Acute Ackee Fruit Intoxication

Complex MONDO:0019140 Pathograph 38 Show in embeddings browser Poisoning

Acute ackee fruit intoxication is an acquired foodborne poisoning associated with hypoglycin A in unripe or improperly processed Blighia sapida fruit and toxic seeds. Bioactivation produces MCPA-CoA, which inhibits selected mitochondrial acyl-CoA dehydrogenases. Impaired fatty-acid oxidation, ketogenesis and hepatic glucose production can cause profound hypoglycemia and neurological deterioration. Vomiting is common, but hypoglycemia and vomiting are not obligatory in every reported case. Human urinary organic-acid findings and comparative animal experiments support the metabolic mechanism; they do not make human poisoning diagnostically indistinguishable from inherited fatty-acid oxidation disorders. Management is prompt glucose correction and supportive care, with prevention through safe harvesting and processing.

Ask OpenScientist

Ask a research question about Acute Ackee Fruit Intoxication. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

Discussions and Knowledge Gaps

How much does co-exposure to methylenecyclopropylglycine contribute to symptomatic human ackee poisoning?

KNOWLEDGE GAP OPEN mcpg_contribution_to_ackee_illness

Attached to

pathophysiology#Hypoglycin A Ingestion

MCPG-related conjugates have been detected after ackee consumption, including in a volunteer study, but an exposed volunteer is not a clinical Jamaican vomiting sickness cohort. HGA remains the main established toxin. Quantitative clinical attribution and potential co-toxin effects remain unresolved.

Proposed experiments

Prospective paired toxin and metabolite sampling

paired_toxin_metabolite_sampling

Measure HGA, MCPG and conjugates over time in clinically characterized poisoning cases and asymptomatic people sharing the implicated food; record dose, preparation, nutritional status and sampling delay.

Decision criterion

Determine whether MCPG exposure or its metabolites associate with clinical severity after accounting for HGA exposure and sampling time.

Supporting outcome

A reproducible adjusted association would support a co-toxin contribution and justify targeted mechanistic testing.

Refuting outcome

Absence of an association would weaken the proposed contribution within the sampled exposures, without proving HGA acts alone.

The 2021 foal report inferred long-chain enoyl-CoA hydratase dysfunction from acylcarnitines; no enzyme assay or genetic confirmation was available. It does not establish a corresponding human ackee mechanism.

Show evidence (2 references)

PMID:30056267 SUPPORT DIRECT BACKGROUND Other

"Both metabolites were detected in urine after ingestion of ackee as well as litchi fruit. These results created a renewed interest in cases of JVS, with respect to whether MCPG may be a causative agent along with HGA."

Background summarizes the healthy-adult exposure result.

PMID:33233889 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Rapid intestinal absorption of the toxins was followed by their slow degradation to methylenecyclopropylacetyl and methylenecyclopropylformyl conjugates."

A single-volunteer metabolic study establishes co-exposure, not a disease-specific causal fraction.

Which hepatic and extrahepatic flux defects dominate in confirmed human poisoning?

KNOWLEDGE GAP OPEN human_isoform_and_flux_translation

Attached to

pathophysiology#Selective Acyl-CoA Dehydrogenase Inactivation pathophysiology#Reduced Hepatic Glucose Production

Purified enzyme, isolated cell and intravenous rat protocols differ in substrates, dose and duration. Human clinical metabolite series are small, and asymptomatic exposure can alter metabolism. Prospective clinically confirmed sampling is needed before assigning universal profiles, isoform inhibition fractions or biomarker prognostic thresholds.

Show evidence (1 reference)

PMID:29483297 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"While we do not have an in vivo method to probe flux through the individual steps of β-oxidation, we are able to infer the step in β-oxidation targeted by the toxin-CoA conjugates"

The rodent authors acknowledge indirect enzyme-step inference.

⚙

Pathophysiology

Hypoglycin A Ingestion

Oral exposure occurs through unripe or inadequately processed arils and toxic seeds. The dose and preparation vary; detection of exposure does not itself establish symptomatic poisoning.

Downstream

Hypoglycin A Transamination Absorbed hypoglycin undergoes metabolic activation.

Vomiting Gastrointestinal toxicity follows exposure; vomiting is not assumed to require antecedent hypoglycemia.

Abdominal pain Abdominal pain was observed after the shared exposure in the Nigerian family.

Diarrhea Delayed loose stools occurred in five exposed siblings, despite being atypical of the classic vomiting syndrome.

Hepatocellular Injury Toxic exposure may contribute to hepatic injury; the severe case is confounded and no single cellular sequence is established.

Muscle weakness This manifestation is reported after exposure, but the precise intervening pathway is not resolved in the cited human evidence.

Hypotonia This manifestation is reported after exposure, but the precise intervening pathway is not resolved in the cited human evidence.

Hypothermia This manifestation is reported after exposure, but the precise intervening pathway is not resolved in the cited human evidence.

Metabolic acidosis This manifestation is reported after exposure, but the precise intervening pathway is not resolved in the cited human evidence.

Dehydration Vomiting-associated fluid loss can cause dehydration.

Show evidence (1 reference)

PMID:26324727 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We report a case series of eight previously well Nigerian siblings who presented at various intervals after ingestion of roasted seeds and aril of the ackee fruit."

A shared meal caused a clinically heterogeneous family cluster; both seeds and arils were consumed.

Hypoglycin A Transamination

Aminotransferase-mediated conversion of hypoglycin A to methylenecyclopropylpyruvate precedes generation of the inhibitory CoA ester.

Downstream

MCPA-CoA Formation Mitochondrial oxidative decarboxylation converts the keto-acid intermediate into the CoA ester.

