Metabolic Intoxication and Acute Decompensation Module

Metabolism Module metabolic_intoxication_decompensation 24 disorders Pathograph 5

A conserved final-common-pathway module for the "intoxication-type" inborn errors of intermediary metabolism: a deficient enzyme (or transporter) in amino-acid, organic-acid, fatty-acid, or urea-cycle metabolism causes accumulation of upstream toxic metabolites and/or a deficit in energy production. A catabolic stress (intercurrent illness, fasting, surgery, childbirth, or a protein load) unmasks the block and precipitates acute metabolic decompensation — the biochemical crisis of metabolic acidosis, hyperammonemia, and/or hypoglycemia. Toxic metabolites and bioenergetic failure then injure the brain, producing acute metabolic encephalopathy that can progress to irreversible neurological injury, multiorgan crisis, coma, or death. The urea-cycle disorders, classic organic acidemias (methylmalonic, propionic, isovaleric), maple syrup urine disease, and fatty-acid oxidation defects differ in the upstream enzymatic lesion and the identity of the accumulating metabolite but converge on this decompensation-to-encephalopathy chain. Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific deficient enzyme and toxic metabolite (e.g., OTC/ammonia in urea-cycle disorders, propionyl-CoA/methylmalonyl-CoA in organic acidemias, leucine/ketoacids in MSUD) while preserving the conserved chain.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

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Biological Processes

Cellular Amino Acid Catabolic Process GO:0009063 ↓ DECREASED Generation of Precursor Metabolites and Energy GO:0006091 ↓ DECREASED Urea Cycle GO:0000050 ↓ DECREASED Glucose Homeostasis GO:0042593 ⚠ ABNORMAL Glutamine Metabolic Process GO:0006541 ↑ INCREASED Neuronal Death GO:0051402 ↑ INCREASED

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "metabolic_intoxication_decompensation#Acute Metabolic Decompensation"). Conforming nodes should substitute the disorder-specific lesion: the deficient enzyme/transporter at the trigger node, the accumulating toxic metabolite at the amplifier node, and the predominant biochemical derangement (hyperammonemia vs. high-anion-gap metabolic acidosis vs. hypoglycemia) at the decompensation node. This module captures the acute intoxication/energy-crisis phenotype shared across urea-cycle disorders, organic acidemias, MSUD, and fatty-acid oxidation defects; it does NOT model the chronic disease-specific sequelae (basal-ganglia injury, cardiomyopathy, optic atrophy), which belong on the individual disorder entries. Chemistry (ammonia, organic acids) is given in prose; modules bind GO and CL terms only and do not use CHEBI bindings.

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Used By Disorder Entries

3-Hydroxy-3-Methylglutaric Aciduria via Acute hypoketotic metabolic decompensation → Acute Metabolic Decompensation

3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency via Acute Hypoketotic Metabolic Decompensation → Acute Metabolic Decompensation

3-Methylcrotonyl-CoA Carboxylase Deficiency via MCCC1/MCCC2-dependent methylcrotonyl-CoA carboxylase deficiency → Enzymatic Block in Intermediary Metabolism , Catabolic-stress acute metabolic decompensation → Acute Metabolic Decompensation

3-Methylglutaconic Aciduria Type I via AUH-dependent 3-methylglutaconyl-CoA hydratase deficiency → Enzymatic Block in Intermediary Metabolism

Arginase Deficiency via ARG1 molecular function deficiency → Enzymatic Block in Intermediary Metabolism

Argininosuccinic Aciduria via Impaired ureagenesis and hyperammonemia → Acute Metabolic Decompensation

Beta-Ketothiolase Deficiency via ACAT1 molecular function deficiency → Enzymatic Block in Intermediary Metabolism , Isoleucine-derived organic acid accumulation → Toxic Metabolite Accumulation and Energy Deficit , Episodic metabolic decompensation → Acute Metabolic Decompensation , Acute ketoacidotic crisis syndrome → Acute Metabolic Encephalopathy , Neurological complications and basal ganglia involvement → Neurological Injury and Multiorgan Crisis

