Propionic Acidemia

Mendelian MONDO:0011628 Pathograph 40 Organic Acidemia Inborn Error of Metabolism

Propionic acidemia is an autosomal recessive organic acidemia caused by deficiency of propionyl-CoA carboxylase (PCC), usually due to biallelic PCCA or PCCB pathogenic variants. Defective propionate metabolism leads to toxic organic acid accumulation, metabolic acidosis, hyperammonemia, and recurrent episodes of life-threatening metabolic decompensation. Long-term complications include cardiomyopathy, prolonged QTc, intellectual disability, basal ganglia necrosis, pancreatitis, chronic kidney disease, and optic atrophy.

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Mappings

Definitions

Inheritance

Histopathology

Subtypes

Differentials

Datasets

Trials

Models

References

Deep Research

🏷

Classifications

Harrison's Chapter

⚙

Pathophysiology

Propionyl-CoA carboxylase molecular function deficiency

Biallelic pathogenic variants in PCCA or PCCB reduce propionyl-CoA carboxylase catalytic activity in mitochondria.

hepatocyte link

PCCA link PCCB link

propionate catabolic process link ↓ DECREASED

propionyl-CoA carboxylase activity link

mitochondrion link

Downstream

Toxic metabolite burden and mitochondrial stress Impaired propionyl-CoA carboxylation causes accumulation of propionyl-CoA-derived toxic metabolites.

Show evidence (1 reference)

PMID:37482098 SUPPORT Other

"Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), which is responsible for converting propionyl-CoA to methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle."

Directly supports deficient PCC function and blocked propionyl-CoA handling.

Toxic metabolite burden and mitochondrial stress

Accumulation of propionyl-CoA related metabolites contributes to metabolic acidosis, secondary hyperammonemia, and cellular energy stress in liver, brain, and myocardium.

tricarboxylic acid cycle link

Downstream

Secondary NAG deficiency and hyperammonemia Accumulated metabolites deplete secondary NAG signaling and impair CPS1-mediated ureagenesis.

Cardiac oxidative stress via circulating propionate Systemic propionate excess increases cardiac propionyl-CoA load and oxidative injury.

Renal mitochondrial quality control impairment Metabolite stress perturbs renal mitochondrial homeostasis, including fission-mitophagy balance.

Metabolic acidosis Accumulated organic acids directly drive high-anion-gap metabolic acidosis during decompensation.

Vomiting Acute toxic metabolite accumulation and metabolic decompensation produce gastrointestinal symptoms including vomiting.

Lethargy Systemic metabolic decompensation and energy stress reduce alertness during acute crises.

Failure to thrive Recurrent catabolic crises, restricted intake, and chronic metabolite stress impair growth.

Global developmental delay Brain energy stress and recurrent metabolic injury contribute to delayed neurodevelopment.

Intellectual disability Metabolic and mitochondrial stress biomarkers track with more severe intellectual disability in PA.

Autism spectrum disorder PA is associated with autism spectrum disorder, but the causal intermediates remain incompletely resolved.

Seizures Acute and chronic neurometabolic injury can lower seizure threshold in PA.

Basal ganglia necrosis Metabolic stroke-like injury from toxic metabolite accumulation affects basal ganglia structures.

Pancreatitis Organic acidemia-related metabolic stress contributes to episodic pancreatic inflammation.

Optic atrophy Chronic mitochondrial and neurometabolic stress provides a mechanistic route to optic nerve degeneration.

Hearing impairment Chronic metabolic disease burden is associated with late-onset hearing loss in PA.

Rhabdomyolysis Severe metabolic decompensation can injure skeletal muscle and produce rhabdomyolysis.

Propionylcarnitine (C3) Excess propionyl-CoA is conjugated with carnitine, producing elevated propionylcarnitine.

2-Methylcitric acid Propionyl-CoA excess is diverted into methylcitric acid formation.

Glycine Disrupted propionate metabolism is reflected in the classical hyperglycinemia biochemical profile.

3-Hydroxypropionate Accumulated propionyl-CoA-derived metabolites include urinary 3-hydroxypropionate.

Propionylglycine Propionyl-CoA excess is conjugated with glycine, producing elevated propionylglycine.

FGF21 and GDF15 Mitochondrial stress signaling in PA is reflected by increased FGF21 and GDF15.

Show evidence (2 references)

PMID:37482098 SUPPORT Other

"When this process is disrupted, propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening cardiac diseases and other metabolic strokes."

Supports toxic metabolite accumulation and multisystem downstream injury.

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Patient-diagnostic review evidence identifies the principal elevated PA metabolite markers.

Secondary NAG deficiency and hyperammonemia

Hyperammonemia in PA is related to secondary deficiency of N-acetylglutamate (NAG), the allosteric activator of carbamoyl phosphate synthetase 1 (CPS1), which is an irreversible rate-limiting enzyme in the urea cycle. CPS1 inhibition by accumulated propionyl-CoA metabolites impairs ureagenesis.

urea cycle link

Downstream

Hyperammonemia Secondary NAG deficiency reduces CPS1 activation and impairs ureagenesis, causing hyperammonemia.

Show evidence (1 reference)

PMID:39695809 SUPPORT Human Clinical

"Hyperammonemia is related to a secondary deficiency of N-acetylglutamate (NAG), the activator of carbamoyl phosphate synthetase 1, which is an irreversible rate-limiting enzyme in the urea cycle."

Directly explains the mechanism of secondary hyperammonemia in PA via NAG/CPS1 pathway.

Cardiac oxidative stress via circulating propionate

In PA, accumulated propionyl-CoA and diminished hepatic propionate clearance lead to elevated circulating propionate. Gut microbiome-derived propionate is the primary cardiac propionyl-CoA source, and prolonged exposure induces significant oxidative stress in cardiomyocytes.

cardiac muscle cell link

response to oxidative stress link

heart link

Downstream

Cardiac multi-mechanism pathogenesis Persistent oxidative injury amplifies broader cardiac mitochondrial and electrophysiologic dysfunction mechanisms.

Show evidence (2 references)

PMID:38992300 SUPPORT Model Organism

"gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source"

Identifies gut-derived propionate as the primary cardiac propionyl-CoA source.

PMID:38992300 SUPPORT Model Organism

"Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice."

Demonstrates cardiac oxidative stress from propionate exposure in PA models.

Renal mitochondrial quality control impairment

In a PA mouse model, kidneys show altered mitochondrial ultrastructure, shifted mitochondrial networks towards fission, marked reduction of mitophagy, and steep reduction of PGC-1-alpha. These disturbances in mitochondrial homeostasis and quality control are involved in chronic kidney disease development.

epithelial cell of proximal tubule link

mitochondrial fission link mitophagy link

kidney link

Downstream

Chronic kidney disease Impaired renal mitochondrial quality control drives progressive kidney dysfunction in PA.

Show evidence (2 references)

PMID:39681572 SUPPORT Model Organism

"altered mitochondrial networks shifted towards fission and a marked reduction of mitophagy"

Demonstrates mitochondrial quality control impairment in PA kidneys.

PMID:39681572 SUPPORT Model Organism

"We observed a steep reduction of PGC-1-α, the key mediator modulating mitochondrial functions and a counter actor of mitochondrial fission."

PGC-1-alpha reduction links mitochondrial dysfunction to CKD pathogenesis.

Cardiac multi-mechanism pathogenesis

Cardiac complications in PA involve multiple cellular pathways including impaired substrate delivery to TCA cycle, secondary mitochondrial electron transport chain dysfunction, oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, and carnitine deficiency.

cardiac muscle cell link

mitochondrial electron transport, NADH to ubiquinone link

heart link

Downstream

Dilated cardiomyopathy PA cardiac mitochondrial and metabolic pathway disruption culminates in dilated cardiomyopathy.

Prolonged QT interval Cardiac metabolic and excitation-contraction abnormalities provide the mechanistic basis for QT prolongation.

Show evidence (1 reference)

PMID:37110221 SUPPORT Other

"12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine..."

Comprehensive review identifying multiple cardiac pathogenetic mechanisms in PA.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 2

Dilated cardiomyopathy FREQUENT Dilated cardiomyopathy (HP:0001644)

Show evidence (2 references)

PMID:38132258 SUPPORT Human Clinical

"DCM (17/23 patients)"

Quantifies dilated cardiomyopathy as frequent in PA patients with cardiac involvement.

PMID:38132258 SUPPORT Human Clinical

"rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA"

Supports high cardiac morbidity in PA.

Prolonged QT interval FREQUENT Prolonged QT interval (HP:0001657)

Show evidence (1 reference)

PMID:37110221 PARTIAL Other

Provides mechanistic pathways compatible with QTc risk but does not directly quantify prolonged QT in patients.

Digestive 2

Vomiting FREQUENT Vomiting (HP:0002013)

Show evidence (1 reference)

PMID:25205257 PARTIAL Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture"

Acute deterioration in PA commonly includes gastrointestinal decompensation symptoms such as vomiting.

Pancreatitis OCCASIONAL Pancreatitis (HP:0001733)

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease"

Lists pancreatitis among late-onset complications.

Ear 1

Hearing impairment OCCASIONAL Hearing impairment (HP:0000365)

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

Lists hearing loss among late-onset complications.

Eye 1

Optic atrophy OCCASIONAL Optic atrophy (HP:0000648)

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

Lists optic atrophy among late-onset complications.

Genitourinary 1

Chronic kidney disease OCCASIONAL Chronic kidney disease (HP:0012622)

Show evidence (2 references)

PMID:39681572 SUPPORT Model Organism

"Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD."

Directly supports CKD as a recognized long-term complication of PA.

PMID:37689673 SUPPORT Human Clinical

Lists CKD among human PA complications.

Metabolism 2

Metabolic acidosis VERY_FREQUENT Metabolic acidosis (HP:0001942)

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture"

Directly supports metabolic acidosis as a frequent presenting phenotype.

Hyperammonemia FREQUENT Hyperammonemia (HP:0001987)

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture"

Directly supports hyperammonemia during PA decompensation.

Musculoskeletal 1

Rhabdomyolysis VERY_RARE Rhabdomyolysis (HP:0003201)

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

Lists rhabdomyolysis among late-onset complications.

Nervous System 6

Lethargy FREQUENT Lethargy (HP:0001254)

Show evidence (1 reference)

PMID:25205257 PARTIAL Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture"

The severe acute decompensation phenotype is consistent with lethargy and reduced responsiveness.

Global developmental delay OCCASIONAL Global developmental delay (HP:0001263)

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"leading to early death or to severe neurological handicap in many survivors."

Supports frequent long-term neurodevelopmental morbidity.

Intellectual disability FREQUENT Intellectual disability (HP:0001249)

Show evidence (2 references)

PMID:38200289 SUPPORT Human Clinical

"Twenty (61%) participants received an ID diagnosis"

Quantifies intellectual disability prevalence in PA cohort.

PMID:38200289 SUPPORT Human Clinical

"Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile."

Links metabolic/mitochondrial biomarkers to severity of intellectual disability.

Autism spectrum disorder FREQUENT Autism (HP:0000717)

Show evidence (1 reference)

PMID:38200289 SUPPORT Human Clinical

"12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD"

Quantifies ASD prevalence at 39% in the PA cohort.

Seizures OCCASIONAL Seizure (HP:0001250)

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

Lists seizures among late-onset complications of PA.

Basal ganglia necrosis OCCASIONAL Basal ganglia necrosis (HP:0012128)

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

Lists basal ganglia lesions among late-onset complications.

Growth 1

Failure to thrive FREQUENT Failure to thrive (HP:0001508)

Show evidence (1 reference)

PMID:25205257 PARTIAL Human Clinical

"leading to early death or to severe neurological handicap in many survivors."

Severe chronic disease burden supports frequent growth and developmental compromise.

🧬

Genetic Associations

PCCA pathogenic variants (Pathogenic Variants)

Autosomal recessive

Show evidence (2 references)

PMID:22593918 SUPPORT Other

"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."

GeneReviews supports biallelic PCCA pathogenic variants as one molecular genetic basis of propionic acidemia.

CGGV:assertion_32a55e25-8632-4f31-84af-3eaf8098ca18-2018-12-13T170000.000Z SUPPORT Other

ClinGen classifies the PCCA-propionic acidemia gene-disease relationship as definitive with autosomal recessive inheritance.

PCCB pathogenic variants (Pathogenic Variants)

Autosomal recessive

Show evidence (2 references)

PMID:22593918 SUPPORT Other

"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."