Show evidence (1 reference)

PMID:26328472 SUPPORT DIRECT BACKGROUND Other

"Once ingested, hypoglycin A is converted by an aminotransferase in the cytosol to methylenecyclopropylpyruvate (MCP-pyruvate)"

The analytical paper summarizes the established transamination step from prior metabolic studies.

MCPA-CoA Formation

Oxidative decarboxylation of the keto-acid intermediate generates methylenecyclopropylacetyl-CoA. Its conjugated excretion products support bioactivation in humans; direct hepatic CoA-ester identification comes from experimental rats.

Animal models

MCPA infusion in fasted conscious rats Rat measures Hepatic MCPA-CoA was identified by LC-MS/MS.

Equine atypical myopathy and seasonal pasture myopathy Horse partially recapitulates The natural disease supplies comparative toxin-conjugate and metabolic-profile measurements.

Hypoglycin A and MCPA immersion in zebrafish embryos and larvae Zebrafish (Danio rerio) partially recapitulates HGA-exposed larvae accumulated the downstream conjugate MCPA-carnitine.

Downstream

Selective Acyl-CoA Dehydrogenase Inactivation The activated toxin interacts with susceptible enzyme active sites and can covalently modify FAD.

Show evidence (2 references)

PMID:26328472 SUPPORT DIRECT BACKGROUND Other

"MCP-pyruvate is then decarboxylated and conjugated as a CoA ester (MCPA-CoA) in the liver by a mitochondrial branched-chain dehydrogenase."

Background pathway describes formation of the inhibitory CoA ester; human urinary detection alone does not measure each reaction.

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We identified the MCPA-CoA adduct by tandem LC-mass spectrometry in MCPA treated rat liver"

The hepatic CoA ester was directly identified after intravenous MCPA, which bypasses hypoglycin transamination.

Selective Acyl-CoA Dehydrogenase Inactivation

MCPA-CoA irreversibly inhibits susceptible flavin-dependent acyl-CoA dehydrogenases. Purified-enzyme studies include short-chain, medium-chain and isovaleryl-CoA dehydrogenases, with different susceptibility of other isoforms. The less-than-2% residual activity in a pig-kidney preparation is not a universal patient value.

acyl-CoA dehydrogenase activity GO:0003995 ↓ DECREASED

Experimental models

Purified mammalian acyl-CoA dehydrogenase inhibition OTHER Purified pig-kidney enzyme loses nearly all activity with covalent FAD modification.

Animal models

Hypoglycin exposure in rats Rat measures Activity measured with butyryl-CoA decreased, while octanoyl- and palmitoyl-CoA activities were unchanged in this preparation.

Downstream

Impaired Fatty Acid Beta-Oxidation Loss of dehydrogenase activity restricts the first reaction of beta-oxidation for susceptible substrates.

Show evidence (2 references)

PMID:7275979 SUPPORT DIRECT PRIMARY RESULT In Vitro

"During inactivation, about 80% of the enzyme FAD is covalently and irreversibly modified with the residual inhibition possibly resulting from modification of the protein."

Purified pig-kidney enzyme establishes covalent FAD modification; the percentage is assay-specific.

PMID:2331485 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Short-chain acyl-CoA (SCADH), medium-chain acyl-CoA (MCADH) and isovaleryl-CoA (IVDH) dehydrogenases were severely and irreversibly inactivated by MCPA-CoA, while 2-methyl-branched chain acyl-CoA dehydrogenase (2-meBCADH) was only slowly and mildly inactivated."

Purified-enzyme comparisons establish selective multi-enzyme inhibition, including MCAD.

Impaired Fatty Acid Beta-Oxidation

Inhibition of selected dehydrogenases impairs fatty-acid oxidation and alters hepatic acyl-CoA pools. Human organic aciduria is consistent with this block, while chain-specific pathway mapping derives mainly from enzyme and rodent experiments.

fatty acid beta-oxidation GO:0006635 ↓ DECREASED

Animal models

Equine atypical myopathy and seasonal pasture myopathy Horse partially recapitulates The natural disease supplies comparative toxin-conjugate and metabolic-profile measurements.

Hypoglycin A and MCPA immersion in zebrafish embryos and larvae Zebrafish (Danio rerio) partially recapitulates Short- and medium-chain acylcarnitine changes provide indirect evidence of disturbed fatty-acid metabolism.

Downstream

Reduced Hepatic Acetyl-CoA Reduced oxidative throughput is associated with diminished production of acetyl-CoA.

Reduced Hepatic ATP Availability Reduced fatty-acid oxidation limits reducing-equivalent supply to oxidative phosphorylation; the rat study measures the resulting nucleotide changes.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Hepatic acetyl-CoA was reduced by 84% (Figure 5E), while other short chain CoAs, including butyryl CoA and hexaryl CoA, were markedly increased"

Hepatic metabolite changes after MCPA support impaired oxidation, particularly of short-chain substrates; individual enzyme flux was not directly measured.

Reduced Hepatic Acetyl-CoA

MCPA-treated fasted rats have reduced hepatic acetyl-CoA together with accumulation of several other short-chain acyl-CoAs.

Animal models

MCPA infusion in fasted conscious rats Rat measures Hepatic acetyl-CoA decreased 84%.

Downstream

Reduced Hepatic Pyruvate Carboxylase Flux Acetyl-CoA allosterically activates pyruvate carboxylase; toxin-associated depletion accompanies lower flux, but this mediator was not selectively restored.

Reduced Ketogenesis Reduced availability of acetyl-CoA substrate contributes to lower hepatic ketone production.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Hepatic acetyl-CoA was reduced by 84% (Figure 5E), while other short chain CoAs, including butyryl CoA and hexaryl CoA, were markedly increased"

The measured hepatic acetyl-CoA reduction follows MCPA exposure in fasted rats.