Carbamoyl Phosphate Synthetase I Deficiency via CPS1 molecular function deficiency → Enzymatic Block in Intermediary Metabolism , Impaired mitochondrial ureagenesis → Toxic Metabolite Accumulation and Energy Deficit , Hyperammonemia-driven neurotoxicity → Acute Metabolic Encephalopathy

Carbonic Anhydrase VA Deficiency via Mitochondrial carbonic anhydrase VA deficiency → Enzymatic Block in Intermediary Metabolism , Hyperammonemic encephalopathy → Acute Metabolic Encephalopathy

Carnitine Palmitoyltransferase II Deficiency via Impaired mitochondrial long-chain fatty acid oxidation → Enzymatic Block in Intermediary Metabolism , LCAC-mediated calcium dyshomeostasis in skeletal muscle → Toxic Metabolite Accumulation and Energy Deficit , Metabolic myofiber injury and rhabdomyolysis → Acute Metabolic Decompensation

Citrin Deficiency via SLC25A13 transporter molecular function deficiency → Enzymatic Block in Intermediary Metabolism , Malate-aspartate shuttle dysfunction and hepatocellular energy crisis → Toxic Metabolite Accumulation and Energy Deficit , Impaired urea cycle and ammonia detoxification → Acute Metabolic Decompensation

Citrullinemia Type I via ASS1 molecular function deficiency → Enzymatic Block in Intermediary Metabolism , Impaired hepatic ureagenesis due to ASS1 deficiency → Toxic Metabolite Accumulation and Energy Deficit , Hyperammonemic neurotoxicity via astrocyte glutamine-osmotic injury → Acute Metabolic Encephalopathy , Secondary metabolic derangements during catabolic stress → Acute Metabolic Decompensation

Fructose-1,6-Bisphosphatase Deficiency via FBP1 Fructose-1,6-Bisphosphatase Deficiency → Enzymatic Block in Intermediary Metabolism , Gluconeogenic Substrate Accumulation and Energy Deficit → Toxic Metabolite Accumulation and Energy Deficit , Acute Metabolic Decompensation , Acute Metabolic Encephalopathy and Multiorgan Crisis → Neurological Injury and Multiorgan Crisis

Holocarboxylase Synthetase Deficiency via HLCS molecular function deficiency → Enzymatic Block in Intermediary Metabolism , Impaired propionate metabolism → Toxic Metabolite Accumulation and Energy Deficit , Secondary organic acidemia and ketotic decompensation → Acute Metabolic Decompensation , Neurologic metabolic decompensation → Acute Metabolic Encephalopathy

Isolated Glycerol Kinase Deficiency via Glycerol Kinase Loss of Function → Enzymatic Block in Intermediary Metabolism , Fasting and Catabolic-Stress Intolerance → Toxic Metabolite Accumulation and Energy Deficit , Hyperketotic Hypoglycaemic Decompensation → Acute Metabolic Decompensation

Isovaleric Acidemia via Deficient leucine catabolic flux → Enzymatic Block in Intermediary Metabolism , Toxic isovaleryl-CoA and organic acid accumulation → Toxic Metabolite Accumulation and Energy Deficit , Catabolic acute metabolic decompensation → Acute Metabolic Decompensation

Lysinuric protein intolerance via Postprandial Hyperammonemic Decompensation → Acute Metabolic Decompensation

Malonic Aciduria via Malonyl-CoA Decarboxylase Deficiency → Enzymatic Block in Intermediary Metabolism , Malonyl-CoA Accumulation → Toxic Metabolite Accumulation and Energy Deficit , Metabolic Decompensation with Acidosis and Hypoglycaemia → Acute Metabolic Decompensation

Maple Syrup Urine Disease via Branched-Chain Alpha-Ketoacid Dehydrogenase Complex Deficiency → Enzymatic Block in Intermediary Metabolism , Systemic BCAA and BCKA Accumulation → Toxic Metabolite Accumulation and Energy Deficit

Methylmalonate Semialdehyde Dehydrogenase Deficiency via ALDH6A1-dependent methylmalonate semialdehyde dehydrogenase deficiency → Enzymatic Block in Intermediary Metabolism

Methylmalonic Acidemia via Acute organic acid decompensation → Acute Metabolic Decompensation , Neurometabolic brain injury → Neurological Injury and Multiorgan Crisis