GeneReviews supports biallelic PCCB pathogenic variants as one molecular genetic basis of propionic acidemia.

CGGV:assertion_1cd49a9b-08c2-49db-8e97-e334f171e34d-2018-12-13T170000.000Z SUPPORT Other

ClinGen classifies the PCCB-propionic acidemia gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

Protein-restricted diet

Action: dietary intervention MAXO:0000088

Restriction of propiogenic amino acids (valine, isoleucine, threonine, methionine) with specialized formula support is the cornerstone of PA management.

Mechanism Target:

MODULATES Toxic metabolite burden and mitochondrial stress — Restricting propiogenic amino acid intake lowers substrate flux into the blocked PCC pathway and limits toxic metabolite production.

Show evidence (1 reference)

PMID:22593918 SUPPORT Other

"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"

GeneReviews directly supports dietary management as substrate-control therapy in PA.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"despite the existence of apparently effective therapy with a low protein diet and carnitine."

Directly supports low-protein dietary treatment in PA.

Carnitine supplementation

Action: carnitine supplementation MAXO:0010006

Adjunctive therapy to support organic acid detoxification and excretion via formation of propionylcarnitine.

Mechanism Target:

MODULATES Toxic metabolite burden and mitochondrial stress — Carnitine supports detoxification of propionyl groups through propionylcarnitine formation and excretion.

Show evidence (1 reference)

PMID:6725560 SUPPORT Human Clinical

"Treatment with L-carnitine greatly enhanced the formation and excretion of short-chain acylcarnitines in three patients with propionic acidemia and in three normal controls."

Patient evidence supports carnitine-mediated acylcarnitine excretion in PA.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"despite the existence of apparently effective therapy with a low protein diet and carnitine."

Directly supports carnitine supplementation in management of PA.

Carglumic acid (CGA)

Action: pharmacotherapy MAXO:0000058

Carglumic acid is a synthetic structural analog of N-acetylglutamate (NAG) approved for treatment of hyperammonemia in PA. Chronic CGA use is associated with reduction in hyperammonemic decompensation episodes and hospital admissions.

Mechanism Target:

BYPASSES Secondary NAG deficiency and hyperammonemia — Carglumic acid bypasses secondary NAG deficiency by stimulating the first step of the urea cycle and reducing hyperammonemia.

Show evidence (1 reference)

PMID:30522498 SUPPORT Other

"Treatment with N-carbamyl-L-glutamate can rapidly normalise ammonia levels by stimulating the first step of the urea cycle."

The review describes the urea-cycle stimulation mechanism of carglumic acid/N-carbamyl-L-glutamate.

Show evidence (2 references)

PMID:39695809 SUPPORT Human Clinical

"Carglumic acid (CGA) is a synthetic structural analog of human NAG and is approved for the treatment of patients with hyperammonemia due to PA or MMA."

Directly supports CGA as an approved treatment for hyperammonemia in PA.

PMID:39695809 SUPPORT Human Clinical

"the addition of CGA is associated with a reduction in hyperammonemic decompensation episodes and admission to hospital, compared with conventional dietary treatment alone."

Supports long-term benefit of CGA in reducing decompensation episodes.

Ammonia-lowering therapy

Action: pharmacotherapy MAXO:0000058

Sodium benzoate or sodium phenylbutyrate for pharmacologic ammonia reduction during hyperammonemic episodes.

Mechanism Target:

MODULATES Secondary NAG deficiency and hyperammonemia — Nitrogen-scavenger pharmacotherapy lowers ammonia burden downstream of impaired ureagenesis.

Show evidence (1 reference)

PMID:30522498 SUPPORT Other

"It may also include the administration of ammonia scavengers such as sodium benzoate or sodium phenylbutyrate."

The organic-acidemia hyperammonemia review directly supports ammonia scavengers as therapy for this branch.

Show evidence (1 reference)

PMID:30522498 SUPPORT Other

"It may also include the administration of ammonia scavengers such as sodium benzoate or sodium phenylbutyrate."

Directly supports ammonia scavengers as ammonia-lowering pharmacotherapy in organic acidemia hyperammonemia.

Acute decompensation management

Action: supportive care MAXO:0000950

Emergency supportive care with reversal of catabolism via high glucose infusion, cessation of protein intake, and correction of metabolic acidosis.

Mechanism Target:

MODULATES Toxic metabolite burden and mitochondrial stress — Emergency reversal of catabolism and temporary protein cessation reduce acute substrate-driven toxic metabolite production.

Show evidence (1 reference)

PMID:22593918 SUPPORT Other

"reverse catabolism by providing intravenous glucose and lipids; manage protein intake to reduce propiogenic precursors; remove toxic compounds using intravenous carnitine"

GeneReviews directly supports reversal of catabolism, precursor reduction, and toxic-compound removal during acute PA management.

MODULATES Secondary NAG deficiency and hyperammonemia — Acute decompensation protocols include correction of hyperammonemia during crises.

Show evidence (1 reference)

PMID:30522498 SUPPORT Other

"Correcting metabolic imbalance and hyperammonaemia are critical to prevent brain damage in affected patients."

The review supports hyperammonemia correction as an acute management target in organic acidemias.

Show evidence (1 reference)

PMID:22593918 SUPPORT Other

"The treatment of individuals with acutely decompensated PA is a medical emergency"

GeneReviews supports emergency management for acute PA decompensation.

Liver transplantation

Action: liver transplantation MAXO:0001175

Considered for severe recurrent decompensation and poor metabolic control. LT improves metabolic stability but does not fully correct the biochemical defect since PCC is expressed in extrahepatic tissues.

Mechanism Target:

MODULATES Toxic metabolite burden and mitochondrial stress — Liver transplantation improves hepatic propionate handling and metabolic stability, while extrahepatic PCC deficiency remains.

Show evidence (1 reference)

PMID:33093405 SUPPORT Human Clinical

"The pooled estimate rates were 0.98 (95% CI, 0.88-1.00) for metabolic stability"

Systematic-review evidence directly supports improved metabolic stability after liver transplantation.

Show evidence (1 reference)

PMID:33093405 SUPPORT Human Clinical

"Despite the risk of transplant-related complications, LT is a viable therapeutic option in PA patients with satisfactory survival rates and clinical outcomes."

Directly supports liver transplantation as a viable option for selected PA patients.

Cardiac pharmacotherapy

Action: pharmacotherapy MAXO:0000058

Standard cardiac therapies including ACE inhibitors, beta-blockers, and coenzyme Q10 supplementation for management of cardiomyopathy and QTc prolongation. Multicenter approaches are needed to strengthen efficacy data.

Mechanism Target:

MODULATES Cardiac multi-mechanism pathogenesis — Standard cardiac medications and coenzyme Q10 target the downstream cardiomyopathy and electrophysiology branch rather than the upstream PCC defect.

Show evidence (1 reference)

PMID:37110221 SUPPORT Other

"The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications."

The cardiac-complication guideline recommendation supports targeting the cardiac pathogenesis branch.

Show evidence (1 reference)

PMID:37110221 SUPPORT Other

"The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications."

Supports standard cardiac pharmacotherapy for PA cardiac complications.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk, and prenatal testing options.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism"

Genetic etiology of PA supports the role of genetic counseling for affected families.

Newborn screening

Action: disease screening MAXO:0000124

PA is detectable by newborn screening via tandem mass spectrometry using elevated C3-acylcarnitine as the primary marker. Early detection allows initiation of treatment before clinical decompensation.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Supports use of propionylcarnitine as newborn screening biomarker.

🔬

Biochemical Markers

Propionylcarnitine (C3) (INCREASED)

Context: Elevated C3-acylcarnitine is a hallmark diagnostic marker for PA, detectable on newborn screening and during metabolic decompensation.

Pathograph Readouts

Readout Of Toxic metabolite burden and mitochondrial stress Positive Diagnostic

Elevated propionylcarnitine reports accumulation of propionyl-CoA-derived metabolites used for PA diagnosis.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Clinical review evidence directly supports propionylcarnitine as a positive diagnostic readout of PA metabolite burden.

Correlates With Intellectual disability Positive Prognostic

Higher plasma propionylcarnitine is associated with a more severe intellectual-disability profile in PA.

Show evidence (1 reference)

PMID:38200289 SUPPORT Human Clinical

Patient biomarker-behavioral data support propionylcarnitine as a positive correlate of ID severity.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Directly supports elevated propionylcarnitine as a diagnostic marker.

2-Methylcitric acid (INCREASED)

Context: 2-Methylcitrate is a characteristic metabolite of PA, reflecting propionyl-CoA entry into the TCA cycle via citrate synthase.

Pathograph Readouts

Readout Of Toxic metabolite burden and mitochondrial stress Positive Diagnostic

Elevated 2-methylcitric acid reports diversion of propionyl-CoA-derived carbon into abnormal organic-acid metabolites.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Clinical review evidence supports 2-methylcitric acid as a positive diagnostic readout of PA metabolite burden.

Correlates With Intellectual disability Positive Prognostic

Higher plasma total 2-methylcitrate is associated with a more severe intellectual-disability profile in PA.

Show evidence (1 reference)

PMID:38200289 SUPPORT Human Clinical

Patient biomarker-behavioral data support 2-methylcitrate as a positive correlate of ID severity.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Directly supports elevated 2-methylcitric acid as a diagnostic marker.

Glycine (INCREASED)

Context: Elevated glycine is a classical feature of PA. Notably, plasma glycine was not meaningfully associated with intellectual disability or ASD severity.

Pathograph Readouts

Readout Of Toxic metabolite burden and mitochondrial stress Positive Diagnostic

Elevated plasma glycine is a diagnostic biochemical readout of the classical PA metabolite profile, but available patient data do not support it as a neurodevelopmental-severity marker.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Clinical review evidence supports glycine as a positive diagnostic readout of PA metabolite burden.

Show evidence (2 references)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Supports elevated glycine as a diagnostic marker.

PMID:38200289 SUPPORT Human Clinical

"Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD."

Confirms glycine elevation but notes it does not predict neurodevelopmental severity.

3-Hydroxypropionate (INCREASED)

Context: Urinary 3-hydroxypropionate is an organic acid marker used in PA diagnosis.

Pathograph Readouts

Readout Of Toxic metabolite burden and mitochondrial stress Positive Diagnostic

Elevated 3-hydroxypropionate reports abnormal propionate-pathway metabolite accumulation in PA.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Clinical review evidence supports 3-hydroxypropionate as a positive diagnostic readout of PA metabolite burden.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Directly supports elevated 3-hydroxypropionate as a diagnostic marker.

Propionylglycine (INCREASED)

Context: Urinary propionylglycine is a conjugated metabolite elevated in PA.

Pathograph Readouts

Readout Of Toxic metabolite burden and mitochondrial stress Positive Diagnostic

Elevated propionylglycine reports glycine conjugation of accumulated propionyl-CoA-derived metabolites.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Clinical review evidence supports propionylglycine as a positive diagnostic readout of PA metabolite burden.

Show evidence (1 reference)

PMID:37689673 SUPPORT Human Clinical

"Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA."

Directly supports elevated propionylglycine as a diagnostic marker.

FGF21 and GDF15 (INCREASED)

Context: Mitochondrial biomarkers FGF21 and GDF15 are elevated in PA and associated with more severe intellectual disability profile, suggesting their potential as surrogate endpoints.

Pathograph Readouts

Readout Of Toxic metabolite burden and mitochondrial stress Positive Monitoring

Increased plasma FGF21 and GDF15 report mitochondrial stress downstream of PA metabolic dysregulation.

Show evidence (1 reference)

PMID:38200289 SUPPORT Human Clinical

Patient biomarker-behavioral data support FGF21 and GDF15 as positive monitoring readouts of mitochondrial stress in PA.

Correlates With Intellectual disability Positive Prognostic

Higher plasma FGF21 and GDF15 are associated with a more severe intellectual-disability profile in PA.

Show evidence (1 reference)

PMID:38200289 SUPPORT Human Clinical

Patient biomarker-behavioral data support FGF21 and GDF15 as positive correlates of ID severity.

Show evidence (1 reference)

PMID:38200289 SUPPORT Human Clinical

Demonstrates FGF21 and GDF15 elevation and association with ID severity.

