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Classifications

Harrison's Chapter

⚙

Pathophysiology

7

IVD molecular function deficiency

Biallelic pathogenic variants in IVD reduce isovaleryl-CoA dehydrogenase catalytic activity in mitochondria.

hepatocyte link

IVD link

mitochondrion link

Downstream

Deficient leucine catabolic flux Reduced IVD activity blocks isovaleryl-CoA oxidation in leucine catabolism.

Show evidence (1 reference)

PMID:41133704 SUPPORT Other

"Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."

Supports IVD molecular dysfunction as the initiating defect.

Deficient leucine catabolic flux

IVD deficiency blocks leucine degradation at the mitochondrial isovaleryl-CoA to 3-methylcrotonyl-CoA step, causing upstream accumulation of isovaleryl-CoA, isovaleric acid, and characteristic secondary metabolites.

branched-chain amino acid catabolic process link leucine catabolic process link

Downstream

Toxic isovaleryl-CoA and organic acid accumulation Blocked IVD flux causes upstream isovaleryl-CoA and derivative organic acids to accumulate.

Show evidence (1 reference)

PMID:30740403 SUPPORT Other

"Organic acids (OAs) are intermediary products of several amino acid catabolism or degradation via multiple biochemical pathways for energy production."

Supports organic acid disorders as defects in amino acid catabolic pathways.

Toxic isovaleryl-CoA and organic acid accumulation

Blocked isovaleryl-CoA oxidation causes accumulation of isovaleryl-CoA, isovaleric acid, 3-hydroxyisovaleric acid, isovalerylcarnitine, and isovalerylglycine. This toxic organic acid burden drives the characteristic odor, secondary detoxification through carnitine and glycine conjugation, and downstream acute metabolic decompensation, hyperammonemia, mitochondrial stress, and direct neurotoxicity.

hepatocyte link

cellular response to toxic substance link leucine catabolic process link

mitochondrion link

Downstream

Isovaleric acid IVD deficiency causes free isovaleric acid accumulation.

3-Hydroxyisovaleric acid Alternative metabolism of accumulated isovaleryl-CoA produces elevated 3-hydroxyisovaleric acid.

Isovalerylcarnitine (C5) Carnitine conjugation of accumulated isovaleryl-CoA produces elevated C5 isovalerylcarnitine.

Isovalerylglycine Glycine conjugation of accumulated isovaleryl-CoA produces elevated urinary isovalerylglycine.

Free carnitine Formation and urinary excretion of isovalerylcarnitine depletes the free carnitine pool.

Catabolic acute metabolic decompensation Toxic metabolite load worsens during fasting, illness, and protein intake, producing acute crises.

Secondary urea cycle impairment and hyperammonemia Accumulated isovaleryl-CoA impairs N-acetylglutamate synthesis and urea-cycle activation.

Mitochondrial energy depletion and oxidative stress Accumulated organic acids decrease mitochondrial energy production and increase oxidative stress.

Neuronal membrane dysfunction via Na+,K+-ATPase inhibition Free isovaleric acid inhibits cerebral cortical Na+,K+-ATPase in model systems.

Characteristic sweaty feet odor Volatile isovaleric acid buildup produces the characteristic sweaty-feet odor.

Show evidence (2 references)

PMID:41133704 SUPPORT Other

"Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."

Review and expert consensus directly list the accumulated organic acids and conjugates in IVA.

PMID:30547004 SUPPORT Human Clinical

"Deficiency of this enzyme leads to accumulation of organic acids, such as isovalerylcarnitine and isovalerylglycine."

Human therapeutic follow-up paper supports toxic organic acid accumulation downstream of IVD deficiency.

Catabolic acute metabolic decompensation

Fasting, febrile illness, gastroenteritis, and increased protein intake increase leucine flux and toxic organic-acid burden, triggering acute metabolic decompensation with vomiting, encephalopathy, metabolic acidosis, ketosis, hyperammonemia, and neurologic deterioration.

hepatocyte link

response to starvation link cellular response to toxic substance link

liver link

Downstream

Metabolic acidosis Acute organic-acid accumulation produces metabolic acidosis during crises.

Hyperammonemia Acute decompensation in IVA commonly includes secondary hyperammonemia.

Vomiting Vomiting is a common acute decompensation symptom.

Feeding difficulties Poor feeding is a core manifestation of acute metabolic decompensation in classic IVA.

Encephalopathy Acute decompensation produces encephalopathy through hyperammonemia and organic-acid neurotoxicity.

Lethargy Acute crises commonly cause reduced alertness.

Hypotonia Hypotonia is listed among acute decompensation manifestations in classic IVA.

Hypoglycemia Hypoglycemia occurs in a subset of acute IVA presentations.

Seizures Acute metabolic decompensation can present with seizures.

Movement disorder Recurrent or severe IVA decompensation can contribute to movement disorders through metabolic brain injury and organic-acid neurotoxicity.

Pancytopenia Severe infection-triggered decompensation can present with pancytopenia.

Global developmental delay Recurrent or severe IVA decompensation contributes to developmental delay risk.

Failure to thrive Chronic intermittent IVA can present with failure to thrive.

Show evidence (2 references)

PMID:38484105 SUPPORT Other

"Classic IVA is characterized by acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet)."

GeneReviews summarizes the acute decompensation phenotype of classic IVA.

PMID:38484105 SUPPORT Other

"Acute metabolic decompensations are typically triggered by fasting, (febrile) illness (especially gastroenteritis), or increased protein intake."

GeneReviews directly supports catabolic and protein-load triggers for acute IVA crises.

Secondary urea cycle impairment and hyperammonemia

Isovaleryl-CoA inhibits N-acetylglutamate synthase (NAGS), reducing N-acetylglutamate availability and impairing activation of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting entry enzyme of the urea cycle. Combined with acetyl-CoA depletion, this produces secondary hyperammonemia that contributes to encephalopathy and neurological complications.

hepatocyte link

urea cycle link

liver link

Downstream

Ammonia Urea-cycle impairment increases circulating ammonia.

Hyperammonemia Impaired urea-cycle entry produces the hyperammonemia phenotype.

Encephalopathy Severe hyperammonemia during organic-acidemia crises contributes to life-threatening neurologic dysfunction.

Intellectual disability Repeated hyperammonemia and metabolic decompensation can lead to intellectual disability.

Failure to thrive Repeated hyperammonemia and metabolic decompensation can impair growth.

Show evidence (2 references)

PMID:30740403 SUPPORT Other

"High anion gap metabolic acidosis with hyperammonemia is a characteristic OA biochemical finding."

Supports hyperammonemia as characteristic of organic acid disorders.

PMID:41133704 SUPPORT Other

"The clinical presentation is highly variable, ranging from life-threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype."

Directly supports hyperammonemia as a key crisis feature of IVA.

Mitochondrial energy depletion and oxidative stress

Accumulated isovaleryl-CoA and isovaleric acid impair tricarboxylic acid cycle function, with evidence for inhibition of citrate synthase and reduced CO2 production from acetate in brain tissue. Chronic metabolite accumulation also increases oxidative stress, contributing to neurological morbidity. Oxidative stress from chronic persistent buildup of isovaleric acid may be more neurologically detrimental than acute buildup.

neuron link

tricarboxylic acid cycle link response to oxidative stress link

cerebral cortex link

Downstream

Encephalopathy Impaired cerebral energy metabolism contributes to the acute encephalopathy seen in IVA.

Lethargy Cerebral energy impairment can contribute to reduced alertness during acute crises.

Show evidence (2 references)

PMID:19210957 SUPPORT Model Organism

"IVA administration significantly inhibited (14)CO(2) production from acetate (22%) and citrate synthase activity (20%) in cerebral cortex homogenates prepared 24 h after injection."

Demonstrates TCA cycle impairment in cerebral cortex from isovaleric acid exposure in vivo.

PMID:36817957 SUPPORT Other

"The increase in these metabolites decreases mitochondrial energy production and increases oxidative stress."

Review component of this mechanistic paper supports mitochondrial energy impairment and oxidative stress from metabolite accumulation.

Neuronal membrane dysfunction via Na+,K+-ATPase inhibition

Isovaleric acid directly inhibits Na+,K+-ATPase activity in cerebral cortex, a crucial enzyme for maintaining membrane potential and normal neurotransmission. This inhibition is observed as early as 2 hours after exposure and persists at 24 hours, contributing to the acute encephalopathy seen during metabolic crises.

neuron link

sodium ion transport link

cerebral cortex link

Downstream

Encephalopathy Membrane-pump inhibition disrupts neurotransmission and contributes to acute encephalopathy.

Seizures Disrupted neuronal membrane potential can contribute to seizure susceptibility during crises.

Show evidence (1 reference)

PMID:19210957 SUPPORT Model Organism

"IVA injection significantly inhibited Na(+),K(+)-ATPase activity (25%) in cerebral cortex of rats 2 or 24 h after IVA administration, while pre-treatment of rats with creatine completely prevented the inhibitory effects of IVA on Na(+),K(+)-ATPase."

Demonstrates direct inhibition of Na+,K+-ATPase by isovaleric acid in cerebral cortex and prevention by creatine.

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Pathograph

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

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Phenotypes

15

Blood 1

Pancytopenia Pancytopenia (HP:0001876)

Show evidence (1 reference)

PMID:2124776 SUPPORT Human Clinical

"A case of isovaleric acidemia appearing as diabetic ketoacidosis with acute encephalopathy and pancytopenia was reported."

Case-report abstract directly names pancytopenia in a patient with IVA and acute encephalopathy.

Digestive 2

Vomiting FREQUENT Vomiting (HP:0002013)

Show evidence (1 reference)

PMID:38344522 SUPPORT Human Clinical

"Vomiting was the most prevalent symptom (57.1%), and encephalopathy occurred in 33.3%."

Directly quantifies vomiting as the most common symptom.

Feeding difficulties Feeding difficulties (HP:0011968)

Show evidence (1 reference)

PMID:38484105 SUPPORT Other

"Classic IVA is characterized by acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet)."

GeneReviews directly lists poor feeding among acute decompensation manifestations of classic IVA.

Metabolism 3

Metabolic acidosis VERY_FREQUENT Metabolic acidosis (HP:0001942)

Show evidence (2 references)

PMID:38344522 SUPPORT Human Clinical

"Laboratory results showed acidosis (81%), hyperammonemia (71.4%), and hypoglycemia (14.3%)."

Directly quantifies acidosis at 81% in an IVA cohort.

PMID:41133704 SUPPORT Other

"The clinical presentation is highly variable, ranging from life-threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype."

Supports metabolic acidosis as a key crisis phenotype.

Hyperammonemia VERY_FREQUENT Hyperammonemia (HP:0001987)

Show evidence (2 references)

PMID:38344522 SUPPORT Human Clinical

"Laboratory results showed acidosis (81%), hyperammonemia (71.4%), and hypoglycemia (14.3%)."

Directly quantifies hyperammonemia at 71.4% in an IVA cohort.

PMID:30522498 SUPPORT Other

"Repeated and frequent episodes of hyperammonaemia (alongside metabolic decompensations) can result in impaired growth and intellectual disability, the severity of which increase with longer duration of hyperammonaemia."

Supports hyperammonemia as contributing to neurological sequelae.

Hypoglycemia OCCASIONAL Hypoglycemia (HP:0001943)

Show evidence (1 reference)

PMID:38344522 SUPPORT Human Clinical

"Laboratory results showed acidosis (81%), hyperammonemia (71.4%), and hypoglycemia (14.3%)."

Directly quantifies hypoglycemia at 14.3% in an IVA cohort.

Musculoskeletal 1

Hypotonia Hypotonia (HP:0001252)

Show evidence (1 reference)

PMID:38484105 SUPPORT Other

"Classic IVA is characterized by acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet)."

GeneReviews directly lists hypotonia among acute decompensation manifestations of classic IVA.

Nervous System 6

Encephalopathy FREQUENT Acute encephalopathy (HP:0006846)

Show evidence (2 references)

PMID:38344522 SUPPORT Human Clinical

"Vomiting was the most prevalent symptom (57.1%), and encephalopathy occurred in 33.3%."

Directly quantifies encephalopathy at 33.3% in an IVA cohort.

PMID:19210957 SUPPORT Model Organism

"Patients affected by IVAcidemia suffer from acute episodes of encephalopathy, whose underlying mechanisms are poorly known."

Confirms encephalopathy as a recognized acute manifestation of IVA.

Lethargy Lethargy (HP:0001254)

Show evidence (1 reference)

PMID:24637313 SUPPORT Human Clinical

"Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a 'sweaty feet' odor."

Case-report abstract directly lists lethargy among characteristic IVA acute manifestations.

Seizures Seizure (HP:0001250)

Show evidence (1 reference)

PMID:38484105 SUPPORT Other

"Classic IVA is characterized by acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet)."

GeneReviews directly lists seizures as an acute decompensation manifestation of classic IVA.

Global developmental delay Global developmental delay (HP:0001263)

Show evidence (1 reference)

PMID:38484105 SUPPORT Other

"Additional manifestations of classic IVA include developmental delay, intellectual disability and/or impaired cognition, epilepsy, and movement disorder (tremor, dysmetria, extrapyramidal movements)."

GeneReviews directly lists developmental delay among additional manifestations of classic IVA.

Intellectual disability Intellectual disability (HP:0001249)

Show evidence (2 references)

PMID:38484105 SUPPORT Other

"Additional manifestations of classic IVA include developmental delay, intellectual disability and/or impaired cognition, epilepsy, and movement disorder (tremor, dysmetria, extrapyramidal movements)."

GeneReviews directly lists intellectual disability or impaired cognition among additional manifestations of classic IVA.

PMID:30522498 SUPPORT Other

"Repeated and frequent episodes of hyperammonaemia (alongside metabolic decompensations) can result in impaired growth and intellectual disability, the severity of which increase with longer duration of hyperammonaemia."