Reduced Hepatic ATP Availability

MCPA reduces hepatic ATP content and ATP/ADP ratio in fasted rats. This is one proposed contributor to reduced gluconeogenesis, not a universal complete loss of cellular energy.

Animal models

MCPA infusion in fasted conscious rats Rat measures Hepatic ATP decreased 13% and ATP/ADP decreased 30%.

Downstream

Reduced Hepatic Glucose Production Reduced energy availability is a proposed additional limitation on energy-requiring gluconeogenic reactions.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the more potent toxin, MCPA, caused a 13% reduction in hepatic ATP content and a 65% increase in hepatic AMP content."

Hepatic nucleotide measurements establish a modest ATP reduction in this rat protocol.

Reduced Hepatic Pyruvate Carboxylase Flux

Estimated hepatic pyruvate-carboxylase flux decreases after MCPA. Reduced acetyl-CoA activation and increased inhibitory short-chain acyl-CoAs are candidate mediators; their separate necessity was not tested by rescue.

pyruvate carboxylase activity GO:0004736 ↓ DECREASED

Animal models

MCPA infusion in fasted conscious rats Rat measures PINTA-estimated absolute PC flux decreased 75%.

Downstream

Reduced Hepatic Glucose Production Reduced entry of pyruvate carbon through oxaloacetate restricts gluconeogenic output.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Accounting for the reduction we observed in EGP, absolute PC flux was reduced by 75% in MCPA treated rats"

Isotope-based PINTA estimates hepatic pyruvate-carboxylase flux in awake rats, not purified enzyme activity.

Reduced Hepatic Glucose Production

Tracer studies show reduced endogenous glucose production after MCPA, without increased glucose clearance. The clinical importance is failure to maintain glucose supply, particularly when fasting reserves are limited.

gluconeogenesis GO:0006094 ↓ DECREASED

Experimental models

Ketohypoglycin in isolated rat hepatocytes PRIMARY CELL CULTURE Gluconeogenesis is inhibited in a substrate-dependent manner.

Animal models

MCPA infusion in fasted conscious rats Rat measures Endogenous production fell by approximately half without changed clearance.

Downstream

Hypoglycemia Reduced endogenous glucose supply contributes to the low glucose observed in clinical poisoning.

Neuroglycopenia The intervening fall in blood glucose limits cerebral fuel availability.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"EGP was assessed at 90–120 minutes after MCPA administration, and was reduced by half (Figure 4C). Glucose clearance, however, was unchanged"

Tracer measurements distinguish reduced endogenous production from increased peripheral disposal.

Reduced Ketogenesis

Ketone production and circulating beta-hydroxybutyrate decrease in MCPA-treated rats. This can restrict an alternative fuel during fasting; it does not establish that all human cases are completely aketotic.

ketone body biosynthetic process GO:0046951 ↓ DECREASED

Animal models

MCPA infusion in fasted conscious rats Rat measures Beta-hydroxybutyrate turnover decreased 82% and concentration 92%.

Downstream

Neuroglycopenia Reduced ketone availability may amplify cerebral energy deprivation during hypoglycemia; direct mediation was not tested in human ackee poisoning.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"After administration of MCPA, β-hydroxybutyrate turnover decreased by 82% and plasma β-hydroxybutyrate concentration fell by 92%, reflecting a near-ablation of ketone body production"

Rat ketone turnover and concentration decrease; no equivalent quantitative human series is available.

Neuroglycopenia

In severe hypoglycemic poisoning, inadequate glucose availability contributes to cerebral dysfunction. Clinical neurological deterioration need not be exclusively neuroglycopenic, particularly with concurrent liver injury or other metabolic disturbances.

Downstream

Encephalopathy Cerebral fuel deprivation can contribute to this severe manifestation; other causes of neurological dysfunction remain possible.

Seizure Cerebral fuel deprivation can contribute to this severe manifestation; other causes of neurological dysfunction remain possible.

Coma Cerebral fuel deprivation can contribute to this severe manifestation; other causes of neurological dysfunction remain possible.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Mortality generally results from profound, untreated hypoglycemia, leading to irreversible cerebral injury and multiorgan failure."

Clinical review links severe untreated hypoglycemia to cerebral injury; other routes to encephalopathy remain possible.

Hepatocellular Injury

Hepatic injury is a reported complication. A fulminant case had bridging and multiacinar necrosis with focal microvesicular steatosis, but exposure was unconfirmed and sickling-related ischemia substantially confounded attribution. The intervening injury mechanism in human ackee poisoning remains incompletely resolved.

Downstream

Elevated hepatic transaminase Hepatocyte injury can elevate circulating liver enzymes.

Acute liver failure Extensive hepatic injury may progress to synthetic dysfunction and liver failure.

Encephalopathy Hepatic dysfunction provides an additional route to encephalopathy independent of documented hypoglycemia.

Show evidence (2 references)

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"There are bridging and multiacinar necroses with approximation of adjacent portal tracts and severe centrilobular congestion and hemorrhage"

Direct pathology finding in one suspected poisoning; unconfirmed toxin exposure and concomitant sickling-related ischemia limit causal attribution.

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Cholestasis and small fat droplets (microvesicular steatosis) are seen in the neighboring hepatocytes"

Direct histology documents focal microvesicular steatosis, without resolving its toxic versus ischemic cause.

⬡

Pathograph

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

●

Phenotypes

Digestive 3

Vomiting HP:0002013

Temporal: ACUTE

Show evidence (1 reference)

PMID:28613753 SUPPORT DIRECT BACKGROUND Human Clinical

"Clinical manifestations typically include repetitive vomiting, altered mental status, and profound hypoglycemia."

Clinical toxicology review documents this manifestation; no population frequency is assigned.