{ }

Source YAML

click to show

name: Propionic Acidemia
category: Mendelian
creation_date: '2026-02-23T00:00:00Z'
updated_date: '2026-05-19T19:38:40Z'
synonyms:
- Propionic aciduria
- PA
- Propionyl-CoA carboxylase deficiency
- Ketotic hyperglycinemia
description: 'Propionic acidemia is an autosomal recessive organic acidemia caused by deficiency of propionyl-CoA carboxylase (PCC), usually due to biallelic PCCA or PCCB pathogenic variants. Defective propionate metabolism leads to toxic organic acid accumulation, metabolic acidosis, hyperammonemia, and recurrent episodes of life-threatening metabolic decompensation. Long-term complications include cardiomyopathy, prolonged QTc, intellectual disability, basal ganglia necrosis, pancreatitis, chronic kidney disease, and optic atrophy.

  '
disease_term:
  preferred_term: propionic acidemia
  term:
    id: MONDO:0011628
    label: propionic acidemia
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
parents:
- Organic Acidemia
- Inborn Error of Metabolism
prevalence:
- population: Global live births
  percentage: 1 in 100,000-150,000
  notes: >-
    Standard clinical guidance places propionic acidemia among the very rare
    organic acidemias, with incidence varying by ascertainment intensity and
    founder effects.
  evidence:
  - reference: PMID:25205257
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100'000 -150,000."
    explanation: Consensus clinical guidelines provide a standard incidence estimate for propionic acidemia.
  - reference: PMID:37689673
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Propionic acidemia (PA) is a rare autosomal recessive congenital disease caused by mutations in the PCCA or PCCB genes."
    explanation: This review confirms the disease's rarity while focusing on regional epidemiology in China.
pathophysiology:
- name: Propionyl-CoA carboxylase molecular function deficiency
  description: 'Biallelic pathogenic variants in PCCA or PCCB reduce propionyl-CoA carboxylase catalytic activity in mitochondria.

    '
  genes:
  - preferred_term: PCCA
    term:
      id: hgnc:8653
      label: PCCA
  - preferred_term: PCCB
    term:
      id: hgnc:8654
      label: PCCB
  biological_processes:
  - preferred_term: propionate catabolic process
    term:
      id: GO:0019543
      label: propionate catabolic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: propionyl-CoA carboxylase activity
    term:
      id: GO:0004658
      label: propionyl-CoA carboxylase activity
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:37482098
    reference_title: "Pathophysiological mechanisms of complications associated with propionic acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), which is responsible for converting propionyl-CoA to methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle.
    explanation: Directly supports deficient PCC function and blocked propionyl-CoA handling.
  downstream:
  - target: Toxic metabolite burden and mitochondrial stress
    description: Impaired propionyl-CoA carboxylation causes accumulation of propionyl-CoA-derived toxic metabolites.
- name: Toxic metabolite burden and mitochondrial stress
  description: 'Accumulation of propionyl-CoA related metabolites contributes to metabolic acidosis, secondary hyperammonemia, and cellular energy stress in liver, brain, and myocardium.

    '
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
  chemical_entities:
  - preferred_term: propionyl-CoA
    term:
      id: CHEBI:15539
      label: propionyl-CoA
    modifier: INCREASED
  - preferred_term: propionylcarnitine
    term:
      id: CHEBI:17387
      label: O-acylcarnitine
    modifier: INCREASED
  - preferred_term: 2-methylcitric acid
    term:
      id: CHEBI:30835
      label: 2-methylcitric acid
    modifier: INCREASED
  - preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
    modifier: INCREASED
  - preferred_term: 3-hydroxypropionate
    term:
      id: CHEBI:16510
      label: 3-hydroxypropionate
    modifier: INCREASED
  - preferred_term: propionylglycine
    term:
      id: CHEBI:89836
      label: propionylglycine
    modifier: INCREASED
  evidence:
  - reference: PMID:37482098
    reference_title: "Pathophysiological mechanisms of complications associated with propionic acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: When this process is disrupted, propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening cardiac diseases and other metabolic strokes.
    explanation: Supports toxic metabolite accumulation and multisystem downstream injury.
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
    explanation: Patient-diagnostic review evidence identifies the principal elevated PA metabolite markers.
  downstream:
  - target: Secondary NAG deficiency and hyperammonemia
    description: Accumulated metabolites deplete secondary NAG signaling and impair CPS1-mediated ureagenesis.
  - target: Cardiac oxidative stress via circulating propionate
    description: Systemic propionate excess increases cardiac propionyl-CoA load and oxidative injury.
  - target: Renal mitochondrial quality control impairment
    description: Metabolite stress perturbs renal mitochondrial homeostasis, including fission-mitophagy balance.
  - target: Metabolic acidosis
    description: Accumulated organic acids directly drive high-anion-gap metabolic acidosis during decompensation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.
      explanation: GeneReviews links PA decompensation to metabolic acidosis.
  - target: Vomiting
    description: Acute toxic metabolite accumulation and metabolic decompensation produce gastrointestinal symptoms including vomiting.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Metabolic decompensation
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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.
      explanation: GeneReviews supports vomiting as part of PA multiorgan disease.
  - target: Lethargy
    description: Systemic metabolic decompensation and energy stress reduce alertness during acute crises.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Metabolic decompensation
    - Progressive encephalopathy
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death.
      explanation: GeneReviews supports lethargy downstream of PA metabolic encephalopathy.
  - target: Failure to thrive
    description: Recurrent catabolic crises, restricted intake, and chronic metabolite stress impair growth.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Recurrent metabolic decompensation
    - Feeding intolerance
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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.
      explanation: GeneReviews supports failure to thrive as part of PA multiorgan disease.
  - target: Global developmental delay
    description: Brain energy stress and recurrent metabolic injury contribute to delayed neurodevelopment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Neurometabolic injury
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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.
      explanation: GeneReviews supports developmental delay or regression in PA.
  - target: Intellectual disability
    description: Metabolic and mitochondrial stress biomarkers track with more severe intellectual disability in PA.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Neurometabolic injury
    - Mitochondrial stress
    evidence:
    - reference: PMID:38200289
      reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile.
      explanation: Patient biomarker data link PA metabolic/mitochondrial stress markers with more severe intellectual disability.
  - target: Autism spectrum disorder
    description: PA is associated with autism spectrum disorder, but the causal intermediates remain incompletely resolved.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:38200289
      reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD.
      explanation: Patient biomarker data support an association between PA biochemical abnormalities and ASD.
  - target: Seizures
    description: Acute and chronic neurometabolic injury can lower seizure threshold in PA.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Neurometabolic injury
    - Progressive encephalopathy
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death.
      explanation: GeneReviews supports seizures downstream of PA metabolic encephalopathy.
  - target: Basal ganglia necrosis
    description: Metabolic stroke-like injury from toxic metabolite accumulation affects basal ganglia structures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Metabolic stroke
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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.
      explanation: GeneReviews supports basal ganglia lesions as a PA manifestation.
  - target: Pancreatitis
    description: Organic acidemia-related metabolic stress contributes to episodic pancreatic inflammation.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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.
      explanation: GeneReviews supports pancreatitis as a PA manifestation.
  - target: Optic atrophy
    description: Chronic mitochondrial and neurometabolic stress provides a mechanistic route to optic nerve degeneration.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Other rarely reported complications include optic atrophy, sensorineural hearing loss, and premature ovarian insufficiency.
      explanation: GeneReviews supports optic atrophy as a rare PA complication.
  - target: Hearing impairment
    description: Chronic metabolic disease burden is associated with late-onset hearing loss in PA.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Other rarely reported complications include optic atrophy, sensorineural hearing loss, and premature ovarian insufficiency.
      explanation: GeneReviews supports hearing loss as a rare PA complication.
  - target: Rhabdomyolysis
    description: Severe metabolic decompensation can injure skeletal muscle and produce rhabdomyolysis.
    causal_link_type: UNKNOWN
    intermediate_mechanisms:
    - Severe metabolic decompensation
    evidence:
    - reference: PMID:37689673
      reference_title: "Prevalence of propionic acidemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease
      explanation: A clinical review lists rhabdomyolysis among PA complications.
  - target: Propionylcarnitine (C3)
    description: Excess propionyl-CoA is conjugated with carnitine, producing elevated propionylcarnitine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Newborns with PA tested by expanded newborn screening (NBS) have elevated C3 (propionylcarnitine).
      explanation: GeneReviews supports elevated C3 as a direct PA biochemical marker.
  - target: 2-Methylcitric acid
    description: Propionyl-CoA excess is diverted into methylcitric acid formation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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.
      explanation: GeneReviews supports methylcitrate as a PA biochemical marker.
  - target: Glycine
    description: Disrupted propionate metabolism is reflected in the classical hyperglycinemia biochemical profile.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Secondary glycine metabolism disruption
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Testing of plasma amino acids generally reveals elevated glycine.
      explanation: GeneReviews supports elevated glycine as a PA biochemical marker.
  - target: 3-Hydroxypropionate
    description: Accumulated propionyl-CoA-derived metabolites include urinary 3-hydroxypropionate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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.
      explanation: GeneReviews supports elevated 3-hydroxypropionate as a PA biochemical marker.
  - target: Propionylglycine
    description: Propionyl-CoA excess is conjugated with glycine, producing elevated propionylglycine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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.
      explanation: GeneReviews supports propionylglycine as a PA biochemical marker.
  - target: FGF21 and GDF15
    description: Mitochondrial stress signaling in PA is reflected by increased FGF21 and GDF15.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mitochondrial stress response
    evidence:
    - reference: PMID:38200289
      reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile.
      explanation: Patient biomarker data support FGF21 and GDF15 as mitochondrial stress markers in PA.
- name: Secondary NAG deficiency and hyperammonemia
  description: 'Hyperammonemia in PA is related to secondary deficiency of N-acetylglutamate (NAG), the allosteric activator of carbamoyl phosphate synthetase 1 (CPS1), which is an irreversible rate-limiting enzyme in the urea cycle. CPS1 inhibition by accumulated propionyl-CoA metabolites impairs ureagenesis.

    '
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
  evidence:
  - reference: PMID:39695809
    reference_title: "Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hyperammonemia is related to a secondary deficiency of N-acetylglutamate (NAG), the activator of carbamoyl phosphate synthetase 1, which is an irreversible rate-limiting enzyme in the urea cycle.
    explanation: Directly explains the mechanism of secondary hyperammonemia in PA via NAG/CPS1 pathway.
  downstream:
  - target: Hyperammonemia
    description: Secondary NAG deficiency reduces CPS1 activation and impairs ureagenesis, causing hyperammonemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39695809
      reference_title: "Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Hyperammonemia is related to a secondary deficiency of N-acetylglutamate (NAG), the activator of carbamoyl phosphate synthetase 1, which is an irreversible rate-limiting enzyme in the urea cycle.
      explanation: Review evidence directly links secondary NAG deficiency to hyperammonemia in PA/MMA.
- name: Cardiac oxidative stress via circulating propionate
  description: 'In PA, accumulated propionyl-CoA and diminished hepatic propionate clearance lead to elevated circulating propionate. Gut microbiome-derived propionate is the primary cardiac propionyl-CoA source, and prolonged exposure induces significant oxidative stress in cardiomyocytes.

    '
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:38992300
    reference_title: "The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source
    explanation: Identifies gut-derived propionate as the primary cardiac propionyl-CoA source.
  - reference: PMID:38992300
    reference_title: "The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice.
    explanation: Demonstrates cardiac oxidative stress from propionate exposure in PA models.
  downstream:
  - target: Cardiac multi-mechanism pathogenesis
    description: Persistent oxidative injury amplifies broader cardiac mitochondrial and electrophysiologic dysfunction mechanisms.
- name: Renal mitochondrial quality control impairment
  description: 'In a PA mouse model, kidneys show altered mitochondrial ultrastructure, shifted mitochondrial networks towards fission, marked reduction of mitophagy, and steep reduction of PGC-1-alpha. These disturbances in mitochondrial homeostasis and quality control are involved in chronic kidney disease development.