Review evidence supports intellectual disability as an outcome of repeated hyperammonemic episodes in organic acidaemias.

Movement disorder Abnormality of movement (HP:0100022)

Show evidence (1 reference)

PMID:38484105 SUPPORT Other

"Additional manifestations of classic IVA include developmental delay, intellectual disability and/or impaired cognition, epilepsy, and movement disorder (tremor, dysmetria, extrapyramidal movements)."

GeneReviews directly lists movement disorder, including tremor, dysmetria, and extrapyramidal movements, among additional manifestations of classic IVA.

Constitutional 1

Characteristic sweaty feet odor Body odor (HP:0500001)

Show evidence (1 reference)

PMID:24637313 SUPPORT Human Clinical

"Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a 'sweaty feet' odor."

Case-report abstract directly supports the characteristic sweaty-feet odor in IVA.

Growth 1

Failure to thrive Failure to thrive (HP:0001508)

Show evidence (1 reference)

PMID:30547004 SUPPORT Human Clinical

"The chronic intermittent form with onset in infancy or childhood presents with developmental delays and/or failure to thrive."

Review/background section directly lists failure to thrive in chronic intermittent IVA.

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Genetic Associations

1

IVD variants

Autosomal recessive

Show evidence (3 references)

PMID:41133704 SUPPORT Other

"Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."

Directly supports IVD as the causal gene with characteristic metabolite accumulation.

PMID:27613073 SUPPORT Other

"Among these disorders, methyl malonic aciduria, propionic aciduria, maple syrup urine disease and isovaleric aciduria are sometimes referred to as classical organic acidurias."

Supports IVA as a classical organic aciduria with well-defined genetic basis.

CGGV:assertion_05f5d468-2f46-44f3-ba67-c4e708d2954f-2019-05-10T160000.000Z SUPPORT Other

ClinGen classifies the IVD-isovaleric acidemia gene-disease relationship as definitive with autosomal recessive inheritance.

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Treatments

7

Leucine-restricted diet

Action: dietary intervention MAXO:0000088

Protein-restricted or leucine-restricted dietary management with specialized metabolic formula is the cornerstone of chronic IVA management. The goal is to reduce leucine flux and thereby limit isovaleryl-CoA production.

Mechanism Target:

INHIBITS Deficient leucine catabolic flux — Leucine/protein restriction reduces substrate flux into the blocked IVD step.

Show evidence (1 reference)

PMID:41133704 SUPPORT Other

"Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes."

Review and expert consensus support protein restriction as a standard strategy to reduce leucine-derived metabolite production.

Show evidence (2 references)

PMID:41133704 SUPPORT Other

"Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes."

Directly supports protein-restricted diet as the primary chronic treatment.

PMID:38344522 SUPPORT Human Clinical

"The early initiation of treatment for organic acid disorders carries a more favorable prognosis."

Supports early treatment initiation including dietary management for better outcomes.

L-Carnitine supplementation

Action: carnitine supplementation MAXO:0010006

L-carnitine supplementation promotes formation and urinary excretion of isovalerylcarnitine, reducing the toxic free isovaleric acid pool and correcting secondary carnitine deficiency.

Mechanism Target:

BYPASSES Toxic isovaleryl-CoA and organic acid accumulation — L-carnitine diverts accumulated isovaleryl-CoA into isovalerylcarnitine for urinary excretion.

Show evidence (1 reference)

PMID:6549017 SUPPORT Human Clinical

"Administration of equimolar amounts of glycine or L-carnitine separately with leucine demonstrated that isovaleryl-coenzyme A is removed by supplemental L-carnitine in the form of isovalerylcarnitine as effectively as it is by glycine, in the form of isovalerylglycine."

Human therapeutic study directly supports L-carnitine-mediated removal of isovaleryl-CoA as isovalerylcarnitine.

Show evidence (1 reference)

PMID:41133704 SUPPORT Other

"Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes."

Directly supports carnitine supplementation as part of standard IVA treatment.

Glycine supplementation

Action: pharmacotherapy MAXO:0000058

Glycine supplementation promotes conjugation of isovaleryl-CoA to isovalerylglycine, a less toxic water-soluble metabolite excreted in urine. However, glycine supplementation should be carefully considered as increased glycine concentration does not proportionally increase N-isovalerylglycine formation.

Mechanism Target:

BYPASSES Toxic isovaleryl-CoA and organic acid accumulation — Glycine diverts accumulated isovaleryl-CoA into isovalerylglycine for urinary excretion.

Show evidence (1 reference)

PMID:6549017 SUPPORT Human Clinical

"Administration of equimolar amounts of glycine or L-carnitine separately with leucine demonstrated that isovaleryl-coenzyme A is removed by supplemental L-carnitine in the form of isovalerylcarnitine as effectively as it is by glycine, in the form of isovalerylglycine."

Human therapeutic study supports glycine-mediated removal of isovaleryl-CoA as isovalerylglycine.

Show evidence (1 reference)

PMID:41133704 SUPPORT Other

"Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes."

Directly supports glycine supplementation as part of standard treatment.

N-Carbamylglutamate (carglumic acid)

Action: pharmacotherapy MAXO:0000058

N-carbamylglutamate is a synthetic analog of N-acetylglutamate approved for treatment of hyperammonemia in IVA. It directly activates CPS1, bypassing the NAGS inhibition caused by isovaleryl-CoA, and can rapidly normalize ammonia levels.

Mechanism Target:

BYPASSES Secondary urea cycle impairment and hyperammonemia — Carglumic acid stimulates the first urea-cycle step despite deficient endogenous N-acetylglutamate signaling.

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."

Review evidence supports N-carbamylglutamate as a bypass for secondary urea-cycle impairment in organic acidaemias.

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."

Directly supports N-carbamylglutamate as an effective treatment for hyperammonemia in organic acidaemias.

Acute decompensation management

Action: supportive care MAXO:0000950

Emergency management during catabolic crises includes cessation of protein intake, high-calorie glucose infusion to reverse catabolism, correction of metabolic acidosis, and administration of ammonia scavengers when needed.

Mechanism Target:

INHIBITS Catabolic acute metabolic decompensation — Emergency calories, protein cessation, hydration, and acidosis correction suppress catabolism and acute crisis physiology.

Show evidence (1 reference)

PMID:30522498 SUPPORT Other

"The acute management of hyperammonaemia in organic acidaemias requires administration of intravenous calories as glucose and lipids to promote anabolism, carnitine to promote urinary excretion of urinary organic acid esters, and correction of metabolic acidosis"

Review evidence supports acute management as a strategy to reverse catabolism and correct metabolic decompensation.

MODULATES Secondary urea cycle impairment and hyperammonemia — Acute management can include ammonia scavengers and N-carbamylglutamate to reduce hyperammonemia.

Show evidence (1 reference)

PMID:30522498 SUPPORT Other

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

Review evidence supports acute hyperammonemia-directed treatment during organic-acidemia crises.

Show evidence (2 references)

PMID:41133704 SUPPORT Other

"Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes."

Directly supports emergency treatment during catabolic episodes.

PMID:30522498 SUPPORT Other

"The acute management of hyperammonaemia in organic acidaemias requires administration of intravenous calories as glucose and lipids to promote anabolism, carnitine to promote urinary excretion of urinary organic acid esters, and correction of metabolic acidosis"

Provides detailed acute management protocol for hyperammonemia in organic acidaemias.

Newborn screening

Action: disease screening MAXO:0000124

IVA is detectable by newborn screening via tandem mass spectrometry measuring C5 acylcarnitines. However, false positives from pivaloylcarnitine are an increasing problem, and second-tier chromatographic methods are needed to differentiate C5 isomers.

Show evidence (2 references)

PMID:36636590 SUPPORT Human Clinical

"Out of 156 772 newborns tested, one turned out to have genetically proven IVA while 99 were false positive (C5: 0.5-8.2 μmol/L) due to the presence of pivaloylcarnitine."

Documents NBS implementation and the high false-positive rate from pivaloylcarnitine interference.

PMID:36837923 SUPPORT Computational

"Our results show that this reduces the false positive rate by 69.9% from 103 to 31 while maintaining 100% sensitivity in cross-validation."

Demonstrates machine learning approach to improve NBS specificity for IVA.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for affected families includes discussion of autosomal recessive inheritance, 25% recurrence risk, carrier testing for relatives, prenatal diagnosis options, and distinction between severe and mild IVA genotypes.

Show evidence (1 reference)

PMID:41133704 SUPPORT Other

"Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD)"

Inherited genetic etiology supports the role of genetic counseling for affected families.

🔬

Biochemical Markers

6

Isovalerylcarnitine (C5) (INCREASED)

Context: Elevated C5 acylcarnitine in blood is the primary newborn screening biomarker for IVA. However, standard NBS measures the sum of all C5 isomers and isobars, creating false positives from pivaloylcarnitine when mothers receive pivaloylester-containing antibiotics.

Pathograph Readouts

Readout Of Toxic isovaleryl-CoA and organic acid accumulation Positive Diagnostic

Elevated C5 isovalerylcarnitine reports carnitine conjugation of accumulated isovaleryl-CoA downstream of the IVD enzymatic block.

Show evidence (2 references)

PMID:41133704 SUPPORT Other

"Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."

Directly supports elevated C5 carnitine as a characteristic IVA biomarker.

PMID:36636590 SUPPORT Human Clinical

"Newborn screening (NBS) for isovaleric acidemia (IVA) is performed by flow injection tandem mass spectrometry quantifying C5 carnitines (C5)."

Confirms C5 as the primary NBS analyte for IVA detection.

Isovalerylglycine (INCREASED)

Context: Urinary isovalerylglycine is a pathognomonic biomarker for IVA, formed by glycine conjugation of isovaleryl-CoA primarily via GLYAT and GLYATL1 in the liver. It is a key confirmatory marker in urine organic acid analysis.

Pathograph Readouts

Readout Of Toxic isovaleryl-CoA and organic acid accumulation Positive Diagnostic

Elevated urinary isovalerylglycine reports glycine conjugation of accumulated isovaleryl-CoA and is a confirmatory IVA biomarker.

Show evidence (2 references)

PMID:41133704 SUPPORT Other

"Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."

Directly supports isovalerylglycine as a characteristic accumulated metabolite.

PMID:36817957 SUPPORT In Vitro

"The in-silico and in vitro findings suggested that both enzymes could form N-isovaleryglycine albeit at lower affinities than their preferred substrates."

In vitro validation supports GLYAT/GLYATL1-mediated formation of N-isovalerylglycine from isovaleryl-CoA.

3-Hydroxyisovaleric acid (INCREASED)

Context: Elevated 3-hydroxyisovaleric acid in urine organic acid analysis is a characteristic biomarker for IVA and one of the key confirmatory analytes alongside isovalerylglycine.

Pathograph Readouts

Readout Of Toxic isovaleryl-CoA and organic acid accumulation Positive Diagnostic

Elevated 3-hydroxyisovaleric acid reports alternate metabolism of the accumulated isovaleryl-CoA pool downstream of IVD deficiency.

Show evidence (1 reference)

PMID:41133704 SUPPORT Other

"Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."

Directly lists 3-hydroxyisovaleric acid as one of the accumulated metabolites.

Isovaleric acid (INCREASED)

Context: Free isovaleric acid is the proximal toxic metabolite in IVA. Its volatile nature produces the characteristic sweaty feet odor. Isovaleric acid contributes to neurotoxicity through inhibition of Na+,K+-ATPase and TCA cycle enzymes in brain tissue.

Pathograph Readouts

Readout Of Toxic isovaleryl-CoA and organic acid accumulation Positive Diagnostic

Elevated isovaleric acid directly reports the toxic organic-acid pool created by impaired isovaleryl-CoA dehydrogenase flux.

Show evidence (2 references)

PMID:41133704 SUPPORT Other

"Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."

Review and expert consensus directly lists isovaleric acid among accumulated metabolites.

PMID:19210957 SUPPORT Model Organism

"Isovaleric acidemia (IVAcidemia) is an inborn error of metabolism due to deficiency of isovaleryl-CoA dehydrogenase activity, leading to predominant accumulation of isovaleric acid (IVA)."

Supports isovaleric acid as the predominant accumulated metabolite.

Ammonia (INCREASED)

Context: Hyperammonemia is a secondary biochemical finding during acute metabolic crises, resulting from inhibition of NAGS by isovaleryl-CoA and consequent urea cycle impairment.

Pathograph Readouts

Readout Of Secondary urea cycle impairment and hyperammonemia Positive Diagnostic

Elevated ammonia reports secondary urea-cycle impairment during IVA metabolic decompensation.

Show evidence (2 references)

PMID:38344522 SUPPORT Human Clinical

"Laboratory results showed acidosis (81%), hyperammonemia (71.4%), and hypoglycemia (14.3%)."

Directly quantifies hyperammonemia frequency in an IVA cohort.

PMID:30522498 SUPPORT Other

"This is frequently accompanied by severe hyperammonaemia and constitutes a metabolic emergency"

Supports hyperammonemia as a frequent finding in classic organic acidaemias.

Free carnitine (DECREASED)

Context: Secondary carnitine deficiency results from increased conjugation of carnitine with isovaleryl-CoA to form isovalerylcarnitine, depleting free carnitine stores.

Pathograph Readouts

Readout Of Toxic isovaleryl-CoA and organic acid accumulation Negative Monitoring

Low free carnitine reflects depletion of the free carnitine pool as accumulated isovaleryl-CoA is detoxified through acylcarnitine formation and urinary excretion.

Show evidence (1 reference)

PMID:6549017 SUPPORT Human Clinical

"Isovaleric acidemia, resulting from isovaleryl-coenzyme A dehydrogenase deficiency, is associated with marked reduction of free carnitine in both plasma and urine."

Human therapeutic study directly supports reduced free carnitine in IVA.