Methylmalonyl-CoA Epimerase Deficiency via MCEE Loss of Function → Enzymatic Block in Intermediary Metabolism , Accumulation of Propionate-Pathway Metabolites → Toxic Metabolite Accumulation and Energy Deficit , Acute Metabolic Decompensation under Catabolic Stress → Acute Metabolic Decompensation , Acute Encephalopathy and Neurological Injury → Acute Metabolic Encephalopathy

Ornithine Carbamoyltransferase Deficiency via Systemic ammonia accumulation → Acute Metabolic Decompensation , Hyperammonemic cerebral injury via astrocyte swelling → Acute Metabolic Encephalopathy

TANGO2 Deficiency Disorder via Impaired Mitochondrial Fatty-Acid Oxidation and Energy Reserve → Toxic Metabolite Accumulation and Energy Deficit , Catabolic-Stress Metabolic Decompensation → Acute Metabolic Decompensation , Acute Metabolic Encephalopathy

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Pathograph

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

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Pathophysiology

Enzymatic Block in Intermediary Metabolism

trigger

The conserved initiating lesion is a loss-of-function deficiency of an enzyme (or cofactor/transporter) in a core intermediary-metabolism pathway — amino-acid catabolism, organic-acid metabolism, mitochondrial fatty-acid beta-oxidation, or the urea cycle. The block interrupts normal substrate flux and primes the cell for accumulation of upstream intermediates whenever metabolic demand rises.

Hepatocyte CL:0000182

Cellular Amino Acid Catabolic Process GO:0009063 ↓ DECREASED

Used by disorders

3-Methylcrotonyl-CoA Carboxylase Deficiency as MCCC1/MCCC2-dependent methylcrotonyl-CoA carboxylase deficiency

3-Methylglutaconic Aciduria Type I as AUH-dependent 3-methylglutaconyl-CoA hydratase deficiency

Arginase Deficiency as ARG1 molecular function deficiency

Beta-Ketothiolase Deficiency as ACAT1 molecular function deficiency

Carbamoyl Phosphate Synthetase I Deficiency as CPS1 molecular function deficiency

Carbonic Anhydrase VA Deficiency as Mitochondrial carbonic anhydrase VA deficiency

Carnitine Palmitoyltransferase II Deficiency as Impaired mitochondrial long-chain fatty acid oxidation

Citrin Deficiency as SLC25A13 transporter molecular function deficiency

Citrullinemia Type I as ASS1 molecular function deficiency

Fructose-1,6-Bisphosphatase Deficiency as FBP1 Fructose-1,6-Bisphosphatase Deficiency

Holocarboxylase Synthetase Deficiency as HLCS molecular function deficiency

Isolated Glycerol Kinase Deficiency as Glycerol Kinase Loss of Function

Isovaleric Acidemia as Deficient leucine catabolic flux

Malonic Aciduria as Malonyl-CoA Decarboxylase Deficiency

Maple Syrup Urine Disease as Branched-Chain Alpha-Ketoacid Dehydrogenase Complex Deficiency

Methylmalonate Semialdehyde Dehydrogenase Deficiency as ALDH6A1-dependent methylmalonate semialdehyde dehydrogenase deficiency

Methylmalonyl-CoA Epimerase Deficiency as MCEE Loss of Function

Downstream

Toxic Metabolite Accumulation and Energy Deficit

Show evidence (1 reference)

PMID:25205257 SUPPORT Other

"Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC)."

Establishes the conserved trigger — deficiency of an intermediary-metabolism enzyme producing accumulation of upstream metabolites. Evidence source is OTHER because this is a review synthesizing the disease class.

Toxic Metabolite Accumulation and Energy Deficit

amplifier

Behind the block, upstream substrates and their derivatives accumulate to toxic concentrations while downstream energy substrates fall. A catabolic stress — intercurrent infection, fasting, surgery, childbirth, or an increased protein load — sharply increases the metabolic flux into the blocked pathway, overwhelming residual enzyme capacity and converting a compensated state into an acute crisis.