    '
  biological_processes:
  - preferred_term: mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
  - preferred_term: mitophagy
    term:
      id: GO:0000422
      label: autophagy of mitochondrion
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:39681572
    reference_title: "Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: altered mitochondrial networks shifted towards fission and a marked reduction of mitophagy
    explanation: Demonstrates mitochondrial quality control impairment in PA kidneys.
  - reference: PMID:39681572
    reference_title: "Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We observed a steep reduction of PGC-1-α, the key mediator modulating mitochondrial functions and a counter actor of mitochondrial fission.
    explanation: PGC-1-alpha reduction links mitochondrial dysfunction to CKD pathogenesis.
  downstream:
  - target: Chronic kidney disease
    description: Impaired renal mitochondrial quality control drives progressive kidney dysfunction in PA.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered mitochondrial fission
    - Reduced mitophagy
    evidence:
    - reference: PMID:39681572
      reference_title: "Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Our results suggest that impairment of mitochondrial homeostasis and quality control are involved in CKD development in PA.
      explanation: Model-organism evidence directly links renal mitochondrial quality-control impairment to CKD development.
- name: Cardiac multi-mechanism pathogenesis
  description: 'Cardiac complications in PA involve multiple cellular pathways including impaired substrate delivery to TCA cycle, secondary mitochondrial electron transport chain dysfunction, oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, and carnitine deficiency.

    '
  biological_processes:
  - preferred_term: mitochondrial electron transport, NADH to ubiquinone
    term:
      id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:37110221
    reference_title: "Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration'
    explanation: Comprehensive review identifying multiple cardiac pathogenetic mechanisms in PA.
  downstream:
  - target: Dilated cardiomyopathy
    description: PA cardiac mitochondrial and metabolic pathway disruption culminates in dilated cardiomyopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mitochondrial electron transport chain dysfunction
    - Oxidative stress
    - Coenzyme Q10 deficiency
    evidence:
    - reference: PMID:37110221
      reference_title: "Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration'
      explanation: Review evidence supports multiple PA cardiac mechanisms that can contribute to cardiomyopathy.
  - target: Prolonged QT interval
    description: Cardiac metabolic and excitation-contraction abnormalities provide the mechanistic basis for QT prolongation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cardiac excitation-contraction coupling alteration
    evidence:
    - reference: PMID:37110221
      reference_title: "Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration'
      explanation: Review evidence supports excitation-contraction and metabolic cardiac mechanisms relevant to QT prolongation.
phenotypes:
- name: Metabolic acidosis
  frequency: VERY_FREQUENT
  description: High-anion-gap metabolic acidosis during decompensation episodes.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture
    explanation: Directly supports metabolic acidosis as a frequent presenting phenotype.
- name: Hyperammonemia
  frequency: FREQUENT
  description: Secondary hyperammonemia, especially in acute illness.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture
    explanation: Directly supports hyperammonemia during PA decompensation.
- name: Vomiting
  frequency: FREQUENT
  description: Recurrent vomiting with poor intake during metabolic instability.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture
    explanation: Acute deterioration in PA commonly includes gastrointestinal decompensation symptoms such as vomiting.
- name: Lethargy
  frequency: FREQUENT
  description: Decreased alertness during acute metabolic decompensation.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture
    explanation: The severe acute decompensation phenotype is consistent with lethargy and reduced responsiveness.
- name: Failure to thrive
  frequency: FREQUENT
  description: Poor growth due to recurrent catabolic crises and feeding difficulties.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: leading to early death or to severe neurological handicap in many survivors.
    explanation: Severe chronic disease burden supports frequent growth and developmental compromise.
- name: Global developmental delay
  frequency: OCCASIONAL
  description: Developmental delay risk in severe or recurrent disease.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: leading to early death or to severe neurological handicap in many survivors.
    explanation: Supports frequent long-term neurodevelopmental morbidity.
- name: Dilated cardiomyopathy
  frequency: FREQUENT
  description: 'Dilated cardiomyopathy is one of the most serious long-term complications of PA. In a cohort study, DCM was observed in 17 of 23 PA patients with cardiac involvement.

    '
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:38132258
    reference_title: "Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: DCM (17/23 patients)
    explanation: Quantifies dilated cardiomyopathy as frequent in PA patients with cardiac involvement.
  - reference: PMID:38132258
    reference_title: "Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA
    explanation: Supports high cardiac morbidity in PA.
- name: Prolonged QT interval
  frequency: FREQUENT
  description: 'QTc prolongation is a recognized arrhythmia risk in PA, associated with metabolic decompensation and chronic disease.

    '
  phenotype_term:
    preferred_term: Prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:37110221
    reference_title: "Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: '12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration'
    explanation: Provides mechanistic pathways compatible with QTc risk but does not directly quantify prolonged QT in patients.
- name: Intellectual disability
  frequency: FREQUENT
  description: 'Intellectual disability is common in PA. In a dedicated natural history study, 61% of participants received an ID diagnosis.

    '
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38200289
    reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Twenty (61%) participants received an ID diagnosis
    explanation: Quantifies intellectual disability prevalence in PA cohort.
  - reference: PMID:38200289
    reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile.
    explanation: Links metabolic/mitochondrial biomarkers to severity of intellectual disability.
- name: Autism spectrum disorder
  frequency: FREQUENT
  description: 'Autism spectrum disorder occurs in approximately 39% of PA patients. ASD was associated with increased serum erythropoietin and decreased plasma glutamine.

    '
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:38200289
    reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD
    explanation: Quantifies ASD prevalence at 39% in the PA cohort.
- name: Seizures
  frequency: OCCASIONAL
  description: 'Seizures may occur in PA, particularly in the context of metabolic decompensation and basal ganglia injury.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease
    explanation: Lists seizures among late-onset complications of PA.
- name: Basal ganglia necrosis
  frequency: OCCASIONAL
  description: 'Bilateral basal ganglia necrosis, particularly of the caudate and putamen, is a recognized neurological complication of PA during metabolic decompensation.

    '
  phenotype_term:
    preferred_term: Basal ganglia necrosis
    term:
      id: HP:0012128
      label: Basal ganglia necrosis
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease
    explanation: Lists basal ganglia lesions among late-onset complications.
- name: Pancreatitis
  frequency: OCCASIONAL
  description: 'Acute pancreatitis is a recognized complication of PA, occurring during or independent of metabolic decompensation episodes.

    '
  phenotype_term:
    preferred_term: Pancreatitis
    term:
      id: HP:0001733
      label: Pancreatitis
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease
    explanation: Lists pancreatitis among late-onset complications.
- name: Chronic kidney disease
  frequency: OCCASIONAL
  description: 'Progressive renal dysfunction is a long-term complication of PA. In mouse models, CKD involves mitochondrial quality control impairment with disturbances in fission/mitophagy balance.

    '
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:39681572
    reference_title: "Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD.
    explanation: Directly supports CKD as a recognized long-term complication of PA.
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease
    explanation: Lists CKD among human PA complications.
- name: Optic atrophy
  frequency: OCCASIONAL
  description: 'Optic atrophy has been reported as a long-term neurological complication of PA.

    '
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease
    explanation: Lists optic atrophy among late-onset complications.
- name: Hearing impairment
  frequency: OCCASIONAL
  description: 'Hearing loss is reported as a late-onset complication of PA.

    '
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease
    explanation: Lists hearing loss among late-onset complications.
- name: Rhabdomyolysis
  frequency: VERY_RARE
  description: 'Rhabdomyolysis can occur in PA, typically during severe metabolic decompensation.

    '
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease
    explanation: Lists rhabdomyolysis among late-onset complications.
biochemical:
- name: Propionylcarnitine (C3)
  presence: INCREASED
  context: 'Elevated C3-acylcarnitine is a hallmark diagnostic marker for PA, detectable on newborn screening and during metabolic decompensation.

    '
  biomarker_term:
    preferred_term: propionylcarnitine
    term:
      id: CHEBI:17387
      label: O-acylcarnitine
  readouts:
  - target: Toxic metabolite burden and mitochondrial stress
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated propionylcarnitine reports accumulation of propionyl-CoA-derived
      metabolites used for PA diagnosis.
    evidence:
    - reference: PMID:37689673
      reference_title: "Prevalence of propionic acidemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
      explanation: Clinical review evidence directly supports propionylcarnitine as a positive diagnostic readout of PA metabolite burden.
  - target: Intellectual disability
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Higher plasma propionylcarnitine is associated with a more severe
      intellectual-disability profile in PA.
    evidence:
    - reference: PMID:38200289
      reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile.
      explanation: Patient biomarker-behavioral data support propionylcarnitine as a positive correlate of ID severity.
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
    explanation: Directly supports elevated propionylcarnitine as a diagnostic marker.
- name: 2-Methylcitric acid
  presence: INCREASED
  context: '2-Methylcitrate is a characteristic metabolite of PA, reflecting propionyl-CoA entry into the TCA cycle via citrate synthase.

    '
  biomarker_term:
    preferred_term: 2-methylcitric acid
    term:
      id: CHEBI:30835
      label: 2-methylcitric acid
  readouts:
  - target: Toxic metabolite burden and mitochondrial stress
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated 2-methylcitric acid reports diversion of propionyl-CoA-derived
      carbon into abnormal organic-acid metabolites.
    evidence:
    - reference: PMID:37689673
      reference_title: "Prevalence of propionic acidemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
      explanation: Clinical review evidence supports 2-methylcitric acid as a positive diagnostic readout of PA metabolite burden.
  - target: Intellectual disability
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Higher plasma total 2-methylcitrate is associated with a more severe
      intellectual-disability profile in PA.
    evidence:
    - reference: PMID:38200289
      reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile.
      explanation: Patient biomarker-behavioral data support 2-methylcitrate as a positive correlate of ID severity.
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
    explanation: Directly supports elevated 2-methylcitric acid as a diagnostic marker.
- name: Glycine
  presence: INCREASED
  context: 'Elevated glycine is a classical feature of PA. Notably, plasma glycine was not meaningfully associated with intellectual disability or ASD severity.

    '
  biomarker_term:
    preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
  readouts:
  - target: Toxic metabolite burden and mitochondrial stress
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated plasma glycine is a diagnostic biochemical readout of the
      classical PA metabolite profile, but available patient data do not support
      it as a neurodevelopmental-severity marker.
    evidence:
    - reference: PMID:37689673
      reference_title: "Prevalence of propionic acidemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
      explanation: Clinical review evidence supports glycine as a positive diagnostic readout of PA metabolite burden.
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
    explanation: Supports elevated glycine as a diagnostic marker.
  - reference: PMID:38200289
    reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD.
    explanation: Confirms glycine elevation but notes it does not predict neurodevelopmental severity.
- name: 3-Hydroxypropionate
  presence: INCREASED
  context: 'Urinary 3-hydroxypropionate is an organic acid marker used in PA diagnosis.

    '
  biomarker_term:
    preferred_term: 3-hydroxypropionate
    term:
      id: CHEBI:16510
      label: 3-hydroxypropionate
  readouts:
  - target: Toxic metabolite burden and mitochondrial stress
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated 3-hydroxypropionate reports abnormal propionate-pathway
      metabolite accumulation in PA.
    evidence:
    - reference: PMID:37689673
      reference_title: "Prevalence of propionic acidemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
      explanation: Clinical review evidence supports 3-hydroxypropionate as a positive diagnostic readout of PA metabolite burden.
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
    explanation: Directly supports elevated 3-hydroxypropionate as a diagnostic marker.
- name: Propionylglycine
  presence: INCREASED
  context: 'Urinary propionylglycine is a conjugated metabolite elevated in PA.

    '
  biomarker_term:
    preferred_term: propionylglycine
    term:
      id: CHEBI:89836
      label: propionylglycine
  readouts:
  - target: Toxic metabolite burden and mitochondrial stress
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated propionylglycine reports glycine conjugation of accumulated
      propionyl-CoA-derived metabolites.
    evidence:
    - reference: PMID:37689673
      reference_title: "Prevalence of propionic acidemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
      explanation: Clinical review evidence supports propionylglycine as a positive diagnostic readout of PA metabolite burden.
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
    explanation: Directly supports elevated propionylglycine as a diagnostic marker.
- name: FGF21 and GDF15
  presence: INCREASED
  context: 'Mitochondrial biomarkers FGF21 and GDF15 are elevated in PA and associated with more severe intellectual disability profile, suggesting their potential as surrogate endpoints.

    '
  notes: 'These are emerging mitochondrial stress biomarkers, not standard diagnostic markers for PA.