Diarrhea HP:0002014

Temporal: ACUTE

Show evidence (1 reference)

PMID:26324727 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"They were asymptomatic and were managed as out patients until 4 days post-ingestion when they developed intermittent abdominal pain and passage of loose, mucoid stools."

Delayed loose stools in one family cluster.

Acute liver failure Acute hepatic failure HP:0006554

Temporal: ACUTE

Show evidence (2 references)

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"On admission, she was in fulminant hepatic failure with hepatic encephalopathy."

The reported patient had liver failure and encephalopathy; exposure was unconfirmed and sickling-related ischemia confounded attribution.

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"After one successful code, her code status was changed to “Do Not Resuscitate.” She expired 6 hours later."

The patient died after emergency transplantation; a single confounded case does not establish a transplant success rate.

Metabolism 5

Hypoglycemia HP:0001943

Temporal: ACUTE Severity: SEVERE

Show evidence (1 reference)

PMID:28613753 SUPPORT DIRECT BACKGROUND Human Clinical

"Clinical manifestations typically include repetitive vomiting, altered mental status, and profound hypoglycemia."

Clinical toxicology review documents this manifestation; no population frequency is assigned.

Hypothermia HP:0002045

Temporal: ACUTE

Show evidence (1 reference)

PMID:28613753 SUPPORT DIRECT BACKGROUND Human Clinical

"Severe toxicity may result in seizures, hypothermia, coma, and death."

Clinical toxicology review documents this manifestation; no population frequency is assigned.

Dehydration HP:0001944

Temporal: ACUTE

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Severe electrolyte disturbances, dehydration secondary to persistent vomiting, metabolic acidosis, and hepatic dysfunction may also occur."

Review describes the volume-loss complication.

Metabolic acidosis HP:0001942

Temporal: ACUTE

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Severe electrolyte disturbances, dehydration secondary to persistent vomiting, metabolic acidosis, and hepatic dysfunction may also occur."

Clinical review supports acidosis without a uniform frequency or cause.

Elevated hepatic transaminase Elevated circulating hepatic transaminase concentration HP:0002910

Temporal: ACUTE

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Diagnostic evaluation typically reveals marked hypoglycemia, high anion gap metabolic acidosis, electrolyte derangements, elevated transaminases, and evidence of hepatic dysfunction."

Secondary clinical summary; individual cases may have normal liver tests.

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"aspartate aminotransferase (AST) 620 U/L (reference range 1–50), alanine aminotransferase (ALT) 478 U/L (reference range 1–53)"

Admission measurements establish transaminase elevation in the confounded severe hepatic case.

Musculoskeletal 2

Muscle weakness HP:0001324

Temporal: ACUTE

Show evidence (1 reference)

PMID:26324727 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her symptoms had started 2 hours after ingestion of six roasted seeds and arils of ackee fruit. Loss of consciousness was preceded by vomiting and extreme body weakness."

Observed weakness in the index child.

Hypotonia HP:0001252

Temporal: ACUTE

Show evidence (1 reference)

PMID:10028981 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The most common symptoms were hypotonia, vomiting, convulsions, and coma. All children died in 2-48 h."

The cohort was selected for fatal encephalopathy and exposure attribution was probabilistic.

Nervous System 3

Encephalopathy HP:0001298

Temporal: ACUTE

Show evidence (3 references)

PMID:28613753 SUPPORT DIRECT BACKGROUND Human Clinical

"Clinical manifestations typically include repetitive vomiting, altered mental status, and profound hypoglycemia."

Clinical toxicology review documents this manifestation; no population frequency is assigned.

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"On admission, she was in fulminant hepatic failure with hepatic encephalopathy."

The reported patient had liver failure and encephalopathy; exposure was unconfirmed and sickling-related ischemia confounded attribution.

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"On presentation she was encephalopathic but not hypoglycemic, although hypoglycemia is a classic sign of JVS"

The hepatic case provides a reported route to encephalopathy without documented hypoglycemia; attribution remains confounded.

Seizure HP:0001250

Temporal: ACUTE

Show evidence (1 reference)

PMID:28613753 SUPPORT DIRECT BACKGROUND Human Clinical

"Severe toxicity may result in seizures, hypothermia, coma, and death."

Clinical toxicology review documents this manifestation; no population frequency is assigned.

Coma HP:0001259

Temporal: ACUTE

Show evidence (1 reference)

PMID:28613753 SUPPORT DIRECT BACKGROUND Human Clinical

"Severe toxicity may result in seizures, hypothermia, coma, and death."

Clinical toxicology review documents this manifestation; no population frequency is assigned.

Constitutional 1

Abdominal pain HP:0002027

Temporal: ACUTE

Show evidence (1 reference)

PMID:26324727 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"They were asymptomatic and were managed as out patients until 4 days post-ingestion when they developed intermittent abdominal pain and passage of loose, mucoid stools."

Primary observation in the less severely affected subgroup.

💊

Medical Actions

Dextrose correction and glucose monitoring

Action: Supportive Care NCIT:C15747

Agent: glucose CHEBI:17234

Prompt intravenous dextrose corrects symptomatic hypoglycemia. Bolus treatment may require a titrated continuous infusion with serial glucose measurements. This supplies glucose during the metabolic block; it is not evidence that the toxin-enzyme lesion has been reversed.

Mechanism Target:

INHIBITS Hypoglycemia — Restores circulating glucose during impaired endogenous production.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Patients require close monitoring for hypoglycemia and should receive dextrose therapy. Initial dextrose boluses may be administered, followed by a continuous infusion titrated to maintain euglycemia."

Toxicology review supports repeated glucose assessment and dextrose titration.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

Toxicology review supports repeated glucose assessment and dextrose titration.

Fluid, electrolyte and gastrointestinal support

Action: Fluid Therapy NCIT:C116537

Rehydrate and correct electrolyte abnormalities; antiemetics may relieve symptoms. Care should follow clinical status and repeated measurements.

