities during acute decompensation include:

• High-anion gap metabolic acidosis
• Lactic acidosis
• Hyperammonemia
• Elevated plasma and urinary ketones
• Low-to-normal blood glucose
• Neutropenia, anemia, and/or thrombocytopenia

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not exclude the diagnosis of propionic acidemia.

Establishing the Diagnosis

The diagnosis of propionic acidemia is established in a proband with biallelic pathogenic (or likely pathogenic) variants in either PCCA or PCCB identified by molecular genetic testing (Table 1) or significantly reduced activity of propionyl-coenzyme A carboxylase (PCC) in lymphocytes or cultured skin fibroblasts. Given the high sensitivity of molecular genetic testing and characteristic findings on biochemical tests, enzymatic testing is rarely used.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous PCCA or PCCB variant of uncertain significance does not establish or rule out the diagnosis.

Scenario 1: Abnormal NBS result. When NBS results and other laboratory findings suggest the diagnosis of propionic acidemia, molecular genetic testing approaches include use of a multigene panel.

A multigene panel that includes PCCA, PCCB, and sometimes other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Scenario 2: A symptomatic individual. When the diagnosis of PA has not been considered (because an individual has atypical findings associated with late-onset PA or untreated infantile-onset PA resulting from NBS not performed, symptoms prior to NBS result, or false negative NBS result), comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Enzyme analysis. In individuals with inconclusive genetic testing results, enzymatic activity measurements can help to establish the diagnosis [Forny et al 2021]. The assay uses lymphocytes or cultured skin fibroblasts to determine enzyme activity of PCC.

Clinical Description

Propionic acidemia (PA) presents with a wide spectrum of symptoms and age of onset. The onset of symptoms in PA varies depending on several factors, including residual enzymatic activity, intake of propiogenic precursors, and the occurrence of catabolic stressors.

Genotype-Phenotype Correlations

Although there is no evidence that identification of the underlying pathogenic variants in PCCA or PCCB can guide management or prognosis of PA, as no genotype-phenotype correlation is known [Pena et al 2012, Forny et al 2021], certain pathogenic variants in PCCA or PCCB may be associated with neonatal-onset or late-onset propionic acidemia [Liu et all 2022].

• Some homozygous missense pathogenic variants, in which partial enzymatic activity is retained, have been associated with a less severe phenotype.
  • The homozygous PCCB c.1606A>G (p.Asn536Asp) pathogenic variant in Amish and Mennonite populations is associated with high residual propionyl-coenzyme A carboxylase (PCC) activity. Individuals homozygous for this variant can be missed by NBS and present with metabolic crisis and cardiomyopathy after the newborn period [Scott Schwoerer et al 2018, Hannah et al 2019, Ehrenberg et al 2022].
  • The homozygous pathogenic variant PCCB c.1304T>C (p.Tyr435Cys) has been detected in apparently asymptomatic or mildly affected children identified through NBS in Japan [Tajima et al 2021].
• However, some PCCB missense pathogenic variants (p.Gly112Asp, p.Arg512Cys, and p.Leu519Pro) that affect heterododecamer formation can result in undetectable PCC enzyme activity and a severe phenotype.
• The homozygous PCCA pathogenic variant c.425G>A (p.Gly142Asp) in the Saudi Arabian population is associated with a severe phenotype with neonatal onset [Al-Hamed et al 2019].

Nomenclature

Propionic acidemia and propionyl-coenzyme A carboxylase deficiency are the two most common terms used to describe this condition. Ketotic hyperglycinemia was used in the 1960s before defects in PCC were determined to be the underlying cause of PA. The term propionic aciduria is used infrequently.

Prevalence

PA is an ultrarare metabolic disorder, and its prevalence varies by population. While PA is included in routine NBS in the United States, many countries still rely on clinical presentation for diagnosis, and therefore, the worldwide incidence of PA remains unknown. However, PA is more frequent in certain ancestral groups due to the founder effect of specific pathogenic variants.

• In the US, the birth incidence of PA is estimated to be ~0.14-0.77 in 100,000 (1 in 129,792 to 1 in 733,000) [Chapman et al 2018, Adhikari et al 2020].
• The incidence in other parts of the world is generally higher [Almási et al 2019]:
  • 0.32-2.20 in 100,000 in Europe
  • 0.05-5.05 in 100,000 in the Asia-Pacific
  • 3.6-8.14 in 100,000 in the Middle East and North Africa

Genetic Disorders

Acquired Disorders and Other Considerations

Maternal B₁₂ deficiency can be associated with elevated C3 (propionylcarnitine) on newborn screening. Additional testing in the mother and newborn usually reveals elevated total plasma homocysteine along with increased methylmalonic acid with or without 2-methylcitrate on urine organic acids. Maternal risk factors for cobalamin deficiency are malabsorption or vegan diet. In maternal vitamin B₁₂ deficiency, the infant's vitamin B₁₂ levels can be in the normal range [Gramer & Hoffmann 2020].