    '
  readouts:
  - target: Toxic metabolite burden and mitochondrial stress
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Increased plasma FGF21 and GDF15 report mitochondrial stress downstream
      of PA metabolic dysregulation.
    evidence:
    - reference: PMID:38200289
      reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile.
      explanation: Patient biomarker-behavioral data support FGF21 and GDF15 as positive monitoring readouts of mitochondrial stress in PA.
  - target: Intellectual disability
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Higher plasma FGF21 and GDF15 are associated with a more severe
      intellectual-disability profile in PA.
    evidence:
    - reference: PMID:38200289
      reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile.
      explanation: Patient biomarker-behavioral data support FGF21 and GDF15 as positive correlates of ID severity.
  evidence:
  - reference: PMID:38200289
    reference_title: "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile.
    explanation: Demonstrates FGF21 and GDF15 elevation and association with ID severity.
genetic:
- name: PCCA pathogenic variants
  gene_term:
    preferred_term: PCCA
    term:
      id: hgnc:8653
      label: PCCA
  association: Pathogenic Variants
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: PA is inherited in an autosomal recessive manner.
      explanation: GeneReviews directly states autosomal recessive inheritance for propionic acidemia.
  variants:
  - name: Various PCCA pathogenic variants
    description: 'PA can result from biallelic pathogenic variants in PCCA, encoding the alpha subunit of propionyl-CoA carboxylase. PCCA variants reduce PCC holoenzyme function and cause the PCCA complementation form of propionic acidemia.

      '
  features: 'Biallelic pathogenic variants in PCCA reduce propionyl-CoA carboxylase activity and define one major genetic form of propionic acidemia.

    '
  evidence:
  - reference: PMID:22593918
    reference_title: "Propionic Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 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.
    explanation: GeneReviews supports biallelic PCCA pathogenic variants as one molecular genetic basis of propionic acidemia.
  - reference: CGGV:assertion_32a55e25-8632-4f31-84af-3eaf8098ca18-2018-12-13T170000.000Z
    reference_title: "PCCA / propionic acidemia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PCCA | HGNC:8653 | propionic acidemia | MONDO:0011628 | AR | Definitive"
    explanation: ClinGen classifies the PCCA-propionic acidemia gene-disease relationship as definitive with autosomal recessive inheritance.
- name: PCCB pathogenic variants
  gene_term:
    preferred_term: PCCB
    term:
      id: hgnc:8654
      label: PCCB
  association: Pathogenic Variants
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: PA is inherited in an autosomal recessive manner.
      explanation: GeneReviews directly states autosomal recessive inheritance for propionic acidemia.
  variants:
  - name: Various PCCB pathogenic variants
    description: 'PA can result from biallelic pathogenic variants in PCCB, encoding the beta subunit of propionyl-CoA carboxylase. PCCB variants reduce PCC holoenzyme function and cause the PCCB complementation form of propionic acidemia.

      '
  features: 'Biallelic pathogenic variants in PCCB reduce propionyl-CoA carboxylase activity and define one major genetic form of propionic acidemia.

    '
  evidence:
  - reference: PMID:22593918
    reference_title: "Propionic Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 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.
    explanation: GeneReviews supports biallelic PCCB pathogenic variants as one molecular genetic basis of propionic acidemia.
  - reference: CGGV:assertion_1cd49a9b-08c2-49db-8e97-e334f171e34d-2018-12-13T170000.000Z
    reference_title: "PCCB / propionic acidemia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PCCB | HGNC:8654 | propionic acidemia | MONDO:0011628 | AR | Definitive"
    explanation: ClinGen classifies the PCCB-propionic acidemia gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Protein-restricted diet
  description: 'Restriction of propiogenic amino acids (valine, isoleucine, threonine, methionine) with specialized formula support is the cornerstone of PA management.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Toxic metabolite burden and mitochondrial stress
    treatment_effect: MODULATES
    description: Restricting propiogenic amino acid intake lowers substrate flux into the blocked PCC pathway and limits toxic metabolite production.
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 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
      explanation: GeneReviews directly supports dietary management as substrate-control therapy in PA.
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: despite the existence of apparently effective therapy with a low protein diet and carnitine.
    explanation: Directly supports low-protein dietary treatment in PA.
- name: Carnitine supplementation
  description: 'Adjunctive therapy to support organic acid detoxification and excretion via formation of propionylcarnitine.

    '
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: MAXO:0010006
      label: carnitine supplementation
  target_mechanisms:
  - target: Toxic metabolite burden and mitochondrial stress
    treatment_effect: MODULATES
    description: Carnitine supports detoxification of propionyl groups through propionylcarnitine formation and excretion.
    evidence:
    - reference: PMID:6725560
      reference_title: "L-carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Treatment with L-carnitine greatly enhanced the formation and excretion of short-chain acylcarnitines in three patients with propionic acidemia and in three normal controls.
      explanation: Patient evidence supports carnitine-mediated acylcarnitine excretion in PA.
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: despite the existence of apparently effective therapy with a low protein diet and carnitine.
    explanation: Directly supports carnitine supplementation in management of PA.
- name: Carglumic acid (CGA)
  description: 'Carglumic acid is a synthetic structural analog of N-acetylglutamate (NAG) approved for treatment of hyperammonemia in PA. Chronic CGA use is associated with reduction in hyperammonemic decompensation episodes and hospital admissions.

    '
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  target_mechanisms:
  - target: Secondary NAG deficiency and hyperammonemia
    treatment_effect: BYPASSES
    description: Carglumic acid bypasses secondary NAG deficiency by stimulating the first step of the urea cycle and reducing hyperammonemia.
    evidence:
    - reference: PMID:30522498
      reference_title: "Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Treatment with N-carbamyl-L-glutamate can rapidly normalise ammonia levels by stimulating the first step of the urea cycle.
      explanation: The review describes the urea-cycle stimulation mechanism of carglumic acid/N-carbamyl-L-glutamate.
  evidence:
  - reference: PMID:39695809
    reference_title: "Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Carglumic acid (CGA) is a synthetic structural analog of human NAG and is approved for the treatment of patients with hyperammonemia due to PA or MMA.
    explanation: Directly supports CGA as an approved treatment for hyperammonemia in PA.
  - reference: PMID:39695809
    reference_title: "Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the addition of CGA is associated with a reduction in hyperammonemic decompensation episodes and admission to hospital, compared with conventional dietary treatment alone.
    explanation: Supports long-term benefit of CGA in reducing decompensation episodes.
- name: Ammonia-lowering therapy
  description: 'Sodium benzoate or sodium phenylbutyrate for pharmacologic ammonia reduction during hyperammonemic episodes.

    '
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  target_mechanisms:
  - target: Secondary NAG deficiency and hyperammonemia
    treatment_effect: MODULATES
    description: Nitrogen-scavenger pharmacotherapy lowers ammonia burden downstream of impaired ureagenesis.
    evidence:
    - reference: PMID:30522498
      reference_title: "Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: It may also include the administration of ammonia scavengers such as sodium benzoate or sodium phenylbutyrate.
      explanation: The organic-acidemia hyperammonemia review directly supports ammonia scavengers as therapy for this branch.
  evidence:
  - reference: PMID:30522498
    reference_title: "Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: It may also include the administration of ammonia scavengers such as sodium benzoate or sodium phenylbutyrate.
    explanation: Directly supports ammonia scavengers as ammonia-lowering pharmacotherapy in organic acidemia hyperammonemia.
- name: Acute decompensation management
  description: 'Emergency supportive care with reversal of catabolism via high glucose infusion, cessation of protein intake, and correction of metabolic acidosis.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Toxic metabolite burden and mitochondrial stress
    treatment_effect: MODULATES
    description: Emergency reversal of catabolism and temporary protein cessation reduce acute substrate-driven toxic metabolite production.
    evidence:
    - reference: PMID:22593918
      reference_title: "Propionic Acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: reverse catabolism by providing intravenous glucose and lipids; manage protein intake to reduce propiogenic precursors; remove toxic compounds using intravenous carnitine
      explanation: GeneReviews directly supports reversal of catabolism, precursor reduction, and toxic-compound removal during acute PA management.
  - target: Secondary NAG deficiency and hyperammonemia
    treatment_effect: MODULATES
    description: Acute decompensation protocols include correction of hyperammonemia during crises.
    evidence:
    - reference: PMID:30522498
      reference_title: "Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Correcting metabolic imbalance and hyperammonaemia are critical to prevent brain damage in affected patients.
      explanation: The review supports hyperammonemia correction as an acute management target in organic acidemias.
  evidence:
  - reference: PMID:22593918
    reference_title: "Propionic Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The treatment of individuals with acutely decompensated PA is a medical emergency
    explanation: GeneReviews supports emergency management for acute PA decompensation.
- name: Liver transplantation
  description: 'Considered for severe recurrent decompensation and poor metabolic control. LT improves metabolic stability but does not fully correct the biochemical defect since PCC is expressed in extrahepatic tissues.

    '
  treatment_term:
    preferred_term: liver transplantation
    term:
      id: MAXO:0001175
      label: liver transplantation
  target_mechanisms:
  - target: Toxic metabolite burden and mitochondrial stress
    treatment_effect: MODULATES
    description: Liver transplantation improves hepatic propionate handling and metabolic stability, while extrahepatic PCC deficiency remains.
    evidence:
    - reference: PMID:33093405
      reference_title: "Liver Transplantation for Propionic Acidemia: Evidence From a Systematic Review and Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The pooled estimate rates were 0.98 (95% CI, 0.88-1.00) for metabolic stability
      explanation: Systematic-review evidence directly supports improved metabolic stability after liver transplantation.
  evidence:
  - reference: PMID:33093405
    reference_title: "Liver Transplantation for Propionic Acidemia: Evidence From a Systematic Review and Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite the risk of transplant-related complications, LT is a viable therapeutic option in PA patients with satisfactory survival rates and clinical outcomes.
    explanation: Directly supports liver transplantation as a viable option for selected PA patients.
- name: Cardiac pharmacotherapy
  description: 'Standard cardiac therapies including ACE inhibitors, beta-blockers, and coenzyme Q10 supplementation for management of cardiomyopathy and QTc prolongation. Multicenter approaches are needed to strengthen efficacy data.

    '
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  target_mechanisms:
  - target: Cardiac multi-mechanism pathogenesis
    treatment_effect: MODULATES
    description: Standard cardiac medications and coenzyme Q10 target the downstream cardiomyopathy and electrophysiology branch rather than the upstream PCC defect.
    evidence:
    - reference: PMID:37110221
      reference_title: "Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications.
      explanation: The cardiac-complication guideline recommendation supports targeting the cardiac pathogenesis branch.
  evidence:
  - reference: PMID:37110221
    reference_title: "Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications.
    explanation: Supports standard cardiac pharmacotherapy for PA cardiac complications.
- name: Genetic counseling
  description: 'Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk, and prenatal testing options.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism
    explanation: Genetic etiology of PA supports the role of genetic counseling for affected families.
- name: Newborn screening
  description: 'PA is detectable by newborn screening via tandem mass spectrometry using elevated C3-acylcarnitine as the primary marker. Early detection allows initiation of treatment before clinical decompensation.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
  evidence:
  - reference: PMID:37689673
    reference_title: "Prevalence of propionic acidemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA.
    explanation: Supports use of propionylcarnitine as newborn screening biomarker.
references:
- reference: PMID:22593918
  title: "Propionic Acidemia."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

PMID:22593918

Propionic Acidemia.

No top-level findings curated for this source.

Deep Research

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 43 citations 2026-02-23T23:20:24.173667

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Propionic Acidemia
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Propionic Acidemia. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Propionic Acidemia (PA): Molecular and Cellular Mechanisms, Disease Progression, and Translational Landscape (focus 2023–2024)

Disease overview and key definitions

Propionic acidemia (PA; also called propionic aciduria) is an autosomal recessive “intoxication-type” organic acidemia caused by deficiency of the mitochondrial, biotin-dependent enzyme propionyl‑CoA carboxylase (PCC), which normally converts propionyl‑CoA to methylmalonyl‑CoA. Pathogenic variants in PCCA (PCC alpha subunit) or PCCB (PCC beta subunit) reduce PCC activity and lead to accumulation of propionyl‑CoA/propionate and related metabolites. (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2)

A core contemporary view is that PA pathophysiology reflects (i) direct or indirect toxicity of accumulating metabolites (propionyl‑CoA and derived organic acids), plus (ii) secondary mitochondrial dysfunction with impaired energy metabolism, redox imbalance, and downstream organ vulnerability (brain, heart, kidney), even under standard-of-care metabolic control. (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2, wang2024theattenuatedhepatic pages 19-21, schumann2024renalphenotypingin pages 1-2)

MONDO ID: Not available from the retrieved evidence in this run (no source text provided a MONDO identifier for PA).