Mechanism Target:

INHIBITS Dehydration — Replaces volume lost during vomiting.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Intravenous fluids are indicated to prevent dehydration, and antiemetics may be used to alleviate symptoms. Vomiting and dehydration can precipitate electrolyte disturbances, which should be corrected promptly."

Supportive care is directed at volume and electrolyte losses.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

Supportive care is directed at volume and electrolyte losses.

Seizure management

Action: Anticonvulsant Therapy NCIT:C64172

Correct hypoglycemia and provide standard acute seizure management when required; benzodiazepines are described in the clinical review.

Mechanism Target:

INHIBITS Seizure — Treats ongoing seizures alongside correction of their metabolic cause.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Benzodiazepines may be employed for seizure management, but hypoglycemia must first be excluded as the underlying cause."

Seizure treatment accompanies assessment and correction of glucose.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Benzodiazepines may be employed for seizure management, but hypoglycemia must first be excluded as the underlying cause."

Seizure treatment accompanies assessment and correction of glucose.

Hospital observation and critical care

Action: Supportive Care NCIT:C15747

Monitor neurological status, glucose, electrolytes and liver/renal function. Persistent hypoglycemia, seizures, acidosis, altered consciousness or poor perfusion may require intensive care. A reported emergency transplant for fulminant liver failure had a fatal outcome and does not establish an ackee-specific transplant success rate.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Patients with persistent hypoglycemia, seizures, metabolic acidosis, altered mental status, or poor perfusion frequently require intensive care unit admission."

Review identifies severe features prompting critical care.

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"On admission, she was in fulminant hepatic failure with hepatic encephalopathy."

The reported patient had liver failure and encephalopathy; exposure was unconfirmed and sickling-related ischemia confounded attribution.

PMID:23259140 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"After one successful code, her code status was changed to “Do Not Resuscitate.” She expired 6 hours later."

The patient died after emergency transplantation; a single confounded case does not establish a transplant success rate.

Toxicology consultation

Consult a poison center or medical toxicologist. Routine gastrointestinal decontamination lacks demonstrated outcome benefit and may be inappropriate with vomiting, seizures or impaired consciousness.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Evidence supporting routine gastrointestinal decontamination improving outcomes is insufficient."

Do not promote charcoal or lavage as an established effective antidote.

Safe harvesting, preparation and exposure prevention

Use fully mature naturally opened fruit, remove seeds and raphe, and follow reliable processing controls. Do not force open or heat-shock immature fruit to accelerate opening; cooking does not make toxic unripe fruit safe. Educate households and evaluate other exposed people after a shared meal.

Mechanism Target:

INHIBITS Hypoglycin A Ingestion — Reduces ingestion of toxin-containing fruit parts or improperly processed product.

Show evidence (2 references)

url:https://www.fda.gov/media/88521/download SUPPORT DIRECT BACKGROUND Other

"Prior to further processing and packaging, the black seeds and raphe are removed, and the arils are visually inspected for damage, blemishes, or signs of spoilage."

Final FDA processing guidance describes removal of unsafe parts.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Cooking the unripe fruit does not mitigate its toxic potential. The seeds retain their toxicity and must not be ingested."

Prevention advice distinguishes natural maturation from heating.

Show evidence (2 references)

url:https://www.fda.gov/media/88521/download SUPPORT DIRECT BACKGROUND Other

"Prior to further processing and packaging, the black seeds and raphe are removed, and the arils are visually inspected for damage, blemishes, or signs of spoilage."

Final FDA processing guidance describes removal of unsafe parts.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Cooking the unripe fruit does not mitigate its toxic potential. The seeds retain their toxicity and must not be ingested."

Prevention advice distinguishes natural maturation from heating.

🌍

Environmental Factors

Ingestion of toxic ackee material

Hazard type: CHEMICAL

Route: ORAL

Duration: ACUTE

The broad toxin exposure term is retained with a specific food-source annotation. The 2011 fruit study measured residual hypoglycin A in ripe Cheese arils (271 mg/kg); maturity is not a claim of zero toxin in every sample. The FDA food action criterion is not a human toxic-dose threshold.

Eating unripe or improperly processed arils, seeds or other toxic fruit parts delivers hypoglycin A. Canned exposure is documented. Natural ripening reduces aril toxin concentration, but seeds and rind remain unsafe; heating does not reliably detoxify unripe fruit.

Show evidence (3 references)

PMID:8185109 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The toxic exposure resulted from the consumption of canned ackee. The epidemiology, diagnosis, theoretical mechanism, and possible therapy of this disease are discussed."

A United States case demonstrates the preserved-product route.

PMID:21410289 SUPPORT DIRECT PRIMARY RESULT Other

"The causal toxin, hypoglycin A, decreases in the edible arilli upon maturity; regulation of hypoglycin A in the arilli is thus critical."

Analytical maturity study directly addresses exposure concentration.

url:https://www.fda.gov/media/88521/download SUPPORT DIRECT BACKGROUND Other

"However, the rind and seeds still have high levels of hypoglycin A when the fruit is fully ripe and should not be consumed."

Final FDA guidance distinguishes edible mature arils from toxic fruit parts.

Mechanism Target:

TRIGGERS Hypoglycin A Ingestion — Oral ingestion delivers the protoxin.

Show evidence (1 reference)

PMID:26324727 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We report a case series of eight previously well Nigerian siblings who presented at various intervals after ingestion of roasted seeds and aril of the ackee fruit."

A shared meal caused a clinically heterogeneous family cluster; both seeds and arils were consumed.

🔬

Biochemical Markers

Urinary dicarboxylic acids (INCREASED)

Context: In two original human cases, several dicarboxylic acids were 70–1000 times the reported normal values. This supports an oxidation defect but is neither a validated severity scale nor a specific diagnostic signature by itself.