Bacterial overgrowth (including Propionibacterium or Lactobacterium) or short gut syndrome [Kumps et al 2002] can be associated with elevated 3-hydroxypropionate.

Valproate treatment can be associated with hyperglycinemia [Ahmad et al 2021].

Conditions included in the commonly used mnemonic MUDPILES: methanol, uremia (chronic kidney failure), diabetic ketoacidosis, propylene glycol, infection, iron, isoniazid, lactic acidosis, ethylene glycol, salicylates can be associated with increased anion-gap metabolic acidosis.

Poisoning and child abuse. In at least one individual with organic acidemia, propionic acid was misidentified as ethylene glycol [Hoffman 1991]. In another case, ethylene glycol poisoning presented with hyperglycinemia and glycolic acid in urine [Woolf et al 1992].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PA, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The mainstay nutritional intervention is modification of diet to control the intake of propiogenic substrates (isoleucine, valine, methionine, and threonine), while ensuring normal protein synthesis and preventing protein catabolism, amino acid deficiencies, and growth restriction.

Home management of metabolic status. The detection and management of metabolic decompensations at home are a critical part of the chronic management of PA. Affected individuals and care providers should notify their medical team about new symptoms and discuss the appropriateness of home management. Strategies to achieve home management should be tailored to each affected individual and family.

Acute metabolic decompensation. Birth, infections, trauma, surgery, postpartum recovery, or other forms of stress and hormonal changes can result in a catabolic response that leads, among other things, to protein breakdown with release of propiogenic amino acids that cannot be adequately broken down in PA. The goal of acute management is to reverse this process through promotion of anabolism and removal of toxic intermediates. Treatment of individuals with acutely decompensated PA is a medical emergency and requires transfer to a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present.

Transitional care from pediatric to adult-centered multidisciplinary care settings. As a lifelong disorder with varying implications according to age, smooth transition of care from the pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties.

• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PA together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise in metabolic diseases is essential.

Prevention of Primary Manifestations

Prevention and proactive management of metabolic crises (see Tables 6, 7, and 8) is important to maximize favorable clinical outcomes of PA.

Orthotopic liver transplantation (OLT) may be indicated in those individuals who, despite adequate medical treatment, continue to experience frequent metabolic decompensations [Yap et al 2020]. Elective liver transplant has been used as a preventive measure for severe phenotypes [Zhou et al 2021]. However, OLT in individuals with PA is not curative. It does not completely protect against metabolic strokes, hyperammonemia, progressive renal dysfunction, or metabolic decompensations [Romano et al 2010, Charbit-Henrion et al 2015, Yap et al 2020, Sivananthan et al 2021].

The indication of liver transplantation for dilated cardiomyopathy with severe heart dysfunction is less clear, with reports showing a short-term improvement or stabilization of heart function [Romano et al 2010, Critelli et al 2018]. However, development of cardiomyopathy after liver transplantation [Yap et al 2020, Zhou et al 2021] and the reoccurrence of cardiomyopathy have been reported by others [Berry et al 2020, Hejazi et al 2023]. Continuous hemofiltration, extracorporeal membrane oxygenation (ECMO), and left ventricular assist devices have been used while waiting for OLT.

The current evidence with short- or medium-term follow up has not demonstrated superiority of unrelated donors compared to heterozygous related donors for liver transplant [Zeng et al 2022].

Close monitoring of metabolic and nutritional status around the perioperative period by a highly specialized team is recommended. Disease-specific metabolites such as 3-hydroxypropionate can be elevated during the anhepatic phase [Quintero et al 2018].

Metabolic decompensation during liver transplantation poses a higher mortality risk [Ryu et al 2013].

Benefits of OLT include decrease in the frequency of metabolic decompensations and potential stabilization of the neurodevelopmental decline [Zhou et al 2021], as well as improved quality of life, increased life expectancy, and lifetime cost savings [Li et al 2015].

Complications of liver transplantation were summarized in a meta-analysis with the following pooled estimated rates [Zhou et al 2021]:

• Patient survival of 0.95 (95% CI: 0.80-1)
• Allograft survival of 0.91 (95% CI: 0.72-1)
• Rejection of 0.20 (95% CI: 0.05-0.39)
• Hepatic artery thrombosis of 0.08 (95% CI: 0.00-0.21)
• Biliary complications of 0.03 (95% CI: 0.00-0.15)
• Cytomegalovirus / Epstein-Barr virus infection of 0.14 (95% CI: 0.00-0.37)

Lifelong post-transplant management is recommended, as well as continuation of L-carnitine supplementation after liver transplantation. The authors recommend continued protein restriction after transplant using the WHO/FAO/UNU recommendations for energy and protein intake [Joint WHO/FAO/UNU Expert Consultation 2007]. However, the current data is insufficient to determine the best approach [Jurecki et al 2019].