Core pathophysiology (molecular/cellular mechanisms)

2.1 Primary metabolic block and toxic metabolite accumulation PCC deficiency leads to accumulation of propionyl‑CoA and downstream/alternative metabolites used clinically as biochemical markers, including propionylcarnitine (C3), 2‑methylcitric acid (2‑methylcitrate; 2MCA), propionylglycine, 3‑hydroxypropionate, and glycine. (zhang2023prevalenceofpropionic pages 1-2)

Mechanistic links between these metabolites and disease include diversion of key TCA-cycle intermediates and inhibition of mitochondrial enzymes. In particular, elevated propionyl‑CoA can compete with acetyl‑CoA at citrate synthase, and propionyl‑CoA plus oxaloacetate yields 2‑methylcitrate, which inhibits multiple TCA enzymes (citrate synthase, aconitase, isocitrate dehydrogenase), creating an anaplerotic deficit and energy failure phenotype. (zhang2023prevalenceofpropionic pages 1-2)

2.2 Mitochondrial dysfunction, TCA-cycle disruption, and oxidative stress Multiple sources converge on secondary mitochondrial dysfunction as a central mediator of organ injury in PA, including inhibition of TCA/respiratory-chain function, oxidative stress, and energetic failure. The Atlas chapter describes that propionyl‑CoA “can inhibit the mitochondrial respiratory chain and tricarboxylic acid cycle and produce an energetic stroke,” consistent with acute neurologic decompensation and basal ganglia vulnerability. (nyhan2024propionicacidemia pages 2-4)

A key 2024 mechanistic development is an explicitly defined liver–heart axis for propionate: impaired hepatic first-pass clearance of microbiome-derived propionate increases circulating propionate, which becomes the dominant source of cardiac propionyl‑CoA load and promotes cardiac oxidative stress. In PA patients, plasma propionate was reported to vary widely (38–506 μM), supporting a plausible exposure–risk relationship for cardiac injury. (wang2024theattenuatedhepatic pages 14-15)

In the Pcca−/−(A138T) mouse model, oral propionate challenge raised plasma propionate to 132 ± 69.9 μM vs 12.1 ± 5.1 μM in wild-type, and was associated with oxidative stress readouts in heart (e.g., decreased GSH/GSSG ratio; increased methionine sulfoxide), and mild diastolic dysfunction signals. (wang2024theattenuatedhepatic pages 12-14)

2.3 Hyperammonemia mechanism (urea-cycle dysfunction via NAG/CPS1 axis) Hyperammonemia in PA is mechanistically linked to secondary deficiency of N‑acetylglutamate (NAG), the obligate allosteric activator of carbamoyl phosphate synthetase 1 (CPS1), the irreversible rate-limiting step of the urea cycle. The 2024 expert review states that cataplerosis/CoA depletion leads to low glutamate/glutamine that “inhibits synthesis of N‑acetylglutamate (NAG),” impairing CPS1 activation and ammonia disposal. (yap2024roleofcarglumic pages 1-2)

Carglumic acid (N‑carbamylglutamate) is a synthetic NAG analog that restores urea-cycle flux by directly activating CPS1; the review states: “CGA, which acts as NAG substitution therapy, ensures continued elimination of ammonia via the urea cycle by direct allosteric activation of CPS1.” (yap2024roleofcarglumic pages 2-5)

Key molecular players (knowledge-base oriented)

3.1 Genes / proteins (HGNC)

Causal genes - PCCA (HGNC: PCCA): encodes PCC alpha subunit; loss reduces PCC activity. (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2) - PCCB (HGNC: PCCB): encodes PCC beta subunit; loss reduces PCC activity. (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2)

Mechanistically implicated metabolic nodes (examples) - CPS1 (carbamoyl phosphate synthetase 1; urea cycle) as the NAG-activated, rate-limiting step affected in secondary hyperammonemia. (yap2024roleofcarglumic pages 1-2, yap2024roleofcarglumic pages 2-5) - NAGS (N‑acetylglutamate synthase) as the producer of NAG; NAG deficiency is central to hyperammonemia rationale. (yap2024roleofcarglumic pages 1-2, head2023newinsightsinto pages 12-13) - PGC‑1α (PPARGC1A; mitochondrial biogenesis regulator) markedly reduced in PA kidney model, linking mitochondrial quality control to CKD. (schumann2024renalphenotypingin pages 4-6) - DRP1 (DNM1L; fission mediator) elevated in PA kidney model, shifting mitochondrial dynamics toward fission. (schumann2024renalphenotypingin pages 4-6)

3.2 Chemical entities / metabolites (CHEBI labels) Representative relevant chemicals (CHEBI names; IDs not provided by retrieved sources) - Propionyl‑CoA (key trapped acyl‑CoA) (zhang2023prevalenceofpropionic pages 1-2, nyhan2024propionicacidemia pages 2-4) - Propionate / propionic acid (circulating substrate; microbiome-derived) (wang2024theattenuatedhepatic pages 14-15, wang2024theattenuatedhepatic pages 12-14) - 2‑methylcitrate / 2‑methylcitric acid (2MCA; toxic anaplerotic/TCA inhibitor) (zhang2023prevalenceofpropionic pages 1-2, shchelochkov2024intellectualdisabilityand pages 3-5) - Propionylcarnitine (C3; biomarker and metabolite sink) (shchelochkov2024intellectualdisabilityand pages 3-5, zhang2023prevalenceofpropionic pages 4-5) - 3‑hydroxypropionate (urinary organic acid marker) (nyhan2024propionicacidemia pages 2-4, wang2025sixchinesepatients pages 1-2) - Glutamine (cataplerosis marker; linked to outcomes) (shchelochkov2024intellectualdisabilityand pages 3-5, shchelochkov2024intellectualdisabilityand pages 1-2) - N‑acetylglutamate (NAG; CPS1 activator) and carglumic acid (NAG analog therapy) (yap2024roleofcarglumic pages 1-2, yap2024roleofcarglumic pages 2-5)

3.3 Cell types (CL term labels) - Hepatocyte (site of major propionate clearance; hepatic PCC deficiency drives systemic propionate) (wang2024theattenuatedhepatic pages 14-15, wang2024theattenuatedhepatic pages 12-14) - Cardiomyocyte (target of propionate-driven CoA trapping/oxidative stress; cardiomyopathy/arrhythmia substrate) (wang2024theattenuatedhepatic pages 19-21, wang2024theattenuatedhepatic pages 12-14) - Neuron and astrocyte (CNS excitotoxicity/energetic failure; basal ganglia vulnerability; astrocytic glutamine/glutamate axis in hyperammonemia) (nyhan2024propionicacidemia pages 1-2) - Renal tubular epithelial cell (proximal/distal tubule mitochondrial network disruption; CKD progression) (schumann2024renalphenotypingin pages 1-2, schumann2024renalphenotypingin pages 6-7)

3.4 Anatomical locations (UBERON term labels) - Liver (first-pass propionate metabolism; key modifier of systemic propionate burden) (wang2024theattenuatedhepatic pages 14-15, wang2024theattenuatedhepatic pages 12-14) - Heart (dilated cardiomyopathy, long-QT, arrhythmia) (maines2023understandingthepathogenesis pages 2-4, passantino2023cardiacinvolvementin pages 1-2) - Brain, especially basal ganglia/striatum (metabolic-stroke-like injury, movement disorders) (nyhan2024propionicacidemia pages 1-2, nyhan2024propionicacidemia pages 2-4) - Kidney (progressive CKD; tubular injury; mitochondrial quality control defects) (schumann2024renalphenotypingin pages 1-2, schumann2024renalphenotypingin pages 4-6)

Dysregulated pathways and biological processes (GO-oriented)

Representative disrupted processes (GO term labels) - Propionate metabolic process / propionyl‑CoA metabolic process (primary enzymatic block at PCC) (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2) - Tricarboxylic acid cycle (TCA cycle) and anaplerotic processes (oxaloacetate diversion to methylcitrate; reduced succinyl‑CoA replenishment) (zhang2023prevalenceofpropionic pages 1-2, maines2023understandingthepathogenesis pages 2-4) - Mitochondrial electron transport / oxidative phosphorylation (secondary OXPHOS dysfunction across organs; energetic deficiency) (nyhan2024propionicacidemia pages 2-4, maines2023understandingthepathogenesis pages 5-7) - Cellular response to oxidative stress / redox homeostasis (heart and kidney oxidative stress markers and antioxidant response) (wang2024theattenuatedhepatic pages 12-14, schumann2024renalphenotypingin pages 1-2) - Mitochondrial fission / fusion and mitophagy (kidney model: fission up, fusion/mitophagy down) (schumann2024renalphenotypingin pages 4-6) - Urea cycle / ammonia detoxification (secondary NAG deficiency and CPS1 activation failure) (yap2024roleofcarglumic pages 1-2, yap2024roleofcarglumic pages 2-5)

Cellular components (where processes occur)

Core subcellular localization - Mitochondrial matrix (PCC and TCA cycle; propionyl‑CoA trapping; urea-cycle-related NAGS/CPS1 activation in liver mitochondria is implicated by mechanism) (nyhan2024propionicacidemia pages 1-2, head2023newinsightsinto pages 12-13) - Mitochondrial inner membrane / respiratory chain (OXPHOS inhibition and energetic failure) (nyhan2024propionicacidemia pages 2-4, maines2023understandingthepathogenesis pages 5-7)

Disease progression model (sequence from trigger to phenotype)

6.1 Initiation and acute decompensation Primary trigger: catabolic stress (infection/fasting) increases propiogenic substrate flux (branched-chain amino acids, odd-chain fatty acids, gut-derived propionate), overwhelming residual PCC capacity and increasing toxic metabolite load, causing metabolic acidosis and hyperammonemia. Clinically, PA presents in neonatal vs later-onset forms; early-onset cases can show rapid acute deterioration soon after birth. (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2)

Mechanistic cascade: metabolite accumulation → TCA/OXPHOS inhibition → ATP deficit and oxidative stress → organ dysfunction. Hyperammonemia contributes to neurotoxicity, with astrocytic glutamine/glutamate shifts contributing to excitotoxic injury. (nyhan2024propionicacidemia pages 1-2, nyhan2024propionicacidemia pages 2-4)

6.2 Chronic disease evolution Despite improved survival, long-term neurologic morbidity may persist; the Atlas chapter notes that early strategies improved survival “but has not modified neurodevelopment.” (nyhan2024propionicacidemia pages 2-4)

End-organ progression may be driven by sustained mitochondrial stress/quality-control failure. For example, in the kidney, a murine hypomorphic Pcca model shows progressive injury with mitochondrial network disorganization, increased fission, reduced mitophagy, and reduced PGC‑1α. (schumann2024renalphenotypingin pages 1-2, schumann2024renalphenotypingin pages 4-6)

Phenotypic manifestations and mechanism links (HP-oriented)

CNS - Intellectual disability and autism spectrum disorder: In an NIH cohort (n=33), 61% had intellectual disability and 39% had ASD. ID severity was associated with higher propionylcarnitine and total 2‑methylcitrate, elevated mitochondrial stress biomarkers FGF21 and GDF15, and reduced in vivo 1‑13C‑propionate oxidation; ASD associated mainly with erythropoietin and glutamine changes. These findings support a model where biochemical severity and mitochondrial dysfunction contribute to CNS outcomes. (shchelochkov2024intellectualdisabilityand pages 1-2, shchelochkov2024intellectualdisabilityand pages 3-5) - Basal ganglia lesions / movement disorders (“metabolic stroke”-like): basal ganglia are described as particularly vulnerable, with movement disorders linked to endothelial and neuronal toxicity. (nyhan2024propionicacidemia pages 1-2)

Heart - Cardiomyopathy and arrhythmia: PA is associated with DCM and acquired long-QT; a 2023 review summarizes DCM prevalence around ~23% in one cohort and cardiomyopathy prevalence 39% in another, with arrhythmia/aLQTS prevalence reported across series. (maines2023understandingthepathogenesis pages 2-4, maines2023understandingthepathogenesis pages 1-2) - Pediatric outcome data: In a pediatric organic aciduria cohort, 5-year major adverse cardiac event rate was 55% in PA patients with cardiomyopathy, and liver transplantation performed for worsening cardiac impairment stabilized metabolic status and cardiac function in transplanted patients. (passantino2023cardiacinvolvementin pages 1-2) - Mechanistic link: propionate-driven CoA trapping and impaired anaplerosis/TCA fuel delivery with oxidative stress/mitochondrial dysfunction. (maines2023understandingthepathogenesis pages 2-4, wang2024theattenuatedhepatic pages 12-14)