Hepatocyte CL:0000182

Generation of Precursor Metabolites and Energy GO:0006091 ↓ DECREASED

Used by disorders

Beta-Ketothiolase Deficiency as Isoleucine-derived organic acid accumulation

Carbamoyl Phosphate Synthetase I Deficiency as Impaired mitochondrial ureagenesis

Carnitine Palmitoyltransferase II Deficiency as LCAC-mediated calcium dyshomeostasis in skeletal muscle

Citrin Deficiency as Malate-aspartate shuttle dysfunction and hepatocellular energy crisis

Citrullinemia Type I as Impaired hepatic ureagenesis due to ASS1 deficiency

Fructose-1,6-Bisphosphatase Deficiency as Gluconeogenic Substrate Accumulation and Energy Deficit

Holocarboxylase Synthetase Deficiency as Impaired propionate metabolism

Isolated Glycerol Kinase Deficiency as Fasting and Catabolic-Stress Intolerance

Isovaleric Acidemia as Toxic isovaleryl-CoA and organic acid accumulation

Malonic Aciduria as Malonyl-CoA Accumulation

Maple Syrup Urine Disease as Systemic BCAA and BCKA Accumulation

Methylmalonyl-CoA Epimerase Deficiency as Accumulation of Propionate-Pathway Metabolites

TANGO2 Deficiency Disorder as Impaired Mitochondrial Fatty-Acid Oxidation and Energy Reserve

Downstream

Acute Metabolic Decompensation

Show evidence (1 reference)

PMID:33409766 SUPPORT Other

"During metabolic stress induced by infection, childbirth or surgery, a catabolic phase leads to the metabolism of a large amount of proteins. This excess intake will exceed the capacity of the urea cycle, especially if it has an enzymatic deficit. A significant production of ammonia then follows."

Defines the catabolic-stress amplifier step in which increased substrate flux exceeds residual enzyme capacity and drives toxic-metabolite accumulation. Evidence source is OTHER because this is a review article.

Acute Metabolic Decompensation

central effector

The crisis manifests biochemically as some combination of high-anion-gap metabolic acidosis (often with lactic acidosis and ketosis), hyperammonemia, and hypoglycemia. The precise pattern depends on the underlying defect — hyperammonemia predominates in urea-cycle disorders, metabolic acidosis and ketosis in organic acidemias, hypoglycemia in fatty-acid oxidation defects — but the decompensated state is the shared central effector that converts the metabolic block into systemic toxicity.

Hepatocyte CL:0000182

Urea Cycle GO:0000050 ↓ DECREASED Glucose Homeostasis GO:0042593 ⚠ ABNORMAL

Used by disorders

3-Hydroxy-3-Methylglutaric Aciduria as Acute hypoketotic metabolic decompensation

3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency as Acute Hypoketotic Metabolic Decompensation

3-Methylcrotonyl-CoA Carboxylase Deficiency as Catabolic-stress acute metabolic decompensation

Argininosuccinic Aciduria as Impaired ureagenesis and hyperammonemia

Beta-Ketothiolase Deficiency as Episodic metabolic decompensation

Carnitine Palmitoyltransferase II Deficiency as Metabolic myofiber injury and rhabdomyolysis

Citrin Deficiency as Impaired urea cycle and ammonia detoxification

Citrullinemia Type I as Secondary metabolic derangements during catabolic stress

Fructose-1,6-Bisphosphatase Deficiency

Holocarboxylase Synthetase Deficiency as Secondary organic acidemia and ketotic decompensation

Isolated Glycerol Kinase Deficiency as Hyperketotic Hypoglycaemic Decompensation

Isovaleric Acidemia as Catabolic acute metabolic decompensation

Lysinuric protein intolerance as Postprandial Hyperammonemic Decompensation

Malonic Aciduria as Metabolic Decompensation with Acidosis and Hypoglycaemia

Methylmalonic Acidemia as Acute organic acid decompensation

Methylmalonyl-CoA Epimerase Deficiency as Acute Metabolic Decompensation under Catabolic Stress

Ornithine Carbamoyltransferase Deficiency as Systemic ammonia accumulation

TANGO2 Deficiency Disorder as Catabolic-Stress Metabolic Decompensation

Downstream

Acute Metabolic Encephalopathy

Show evidence (2 references)

PMID:22593918 SUPPORT Other

"It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias."