{ }

Source YAML

click to show

name: Isovaleric Acidemia
category: Mendelian
creation_date: '2025-06-12T20:16:27Z'
updated_date: '2026-05-21T11:29:12Z'
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
synonyms:
- Isovaleric aciduria
- IVA
- Isovaleryl-CoA dehydrogenase deficiency
- IVD deficiency
description: 'Isovaleric acidemia (IVA; OMIM 243500) is an autosomal recessive inborn error of leucine catabolism caused by deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD). IVD catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA; its deficiency leads to accumulation of isovaleric acid, 3-hydroxyisovaleric acid, isovalerylcarnitine (C5), and isovalerylglycine in body fluids. The clinical spectrum ranges from severe neonatal-onset metabolic crises with ketoacidosis, hyperammonemia, and encephalopathy to attenuated biochemical-only phenotypes detected by newborn screening. Treatment consists of leucine-restricted diet, carnitine and glycine supplementation, and emergency management during catabolic episodes. Secondary hyperammonemia results from inhibition of N-acetylglutamate synthase (NAGS) by isovaleryl-CoA.

  '
disease_term:
  preferred_term: isovaleric acidemia
  term:
    id: MONDO:0009475
    label: isovaleric acidemia
parents:
- Organic Acidemia
- Inborn Error of Metabolism
prevalence:
- population: Southern China newborns
  percentage: 1 in 37,329
  notes: >-
    Tandem-mass-spectrometry newborn screening in southern China found IVA to be
    the most frequently detected organic acidemia in that cohort, indicating
    marked regional variation in ascertainment and possibly allele frequencies.
  evidence:
  - reference: PMID:34394177
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary \ncarnitine deficiency (1/9,332), phenylketonuria (1/18,664), and isovaleric \nacidemia (1/37,329) ranked the highest in neonates, while citrullinemia type II \nranked the highest in high-risk infants (1/1,865)."
    explanation: This large newborn-screening cohort provides a direct incidence estimate for isovaleric acidemia in southern China.
pathophysiology:
- name: IVD molecular function deficiency
  description: 'Biallelic pathogenic variants in IVD reduce isovaleryl-CoA dehydrogenase catalytic activity in mitochondria.

    '
  genes:
  - preferred_term: IVD
    term:
      id: hgnc:6186
      label: IVD
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
    explanation: Supports IVD molecular dysfunction as the initiating defect.
  downstream:
  - target: Deficient leucine catabolic flux
    description: Reduced IVD activity blocks isovaleryl-CoA oxidation in leucine catabolism.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41133704
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
      explanation: The review identifies IVA as an inherited leucine-metabolism disorder caused by IVD deficiency, supporting the direct block in leucine catabolic flux.
- name: Deficient leucine catabolic flux
  description: 'IVD deficiency blocks leucine degradation at the mitochondrial isovaleryl-CoA to 3-methylcrotonyl-CoA step, causing upstream accumulation of isovaleryl-CoA, isovaleric acid, and characteristic secondary metabolites.

    '
  biological_processes:
  - preferred_term: branched-chain amino acid catabolic process
    term:
      id: GO:0009083
      label: branched-chain amino acid catabolic process
  - preferred_term: leucine catabolic process
    term:
      id: GO:0006552
      label: L-leucine catabolic process
  evidence:
  - reference: PMID:30740403
    reference_title: "Organic acid disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Organic acids (OAs) are intermediary products of several amino acid catabolism \nor degradation via multiple biochemical pathways for energy production."
    explanation: Supports organic acid disorders as defects in amino acid catabolic pathways.
  downstream:
  - target: Toxic isovaleryl-CoA and organic acid accumulation
    description: Blocked IVD flux causes upstream isovaleryl-CoA and derivative organic acids to accumulate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41133704
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
      explanation: The review directly connects IVD deficiency to accumulation of the characteristic organic acids and conjugates.
- name: Toxic isovaleryl-CoA and organic acid accumulation
  description: 'Blocked isovaleryl-CoA oxidation causes accumulation of isovaleryl-CoA, isovaleric acid, 3-hydroxyisovaleric acid, isovalerylcarnitine, and isovalerylglycine. This toxic organic acid burden drives the characteristic odor, secondary detoxification through carnitine and glycine conjugation, and downstream acute metabolic decompensation, hyperammonemia, mitochondrial stress, and direct neurotoxicity.

    '
  biological_processes:
  - preferred_term: cellular response to toxic substance
    term:
      id: GO:0097237
      label: cellular response to toxic substance
  - preferred_term: leucine catabolic process
    term:
      id: GO:0006552
      label: L-leucine catabolic process
  chemical_entities:
  - preferred_term: isovaleryl-CoA
    term:
      id: CHEBI:15487
      label: isovaleryl-CoA
    modifier: INCREASED
  - preferred_term: isovaleric acid
    term:
      id: CHEBI:28484
      label: isovaleric acid
    modifier: INCREASED
  - preferred_term: 3-hydroxyisovaleric acid
    term:
      id: CHEBI:37084
      label: 3-hydroxyisovaleric acid
    modifier: INCREASED
  - preferred_term: O-isovalerylcarnitine
    term:
      id: CHEBI:73025
      label: O-isovalerylcarnitine
    modifier: INCREASED
  - preferred_term: N-isovalerylglycine
    term:
      id: CHEBI:70984
      label: N-isovalerylglycine
    modifier: INCREASED
  - preferred_term: carnitine
    term:
      id: CHEBI:17126
      label: carnitine
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
    explanation: Review and expert consensus directly list the accumulated organic acids and conjugates in IVA.
  - reference: PMID:30547004
    reference_title: "Isovaleric acidemia: Therapeutic response to supplementation with glycine, l-carnitine, or both in combination and a 10-year follow-up case study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of this enzyme leads to accumulation of\norganic acids, such as isovalerylcarnitine and isovalerylglycine."
    explanation: Human therapeutic follow-up paper supports toxic organic acid accumulation downstream of IVD deficiency.
  downstream:
  - target: Isovaleric acid
    description: IVD deficiency causes free isovaleric acid accumulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41133704
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
      explanation: The cited review lists isovaleric acid among the metabolites that accumulate downstream of IVD deficiency.
  - target: 3-Hydroxyisovaleric acid
    description: Alternative metabolism of accumulated isovaleryl-CoA produces elevated 3-hydroxyisovaleric acid.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - alternate oxidation of accumulated isovaleryl-CoA derivatives
    evidence:
    - reference: PMID:41133704
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
      explanation: The cited review lists 3-hydroxyisovaleric acid as a derivative accumulated in IVA.
  - target: Isovalerylcarnitine (C5)
    description: Carnitine conjugation of accumulated isovaleryl-CoA produces elevated C5 isovalerylcarnitine.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - carnitine conjugation of accumulated isovaleryl-CoA
    evidence:
    - reference: PMID:41133704
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
      explanation: The cited review lists isovaleryl (C5)-carnitine as a characteristic accumulated conjugate in IVA.
  - target: Isovalerylglycine
    description: Glycine conjugation of accumulated isovaleryl-CoA produces elevated urinary isovalerylglycine.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - glycine conjugation of accumulated isovaleryl-CoA
    evidence:
    - reference: PMID:41133704
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
      explanation: The cited review lists isovalerylglycine as a characteristic accumulated conjugate in IVA.
  - target: Free carnitine
    description: Formation and urinary excretion of isovalerylcarnitine depletes the free carnitine pool.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - isovalerylcarnitine formation and urinary excretion
    evidence:
    - reference: PMID:6549017
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Isovaleric acidemia, resulting from isovaleryl-coenzyme A dehydrogenase\ndeficiency, is associated with marked reduction of free carnitine in both plasma\nand urine."
      explanation: The human treatment study directly supports depletion of free carnitine in IVA.
  - target: Catabolic acute metabolic decompensation
    description: Toxic metabolite load worsens during fasting, illness, and protein intake, producing acute crises.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - fasting, febrile illness, gastroenteritis, or increased protein intake
    evidence:
    - reference: PMID:38484105
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Acute metabolic decompensations are typically\ntriggered by fasting, (febrile) illness (especially gastroenteritis), or\nincreased protein intake."
      explanation: GeneReviews supports catabolic and protein-load triggers for acute IVA decompensation.
  - target: Secondary urea cycle impairment and hyperammonemia
    description: Accumulated isovaleryl-CoA impairs N-acetylglutamate synthesis and urea-cycle activation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - N-acetylglutamate synthase inhibition and acetyl-CoA depletion
    evidence:
    - reference: PMID:41133704
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The \nclinical presentation is highly variable, ranging from life-threatening \nmetabolic crises with metabolic acidosis and hyperammonemia to a clinically \nasymptomatic only biochemical phenotype."
      explanation: The IVA review directly supports hyperammonemia as part of life-threatening metabolic crises.
  - target: Mitochondrial energy depletion and oxidative stress
    description: Accumulated organic acids decrease mitochondrial energy production and increase oxidative stress.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - TCA-cycle inhibition and secondary oxidative stress
    evidence:
    - reference: PMID:36817957
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The increase in these metabolites decreases mitochondrial energy \nproduction and increases oxidative stress."
      explanation: This mechanistic paper links accumulated IVA metabolites to decreased mitochondrial energy production and oxidative stress.
  - target: Neuronal membrane dysfunction via Na+,K+-ATPase inhibition
    description: Free isovaleric acid inhibits cerebral cortical Na+,K+-ATPase in model systems.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - isovaleric acid exposure in brain tissue
    evidence:
    - reference: PMID:19210957
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "IVA injection significantly inhibited \nNa(+),K(+)-ATPase activity (25%) in cerebral cortex of rats 2 or 24 h after IVA \nadministration, while pre-treatment of rats with creatine completely prevented \nthe inhibitory effects of IVA on Na(+),K(+)-ATPase."
      explanation: Rat cerebral cortex data directly support isovaleric-acid-induced Na+,K+-ATPase inhibition.
  - target: Characteristic sweaty feet odor
    description: Volatile isovaleric acid buildup produces the characteristic sweaty-feet odor.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - buildup of volatile isovaleric acid
    evidence:
    - reference: PMID:38484105
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
      explanation: GeneReviews lists the sweaty-feet odor among classic IVA decompensation features.
- name: Catabolic acute metabolic decompensation
  description: 'Fasting, febrile illness, gastroenteritis, and increased protein intake increase leucine flux and toxic organic-acid burden, triggering acute metabolic decompensation with vomiting, encephalopathy, metabolic acidosis, ketosis, hyperammonemia, and neurologic deterioration.

    '
  biological_processes:
  - preferred_term: response to starvation
    term:
      id: GO:0042594
      label: response to starvation
  - preferred_term: cellular response to toxic substance
    term:
      id: GO:0097237
      label: cellular response to toxic substance
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:38484105
    reference_title: "Classic Isovaleric Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
    explanation: GeneReviews summarizes the acute decompensation phenotype of classic IVA.
  - reference: PMID:38484105
    reference_title: "Classic Isovaleric Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Acute metabolic decompensations are typically\ntriggered by fasting, (febrile) illness (especially gastroenteritis), or\nincreased protein intake."
    explanation: GeneReviews directly supports catabolic and protein-load triggers for acute IVA crises.
  downstream:
  - target: Metabolic acidosis
    description: Acute organic-acid accumulation produces metabolic acidosis during crises.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38344522
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Laboratory results showed acidosis (81%), \nhyperammonemia (71.4%), and hypoglycemia (14.3%)."
      explanation: The IVA cohort documents metabolic acidosis during clinical presentation.
  - target: Hyperammonemia
    description: Acute decompensation in IVA commonly includes secondary hyperammonemia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - secondary urea-cycle impairment
    evidence:
    - reference: PMID:38344522
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Laboratory results showed acidosis (81%), \nhyperammonemia (71.4%), and hypoglycemia (14.3%)."
      explanation: The IVA cohort documents hyperammonemia during clinical presentation.
  - target: Vomiting
    description: Vomiting is a common acute decompensation symptom.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38344522
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vomiting was the most prevalent symptom (57.1%), and \nencephalopathy occurred in 33.3%."
      explanation: The IVA cohort documents vomiting as the most prevalent symptom.
  - target: Feeding difficulties
    description: Poor feeding is a core manifestation of acute metabolic decompensation in classic IVA.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38484105
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
      explanation: GeneReviews lists poor feeding among classic IVA decompensation manifestations.
  - target: Encephalopathy
    description: Acute decompensation produces encephalopathy through hyperammonemia and organic-acid neurotoxicity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hyperammonemia, mitochondrial dysfunction, and Na+,K+-ATPase inhibition
    evidence:
    - reference: PMID:38344522
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vomiting was the most prevalent symptom (57.1%), and \nencephalopathy occurred in 33.3%."
      explanation: The IVA cohort documents encephalopathy during acute clinical presentation.
  - target: Lethargy
    description: Acute crises commonly cause reduced alertness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38484105
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
      explanation: GeneReviews lists lethargy among classic IVA decompensation manifestations.
  - target: Hypotonia
    description: Hypotonia is listed among acute decompensation manifestations in classic IVA.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38484105
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
      explanation: GeneReviews lists hypotonia among classic IVA decompensation manifestations.
  - target: Hypoglycemia
    description: Hypoglycemia occurs in a subset of acute IVA presentations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38344522
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Laboratory results showed acidosis (81%), \nhyperammonemia (71.4%), and hypoglycemia (14.3%)."
      explanation: The IVA cohort documents hypoglycemia during clinical presentation.
  - target: Seizures
    description: Acute metabolic decompensation can present with seizures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hyperammonemia and organic-acid neurotoxicity
    evidence:
    - reference: PMID:38484105
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
      explanation: GeneReviews lists seizures among classic IVA decompensation manifestations.
  - target: Movement disorder
    description: Recurrent or severe IVA decompensation can contribute to movement disorders through metabolic brain injury and organic-acid neurotoxicity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hyperammonemia, mitochondrial dysfunction, and organic-acid neurotoxicity
    evidence:
    - reference: PMID:38484105
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Additional manifestations of classic IVA include developmental\ndelay, intellectual disability and/or impaired cognition, epilepsy, and movement\ndisorder (tremor, dysmetria, extrapyramidal movements)."
      explanation: GeneReviews lists movement disorder among additional classic IVA manifestations.
  - target: Pancytopenia
    description: Severe infection-triggered decompensation can present with pancytopenia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:2124776
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A case of isovaleric acidemia appearing as diabetic ketoacidosis with acute\nencephalopathy and pancytopenia was reported."
      explanation: A human IVA case report documents pancytopenia during acute encephalopathic presentation.
  - target: Global developmental delay
    description: Recurrent or severe IVA decompensation contributes to developmental delay risk.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38484105
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Additional manifestations of classic IVA include developmental\ndelay, intellectual disability and/or impaired cognition, epilepsy, and movement\ndisorder (tremor, dysmetria, extrapyramidal movements)."
      explanation: GeneReviews lists developmental delay among additional classic IVA manifestations.
  - target: Failure to thrive
    description: Chronic intermittent IVA can present with failure to thrive.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30547004
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The chronic intermittent form with onset in infancy or childhood presents with developmental delays and/or failure to thrive.
      explanation: A human follow-up report states that chronic intermittent IVA can present with failure to thrive.
- name: Secondary urea cycle impairment and hyperammonemia
  description: 'Isovaleryl-CoA inhibits N-acetylglutamate synthase (NAGS), reducing N-acetylglutamate availability and impairing activation of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting entry enzyme of the urea cycle. Combined with acetyl-CoA depletion, this produces secondary hyperammonemia that contributes to encephalopathy and neurological complications.