Kidney - CKD: PA is associated with chronic kidney disease; one 2024 murine phenotyping paper notes that CKD can begin in childhood and that ~50% of adults have GFR <60 mL/min, consistent with clinically significant progressive nephropathy. (schumann2024renalphenotypingin pages 1-2)

Recent developments and latest research (prioritizing 2023–2024)

8.1 2024: Liver–heart axis for circulating propionate and cardiac oxidative stress Wang et al. (Jul 2024) provide mechanistic evidence that gut microbiome-derived circulating propionate is the dominant source of cardiac propionyl‑CoA (~74% in their tracing context), and that attenuated hepatic clearance increases systemic propionate and cardiac oxidative stress. The work includes quantitative human plasma propionate ranges (38–506 μM) and mouse challenge data (132 ± 69.9 μM vs 12.1 ± 5.1 μM WT). (wang2024theattenuatedhepatic pages 14-15, wang2024theattenuatedhepatic pages 12-14)

8.2 2024: Biomarker–behavior links implicating mitochondrial dysfunction in CNS outcomes Shchelochkov et al. (Jan 2024) quantified neurodevelopmental burden and identified associations between ID and biochemical/mitochondrial biomarkers (propionylcarnitine, 2‑methylcitrate, FGF21, GDF15, erythropoietin, glutamine, 1‑13C‑propionate oxidation). This supports biomarker-driven stratification and reinforces mitochondrial biology as a mechanistic bridge from metabolic block to neurodevelopmental phenotype. (shchelochkov2024intellectualdisabilityand pages 1-2, shchelochkov2024intellectualdisabilityand pages 3-5, shchelochkov2024intellectualdisabilityand pages 5-6)

8.3 2024: Renal mitochondrial quality-control mechanisms as candidate drivers of CKD Schumann et al. (Dec 2024) demonstrate renal mitochondrial-network alterations, oxidative stress activation, TCA-cycle metabolic signatures, increased fission (Drp1 ~threefold), reduced fusion proteins (OPA1 ~0.4-fold; Mfn1/2 ~0.5-fold), reduced PINK1 (~0.3–0.5-fold), and reduced PGC‑1α (~0.7-fold) in a hypomorphic Pcca model, implicating mitochondrial dynamics and impaired mitophagy as actionable mechanistic nodes. (schumann2024renalphenotypingin pages 4-6)

Current applications and real-world implementations

9.1 Newborn screening (NBS) and diagnosis Primary NBS markers include elevated propionylcarnitine (C3) and increased C3/C2 ratio. A 2023 review reports typical screening reference ranges of C3 = 0.2–4.3 μmol/L and C3/C2 = 0.03–0.2, and notes confirmatory urine organic-acid markers (2‑methylcitrate, 3‑hydroxypropionate, propionylglycine). (zhang2023prevalenceofpropionic pages 2-4, wang2025sixchinesepatients pages 1-2)

Epidemiology: the 2023 China review reports wide global incidence ranges (e.g., US ~1/105,000–1/130,000) and variable incidences across regions and Chinese provinces, highlighting dependence on screening scope and population genetics. (zhang2023prevalenceofpropionic pages 4-5, zhang2023prevalenceofpropionic pages 5-7)

9.2 Nutritional and medical management Standard chronic management includes energy support and protein restriction by oral/enteral nutrition with individualized titration to maximize natural protein while maintaining metabolic stability. (yap2024roleofcarglumic pages 9-10, yap2024roleofcarglumic pages 2-5)

9.3 Hyperammonemia: carglumic acid (carglumic acid / N‑carbamylglutamate) Mechanism: Carglumic acid is a NAG analog that allosterically activates CPS1 to restore ureagenesis. (yap2024roleofcarglumic pages 1-2, yap2024roleofcarglumic pages 2-5)

Clinical effectiveness (long-term): the 2024 expert review summarizes evidence that adding carglumic acid to dietary management can reduce acute decompensations and hospital use; reported outcomes include a 51% reduction in emergency room admissions over 2 years and fewer inpatient days (32.8 vs 51.3). (yap2024roleofcarglumic pages 2-5)

Trial/real-world quantitative data include an open-label randomized study reporting reduced hospitalizations (1.2 vs 4.3; p=0.013) and lower plasma ammonia (means reported as 69.6 vs 55.3 μmol/L in evaluable patients) with long-term dosing, and Table 1 summarizes multiple long-term studies and NCT identifiers. (yap2024roleofcarglumic pages 5-6, yap2024roleofcarglumic media 5814ca18)

9.4 Liver transplantation Liver transplantation is used for selected severe phenotypes and can stabilize metabolic status and, in some cases, cardiac function; however it is not curative and does not eliminate all metabolite abnormalities or organ risks. (passantino2023cardiacinvolvementin pages 1-2, yap2024roleofcarglumic pages 10-12)

9.5 Emerging disease-modifying therapies mRNA therapy: The 2024 review reports an ongoing phase I/II trial of mRNA-3927 with 16 patients enrolled and interim data suggesting ~70% reduction in risk of metabolic decompensation events among eight patients with prior events. (yap2024roleofcarglumic pages 10-12, yap2024roleofcarglumic pages 9-10)

Expert interpretation and analysis (authoritative synthesis)

Cardiac disease in PA appears multifactorial, integrating impaired TCA substrate delivery/anaplerosis, CoA trapping, mitochondrial dysfunction, oxidative stress, and additional modifiers (e.g., CoQ10 status, neurohormonal activation). The 2023 cardiac-focused review emphasizes that “multiple cellular pathways” are involved and argues for therapies that target dysregulated mechanisms beyond merely correcting the enzymatic defect. (maines2023understandingthepathogenesis pages 2-4)

The 2024 liver–heart axis work reframes cardiac risk toward systemic propionate exposure (microbiome-derived plus impaired hepatic clearance), suggesting that interventions reducing circulating propionate and improving hepatic disposal could have direct cardioprotective effects. (wang2024theattenuatedhepatic pages 15-17, wang2024theattenuatedhepatic pages 12-14)

Evidence items (PMID-oriented)

PMIDs were not available in the tool-returned evidence snippets for the key 2023–2024 articles in this run. The report therefore cites each source using DOI URLs and PaperQA context IDs. (zhang2023prevalenceofpropionic pages 1-2, maines2023understandingthepathogenesis pages 2-4, wang2024theattenuatedhepatic pages 14-15, shchelochkov2024intellectualdisabilityand pages 3-5, schumann2024renalphenotypingin pages 4-6, yap2024roleofcarglumic pages 2-5)

Ontology-oriented annotation summary (for knowledge-base ingestion)

Disease entity - Propionic acidemia / propionic aciduria (genetic organic acidemia) (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2)

Causal genes (HGNC) - PCCA; PCCB (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2)

Representative disrupted GO biological processes (labels) - Propionyl-CoA metabolic process; propionate metabolic process (nyhan2024propionicacidemia pages 1-2, zhang2023prevalenceofpropionic pages 1-2) - Tricarboxylic acid cycle; anaplerotic processes (zhang2023prevalenceofpropionic pages 1-2, maines2023understandingthepathogenesis pages 2-4) - Oxidative phosphorylation; mitochondrial electron transport (nyhan2024propionicacidemia pages 2-4, maines2023understandingthepathogenesis pages 5-7) - Response to oxidative stress / redox homeostasis (wang2024theattenuatedhepatic pages 12-14, schumann2024renalphenotypingin pages 1-2) - Mitophagy; mitochondrial fission/fusion dynamics (schumann2024renalphenotypingin pages 4-6) - Urea cycle / ammonia detoxification (CPS1 activation via NAG) (yap2024roleofcarglumic pages 1-2, yap2024roleofcarglumic pages 2-5)

Representative cellular components (labels) - Mitochondrial matrix; mitochondrial inner membrane (nyhan2024propionicacidemia pages 1-2, nyhan2024propionicacidemia pages 2-4)

Representative phenotypes (HP term labels) - Metabolic acidosis; hyperammonemia; developmental delay/intellectual disability; autism spectrum disorder; cardiomyopathy; long QT/arrhythmia; basal ganglia lesions; chronic kidney disease. (nyhan2024propionicacidemia pages 1-2, shchelochkov2024intellectualdisabilityand pages 1-2, passantino2023cardiacinvolvementin pages 1-2, schumann2024renalphenotypingin pages 1-2)

Representative cell types (CL term labels) - Hepatocyte; cardiomyocyte; neuron; astrocyte; renal tubular epithelial cell. (nyhan2024propionicacidemia pages 1-2, wang2024theattenuatedhepatic pages 12-14, schumann2024renalphenotypingin pages 4-6)

Representative anatomical sites (UBERON term labels) - Liver; heart; basal ganglia/brain; kidney tubules. (nyhan2024propionicacidemia pages 1-2, wang2024theattenuatedhepatic pages 14-15, schumann2024renalphenotypingin pages 4-6)

Representative chemicals (CHEBI labels) - Propionyl‑CoA; propionate; 2‑methylcitrate; propionylcarnitine; 3‑hydroxypropionate; glutamine; N‑acetylglutamate; carglumic acid. (zhang2023prevalenceofpropionic pages 1-2, shchelochkov2024intellectualdisabilityand pages 3-5, yap2024roleofcarglumic pages 2-5)

Key URLs and publication dates (selected) - Zhang et al. “Prevalence of propionic acidemia in China.” Orphanet J Rare Dis. Sep 2023. https://doi.org/10.1186/s13023-023-02898-w (zhang2023prevalenceofpropionic pages 4-5) - Maines et al. “Understanding the Pathogenesis of Cardiac Complications in… Propionic Acidemia…” Metabolites. Apr 2023. https://doi.org/10.3390/metabo13040563 (maines2023understandingthepathogenesis pages 2-4) - Shchelochkov et al. “Intellectual disability and autism in propionic acidemia…” Molecular Psychiatry. Jan 2024. https://doi.org/10.1038/s41380-023-02385-5 (shchelochkov2024intellectualdisabilityand pages 1-2) - Wang et al. “The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.” Basic Res Cardiol. Jul 2024. https://doi.org/10.1007/s00395-024-01066-w (wang2024theattenuatedhepatic pages 12-14) - Schumann et al. “Renal phenotyping in a hypomorphic murine model of propionic aciduria…” Scientific Reports. Dec 2024. https://doi.org/10.1038/s41598-024-79572-z (schumann2024renalphenotypingin pages 1-2) - Yap et al. “Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias.” Orphanet J Rare Dis. Dec 2024. https://doi.org/10.1186/s13023-024-03468-4 (yap2024roleofcarglumic pages 2-5)