Enumerates the conserved biochemical hallmarks of acute decompensation (anion-gap metabolic acidosis, hyperammonemia, hypoglycemia). Evidence source is OTHER because this is a GeneReviews-type review.

PMID:27653704 SUPPORT Other

"During decompensation, acidosis in these patients occurs due to accumulation of organic acids and ketoacids, while lactic acidosis also occurs, particularly in severe decompensation or with severe secondary mitochondrial dysfunction"

Links toxic-metabolite accumulation and secondary mitochondrial dysfunction to the acidosis of decompensation. Evidence source is OTHER because this is a review article.

Acute Metabolic Encephalopathy

effector

Circulating toxic metabolites — ammonia in particular — cross the blood-brain barrier and exert direct neurotoxicity. Ammonia is detoxified in astrocytes via glutamine synthesis; glutamine is the brain's main intracellular osmole, so its accumulation drives astrocyte swelling and cytotoxic cerebral edema. The result is acute encephalopathy presenting as lethargy, feeding refusal, hypotonia, seizures, and progressive depression of consciousness.

Astrocyte CL:0000127 Neuron CL:0000540

Glutamine Metabolic Process GO:0006541 ↑ INCREASED

Used by disorders

Beta-Ketothiolase Deficiency as Acute ketoacidotic crisis syndrome

Carbamoyl Phosphate Synthetase I Deficiency as Hyperammonemia-driven neurotoxicity

Carbonic Anhydrase VA Deficiency as Hyperammonemic encephalopathy

Citrullinemia Type I as Hyperammonemic neurotoxicity via astrocyte glutamine-osmotic injury

Holocarboxylase Synthetase Deficiency as Neurologic metabolic decompensation

Methylmalonyl-CoA Epimerase Deficiency as Acute Encephalopathy and Neurological Injury

Ornithine Carbamoyltransferase Deficiency as Hyperammonemic cerebral injury via astrocyte swelling

TANGO2 Deficiency Disorder

Downstream

Neurological Injury and Multiorgan Crisis

Show evidence (2 references)

PMID:33409766 SUPPORT Other

"Ammonia passes into the circulation and crosses the blood–brain barrier. The ammonia will exert a direct toxic effect on the neurotransmission responsible for part of the neurological symptomatology."

Establishes ammonia crossing the blood-brain barrier as the proximate cause of metabolic encephalopathy. Evidence source is OTHER because this is a review article.

PMID:33409766 SUPPORT Other

"Glutamine is the main intracellular osmole of the brain. Its accumulation causes the swelling of astrocytes during hyperammonemia"

Describes the astrocyte glutamine-osmole mechanism of cytotoxic cerebral edema in hyperammonemic encephalopathy. Evidence source is OTHER because this is a review article.

Neurological Injury and Multiorgan Crisis

consequence

If decompensation is not rapidly reversed, the combination of metabolite toxicity and bioenergetic failure produces irreversible neurological injury and multiorgan compromise. Acutely this is intracranial hypertension, coma, and death; survivors may carry chronic sequelae. End-organ injury reflects both the direct toxicity of accumulating metabolites and the secondary failure of the Krebs cycle and oxidative phosphorylation.

Neuron CL:0000540

Neuronal Death GO:0051402 ↑ INCREASED

Used by disorders

Beta-Ketothiolase Deficiency as Neurological complications and basal ganglia involvement

Fructose-1,6-Bisphosphatase Deficiency as Acute Metabolic Encephalopathy and Multiorgan Crisis

Methylmalonic Acidemia as Neurometabolic brain injury

Show evidence (2 references)

PMID:37938118 SUPPORT Other

"Urea cycle disorders (UCDs) cause elevations in ammonia which, when severe, cause irreversible neurologic injury."

Links severe decompensation to irreversible neurological injury, the consequence step of this module. Evidence source is OTHER because this is a review-style statement of the disease class.

PMID:27653704 SUPPORT Other

"End-organ injury occurs due to both primary toxicity of both the accumulating primary and secondary metabolites and deficiency of succinyl-CoA resulting in Kreb cycle and oxidative phosphorylation dysfunction."

Defines the dual mechanism of end-organ injury — metabolite toxicity plus bioenergetic (Krebs/OXPHOS) failure. Evidence source is OTHER because this is a review article.