Other transplantation. Successful kidney transplantation has been reported in an adult with kidney failure [Lam et al 2011]. Heart transplantation was reported in an adolescent with secondary cardiomyopathy [Seguchi et al 2022].

Prevention of Secondary Complications

One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be offered expediently during intercurrent illnesses or other catabolic stressors (see also Tables 6 and 7).

Surveillance

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Table 10 are recommended.

Agents/Circumstances to Avoid

Avoid prolonged fasting, catabolic stressors, and excessive protein intake.

Lactated Ringer's solution is not recommended in individuals with organic acidemias.

In individuals with QT interval abnormalities, avoid medications that can prolong the QT interval.

Ondansetron, an antiemetic drug used to control nausea, has been associated with QT interval prolongation on EKG [Tay et al 2014] and therefore should be used cautiously in individuals with PA who have cardiomyopathy and QT interval abnormalities.

Nephrotoxic medications (e.g., aminoglycosides) should be avoided.

Neuroleptic antiemetics (e.g., promethazine) can mask symptoms of progressive encephalopathy and are best avoided.

Evaluation of Relatives at Risk

Testing 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.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although successful pregnancy outcomes have been reported in individuals with PA [Van Calcar et al 1992, Langendonk et al 2012], pregnancy can pose a significant management challenge. Hyperemesis gravidarum may require the use of an antiemetic, but the risk of QT interval prolongation and the effect on the central nervous system need to be considered [Baumgartner et al 2014]. Baseline evaluation and monitoring of cardiomyopathy before, during, and after pregnancy is recommended. Reference ranges for total and free plasma carnitine differ during pregnancy [Schoderbeck et al 1995]. Close nutritional follow up and fetal growth monitoring is necessary, as energy and protein requirements change throughout pregnancy. Close postpartum clinical and biochemical follow up and delayed discharge from the hospital are recommended. In the postpartum period, increased caloric and protein needs during lactation should be taken into consideration.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Propionic acidemia (PA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a PCCA or PCCB pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a PCCA or PCCB pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a PCCA or PCCB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has PA or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in PCCA or PCCB.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a PCCA or PCCB pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the PCCA or PCCB pathogenic variants in the family.

Biochemical testing. Quantitative plasma amino acids, urine organic acids, acylcarnitine profile, and fibroblast enzymatic analyses are not reliable for detection of heterozygotes.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PA, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see Table 11).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PCCA or PCCB pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

If biallelic PCCA or PCCB pathogenic variants have not been identified in an affected family member, biochemical prenatal testing may be considered. Metabolite analysis of amniotic fluid for prenatal diagnosis of PA has been reported [Dai et al 2020].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Propionic acidemia (PA) is caused by deficiency of the mitochondrial multimeric enzyme propionyl-coenzyme A carboxylase (PCC), a biotin-dependent carboxylase located in the mitochondrial inner space that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. The enzyme is composed of alpha and beta subunits encoded by their respective genes, PCCA and PCCB. Deficient activity of propionyl-CoA carboxylase results in accumulation of propionic acid and propionyl-CoA-related metabolites, which can be detected biochemically.

PCC is a heterododecamer (α6β6) composed of six alpha subunits encoded by PCCA and six beta subunits encoded by PCCB [Huang et al 2010]. The beta subunits form a central core, and each of the alpha subunits attaches to a beta subunit (see Figure 2).

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 a side chain of cholesterol. Gut bacteria (e.g., 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.

Mechanism of disease causation. Loss of function

For a list of variants reported as pathogenic for PA, see ClinVar Miner.

Author Notes

Dr Carolina Galarreta Aima, Dr Oleg A Shchelochkov, and Dr Venditti are physicians at the NIH Clinical Center and specialize in pediatrics and biochemical genetics. Dr Teodoro Jerves is a pediatric biochemical geneticist at Yale University. Dr Venditti is the Director of the Organic Acid Research Section at the National Human Genome Research Institute.

Acknowledgements

The authors wish to express their appreciation to Christopher P Jordan, MD, and Jennifer L Sloan, PhD, for their valuable contributions to this chapter.

Author History

Nuria Carrillo, MD; National Human Genome Research Institute (2012-2024)
Carolina I Galarreta Aima, MD (2024-present)
Teodoro Jerves Serrano, MD (2024-present)
Oleg A Shchelochkov, MD (2016-present)
Charles P Venditti, MD, PhD (2012-present)

Revision History

• 26 September 2024 (gf) Comprehensive update posted live
• 6 October 2016 (ha) Comprehensive update posted live
• 17 May 2012 (me) Review posted live
• 28 October 2011 (nc) Original submission

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