References

(nyhan2024propionicacidemia pages 1-2): W. Nyhan, G. Hoffmann, A. Al-aqeel, and B. Barshop. Propionic acidemia. Atlas of Inherited Metabolic Diseases, Feb 2024. URL: https://doi.org/10.1016/b978-0-12-374105-9.00373-7, doi:10.1016/b978-0-12-374105-9.00373-7. This article has 75 citations.
(zhang2023prevalenceofpropionic pages 1-2): Yixing Zhang, Chuwen Peng, Lifang Wang, Sitong Chen, Junwei Wang, Ziheng Tian, Chuangong Wang, Xiaoxin Chen, Suhong Zhu, Guo-Fang Zhang, and You Wang. Prevalence of propionic acidemia in china. Orphanet Journal of Rare Diseases, Sep 2023. URL: https://doi.org/10.1186/s13023-023-02898-w, doi:10.1186/s13023-023-02898-w. This article has 19 citations and is from a peer-reviewed journal.
(wang2024theattenuatedhepatic pages 19-21): You Wang, Suhong Zhu, Wentao He, Hannah Marchuk, Eva Richard, Lourdes R. Desviat, Sarah P. Young, Dwight Koeberl, Takhar Kasumov, Xiaoxin Chen, and Guo-Fang Zhang. The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia. Basic research in cardiology, 119:1045-1062, Jul 2024. URL: https://doi.org/10.1007/s00395-024-01066-w, doi:10.1007/s00395-024-01066-w. This article has 8 citations and is from a domain leading peer-reviewed journal.
(schumann2024renalphenotypingin pages 1-2): Anke Schumann, Ainhoa Martinez-Pizarro, Eva Richard, Christoph Schell, Anna Laura Kössinger, Karina A. Zeyer, Stefan Tholen, Oliver Schilling, Michael Barry, Björn Neubauer, Michael Köttgen, Luciana Hannibal, Lourdes R. Desviat, and Ute Spiekerkötter. Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias. Scientific Reports, Dec 2024. URL: https://doi.org/10.1038/s41598-024-79572-z, doi:10.1038/s41598-024-79572-z. This article has 0 citations and is from a peer-reviewed journal.
(nyhan2024propionicacidemia pages 2-4): W. Nyhan, G. Hoffmann, A. Al-aqeel, and B. Barshop. Propionic acidemia. Atlas of Inherited Metabolic Diseases, Feb 2024. URL: https://doi.org/10.1016/b978-0-12-374105-9.00373-7, doi:10.1016/b978-0-12-374105-9.00373-7. This article has 75 citations.
(wang2024theattenuatedhepatic pages 14-15): You Wang, Suhong Zhu, Wentao He, Hannah Marchuk, Eva Richard, Lourdes R. Desviat, Sarah P. Young, Dwight Koeberl, Takhar Kasumov, Xiaoxin Chen, and Guo-Fang Zhang. The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia. Basic research in cardiology, 119:1045-1062, Jul 2024. URL: https://doi.org/10.1007/s00395-024-01066-w, doi:10.1007/s00395-024-01066-w. This article has 8 citations and is from a domain leading peer-reviewed journal.
(wang2024theattenuatedhepatic pages 12-14): You Wang, Suhong Zhu, Wentao He, Hannah Marchuk, Eva Richard, Lourdes R. Desviat, Sarah P. Young, Dwight Koeberl, Takhar Kasumov, Xiaoxin Chen, and Guo-Fang Zhang. The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia. Basic research in cardiology, 119:1045-1062, Jul 2024. URL: https://doi.org/10.1007/s00395-024-01066-w, doi:10.1007/s00395-024-01066-w. This article has 8 citations and is from a domain leading peer-reviewed journal.
(yap2024roleofcarglumic pages 1-2): Sufin Yap, Serena Gasperini, Shirou Matsumoto, and François Feillet. Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03468-4, doi:10.1186/s13023-024-03468-4. This article has 5 citations and is from a peer-reviewed journal.
(yap2024roleofcarglumic pages 2-5): Sufin Yap, Serena Gasperini, Shirou Matsumoto, and François Feillet. Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03468-4, doi:10.1186/s13023-024-03468-4. This article has 5 citations and is from a peer-reviewed journal.
(head2023newinsightsinto pages 12-13): PamelaSara E. Head, Jordan L. Meier, and Charles P. Venditti. New insights into the pathophysiology of methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:436-449, May 2023. URL: https://doi.org/10.1002/jimd.12617, doi:10.1002/jimd.12617. This article has 38 citations and is from a peer-reviewed journal.
(schumann2024renalphenotypingin pages 4-6): Anke Schumann, Ainhoa Martinez-Pizarro, Eva Richard, Christoph Schell, Anna Laura Kössinger, Karina A. Zeyer, Stefan Tholen, Oliver Schilling, Michael Barry, Björn Neubauer, Michael Köttgen, Luciana Hannibal, Lourdes R. Desviat, and Ute Spiekerkötter. Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias. Scientific Reports, Dec 2024. URL: https://doi.org/10.1038/s41598-024-79572-z, doi:10.1038/s41598-024-79572-z. This article has 0 citations and is from a peer-reviewed journal.
(shchelochkov2024intellectualdisabilityand pages 3-5): Oleg A. Shchelochkov, Cristan A. Farmer, Colby Chlebowski, Dee Adedipe, Susan Ferry, Irini Manoli, Alexandra Pass, Samantha McCoy, Carol Van Ryzin, Jennifer Sloan, Audrey Thurm, and Charles P. Venditti. Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology. Molecular Psychiatry, 29:974-981, Jan 2024. URL: https://doi.org/10.1038/s41380-023-02385-5, doi:10.1038/s41380-023-02385-5. This article has 13 citations and is from a highest quality peer-reviewed journal.
(zhang2023prevalenceofpropionic pages 4-5): Yixing Zhang, Chuwen Peng, Lifang Wang, Sitong Chen, Junwei Wang, Ziheng Tian, Chuangong Wang, Xiaoxin Chen, Suhong Zhu, Guo-Fang Zhang, and You Wang. Prevalence of propionic acidemia in china. Orphanet Journal of Rare Diseases, Sep 2023. URL: https://doi.org/10.1186/s13023-023-02898-w, doi:10.1186/s13023-023-02898-w. This article has 19 citations and is from a peer-reviewed journal.
(wang2025sixchinesepatients pages 1-2): Shunan Wang, Lulu Li, Yulan Ma, Hai-he Yang, Yuting Sang, Yueling Tang, L. Gong, Jin-qi Zhao, Lijin Gu, Yuanyuan Kong, and Xinmei Mao. Six chinese patients with propionic acidemia: from asymptomatic to death in the neonatal period. Orphanet Journal of Rare Diseases, Mar 2025. URL: https://doi.org/10.1186/s13023-025-03622-6, doi:10.1186/s13023-025-03622-6. This article has 0 citations and is from a peer-reviewed journal.
(shchelochkov2024intellectualdisabilityand pages 1-2): Oleg A. Shchelochkov, Cristan A. Farmer, Colby Chlebowski, Dee Adedipe, Susan Ferry, Irini Manoli, Alexandra Pass, Samantha McCoy, Carol Van Ryzin, Jennifer Sloan, Audrey Thurm, and Charles P. Venditti. Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology. Molecular Psychiatry, 29:974-981, Jan 2024. URL: https://doi.org/10.1038/s41380-023-02385-5, doi:10.1038/s41380-023-02385-5. This article has 13 citations and is from a highest quality peer-reviewed journal.
(schumann2024renalphenotypingin pages 6-7): Anke Schumann, Ainhoa Martinez-Pizarro, Eva Richard, Christoph Schell, Anna Laura Kössinger, Karina A. Zeyer, Stefan Tholen, Oliver Schilling, Michael Barry, Björn Neubauer, Michael Köttgen, Luciana Hannibal, Lourdes R. Desviat, and Ute Spiekerkötter. Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias. Scientific Reports, Dec 2024. URL: https://doi.org/10.1038/s41598-024-79572-z, doi:10.1038/s41598-024-79572-z. This article has 0 citations and is from a peer-reviewed journal.
(maines2023understandingthepathogenesis pages 2-4): Evelina Maines, Michele Moretti, Nicola Vitturi, Giorgia Gugelmo, Ilaria Fasan, Livia Lenzini, Giovanni Piccoli, Vincenza Gragnaniello, Arianna Maiorana, Massimo Soffiati, Alberto Burlina, and Roberto Franceschi. Understanding the pathogenesis of cardiac complications in patients with propionic acidemia and exploring therapeutic alternatives for those who are not eligible or are waiting for liver transplantation. Metabolites, 13(4):563, Apr 2023. URL: https://doi.org/10.3390/metabo13040563, doi:10.3390/metabo13040563. This article has 5 citations.
(passantino2023cardiacinvolvementin pages 1-2): Silvia Passantino, Serena Chiellino, Francesca Girolami, Mattia Zampieri, Giovanni Calabri, Gaia Spaziani, Elena Bennati, Giulio Porcedda, Elena Procopio, Iacopo Olivotto, and Silvia Favilli. Cardiac involvement in classical organic acidurias: clinical profile and outcome in a pediatric cohort. Diagnostics, 13:3674, Dec 2023. URL: https://doi.org/10.3390/diagnostics13243674, doi:10.3390/diagnostics13243674. This article has 1 citations.
(maines2023understandingthepathogenesis pages 5-7): Evelina Maines, Michele Moretti, Nicola Vitturi, Giorgia Gugelmo, Ilaria Fasan, Livia Lenzini, Giovanni Piccoli, Vincenza Gragnaniello, Arianna Maiorana, Massimo Soffiati, Alberto Burlina, and Roberto Franceschi. Understanding the pathogenesis of cardiac complications in patients with propionic acidemia and exploring therapeutic alternatives for those who are not eligible or are waiting for liver transplantation. Metabolites, 13(4):563, Apr 2023. URL: https://doi.org/10.3390/metabo13040563, doi:10.3390/metabo13040563. This article has 5 citations.
(maines2023understandingthepathogenesis pages 1-2): Evelina Maines, Michele Moretti, Nicola Vitturi, Giorgia Gugelmo, Ilaria Fasan, Livia Lenzini, Giovanni Piccoli, Vincenza Gragnaniello, Arianna Maiorana, Massimo Soffiati, Alberto Burlina, and Roberto Franceschi. Understanding the pathogenesis of cardiac complications in patients with propionic acidemia and exploring therapeutic alternatives for those who are not eligible or are waiting for liver transplantation. Metabolites, 13(4):563, Apr 2023. URL: https://doi.org/10.3390/metabo13040563, doi:10.3390/metabo13040563. This article has 5 citations.
(shchelochkov2024intellectualdisabilityand pages 5-6): Oleg A. Shchelochkov, Cristan A. Farmer, Colby Chlebowski, Dee Adedipe, Susan Ferry, Irini Manoli, Alexandra Pass, Samantha McCoy, Carol Van Ryzin, Jennifer Sloan, Audrey Thurm, and Charles P. Venditti. Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology. Molecular Psychiatry, 29:974-981, Jan 2024. URL: https://doi.org/10.1038/s41380-023-02385-5, doi:10.1038/s41380-023-02385-5. This article has 13 citations and is from a highest quality peer-reviewed journal.
(zhang2023prevalenceofpropionic pages 2-4): Yixing Zhang, Chuwen Peng, Lifang Wang, Sitong Chen, Junwei Wang, Ziheng Tian, Chuangong Wang, Xiaoxin Chen, Suhong Zhu, Guo-Fang Zhang, and You Wang. Prevalence of propionic acidemia in china. Orphanet Journal of Rare Diseases, Sep 2023. URL: https://doi.org/10.1186/s13023-023-02898-w, doi:10.1186/s13023-023-02898-w. This article has 19 citations and is from a peer-reviewed journal.
(zhang2023prevalenceofpropionic pages 5-7): Yixing Zhang, Chuwen Peng, Lifang Wang, Sitong Chen, Junwei Wang, Ziheng Tian, Chuangong Wang, Xiaoxin Chen, Suhong Zhu, Guo-Fang Zhang, and You Wang. Prevalence of propionic acidemia in china. Orphanet Journal of Rare Diseases, Sep 2023. URL: https://doi.org/10.1186/s13023-023-02898-w, doi:10.1186/s13023-023-02898-w. This article has 19 citations and is from a peer-reviewed journal.
(yap2024roleofcarglumic pages 9-10): Sufin Yap, Serena Gasperini, Shirou Matsumoto, and François Feillet. Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03468-4, doi:10.1186/s13023-024-03468-4. This article has 5 citations and is from a peer-reviewed journal.
(yap2024roleofcarglumic pages 5-6): Sufin Yap, Serena Gasperini, Shirou Matsumoto, and François Feillet. Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03468-4, doi:10.1186/s13023-024-03468-4. This article has 5 citations and is from a peer-reviewed journal.
(yap2024roleofcarglumic media 5814ca18): Sufin Yap, Serena Gasperini, Shirou Matsumoto, and François Feillet. Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03468-4, doi:10.1186/s13023-024-03468-4. This article has 5 citations and is from a peer-reviewed journal.
(yap2024roleofcarglumic pages 10-12): Sufin Yap, Serena Gasperini, Shirou Matsumoto, and François Feillet. Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03468-4, doi:10.1186/s13023-024-03468-4. This article has 5 citations and is from a peer-reviewed journal.
(wang2024theattenuatedhepatic pages 15-17): You Wang, Suhong Zhu, Wentao He, Hannah Marchuk, Eva Richard, Lourdes R. Desviat, Sarah P. Young, Dwight Koeberl, Takhar Kasumov, Xiaoxin Chen, and Guo-Fang Zhang. The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia. Basic research in cardiology, 119:1045-1062, Jul 2024. URL: https://doi.org/10.1007/s00395-024-01066-w, doi:10.1007/s00395-024-01066-w. This article has 8 citations and is from a domain leading peer-reviewed journal.

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