Pathograph Readouts

Readout Of Impaired Fatty Acid Beta-Oxidation Positive Diagnostic

Elevated organic acids are compatible with impaired oxidation; urinary concentration does not directly quantify hepatic flux.

Show evidence (1 reference)

PMID:940578 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"The amounts of these dicarboxylic acids were 70 to 1000 times higher than normal."

Case-specific comparison with normal values.

Show evidence (1 reference)

PMID:940578 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Excretion of unusual dicarboxylic acids such as 2-ethylmalonic, 2-methylsuccinic, glutaric, adipic and dicarboxylic acids with eight and 10 carbon chains were also detected in both patients."

Direct biochemical observations in two patients.

Urinary short-chain fatty acids (INCREASED)

Context: Up to 300-fold elevation was reported in the same two human cases. These values are not a population reference interval.

Show evidence (1 reference)

PMID:940578 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Urinary excretion of short-chain fatty acids was also increased up to 300 times higher than normal."

Direct human urinary measurement.

Urinary MCPA after hydrolysis (PRESENT)

Context: The historical patient result supports excretion of conjugated toxin metabolites. The later analytical paper clarifies that MCPA was detected after hydrolysis; it should not be represented as a measurement of free urinary MCPA-CoA.

Show evidence (2 references)

PMID:940578 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified methylenecyclopropylacetic acid, a known metabolite of hypoglycin A, in the urine of two patients with Jamaican vomiting sickness."

Human toxin-metabolite evidence.

PMID:26328472 SUPPORT DIRECT BACKGROUND Other

"When the patients’ urine samples were treated with the hydrolyzing agent barium hydroxide, the samples tested positive for MCPAA, which suggests the majority of the metabolite had been conjugated prior to excretion."

Full analytical background clarifies the processing and analyte identity.

Hypoglycin A in gastric contents (PRESENT)

Context: GC-MS demonstrated hypoglycin A in gastric fluid from one deceased child in a cluster of 16 deaths. This confirms exposure in that child, not laboratory confirmation of every cluster case.

Show evidence (1 reference)

PMID:21324617 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We have developed a GC-MS procedure allowing us to demonstrate the presence of hypoglycin-A in the gastric fluid of one of the deceased children"

Direct toxin identification in one patient.

Hypoglycin A and methylenecyclopropylglycine exposure assays

Context: Specialized plasma HGA/MCPG and urinary MCPA-Gly/MCPF-Gly assays can document exposure. The plasma validation used commercial and spiked samples, and the urinary field application involved suspected acute encephalitis cases rather than an ackee-specific validation cohort. A positive exposure marker is not a validated clinical severity threshold.

Show evidence (2 references)

PMID:30056267 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This method was applied to a commercial convenience set consisting of 100 individual plasma samples that served as a reference range for HGA and MCPG expected in a commercially available, unexposed population."

Analytical validation scope, not a symptomatic case-control accuracy study.

PMID:26328472 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The method was further applied in a laboratory analysis of specimens collected from suspected AES cases. Of the samples (n=73) analyzed, 66% of the samples were found positive for MCPF-Gly and/or MCPA-Gly."

The field demonstration was in suspected AES, not confirmed Jamaican vomiting sickness.

🔬

Diagnosis

Exposure history and clinical assessment

Obtain a detailed food and preparation history, including preserved ackee and illness in other people sharing the meal. Evaluate compatible gastrointestinal or neurological illness promptly; absence of vomiting or a single normal glucose measurement does not exclude exposure-related illness.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Vomiting is common, but its absence does not exclude the diagnosis."

Clinical review explicitly cautions against a required vomiting criterion.

PMID:26324727 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The remaining five children aged between 4 and 10 years were brought in for evaluation after requests by the managing team."

The family report supports assessment of other exposed children.

Immediate and serial metabolic assessment

Measure glucose promptly and serially, with electrolytes, liver and renal tests, lactate, ketones and blood gases as clinically indicated. Monitoring is directed at treatable metabolic deterioration and organ injury.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Diagnostic evaluation should include blood glucose, serum electrolytes, liver function tests, renal function, lactate, ketones, and blood gases."

Clinical toxicology evaluation guidance.

Specialized toxin and metabolite testing

Urinary organic acids and specific HGA-related metabolites can support the diagnosis when available. Timing and assay limitations matter, and emergency glucose correction should not depend on a specialized toxicology result. Veterinary acylcarnitine concentrations are not human diagnostic thresholds.

Show evidence (2 references)

PMID:26328472 SUPPORT DIRECT BACKGROUND Other

"Since the clearance rate of the metabolites is still unknown, the time lapse between collection and exposure could significantly affect the amount of metabolite remaining at the time of analysis."

Analytical source emphasizes uncertainty in sampling-time interpretation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

Prompt treatment and monitoring are required regardless of specialized test availability.

Reassessment for competing causes

Consider other toxic, infectious and metabolic causes of hypoglycemia or encephalopathy. Persistent or recurrent unexplained biochemical abnormalities warrant specialist evaluation for inherited fatty-acid oxidation disease. Negative ETFA/ETFB/ETFDH or ACADM sequencing is not a mandatory diagnostic criterion for ackee poisoning.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Diagnosis must be established through careful evaluation of presenting symptoms, laboratory data, and confirmation of recent unripe"

Clinical review bases diagnosis on integrated findings; it does not require negative genetic sequencing.

📈

Progression

Exposure and onset

Symptoms often begin within 6–48 hours, but severe onset at two hours and delayed gastrointestinal symptoms at four days occurred in one family. Dose, food preparation and nutritional context vary.