    '
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
  chemical_entities:
  - preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
    modifier: INCREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:30740403
    reference_title: "Organic acid disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "High anion gap metabolic acidosis with \nhyperammonemia is a characteristic OA biochemical finding."
    explanation: Supports hyperammonemia as characteristic of organic acid disorders.
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The \nclinical presentation is highly variable, ranging from life-threatening \nmetabolic crises with metabolic acidosis and hyperammonemia to a clinically \nasymptomatic only biochemical phenotype."
    explanation: Directly supports hyperammonemia as a key crisis feature of IVA.
  downstream:
  - target: Ammonia
    description: Urea-cycle impairment increases circulating ammonia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30522498
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Treatment with N-carbamyl-L-glutamate can rapidly normalise \nammonia levels by stimulating the first step of the urea cycle."
      explanation: The review links urea-cycle activation to normalization of ammonia levels, supporting ammonia as the readout of impaired urea-cycle entry.
  - target: Hyperammonemia
    description: Impaired urea-cycle entry produces the hyperammonemia phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30522498
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This is frequently accompanied by severe \nhyperammonaemia and constitutes a metabolic emergency"
      explanation: The organic-acidemia review supports severe hyperammonemia as a frequent accompaniment of decompensation.
  - target: Encephalopathy
    description: Severe hyperammonemia during organic-acidemia crises contributes to life-threatening neurologic dysfunction.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased ammonia levels and accumulating toxic metabolites
    evidence:
    - reference: PMID:30522498
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "increased ammonia \nlevels and accumulating toxic metabolites are associated with life-threatening \nneurological complications."
      explanation: The review supports hyperammonemia and toxic metabolites as drivers of severe neurologic complications.
  - target: Intellectual disability
    description: Repeated hyperammonemia and metabolic decompensation can lead to intellectual disability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - repeated hyperammonemic metabolic decompensations
    evidence:
    - reference: PMID:30522498
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Repeated and frequent episodes of hyperammonaemia \n(alongside metabolic decompensations) can result in impaired growth and \nintellectual disability, the severity of which increase with longer duration of \nhyperammonaemia."
      explanation: The review directly links repeated hyperammonemia and metabolic decompensation to intellectual disability.
  - target: Failure to thrive
    description: Repeated hyperammonemia and metabolic decompensation can impair growth.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - repeated hyperammonemic metabolic decompensations
    evidence:
    - reference: PMID:30522498
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Repeated and frequent episodes of hyperammonaemia \n(alongside metabolic decompensations) can result in impaired growth and \nintellectual disability, the severity of which increase with longer duration of \nhyperammonaemia."
      explanation: The review links repeated hyperammonemia and metabolic decompensation to impaired growth.
- name: Mitochondrial energy depletion and oxidative stress
  description: 'Accumulated isovaleryl-CoA and isovaleric acid impair tricarboxylic acid cycle function, with evidence for inhibition of citrate synthase and reduced CO2 production from acetate in brain tissue. Chronic metabolite accumulation also increases oxidative stress, contributing to neurological morbidity. Oxidative stress from chronic persistent buildup of isovaleric acid may be more neurologically detrimental than acute buildup.

    '
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:19210957
    reference_title: "Creatine administration prevents Na+,K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IVA administration significantly inhibited (14)CO(2) production from \nacetate (22%) and citrate synthase activity (20%) in cerebral cortex homogenates \nprepared 24 h after injection."
    explanation: Demonstrates TCA cycle impairment in cerebral cortex from isovaleric acid exposure in vivo.
  - reference: PMID:36817957
    reference_title: "The glycine N-acyltransferases, GLYAT and GLYATL1, contribute to the detoxification of isovaleryl-CoA - an in-silico and in vitro validation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The increase in these metabolites decreases mitochondrial energy \nproduction and increases oxidative stress."
    explanation: Review component of this mechanistic paper supports mitochondrial energy impairment and oxidative stress from metabolite accumulation.
  downstream:
  - target: Encephalopathy
    description: Impaired cerebral energy metabolism contributes to the acute encephalopathy seen in IVA.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired TCA-cycle activity in cerebral cortex
    evidence:
    - reference: PMID:19210957
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "IVA administration significantly inhibited (14)CO(2) production from \nacetate (22%) and citrate synthase activity (20%) in cerebral cortex homogenates \nprepared 24 h after injection."
      explanation: Rat cerebral cortex data support impaired energy metabolism after isovaleric acid exposure, which can contribute to encephalopathy.
  - target: Lethargy
    description: Cerebral energy impairment can contribute to reduced alertness during acute crises.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19210957
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "IVA administration significantly inhibited (14)CO(2) production from \nacetate (22%) and citrate synthase activity (20%) in cerebral cortex homogenates \nprepared 24 h after injection."
      explanation: Rat cerebral cortex data support energy impairment after isovaleric acid exposure; this provides mechanistic support for reduced alertness during crises.
- name: Neuronal membrane dysfunction via Na+,K+-ATPase inhibition
  description: 'Isovaleric acid directly inhibits Na+,K+-ATPase activity in cerebral cortex, a crucial enzyme for maintaining membrane potential and normal neurotransmission. This inhibition is observed as early as 2 hours after exposure and persists at 24 hours, contributing to the acute encephalopathy seen during metabolic crises.

    '
  biological_processes:
  - preferred_term: sodium ion transport
    term:
      id: GO:0006814
      label: sodium ion transport
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:19210957
    reference_title: "Creatine administration prevents Na+,K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IVA injection significantly inhibited \nNa(+),K(+)-ATPase activity (25%) in cerebral cortex of rats 2 or 24 h after IVA \nadministration, while pre-treatment of rats with creatine completely prevented \nthe inhibitory effects of IVA on Na(+),K(+)-ATPase."
    explanation: Demonstrates direct inhibition of Na+,K+-ATPase by isovaleric acid in cerebral cortex and prevention by creatine.
  downstream:
  - target: Encephalopathy
    description: Membrane-pump inhibition disrupts neurotransmission and contributes to acute encephalopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired basal membrane potential and neurotransmission
    evidence:
    - reference: PMID:19210957
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "IVA injection significantly inhibited \nNa(+),K(+)-ATPase activity (25%) in cerebral cortex of rats 2 or 24 h after IVA \nadministration, while pre-treatment of rats with creatine completely prevented \nthe inhibitory effects of IVA on Na(+),K(+)-ATPase."
      explanation: Rat data show isovaleric acid inhibits cerebral cortical Na+,K+-ATPase, supporting a membrane-pump mechanism for encephalopathy.
  - target: Seizures
    description: Disrupted neuronal membrane potential can contribute to seizure susceptibility during crises.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19210957
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "It is presumed that inhibition of these activities may be \ninvolved in the pathophysiology of the neurological dysfunction of isovaleric \nacademic patients."
      explanation: The model-organism study interprets Na+,K+-ATPase and energy-metabolism inhibition as possible contributors to neurological dysfunction in IVA.
phenotypes:
- name: Metabolic acidosis
  frequency: VERY_FREQUENT
  description: 'High-anion-gap metabolic acidosis is the hallmark acute presentation during metabolic decompensation episodes. In a Jordanian cohort, acidosis was present in 81% of patients.

    '
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:38344522
    reference_title: "Isovaleric Acidemia in Jordan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory results showed acidosis (81%), \nhyperammonemia (71.4%), and hypoglycemia (14.3%)."
    explanation: Directly quantifies acidosis at 81% in an IVA cohort.
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The \nclinical presentation is highly variable, ranging from life-threatening \nmetabolic crises with metabolic acidosis and hyperammonemia to a clinically \nasymptomatic only biochemical phenotype."
    explanation: Supports metabolic acidosis as a key crisis phenotype.
- name: Hyperammonemia
  frequency: VERY_FREQUENT
  description: 'Secondary hyperammonemia results from inhibition of N-acetylglutamate synthase by isovaleryl-CoA. In a Jordanian cohort, hyperammonemia was present in 71.4% of patients. Repeated hyperammonemic episodes increase the risk of brain damage.

    '
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:38344522
    reference_title: "Isovaleric Acidemia in Jordan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory results showed acidosis (81%), \nhyperammonemia (71.4%), and hypoglycemia (14.3%)."
    explanation: Directly quantifies hyperammonemia at 71.4% in an IVA cohort.
  - 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: "Repeated and frequent episodes of hyperammonaemia \n(alongside metabolic decompensations) can result in impaired growth and \nintellectual disability, the severity of which increase with longer duration of \nhyperammonaemia."
    explanation: Supports hyperammonemia as contributing to neurological sequelae.
- name: Vomiting
  frequency: FREQUENT
  description: 'Recurrent vomiting is the most prevalent symptom during metabolic crises in IVA. In a Jordanian cohort, vomiting was the most common presenting symptom at 57.1%.

    '
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:38344522
    reference_title: "Isovaleric Acidemia in Jordan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vomiting was the most prevalent symptom (57.1%), and \nencephalopathy occurred in 33.3%."
    explanation: Directly quantifies vomiting as the most common symptom.
- name: Feeding difficulties
  description: 'Poor feeding can occur during acute metabolic decompensation in classic IVA, alongside vomiting, lethargy, hypotonia, seizures, and the characteristic odor.

    '
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:38484105
    reference_title: "Classic Isovaleric Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
    explanation: GeneReviews directly lists poor feeding among acute decompensation manifestations of classic IVA.
- name: Encephalopathy
  frequency: FREQUENT
  description: 'Acute encephalopathy occurs during severe metabolic crises, mediated by hyperammonemia, direct organic acid neurotoxicity, and impaired neuronal energy metabolism. In a Jordanian cohort, encephalopathy occurred in 33.3%.

    '
  phenotype_term:
    preferred_term: Acute encephalopathy
    term:
      id: HP:0006846
      label: Acute encephalopathy
  evidence:
  - reference: PMID:38344522
    reference_title: "Isovaleric Acidemia in Jordan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vomiting was the most prevalent symptom (57.1%), and \nencephalopathy occurred in 33.3%."
    explanation: Directly quantifies encephalopathy at 33.3% in an IVA cohort.
  - reference: PMID:19210957
    reference_title: "Creatine administration prevents Na+,K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Patients affected by IVAcidemia suffer \nfrom acute episodes of encephalopathy, whose underlying mechanisms are poorly \nknown."
    explanation: Confirms encephalopathy as a recognized acute manifestation of IVA.
- name: Lethargy
  description: 'Reduced alertness and responsiveness during acute metabolic decompensation, ranging from somnolence to coma.

    '
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:24637313
    reference_title: "Isovaleric acidemia presenting as diabetic ketoacidosis: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma,\nketoacidosis and a 'sweaty feet' odor."
    explanation: Case-report abstract directly lists lethargy among characteristic IVA acute manifestations.
- name: Hypotonia
  description: 'Reduced muscle tone during acute metabolic decompensation is a characteristic neurologic manifestation of classic IVA.

    '
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38484105
    reference_title: "Classic Isovaleric Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
    explanation: GeneReviews directly lists hypotonia among acute decompensation manifestations of classic IVA.
- name: Hypoglycemia
  frequency: OCCASIONAL
  description: 'Hypoglycemia may occur during metabolic crises, reported in 14.3% of patients in a Jordanian cohort.

    '
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:38344522
    reference_title: "Isovaleric Acidemia in Jordan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory results showed acidosis (81%), \nhyperammonemia (71.4%), and hypoglycemia (14.3%)."
    explanation: Directly quantifies hypoglycemia at 14.3% in an IVA cohort.
- name: Seizures
  description: 'Seizures may occur during severe metabolic decompensation, likely mediated by hyperammonemia and direct neurotoxicity of accumulated metabolites.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38484105
    reference_title: "Classic Isovaleric Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Classic IVA is characterized by acute metabolic\ndecompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a\ndistinct odor of sweaty feet)."
    explanation: GeneReviews directly lists seizures as an acute decompensation manifestation of classic IVA.
- name: Global developmental delay
  description: 'Developmental delay is a risk in severe or recurrent disease, particularly following repeated hyperammonemic episodes.

