Metabolic Intoxication and Acute Decompensation Module

Metabolism Module metabolic_intoxication_decompensation 19 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 , Impaired bicarbonate supply to mitochondrial carboxylases → Toxic Metabolite Accumulation and Energy Deficit , Acute hyperammonemic metabolic crisis → Acute Metabolic Decompensation , 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

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

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

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

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

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

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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

Holocarboxylase Synthetase Deficiency as HLCS molecular function deficiency

Isovaleric Acidemia as Deficient leucine catabolic flux

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

Downstream

Toxic Metabolite Accumulation and Energy Deficit

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

Carbonic Anhydrase VA Deficiency as Impaired bicarbonate supply to mitochondrial carboxylases

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

Holocarboxylase Synthetase Deficiency as Impaired propionate metabolism

Isovaleric Acidemia as Toxic isovaleryl-CoA and organic acid accumulation

Maple Syrup Urine Disease as Systemic BCAA and BCKA Accumulation

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

Downstream

Acute Metabolic Decompensation

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

Carbonic Anhydrase VA Deficiency as Acute hyperammonemic metabolic crisis

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

Holocarboxylase Synthetase Deficiency as Secondary organic acidemia and ketotic decompensation

Isovaleric Acidemia as Catabolic acute metabolic decompensation

Lysinuric protein intolerance as Postprandial Hyperammonemic Decompensation

Methylmalonic Acidemia as Acute organic acid decompensation

Ornithine Carbamoyltransferase Deficiency as Systemic ammonia accumulation

TANGO2 Deficiency Disorder as Catabolic-Stress Metabolic Decompensation

Downstream

Acute Metabolic Encephalopathy

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

Ornithine Carbamoyltransferase Deficiency as Hyperammonemic cerebral injury via astrocyte swelling

TANGO2 Deficiency Disorder

Downstream

Neurological Injury and Multiorgan Crisis

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

Methylmalonic Acidemia as Neurometabolic brain injury