Show evidence (2 references)

PMID:26324727 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her symptoms had started 2 hours after ingestion of six roasted seeds and arils of ackee fruit. Loss of consciousness was preceded by vomiting and extreme body weakness."

Direct case timing, not a universal incubation interval.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"Hypoglycemia may not manifest until several hours after ingestion. This metabolic derangement progresses rapidly once established."

The review emphasizes delayed glucose deterioration.

Recovery or severe deterioration

Survivors may recover over several days with supportive care; severe cases can deteriorate rapidly. One of eight siblings died and the index child recovered by day six. Fatal-outbreak series are selected and do not establish a general case-fatality rate.

Show evidence (2 references)

PMID:26324727 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had frequent monitoring of vital signs and was discharged on the sixth day of admission after full recovery."

Observed recovery under combined supportive treatment.

PMID:10028981 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"29 cases of EFE were identified from January to May, 1998."

Fatal encephalopathy ascertainment selects the most severe end of the spectrum.

🌍

Epidemiology

Geographic and outbreak distribution

Reported in Jamaica and other Caribbean settings, West Africa and imported-food settings. Reliable contemporary population incidence and prevalence are not established. Household clusters reflect shared exposure rather than inheritance.

The Burkina Faso study defined fatal encephalopathy; its all-fatal series must not be read as the case-fatality rate for unselected ackee exposure. The Haiti abstract uses over 100 illnesses/deaths; secondary reports use different denominators that are not combined here.

Show evidence (2 references)

PMID:16749544 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The Centers for Disease Control and Prevention (CDC) provided technical assistance to the Ministry of Health of Haiti during an outbreak of over 100 cases of acute illness and death in the northern region of Haiti during a 4-month period beginning in November 2000."

Primary outbreak report abstract; no narrower case denominator or modern incidence inferred.

PMID:10028981 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The only factor associated with EFE was the presence of ackee trees (Blighia sapida) within 100 m of households"

Household association supports probable etiology, not individual confirmed ingestion in every case.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Acute Ackee Fruit Intoxication:

Multiple acyl-CoA dehydrogenase deficiency MONDO:0009282

Overlapping Features Inherited multiple acyl-CoA dehydrogenase deficiency and toxin-induced inhibition overlap metabolically but have different upstream causes. Broad acylcarnitine and organic-acid patterns in hypoglycin-exposed horses support a comparative acquired-MADD mechanism; they do not prove that every human poisoning profile is identical to inherited MADD.

Distinguishing Features

A compatible shared-food or preserved-ackee exposure supports poisoning.
Toxin-specific metabolites support exposure when demonstrable; absence depends on sampling and assay.
Persistent or unexplained recurrent abnormalities require a metabolic differential rather than an assumed food attribution.

Show evidence (1 reference)

PMID:23167695 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Serum acylcarnitines and urine organic acid profiles in SPM horses were typical for MADD."

The MADD-like biochemical pattern was measured in horses, so its use for human differential diagnosis is indirect.

Medium-chain acyl-CoA dehydrogenase deficiency MONDO:0008721

Overlapping Features Inherited MCAD deficiency can cause fasting-associated hypoglycemia and organic acid abnormalities. MCPA-CoA can inhibit purified MCAD as well as other dehydrogenases, so MCAD is neither excluded as a toxin target nor sufficient to describe the entire poisoning mechanism. Substrate protection of an enzyme is not evidence that the enzyme is toxin-insensitive.

Distinguishing Features

A compatible toxic exposure and specific metabolites support ackee poisoning.
A persistent characteristic acylcarnitine profile or unexplained recurrent fasting crises warrants metabolic evaluation.

Show evidence (2 references)

PMID:7275979 SUPPORT DIRECT PRIMARY RESULT In Vitro

"During inactivation, about 80% of the enzyme FAD is covalently and irreversibly modified with the residual inhibition possibly resulting from modification of the protein."

Purified pig-kidney enzyme establishes covalent FAD modification; the percentage is assay-specific.

PMID:2331485 SUPPORT DIRECT PRIMARY RESULT In Vitro

Purified-enzyme comparisons establish selective multi-enzyme inhibition, including MCAD.

Reye syndrome

Overlapping Features Reye syndrome can resemble severe ackee poisoning clinically and histologically. The original two-case biochemical comparison found marked abnormal urinary organic acids in ackee poisoning that were not appreciably elevated in the Reye comparator literature.

Distinguishing Features

A compatible ackee exposure with specific toxin metabolites supports poisoning.
Marked dicarboxylic aciduria supported the distinction in the historical comparison; it is not a modern standalone exclusion test.

Show evidence (1 reference)

PMID:940578 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"despite their clinical and histologic similarities, the cause and biochemical mechanisms of Jamaican vomiting sickness differ distinctly from those of Reye's syndrome"

States both the resemblance and the biochemical basis for separating them, in the paper that made the distinction.

Other acute poisonings and hypoglycemic illnesses

Overlapping Features Other ingestions, sulfonylurea toxicity, acute gastrointestinal illnesses and meningitis can overlap with the presentation. Dietary and medication histories, bedside glucose and targeted clinical investigation determine the differential.

Distinguishing Features

Identify alternative ingestions or medication exposure.
Investigate fever, focal findings and other clinical features inconsistent with an isolated metabolic food poisoning.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/ SUPPORT DIRECT BACKGROUND Human Clinical

"The differential diagnosis should include disorders presenting with gastrointestinal symptoms, altered mental status, or metabolic disturbances similar to those observed in ackee fruit toxicity."

Review supports a broader acute differential.

🧫

Experimental Models

Purified mammalian acyl-CoA dehydrogenase inhibition OTHER

Purified-enzyme experiments test direct MCPA-CoA susceptibility and flavin modification. Pig-kidney general enzyme is strongly inhibited, and subsequent distinct-enzyme comparisons establish different susceptibility across dehydrogenases.