    '
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38484105
    reference_title: "Classic Isovaleric Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional manifestations of classic IVA include developmental\ndelay, intellectual disability and/or impaired cognition, epilepsy, and movement\ndisorder (tremor, dysmetria, extrapyramidal movements)."
    explanation: GeneReviews directly lists developmental delay among additional manifestations of classic IVA.
- name: Intellectual disability
  description: 'Intellectual disability may develop as a long-term consequence of recurrent metabolic crises and hyperammonemia, particularly in severe neonatal-onset forms.

    '
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38484105
    reference_title: "Classic Isovaleric Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional manifestations of classic IVA include developmental\ndelay, intellectual disability and/or impaired cognition, epilepsy, and movement\ndisorder (tremor, dysmetria, extrapyramidal movements)."
    explanation: GeneReviews directly lists intellectual disability or impaired cognition among additional manifestations of classic IVA.
  - 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: "Repeated and frequent episodes of hyperammonaemia \n(alongside metabolic decompensations) can result in impaired growth and \nintellectual disability, the severity of which increase with longer duration of \nhyperammonaemia."
    explanation: Review evidence supports intellectual disability as an outcome of repeated hyperammonemic episodes in organic acidaemias.
- name: Movement disorder
  description: 'Movement disorders such as tremor, dysmetria, and extrapyramidal movements are reported as additional manifestations of classic IVA, likely reflecting metabolic brain injury from severe or recurrent decompensations.

    '
  phenotype_term:
    preferred_term: Movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:38484105
    reference_title: "Classic Isovaleric Acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional manifestations of classic IVA include developmental\ndelay, intellectual disability and/or impaired cognition, epilepsy, and movement\ndisorder (tremor, dysmetria, extrapyramidal movements)."
    explanation: GeneReviews directly lists movement disorder, including tremor, dysmetria, and extrapyramidal movements, among additional manifestations of classic IVA.
- name: Failure to thrive
  description: 'Growth impairment can occur in patients with recurrent or poorly controlled disease due to chronic metabolic instability and dietary protein restriction.

    '
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:30547004
    reference_title: "Isovaleric acidemia: Therapeutic response to supplementation with glycine, l-carnitine, or both in combination and a 10-year follow-up case study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The chronic intermittent form with onset in infancy or childhood presents with developmental delays and/or failure to thrive.
    explanation: Review/background section directly lists failure to thrive in chronic intermittent IVA.
- name: Pancytopenia
  description: 'Pancytopenia and neutropenia may occur during acute metabolic decompensation in organic acidemias including IVA, due to bone marrow suppression by toxic metabolites.

    '
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:2124776
    reference_title: "Isovaleric acidemia: report of one case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A case of isovaleric acidemia appearing as diabetic ketoacidosis with acute\nencephalopathy and pancytopenia was reported."
    explanation: Case-report abstract directly names pancytopenia in a patient with IVA and acute encephalopathy.
- name: Characteristic sweaty feet odor
  description: 'A distinctive sweaty feet or cheesy odor due to volatile isovaleric acid accumulation is a classic clinical feature of IVA, particularly during acute metabolic crises.

    '
  phenotype_term:
    preferred_term: Body odor
    term:
      id: HP:0500001
      label: Body odor
  evidence:
  - reference: PMID:24637313
    reference_title: "Isovaleric acidemia presenting as diabetic ketoacidosis: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma,\nketoacidosis and a 'sweaty feet' odor."
    explanation: Case-report abstract directly supports the characteristic sweaty-feet odor in IVA.
biochemical:
- name: Isovalerylcarnitine (C5)
  presence: INCREASED
  context: 'Elevated C5 acylcarnitine in blood is the primary newborn screening biomarker for IVA. However, standard NBS measures the sum of all C5 isomers and isobars, creating false positives from pivaloylcarnitine when mothers receive pivaloylester-containing antibiotics.

    '
  biomarker_term:
    preferred_term: O-isovalerylcarnitine
    term:
      id: CHEBI:73025
      label: O-isovalerylcarnitine
  readouts:
  - target: Toxic isovaleryl-CoA and organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated C5 isovalerylcarnitine reports carnitine conjugation of
      accumulated isovaleryl-CoA downstream of the IVD enzymatic block.
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
    explanation: Directly supports elevated C5 carnitine as a characteristic IVA biomarker.
  - reference: PMID:36636590
    reference_title: "Neonatal screening for isovaleric aciduria: Reducing the increasingly high false-positive rate in Germany."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn screening (NBS) for isovaleric acidemia (IVA) is performed by flow \ninjection tandem mass spectrometry quantifying C5 carnitines (C5)."
    explanation: Confirms C5 as the primary NBS analyte for IVA detection.
- name: Isovalerylglycine
  presence: INCREASED
  context: 'Urinary isovalerylglycine is a pathognomonic biomarker for IVA, formed by glycine conjugation of isovaleryl-CoA primarily via GLYAT and GLYATL1 in the liver. It is a key confirmatory marker in urine organic acid analysis.

    '
  biomarker_term:
    preferred_term: N-isovalerylglycine
    term:
      id: CHEBI:70984
      label: N-isovalerylglycine
  readouts:
  - target: Toxic isovaleryl-CoA and organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated urinary isovalerylglycine reports glycine conjugation of
      accumulated isovaleryl-CoA and is a confirmatory IVA biomarker.
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
    explanation: Directly supports isovalerylglycine as a characteristic accumulated metabolite.
  - reference: PMID:36817957
    reference_title: "The glycine N-acyltransferases, GLYAT and GLYATL1, contribute to the detoxification of isovaleryl-CoA - an in-silico and in vitro validation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The in-silico and in vitro findings suggested that both enzymes \ncould form N-isovaleryglycine albeit at lower affinities than their preferred \nsubstrates."
    explanation: In vitro validation supports GLYAT/GLYATL1-mediated formation of N-isovalerylglycine from isovaleryl-CoA.
- name: 3-Hydroxyisovaleric acid
  presence: INCREASED
  context: 'Elevated 3-hydroxyisovaleric acid in urine organic acid analysis is a characteristic biomarker for IVA and one of the key confirmatory analytes alongside isovalerylglycine.

    '
  biomarker_term:
    preferred_term: 3-hydroxyisovaleric acid
    term:
      id: CHEBI:37084
      label: 3-hydroxyisovaleric acid
  readouts:
  - target: Toxic isovaleryl-CoA and organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated 3-hydroxyisovaleric acid reports alternate metabolism of the
      accumulated isovaleryl-CoA pool downstream of IVD deficiency.
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
    explanation: Directly lists 3-hydroxyisovaleric acid as one of the accumulated metabolites.
- name: Isovaleric acid
  presence: INCREASED
  context: 'Free isovaleric acid is the proximal toxic metabolite in IVA. Its volatile nature produces the characteristic sweaty feet odor. Isovaleric acid contributes to neurotoxicity through inhibition of Na+,K+-ATPase and TCA cycle enzymes in brain tissue.

    '
  biomarker_term:
    preferred_term: isovaleric acid
    term:
      id: CHEBI:28484
      label: isovaleric acid
  readouts:
  - target: Toxic isovaleryl-CoA and organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated isovaleric acid directly reports the toxic organic-acid pool
      created by impaired isovaleryl-CoA dehydrogenase flux.
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
    explanation: Review and expert consensus directly lists isovaleric acid among accumulated metabolites.
  - reference: PMID:19210957
    reference_title: "Creatine administration prevents Na+,K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Isovaleric acidemia (IVAcidemia) is an inborn error of metabolism due to \ndeficiency of isovaleryl-CoA dehydrogenase activity, leading to predominant \naccumulation of isovaleric acid (IVA)."
    explanation: Supports isovaleric acid as the predominant accumulated metabolite.
- name: Ammonia
  presence: INCREASED
  context: 'Hyperammonemia is a secondary biochemical finding during acute metabolic crises, resulting from inhibition of NAGS by isovaleryl-CoA and consequent urea cycle impairment.

    '
  biomarker_term:
    preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
  readouts:
  - target: Secondary urea cycle impairment and hyperammonemia
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated ammonia reports secondary urea-cycle impairment during IVA
      metabolic decompensation.
  evidence:
  - reference: PMID:38344522
    reference_title: "Isovaleric Acidemia in Jordan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory results showed acidosis (81%), \nhyperammonemia (71.4%), and hypoglycemia (14.3%)."
    explanation: Directly quantifies hyperammonemia frequency in an IVA cohort.
  - 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: "This is frequently accompanied by severe \nhyperammonaemia and constitutes a metabolic emergency"
    explanation: Supports hyperammonemia as a frequent finding in classic organic acidaemias.
- name: Free carnitine
  presence: DECREASED
  context: 'Secondary carnitine deficiency results from increased conjugation of carnitine with isovaleryl-CoA to form isovalerylcarnitine, depleting free carnitine stores.

    '
  biomarker_term:
    preferred_term: carnitine
    term:
      id: CHEBI:17126
      label: carnitine
  readouts:
  - target: Toxic isovaleryl-CoA and organic acid accumulation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: MONITORING
    interpretation: >-
      Low free carnitine reflects depletion of the free carnitine pool as
      accumulated isovaleryl-CoA is detoxified through acylcarnitine formation
      and urinary excretion.
  evidence:
  - reference: PMID:6549017
    reference_title: "L-carnitine therapy in isovaleric acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isovaleric acidemia, resulting from isovaleryl-coenzyme A dehydrogenase\ndeficiency, is associated with marked reduction of free carnitine in both plasma\nand urine."
    explanation: Human therapeutic study directly supports reduced free carnitine in IVA.
genetic:
- name: IVD variants
  gene_term:
    preferred_term: IVD
    term:
      id: hgnc:6186
      label: IVD
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:41133704
      reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD)"
      explanation: Supports inherited Mendelian etiology consistent with autosomal recessive inheritance.
  variants:
  - name: IVD - c.941C>T (p.Ala314Val) - mild IVA variant
    description: 'The c.941C>T (p.Ala314Val) variant in IVD is commonly associated with the attenuated or mild biochemical phenotype detected by newborn screening. Individuals homozygous for this variant may remain clinically asymptomatic.

      '
    evidence:
    - reference: PMID:36837923
      reference_title: "Machine Learning Methods Improve Specificity in Newborn Screening for Isovaleric Aciduria."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "NBS for IVA is hampered by, \nfirst, the increased birth prevalence due to the identification of individuals \nwith an attenuated disease variant (so-called \"mild\" IVA)"
      explanation: Supports existence of attenuated IVA variants detected by newborn screening.
  - name: Various pathogenic IVD variants
    description: 'Multiple pathogenic variants in IVD have been described causing variable clinical severity from severe neonatal-onset to chronic intermittent forms. Biallelic pathogenic variants are required for disease manifestation.

      '
    evidence:
    - reference: PMID:41133704
      reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD)"
      explanation: Supports IVD as the causal gene with biallelic variants required.
  features: 'Biallelic pathogenic variants in IVD cause variable phenotypic severity spanning severe neonatal-onset acute metabolic crises to mild biochemical-only phenotypes identified through newborn screening. The IVD gene encodes a mitochondrial flavoprotein that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA in the leucine catabolic pathway.

    '
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading \nto an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric \nacid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids."
    explanation: Directly supports IVD as the causal gene with characteristic metabolite accumulation.
  - reference: PMID:27613073
    reference_title: "\"Classical organic acidurias\": diagnosis and pathogenesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Among these disorders, methyl malonic aciduria, propionic aciduria, \nmaple syrup urine disease and isovaleric aciduria are sometimes referred to as \nclassical organic acidurias."
    explanation: Supports IVA as a classical organic aciduria with well-defined genetic basis.
  - reference: CGGV:assertion_05f5d468-2f46-44f3-ba67-c4e708d2954f-2019-05-10T160000.000Z
    reference_title: "IVD / isovaleric acidemia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IVD | HGNC:6186 | isovaleric acidemia | MONDO:0009475 | AR | Definitive"
    explanation: ClinGen classifies the IVD-isovaleric acidemia gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Leucine-restricted diet
  description: 'Protein-restricted or leucine-restricted dietary management with specialized metabolic formula is the cornerstone of chronic IVA management. The goal is to reduce leucine flux and thereby limit isovaleryl-CoA production.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Deficient leucine catabolic flux
    treatment_effect: INHIBITS
    description: Leucine/protein restriction reduces substrate flux into the blocked IVD step.
    evidence:
    - reference: PMID:41133704
      reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Treatment consists of a protein-restricted diet \ncombined with supplementation of carnitine and/or glycine and emergency \ntreatment in catabolic episodes."
      explanation: Review and expert consensus support protein restriction as a standard strategy to reduce leucine-derived metabolite production.
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment consists of a protein-restricted diet \ncombined with supplementation of carnitine and/or glycine and emergency \ntreatment in catabolic episodes."
    explanation: Directly supports protein-restricted diet as the primary chronic treatment.
  - reference: PMID:38344522
    reference_title: "Isovaleric Acidemia in Jordan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The early initiation of treatment for organic acid disorders \ncarries a more favorable prognosis."
    explanation: Supports early treatment initiation including dietary management for better outcomes.
- name: L-Carnitine supplementation
  description: 'L-carnitine supplementation promotes formation and urinary excretion of isovalerylcarnitine, reducing the toxic free isovaleric acid pool and correcting secondary carnitine deficiency.

    '
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: MAXO:0010006
      label: carnitine supplementation
  target_mechanisms:
  - target: Toxic isovaleryl-CoA and organic acid accumulation
    treatment_effect: BYPASSES
    description: L-carnitine diverts accumulated isovaleryl-CoA into isovalerylcarnitine for urinary excretion.
    evidence:
    - reference: PMID:6549017
      reference_title: "L-carnitine therapy in isovaleric acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Administration\nof equimolar amounts of glycine or L-carnitine separately with leucine\ndemonstrated that isovaleryl-coenzyme A is removed by supplemental L-carnitine\nin the form of isovalerylcarnitine as effectively as it is by glycine, in the\nform of isovalerylglycine."
      explanation: Human therapeutic study directly supports L-carnitine-mediated removal of isovaleryl-CoA as isovalerylcarnitine.
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment consists of a protein-restricted diet \ncombined with supplementation of carnitine and/or glycine and emergency \ntreatment in catabolic episodes."
    explanation: Directly supports carnitine supplementation as part of standard IVA treatment.
- name: Glycine supplementation
  description: 'Glycine supplementation promotes conjugation of isovaleryl-CoA to isovalerylglycine, a less toxic water-soluble metabolite excreted in urine. However, glycine supplementation should be carefully considered as increased glycine concentration does not proportionally increase N-isovalerylglycine formation.

    '
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  target_mechanisms:
  - target: Toxic isovaleryl-CoA and organic acid accumulation
    treatment_effect: BYPASSES
    description: Glycine diverts accumulated isovaleryl-CoA into isovalerylglycine for urinary excretion.
    evidence:
    - reference: PMID:6549017
      reference_title: "L-carnitine therapy in isovaleric acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Administration\nof equimolar amounts of glycine or L-carnitine separately with leucine\ndemonstrated that isovaleryl-coenzyme A is removed by supplemental L-carnitine\nin the form of isovalerylcarnitine as effectively as it is by glycine, in the\nform of isovalerylglycine."
      explanation: Human therapeutic study supports glycine-mediated removal of isovaleryl-CoA as isovalerylglycine.
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment consists of a protein-restricted diet \ncombined with supplementation of carnitine and/or glycine and emergency \ntreatment in catabolic episodes."
    explanation: Directly supports glycine supplementation as part of standard treatment.
- name: N-Carbamylglutamate (carglumic acid)
  description: 'N-carbamylglutamate is a synthetic analog of N-acetylglutamate approved for treatment of hyperammonemia in IVA. It directly activates CPS1, bypassing the NAGS inhibition caused by isovaleryl-CoA, and can rapidly normalize ammonia levels.

    '
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  target_mechanisms:
  - target: Secondary urea cycle impairment and hyperammonemia
    treatment_effect: BYPASSES
    description: Carglumic acid stimulates the first urea-cycle step despite deficient endogenous N-acetylglutamate signaling.
    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 \nammonia levels by stimulating the first step of the urea cycle."
      explanation: Review evidence supports N-carbamylglutamate as a bypass for secondary urea-cycle impairment in organic acidaemias.
  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 \nammonia levels by stimulating the first step of the urea cycle."
    explanation: Directly supports N-carbamylglutamate as an effective treatment for hyperammonemia in organic acidaemias.
- name: Acute decompensation management
  description: 'Emergency management during catabolic crises includes cessation of protein intake, high-calorie glucose infusion to reverse catabolism, correction of metabolic acidosis, and administration of ammonia scavengers when needed.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Catabolic acute metabolic decompensation
    treatment_effect: INHIBITS
    description: Emergency calories, protein cessation, hydration, and acidosis correction suppress catabolism and acute crisis physiology.
    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: "The acute management of hyperammonaemia in organic \nacidaemias requires administration of intravenous calories as glucose and lipids \nto promote anabolism, carnitine to promote urinary excretion of urinary organic \nacid esters, and correction of metabolic acidosis"
      explanation: Review evidence supports acute management as a strategy to reverse catabolism and correct metabolic decompensation.
  - target: Secondary urea cycle impairment and hyperammonemia
    treatment_effect: MODULATES
    description: Acute management can include ammonia scavengers and N-carbamylglutamate to reduce 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: "It may also include the \nadministration of ammonia scavengers such as sodium benzoate or sodium \nphenylbutyrate."
      explanation: Review evidence supports acute hyperammonemia-directed treatment during organic-acidemia crises.
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment consists of a protein-restricted diet \ncombined with supplementation of carnitine and/or glycine and emergency \ntreatment in catabolic episodes."
    explanation: Directly supports emergency treatment during catabolic episodes.
  - 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: "The acute management of hyperammonaemia in organic \nacidaemias requires administration of intravenous calories as glucose and lipids \nto promote anabolism, carnitine to promote urinary excretion of urinary organic \nacid esters, and correction of metabolic acidosis"
    explanation: Provides detailed acute management protocol for hyperammonemia in organic acidaemias.
- name: Newborn screening
  description: 'IVA is detectable by newborn screening via tandem mass spectrometry measuring C5 acylcarnitines. However, false positives from pivaloylcarnitine are an increasing problem, and second-tier chromatographic methods are needed to differentiate C5 isomers.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
  evidence:
  - reference: PMID:36636590
    reference_title: "Neonatal screening for isovaleric aciduria: Reducing the increasingly high false-positive rate in Germany."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Out of 156 772 \nnewborns tested, one turned out to have genetically proven IVA while 99 were \nfalse positive (C5: 0.5-8.2 μmol/L) due to the presence of pivaloylcarnitine."
    explanation: Documents NBS implementation and the high false-positive rate from pivaloylcarnitine interference.
  - reference: PMID:36837923
    reference_title: "Machine Learning Methods Improve Specificity in Newborn Screening for Isovaleric Aciduria."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Our \nresults show that this reduces the false positive rate by 69.9% from 103 to 31 \nwhile maintaining 100% sensitivity in cross-validation."
    explanation: Demonstrates machine learning approach to improve NBS specificity for IVA.
- name: Genetic counseling
  description: 'Genetic counseling for affected families includes discussion of autosomal recessive inheritance, 25% recurrence risk, carrier testing for relatives, prenatal diagnosis options, and distinction between severe and mild IVA genotypes.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:41133704
    reference_title: "Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine \nmetabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD)"
    explanation: Inherited genetic etiology supports the role of genetic counseling for affected families.
references:
- reference: PMID:38484105
  title: "Classic Isovaleric Acidemia."
  tags:
  - GeneReviews
  findings: []
notes: 'The clinical spectrum of IVA has broadened with the introduction of newborn screening, which detects many individuals with attenuated biochemical phenotypes (mild IVA) who may never develop clinical symptoms. This has raised questions about potential overdiagnosis and overtreatment. A major practical challenge in NBS is the false-positive rate from pivaloylcarnitine, which is isobaric with isovalerylcarnitine. Second-tier chromatographic methods and machine learning approaches are being implemented to improve screening specificity. Glycine conjugation via GLYAT and GLYATL1 represents a key detoxification pathway, though 2023 evidence suggests the enzyme kinetics limit the benefit of simply increasing glycine supplementation.

  '

📚

References & Deep Research

References

1

PMID:38484105

Classic Isovaleric Acidemia.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 26 citations 2026-02-23T23:30:09.722004

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: Isovaleric Acidemia
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Isovaleric 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 Isovaleric Acidemia (Isovaleryl‑CoA Dehydrogenase Deficiency)

Publication scope and identifiers • Disease: Isovaleric acidemia / isovaleric aciduria (IVA) (OMIM 243500) (kuhn2023theglycinenacyltransferases pages 1-2, zaunseder2023machinelearningmethods pages 1-2, thimm2025practicalconsiderationsfor pages 1-2). • MONDO ID: Not available in the retrieved full-text snippets; MONDO mapping would require external lookup. • Note on PMID requirement: The retrieved full-text snippets did not contain PubMed identifiers (“PMID: …”). Therefore, PMIDs cannot be provided from tool-evidence in this run; all claims below are supported by the cited full-text evidence IDs and include DOI URLs and dates where available.

Key concepts and definitions (current understanding)

1.1 Definition and biochemical lesion IVA is an inborn error of leucine catabolism caused by deficiency of isovaleryl‑CoA dehydrogenase (IVD), a mitochondrial enzyme. A core definition used in multiple sources is that IVD “catalyzes the conversion of isovaleryl‑CoA to 3‑methylcrotonyl‑CoA,” and deficiency causes accumulation of isovaleric acid and characteristic derivatives (thimm2025practicalconsiderationsfor pages 1-2).

1.2 Diagnostic biochemical signature (metabolite pattern) The pathognomonic biochemical pattern is accumulation of isovaleryl‑CoA and appearance of downstream “derivates 3‑hydroxyisovaleric acid, isovaleryl (C5)‑carnitine and isovalerylglycine in body fluids” (thimm2025practicalconsiderationsfor pages 1-2). Reviews concur that urine organic acids are typically positive for “isovalerylglycine and 3‑hydroxyisovaleric acid,” and acylcarnitine profiling detects “isovalerylcarnitine (a C5 acylcarnitine)” (ramsay2018organicaciddisorders. pages 3-5).

1.3 Clinical phenotype spectrum IVA spans severe neonatal intoxication-type crises (ketoacidosis, encephalopathy) through attenuated “mild IVA” detected by newborn screening (NBS). The expert review notes clinical presentation “ranging from life‑threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype” (thimm2025practicalconsiderationsfor pages 1-2).

Core pathophysiology (molecular and cellular mechanisms)

2.1 Primary pathophysiological mechanisms A. Toxic metabolite accumulation and CoA trapping The fundamental lesion is upstream accumulation of isovaleryl‑CoA and isovaleric acid derivatives (thimm2025practicalconsiderationsfor pages 1-2, kuhn2023theglycinenacyltransferases pages 1-2). This is consistent with the “toxic metabolite” model of organic acidemias.

B. Secondary mitochondrial/TCA cycle dysfunction and bioenergetic compromise Mechanistic hypotheses include “impairment of the tricarboxylic acid cycle through the inhibition of citrate synthase and isocitrate dehydrogenase,” with “increased oxidative stress” and energy/acetyl‑CoA perturbation (thimm2025practicalconsiderationsfor pages 1-2). A broader “classical organic acidurias” synthesis frames neurologic injury as involving disruption of mitochondrial homeostasis, inhibition of respiratory chain/TCA enzymes, energy depletion, oxidative stress, and apoptosis-related pathways (villani2017“classicalorganicacidurias” pages 8-10, villani2017“classicalorganicacidurias” pages 14-16).

C. Urea cycle dysregulation → hyperammonemia Hyperammonemia in IVA is mechanistically linked to inhibition of N‑acetylglutamate synthase (NAGS), the enzyme generating the essential allosteric activator of CPS1. One review states explicitly: “Isovaleryl‑CoA functions as an N‑acetyl‑glutamate synthetase (NAGS) inhibitor leading to urea cycle impairment and hyperammonemia” (ramsay2018organicaciddisorders. pages 3-5). The expert review similarly attributes hyperammonemia to “the inhibition of N‑acetylglutamate synthase (NAGS) and acetyl‑CoA depletion” (thimm2025practicalconsiderationsfor pages 1-2). A classic organic aciduria review also connects hyperammonemia to isovaleryl‑CoA inhibition of N‑acetylglutamate synthetase and reduced urea cycle function (villani2017“classicalorganicacidurias” pages 8-10).

2.2 Dysregulated molecular pathways Key dysregulated pathways in IVA pathophysiology evidenced in the retrieved sources: • Leucine catabolic pathway (mitochondrial IVD step) (ramsay2018organicaciddisorders. pages 3-5, thimm2025practicalconsiderationsfor pages 1-2). • TCA cycle perturbation (citrate synthase, isocitrate dehydrogenase inhibition hypotheses) (thimm2025practicalconsiderationsfor pages 1-2). • Urea cycle control via NAGS→N‑acetylglutamate→CPS1 activation, with failure producing hyperammonemia (haberle2018hyperammonaemiainclassic pages 2-4, ramsay2018organicaciddisorders. pages 3-5). • Oxidative stress / ROS increase and impaired antioxidant defense in classic organic acidurias including IVA-relevant metabolite toxicity (villani2017“classicalorganicacidurias” pages 14-16, haberle2018hyperammonaemiainclassic pages 2-4).

2.3 Cellular processes affected Evidence-supported affected cellular processes include: • Mitochondrial energy metabolism / oxidative phosphorylation disruption in organic acidurias broadly, and mitochondrial energy reduction noted for IVA metabolites (haberle2018hyperammonaemiainclassic pages 2-4, kuhn2023theglycinenacyltransferases pages 1-2). • Oxidative damage and lipid peroxidation signaling (villani2017“classicalorganicacidurias” pages 14-16, kuhn2023theglycinenacyltransferases pages 2-3). • Ion homeostasis at neuronal membranes (Na+,K+-ATPase inhibition) (ribeiro2009creatineadministrationprevents pages 1-2, ribeiro2009creatineadministrationprevents pages 2-4).

Key molecular players (genes/proteins, metabolites, cells, anatomy)

3.1 Genes/proteins (HGNC-style symbol naming) • IVD (isovaleryl‑CoA dehydrogenase): deficient enzyme; mitochondrial flavoprotein; catalyzes isovaleryl‑CoA → 3‑methylcrotonyl‑CoA (thimm2025practicalconsiderationsfor pages 1-2). • NAGS (N‑acetylglutamate synthase): inhibited by isovaleryl‑CoA → reduced urea-cycle activation (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • CPS1 (carbamoyl phosphate synthetase 1): urea-cycle entry enzyme functionally impaired when N‑acetylglutamate is low (mechanistic description of NAGS→CPS1 regulation) (haberle2018hyperammonaemiainclassic pages 2-4). • GLYAT and GLYATL1 (glycine N‑acyltransferases): implicated in detoxification via glycine conjugation to form N‑isovalerylglycine; 2023 study provides in‑silico/in‑vitro validation that both can form N‑isovalerylglycine, but with “lower affinities” and with the notable observation that “an increase in glycine concentration does not result in an increase in N‑isovalerylglycine formation” (kuhn2023theglycinenacyltransferases pages 1-2).

3.2 Chemical entities (metabolites and therapeutics; CHEBI-style naming) Disease-relevant metabolites/biomarkers: • Isovaleryl‑CoA (toxic intermediate; CoA sequestration) (kuhn2023theglycinenacyltransferases pages 1-2). • Isovaleric acid (free acid; volatile; implicated in neurotoxicity/oxidative injury hypotheses) (thimm2025practicalconsiderationsfor pages 1-2, ribeiro2009creatineadministrationprevents pages 1-2). • Isovalerylglycine (N‑isovalerylglycine; urinary biomarker; detoxification product) (thimm2025practicalconsiderationsfor pages 1-2, villani2017“classicalorganicacidurias” pages 8-10). • Isovalerylcarnitine (C5 acylcarnitine; blood biomarker; NBS analyte) (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • 3‑hydroxyisovaleric acid (urine organic acid biomarker) (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5).

Therapeutically relevant small molecules: • Glycine (used to promote glycine conjugation; risk of hyperglycinemia noted; supplementation “should be carefully considered”) (kuhn2023theglycinenacyltransferases pages 2-3). • L‑carnitine (promotes acylcarnitine formation/excretion; noted to decrease free isovaleric acid during acute decompensation) (kuhn2023theglycinenacyltransferases pages 2-3). • N‑carbamylglutamate (a.k.a. carglumic acid): “approved pharmacological agent for the treatment of acute and chronic hyperammonemia in IVA” (kuhn2023theglycinenacyltransferases pages 2-3). • Creatine (experimental neuroprotection in rat model; see §4.2) (ribeiro2009creatineadministrationprevents pages 2-4).

3.3 Cell types primarily implicated (CL-style) Directly referenced cell types in the retrieved evidence: • Periportal hepatocytes and pericentral hepatocytes in the hepatic handling of ammonia/urea cycle and glutamine formation (haberle2018hyperammonaemiainclassic pages 2-4). • “Neuronal and glial cells” referenced in the context of metabolite effects on protein phosphorylation/cytoskeleton signaling in organic acidurias (villani2017“classicalorganicacidurias” pages 14-16, haberle2018hyperammonaemiainclassic pages 2-4).

3.4 Anatomical locations and organs involved (UBERON-style) • Liver (site of urea cycle; “complete urea cycle is mostly active in the liver”; site of phase II glycine conjugation) (haberle2018hyperammonaemiainclassic pages 2-4, kuhn2023theglycinenacyltransferases pages 1-2). • Brain, with explicit brain regions in pathogenesis discussion: “hippocampus,” “striatum,” and “cerebral cortex” (villani2017“classicalorganicacidurias” pages 14-16). • Cerebral cortex (site of Na+,K+-ATPase inhibition experiments) (ribeiro2009creatineadministrationprevents pages 1-2, ribeiro2009creatineadministrationprevents pages 2-4). • Expression sites noted for IVD include “thyroid, liver, and kidney” (kuhn2023theglycinenacyltransferases pages 1-2).

Disease progression model (sequence from trigger to clinical manifestations)

4.1 Trigger → catabolic stress → metabolite surge Clinical decompensations typically follow catabolic triggers (e.g., illness/fasting) and manifest as metabolic acidosis/ketosis and often hyperammonemia (thimm2025practicalconsiderationsfor pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4). Mechanistically, catabolism increases leucine flux, increasing isovaleryl‑CoA production upstream of the IVD block (thimm2025practicalconsiderationsfor pages 1-2).

4.2 Acute crisis phase mechanisms • Organic acid accumulation drives high-anion-gap metabolic acidosis and ketosis (thimm2025practicalconsiderationsfor pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4). • Hyperammonemia can emerge from urea-cycle inhibition due to NAGS inhibition and acetyl‑CoA depletion (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • Neurotoxicity can be mediated through impaired neuronal membrane ion homeostasis and TCA flux reduction. In a rat model, intracerebroventricular isovaleric acid inhibited Na+,K+-ATPase “up to ~25%” at both 2 h and 24 h after administration (ribeiro2009creatineadministrationprevents pages 2-4). The same study reports TCA-related effects at 24 h (e.g., ~22% reduced 14CO2 production from acetate; ~20% reduced citrate synthase activity) (ribeiro2009creatineadministrationprevents pages 1-2).

4.3 Chronic/long-term phase A central expert view is that oxidative stress and mitochondrial dysfunction contribute to neurological morbidity over time; one review states that “oxidative stress from chronic, persistent buildup of isovaleric acid is more neurologically detrimental than acute buildup” (ramsay2018organicaciddisorders. pages 3-5). Chronic complications are likely influenced by cumulative metabolic instability and repeated hyperammonemic episodes, where severity increases with longer duration of hyperammonemia (haberle2018hyperammonaemiainclassic pages 2-4).

Phenotypic manifestations and mechanistic linkage

5.1 Core clinical phenotypes (HP-style) Evidence-supported frequent manifestations include vomiting, encephalopathy, metabolic acidosis, hyperammonemia, and hypoglycemia. • A recent (2010–2023) Jordan cohort (n=21) reported vomiting 57.1%, encephalopathy 33.3%, acidosis 81%, hyperammonemia 71.4%, and hypoglycemia 14.3% (published 2024‑01‑10) (megdadi2024isovalericacidemiain pages 1-2, megdadi2024isovalericacidemiain pages 2-3).

5.2 Mechanistic linkage • Encephalopathy aligns with hyperammonemia and direct/indirect neurotoxic effects of metabolites and oxidative stress (haberle2018hyperammonaemiainclassic pages 2-4, villani2017“classicalorganicacidurias” pages 14-16). • Metabolic acidosis and ketosis reflect the intoxication phenotype of organic acid buildup (haberle2018hyperammonaemiainclassic pages 2-4).

Biological process (GO-style) and cellular component mapping (knowledge-base ready)

6.1 Disrupted biological processes (candidate GO terms) Based on explicit phrasing in the evidence: • Leucine catabolic process / branched-chain amino acid catabolism (IVD step) (thimm2025practicalconsiderationsfor pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4). • Urea cycle (via NAGS→CPS1 activation) and ammonia detoxification (haberle2018hyperammonaemiainclassic pages 2-4, thimm2025practicalconsiderationsfor pages 1-2). • Tricarboxylic acid cycle (hypothesized inhibition of citrate synthase/isocitrate dehydrogenase; and in vivo reduction of citrate synthase activity in cortex model) (thimm2025practicalconsiderationsfor pages 1-2, ribeiro2009creatineadministrationprevents pages 1-2). • Response to oxidative stress / ROS metabolic process (villani2017“classicalorganicacidurias” pages 14-16, haberle2018hyperammonaemiainclassic pages 2-4). • Glycine conjugation / acyl-CoA metabolic process (GLYAT/GLYATL1-mediated formation of N-isovalerylglycine) (kuhn2023theglycinenacyltransferases pages 1-2). • Ion transport and maintenance of membrane potential (Na+,K+-ATPase activity) (ribeiro2009creatineadministrationprevents pages 2-4).

6.2 Cellular components (candidate GO CC terms) • Mitochondrion / mitochondrial matrix: IVD is described as a “mitochondrial” enzyme; hepatic urea-cycle steps described in “mitochondrial matrix and cytosol of periportal hepatocytes” (thimm2025practicalconsiderationsfor pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4). • Synaptic plasma membrane / neuronal membrane systems (Na+,K+-ATPase assays in synaptic membrane preparations) (ribeiro2009creatineadministrationprevents pages 2-4).

Current applications and real-world implementations

7.1 Newborn screening (NBS): first-tier and confirmatory strategy NBS is widely implemented using tandem MS/MS measurement of C5 acylcarnitines. However, “standard NBS are the sum of all C5 isomers and isobars,” which creates a known false-positive problem when pivaloylcarnitine co-elutes/isobarically overlaps (murko2023neonatalscreeningfor pages 2-5). The practical diagnostic workflow emphasized across sources includes acylcarnitine profiling plus confirmatory urine organic acids (isovalerylglycine, 3‑hydroxyisovaleric acid) (thimm2025practicalconsiderationsfor pages 4-6, ramsay2018organicaciddisorders. pages 3-5).

7.2 Second-tier LC/UPLC-MS/MS to reduce false positives (implementation evidence) A 2023 German implementation study developed a second-tier UPLC‑MS/MS assay achieving “Excellent separation of pivaloyl-, 2-methylbutyryl-, isovaleryl-, and valerylcarnitine” (murko2023neonatalscreeningfor pages 2-5). In Hamburg (2019–2021), among 156,772 newborns, 100 had elevated C5 but only one was genetically confirmed IVA; 99 were attributed to pivaloylcarnitine (C5 0.5–8.2 μmol/L), with false positives rising “from 20 cases in 2019 to 53 cases in 2021” (murko2023neonatalscreeningfor pages 2-5). Figure evidence shows both chromatographic separation (Figure 1) and the cohort counts/summary (Figure 2) (murko2023neonatalscreeningfor media 6de62afe, murko2023neonatalscreeningfor media 78fa9051).

7.3 Machine learning as a “digital-tier” to improve specificity A 2023 study using 2,106,090 newborns screened in Heidelberg reported that ML reduced the false positive rate by 69.9% “from 103 to 31” while maintaining “100% sensitivity in cross-validation” (published 2023‑02‑18) (zaunseder2023machinelearningmethods pages 1-2). The cleaned dataset contained 22 mild IVA and 6 classic IVA cases, enabling computational separation of mild vs classic IVA from normal profiles using NBS metabolite features (zaunseder2023machinelearningmethods pages 2-3).

Recent developments (prioritizing 2023–2024)

8.1 Mechanistic/biochemical detoxification advances (2023) A 2023 mechanistic study addressed a long-standing uncertainty: which enzymes form N‑isovalerylglycine in humans. It reiterates that “GLYAT forms part of the phase II glycine conjugation pathway in the liver” and provides in‑silico/in‑vitro evidence that “both enzymes could form N-isovaleryglycine albeit at lower affinities,” with the key nuance that “an increase in glycine concentration does not result in an increase in N-isovalerylglycine formation” (available online 2023‑01‑31) (kuhn2023theglycinenacyltransferases pages 1-2).

8.2 Diagnostic innovation and implementation (2023–2024) • Second-tier chromatography to separate C5 isomers was operationalized with explicit platform parameters and strong linearity (R2 > 0.998) in a programmatic NBS setting (murko2023neonatalscreeningfor pages 2-5). • ML “digital-tier” approaches were shown to reduce false positives without sacrificing sensitivity in a >2 million sample dataset (zaunseder2023machinelearningmethods pages 1-2).

8.3 Updated cohort-level phenotype frequencies (2024) A 2024 (Jan) national center case-series provides contemporary frequencies for common presentations (acidosis, hyperammonemia, vomiting, encephalopathy) in a middle-income setting and argues for NBS implementation (megdadi2024isovalericacidemiain pages 1-2).

Expert opinions and analysis (authoritative synthesis)

9.1 Hyperammonemia framing and urgency An authoritative review emphasizes that hyperammonemia and accumulating toxic metabolites are “associated with life-threatening neurological complications” and that brain injury is multifactorial, including TCA/oxidative phosphorylation effects and oxidative stress mechanisms (haberle2018hyperammonaemiainclassic pages 2-4). This mechanistic framing supports aggressive acute management strategies.

9.2 Screening interpretation and “mild IVA” overdiagnosis risk NBS has increased apparent prevalence by detecting attenuated biochemical variants; ML and second-tier LC are proposed/implemented responses to reduce false positives and to mitigate burdens of over-referral/over-treatment (zaunseder2023machinelearningmethods pages 1-2, murko2023neonatalscreeningfor pages 2-5).

Relevant statistics and quantitative data (selected)

10.1 Screening and false positive statistics • Germany (Hamburg NBS cohort): 156,772 newborns; 100 elevated C5; 1 true IVA; 99 false positives due to pivaloylcarnitine; C5 false positive range 0.5–8.2 μmol/L; false positives increased from 20 (2019) to 53 (2021) (murko2023neonatalscreeningfor pages 2-5). (murko2023neonatalscreeningfor media 6de62afe, murko2023neonatalscreeningfor media 78fa9051) • Heidelberg ML dataset: final cleaned dataset 2,106,960 profiles including 103 false positives, 22 mild IVA, 6 classic IVA; ML reduced false positives by 69.9% (103→31) with 100% sensitivity in cross-validation (zaunseder2023machinelearningmethods pages 2-3, zaunseder2023machinelearningmethods pages 1-2).

10.2 Clinical cohort statistics (2024 case series) • Jordan cohort (n=21): acidosis 81%, hyperammonemia 71.4%, vomiting 57.1%, encephalopathy 33.3%, hypoglycemia 14.3% (megdadi2024isovalericacidemiain pages 1-2).

10.3 Experimental neurotoxicity quantitative data • Rat cerebral cortex model: intracerebroventricular IVA (5 μmol; 2 μL of 2.5 M per ventricle) inhibited Na+,K+-ATPase up to ~25% at 2 h and 24 h; creatine pre-treatment (50 mg/kg i.p., twice daily ×7 days) prevented the inhibition (ribeiro2009creatineadministrationprevents pages 2-4).

Structured knowledge-base entry elements (ontology-ready)

11.1 Pathophysiology description (narrative) IVA (OMIM 243500) is caused by deficiency of mitochondrial isovaleryl‑CoA dehydrogenase (IVD), blocking isovaleryl‑CoA conversion to 3‑methylcrotonyl‑CoA in leucine catabolism and causing accumulation of isovaleric acid and characteristic metabolites (3‑hydroxyisovaleric acid, isovaleryl‑carnitine/C5, isovalerylglycine). Accumulated metabolites and CoA sequestration disrupt mitochondrial and cellular homeostasis, with evidence and hypotheses spanning TCA cycle inhibition (citrate synthase/isocitrate dehydrogenase), oxidative stress/ROS, and membrane ion-pump dysfunction (Na+,K+-ATPase inhibition). A key systemic mechanism is secondary urea-cycle impairment: isovaleryl‑CoA inhibits NAGS and contributes to acetyl‑CoA depletion, reducing N‑acetylglutamate availability and impairing CPS1 activation, producing hyperammonemia and encephalopathy risk. Detoxification is supported clinically by shunting isovaleryl‑CoA into less toxic conjugates (isovalerylglycine, isovalerylcarnitine) via glycine/carnitine supplementation; mechanistically, 2023 work supports roles for GLYAT and GLYATL1 in N‑isovalerylglycine formation.

11.2 Gene/protein annotations (examples) • IVD: mitochondrial isovaleryl‑CoA dehydrogenase; leucine catabolism step; deficiency causes IVA (thimm2025practicalconsiderationsfor pages 1-2). • NAGS: inhibited by isovaleryl‑CoA; links IVA to hyperammonemia (ramsay2018organicaciddisorders. pages 3-5). • GLYAT/GLYATL1: glycine N‑acyltransferases implicated in isovaleryl‑CoA detoxification via N‑isovalerylglycine (kuhn2023theglycinenacyltransferases pages 1-2).

11.3 Phenotype associations (HP-style; evidence examples) • Metabolic acidosis: frequent in IVA cohort (81%) (megdadi2024isovalericacidemiain pages 1-2). • Hyperammonemia: frequent in IVA cohort (71.4%); mechanistically NAGS inhibition (megdadi2024isovalericacidemiain pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • Encephalopathy: reported 33.3% in cohort; linked to hyperammonemia and neurotoxicity mechanisms (megdadi2024isovalericacidemiain pages 1-2, haberle2018hyperammonaemiainclassic pages 2-4).

11.4 Cell-type involvement (CL-style; evidence examples) • Periportal hepatocytes / pericentral hepatocytes: urea-cycle localization and glutamine buffering described in organic acidemia hyperammonemia review (haberle2018hyperammonaemiainclassic pages 2-4). • Neuronal and glial cells: affected by toxic metabolites via signaling/cytoskeletal regulation in organic acidurias (villani2017“classicalorganicacidurias” pages 14-16).

11.5 Anatomical locations (UBERON-style; evidence examples) • Liver (urea cycle; glycine conjugation) (haberle2018hyperammonaemiainclassic pages 2-4, kuhn2023theglycinenacyltransferases pages 1-2). • Brain regions: cerebral cortex, hippocampus, striatum (villani2017“classicalorganicacidurias” pages 14-16).

11.6 Chemical entities (CHEBI-style; evidence examples) • Isovaleryl‑CoA, isovaleric acid, isovalerylglycine, isovalerylcarnitine, 3‑hydroxyisovaleric acid (thimm2025practicalconsiderationsfor pages 1-2, ramsay2018organicaciddisorders. pages 3-5). • N‑carbamylglutamate (carglumic acid) as approved therapy for IVA-related hyperammonemia (kuhn2023theglycinenacyltransferases pages 2-3).

Evidence items (selected; includes URLs and publication dates)

• Kühn et al. (Computational and Structural Biotechnology Journal). Available online 31 Jan 2023. DOI: https://doi.org/10.1016/j.csbj.2023.01.041. OMIM: 243500 stated. Evidence for GLYAT/GLYATL1 roles and constraints on glycine-driven conjugation (kuhn2023theglycinenacyltransferases pages 1-2). • Zaunseder et al. (Metabolites). Published 18 Feb 2023. DOI: https://doi.org/10.3390/metabo13020304. ML reduced false positives 69.9% with 100% sensitivity (zaunseder2023machinelearningmethods pages 1-2). • Murko et al. (JIMD Reports). Oct 2023. DOI: https://doi.org/10.1002/jmd2.12345. Second-tier UPLC‑MS/MS implementation; Hamburg cohort false positives largely pivaloylcarnitine; includes chromatographic figures (murko2023neonatalscreeningfor pages 1-2, murko2023neonatalscreeningfor pages 2-5, murko2023neonatalscreeningfor media 6de62afe). • Megdadi et al. (Cureus). Published 10 Jan 2024. DOI: https://doi.org/10.7759/cureus.52039. Cohort frequencies for acidosis/hyperammonemia/vomiting/encephalopathy (megdadi2024isovalericacidemiain pages 1-2).

Limitations • MONDO and PMIDs: not present in retrieved full text; therefore not included. OMIM 243500 is supported by multiple retrieved sources (kuhn2023theglycinenacyltransferases pages 1-2, zaunseder2023machinelearningmethods pages 1-2, thimm2025practicalconsiderationsfor pages 1-2). • Some mechanistic claims in classic organic aciduria reviews (e.g., apoptosis signaling, kinase/phosphatase perturbation) are discussed as broader OA mechanisms and may not be uniquely validated for IVA; this is indicated in those sources (villani2017“classicalorganicacidurias” pages 14-16, haberle2018hyperammonaemiainclassic pages 2-4).

References

(kuhn2023theglycinenacyltransferases pages 1-2): Stefan Kühn, Monray E. Williams, Marli Dercksen, Jörn Oliver Sass, and Rencia van der Sluis. The glycine n-acyltransferases, glyat and glyatl1, contribute to the detoxification of isovaleryl-coa - an in-silico and in vitro validation. Computational and Structural Biotechnology Journal, 21:1236-1248, Jan 2023. URL: https://doi.org/10.1016/j.csbj.2023.01.041, doi:10.1016/j.csbj.2023.01.041. This article has 12 citations and is from a peer-reviewed journal.
(zaunseder2023machinelearningmethods pages 1-2): Elaine Zaunseder, Ulrike Mütze, Sven F. Garbade, Saskia Haupt, Patrik Feyh, Georg F. Hoffmann, Vincent Heuveline, and Stefan Kölker. Machine learning methods improve specificity in newborn screening for isovaleric aciduria. Metabolites, 13:304, Feb 2023. URL: https://doi.org/10.3390/metabo13020304, doi:10.3390/metabo13020304. This article has 20 citations.
(thimm2025practicalconsiderationsfor pages 1-2): Eva Thimm, Anselma Riederer, Jerry Vockley, Dries Dobbelaere, Monique Williams, Anita MacDonald, Katharina Dokoupil, Ulrich A. Schatz, and Regina Ensenauer. Practical considerations for the diagnosis and management of isovaleryl-coa-dehydrogenase deficiency (isovaleric acidemia): systematic search and review and expert opinions. International Journal of Neonatal Screening, 11:92, Oct 2025. URL: https://doi.org/10.3390/ijns11040092, doi:10.3390/ijns11040092. This article has 0 citations.
(ramsay2018organicaciddisorders. pages 3-5): Jessica Ramsay, Jacob Morton, Marie Norris, and Shibani Kanungo. Organic acid disorders. Annals of translational medicine, 6 24:472, Dec 2018. URL: https://doi.org/10.21037/atm.2018.12.39, doi:10.21037/atm.2018.12.39. This article has 68 citations.
(villani2017“classicalorganicacidurias” pages 8-10): Guglielmo RD Villani, Giovanna Gallo, Emanuela Scolamiero, Francesco Salvatore, and Margherita Ruoppolo. “classical organic acidurias”: diagnosis and pathogenesis. Clinical and Experimental Medicine, 17:305-323, Aug 2017. URL: https://doi.org/10.1007/s10238-016-0435-0, doi:10.1007/s10238-016-0435-0. This article has 120 citations and is from a peer-reviewed journal.
(villani2017“classicalorganicacidurias” pages 14-16): Guglielmo RD Villani, Giovanna Gallo, Emanuela Scolamiero, Francesco Salvatore, and Margherita Ruoppolo. “classical organic acidurias”: diagnosis and pathogenesis. Clinical and Experimental Medicine, 17:305-323, Aug 2017. URL: https://doi.org/10.1007/s10238-016-0435-0, doi:10.1007/s10238-016-0435-0. This article has 120 citations and is from a peer-reviewed journal.
(haberle2018hyperammonaemiainclassic pages 2-4): Johannes Häberle, Anupam Chakrapani, Nicholas Ah Mew, and Nicola Longo. Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories. Orphanet Journal of Rare Diseases, Dec 2018. URL: https://doi.org/10.1186/s13023-018-0963-7, doi:10.1186/s13023-018-0963-7. This article has 84 citations and is from a peer-reviewed journal.
(kuhn2023theglycinenacyltransferases pages 2-3): Stefan Kühn, Monray E. Williams, Marli Dercksen, Jörn Oliver Sass, and Rencia van der Sluis. The glycine n-acyltransferases, glyat and glyatl1, contribute to the detoxification of isovaleryl-coa - an in-silico and in vitro validation. Computational and Structural Biotechnology Journal, 21:1236-1248, Jan 2023. URL: https://doi.org/10.1016/j.csbj.2023.01.041, doi:10.1016/j.csbj.2023.01.041. This article has 12 citations and is from a peer-reviewed journal.
(ribeiro2009creatineadministrationprevents pages 1-2): César Augusto João Ribeiro, Guilhian Leipnitz, Alexandre Umpierrez Amaral, Giorgia de Bortoli, Bianca Seminotti, and Moacir Wajner. Creatine administration prevents na+,k+-atpase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats. Brain Research, 1262:81-88, Mar 2009. URL: https://doi.org/10.1016/j.brainres.2009.01.005, doi:10.1016/j.brainres.2009.01.005. This article has 25 citations and is from a peer-reviewed journal.
(ribeiro2009creatineadministrationprevents pages 2-4): César Augusto João Ribeiro, Guilhian Leipnitz, Alexandre Umpierrez Amaral, Giorgia de Bortoli, Bianca Seminotti, and Moacir Wajner. Creatine administration prevents na+,k+-atpase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats. Brain Research, 1262:81-88, Mar 2009. URL: https://doi.org/10.1016/j.brainres.2009.01.005, doi:10.1016/j.brainres.2009.01.005. This article has 25 citations and is from a peer-reviewed journal.
(megdadi2024isovalericacidemiain pages 1-2): Noor Megdadi, Mo'men Alakil, Lina Ghanmiyin, Omar Maaita, and Amjad Abulannaz. Isovaleric acidemia in jordan. Cureus, Jan 2024. URL: https://doi.org/10.7759/cureus.52039, doi:10.7759/cureus.52039. This article has 0 citations.
(megdadi2024isovalericacidemiain pages 2-3): Noor Megdadi, Mo'men Alakil, Lina Ghanmiyin, Omar Maaita, and Amjad Abulannaz. Isovaleric acidemia in jordan. Cureus, Jan 2024. URL: https://doi.org/10.7759/cureus.52039, doi:10.7759/cureus.52039. This article has 0 citations.
(murko2023neonatalscreeningfor pages 2-5): Simona Murko, Asra Dadkhah Aseman, Friederike Reinhardt, Gwendolyn Gramer, Jürgen Günther Okun, Ulrike Mütze, and René Santer. Neonatal screening for isovaleric aciduria: reducing the increasingly high false‐positive rate in germany. JIMD Reports, 64:114-120, Oct 2023. URL: https://doi.org/10.1002/jmd2.12345, doi:10.1002/jmd2.12345. This article has 17 citations and is from a peer-reviewed journal.
(thimm2025practicalconsiderationsfor pages 4-6): Eva Thimm, Anselma Riederer, Jerry Vockley, Dries Dobbelaere, Monique Williams, Anita MacDonald, Katharina Dokoupil, Ulrich A. Schatz, and Regina Ensenauer. Practical considerations for the diagnosis and management of isovaleryl-coa-dehydrogenase deficiency (isovaleric acidemia): systematic search and review and expert opinions. International Journal of Neonatal Screening, 11:92, Oct 2025. URL: https://doi.org/10.3390/ijns11040092, doi:10.3390/ijns11040092. This article has 0 citations.
(murko2023neonatalscreeningfor media 6de62afe): Simona Murko, Asra Dadkhah Aseman, Friederike Reinhardt, Gwendolyn Gramer, Jürgen Günther Okun, Ulrike Mütze, and René Santer. Neonatal screening for isovaleric aciduria: reducing the increasingly high false‐positive rate in germany. JIMD Reports, 64:114-120, Oct 2023. URL: https://doi.org/10.1002/jmd2.12345, doi:10.1002/jmd2.12345. This article has 17 citations and is from a peer-reviewed journal.
(murko2023neonatalscreeningfor media 78fa9051): Simona Murko, Asra Dadkhah Aseman, Friederike Reinhardt, Gwendolyn Gramer, Jürgen Günther Okun, Ulrike Mütze, and René Santer. Neonatal screening for isovaleric aciduria: reducing the increasingly high false‐positive rate in germany. JIMD Reports, 64:114-120, Oct 2023. URL: https://doi.org/10.1002/jmd2.12345, doi:10.1002/jmd2.12345. This article has 17 citations and is from a peer-reviewed journal.
(zaunseder2023machinelearningmethods pages 2-3): Elaine Zaunseder, Ulrike Mütze, Sven F. Garbade, Saskia Haupt, Patrik Feyh, Georg F. Hoffmann, Vincent Heuveline, and Stefan Kölker. Machine learning methods improve specificity in newborn screening for isovaleric aciduria. Metabolites, 13:304, Feb 2023. URL: https://doi.org/10.3390/metabo13020304, doi:10.3390/metabo13020304. This article has 20 citations.
(murko2023neonatalscreeningfor pages 1-2): Simona Murko, Asra Dadkhah Aseman, Friederike Reinhardt, Gwendolyn Gramer, Jürgen Günther Okun, Ulrike Mütze, and René Santer. Neonatal screening for isovaleric aciduria: reducing the increasingly high false‐positive rate in germany. JIMD Reports, 64:114-120, Oct 2023. URL: https://doi.org/10.1002/jmd2.12345, doi:10.1002/jmd2.12345. This article has 17 citations and is from a peer-reviewed journal.

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