Publication

PMID:7275979

Pathograph links

Selective Acyl-CoA Dehydrogenase Inactivation measures fidelity: moderate Purified pig-kidney enzyme loses nearly all activity with covalent FAD modification.

Limitations: The assay-specific residual activity is not a human tissue measurement; protection by octanoyl-CoA indicates active-site competition, not MCAD sparing.

Readouts

Purified enzyme activity

Direction: DECREASED

Interpretation: Purified pig-kidney enzyme loses nearly all activity with covalent FAD modification.

Show evidence (2 references)

PMID:7275979 SUPPORT DIRECT PRIMARY RESULT In Vitro

"During inactivation, about 80% of the enzyme FAD is covalently and irreversibly modified with the residual inhibition possibly resulting from modification of the protein."

Purified pig-kidney enzyme establishes covalent FAD modification; the percentage is assay-specific.

+ 1 more reference

Show evidence (2 references)

PMID:7275979 SUPPORT DIRECT PRIMARY RESULT In Vitro

"During inactivation, about 80% of the enzyme FAD is covalently and irreversibly modified with the residual inhibition possibly resulting from modification of the protein."

Purified pig-kidney enzyme establishes covalent FAD modification; the percentage is assay-specific.

+ 1 more reference

Ketohypoglycin in isolated rat hepatocytes PRIMARY_CELL_CULTURE

Methylenecyclopropylpyruvate inhibited gluconeogenesis from several substrates, with fructose spared. Ketogenesis was inhibited without lactate; lactate masked this effect. ATP/ADP content was unchanged under the specified lactate/palmitate conditions.

Cell source

Isolated rat liver cells

Publication

PMID:518564

Pathograph links

Reduced Hepatic Glucose Production measures fidelity: moderate Gluconeogenesis is inhibited in a substrate-dependent manner.

Limitations: This is a cultured rat-cell keto-acid exposure, not a human clinical assay or uniform energetic collapse.

Readouts

Hepatocyte glucose production

Direction: DECREASED

Interpretation: Gluconeogenesis is inhibited in a substrate-dependent manner.

Show evidence (1 reference)

PMID:518564 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Methylenecyclopropylpyruvate at 0.3 mM inhibits gluconeogenesis from all substrates tested, except fructose."

Direct isolated-cell functional observation.

Show evidence (1 reference)

PMID:518564 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Methylenecyclopropylpyruvate at 0.3 mM inhibits gluconeogenesis from all substrates tested, except fructose."

Direct isolated-cell functional observation.

🐁

Animal Models

MCPA infusion in fasted conscious rats

Male Sprague-Dawley/CD rats fasted 18–20 hours received intravenous MCPA 80 mg/kg; a two-hour isotope-infusion protocol measured glucose and ketone turnover, PC flux and hepatic metabolites. Dextrose maintained euglycemia in treated rats. This bypasses oral hypoglycin exposure and does not reproduce the full human syndrome.

Species

Rat

Publication

PMID:29483297

Pathograph links

MCPA-CoA Formation measures fidelity: moderate Hepatic MCPA-CoA was identified by LC-MS/MS.

Limitations: The parent amino acid and its transamination were bypassed.

Readouts

Hepatic MCPA-CoA detection

Direction: INCREASED

Interpretation: Hepatic MCPA-CoA was identified by LC-MS/MS.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We identified the MCPA-CoA adduct by tandem LC-mass spectrometry in MCPA treated rat liver"

The hepatic CoA ester was directly identified after intravenous MCPA, which bypasses hypoglycin transamination.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We identified the MCPA-CoA adduct by tandem LC-mass spectrometry in MCPA treated rat liver"

The hepatic CoA ester was directly identified after intravenous MCPA, which bypasses hypoglycin transamination.

Reduced Hepatic Acetyl-CoA measures fidelity: moderate Hepatic acetyl-CoA decreased 84%.

Limitations: Single acute high-dose fasted-rat protocol; no human residual-function threshold.

Readouts

Hepatic acetyl-CoA content

Direction: DECREASED

Interpretation: Hepatic acetyl-CoA decreased 84%.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Hepatic acetyl-CoA was reduced by 84% (Figure 5E), while other short chain CoAs, including butyryl CoA and hexaryl CoA, were markedly increased"

The measured hepatic acetyl-CoA reduction follows MCPA exposure in fasted rats.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Hepatic acetyl-CoA was reduced by 84% (Figure 5E), while other short chain CoAs, including butyryl CoA and hexaryl CoA, were markedly increased"

The measured hepatic acetyl-CoA reduction follows MCPA exposure in fasted rats.

Reduced Hepatic ATP Availability measures fidelity: moderate Hepatic ATP decreased 13% and ATP/ADP decreased 30%.

Limitations: The ATP contribution was not isolated by rescue; complete ATP depletion was not observed.

Readouts

Hepatic ATP content

Direction: DECREASED

Interpretation: Hepatic ATP decreased 13% and ATP/ADP decreased 30%.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the more potent toxin, MCPA, caused a 13% reduction in hepatic ATP content and a 65% increase in hepatic AMP content."

Hepatic nucleotide measurements establish a modest ATP reduction in this rat protocol.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the more potent toxin, MCPA, caused a 13% reduction in hepatic ATP content and a 65% increase in hepatic AMP content."

Hepatic nucleotide measurements establish a modest ATP reduction in this rat protocol.

Reduced Hepatic Pyruvate Carboxylase Flux measures fidelity: moderate PINTA-estimated absolute PC flux decreased 75%.

Limitations: Flux is model-based; no direct enzyme-binding or causal mediator rescue was performed.

Readouts

Estimated hepatic PC flux

Direction: DECREASED

Interpretation: PINTA-estimated absolute PC flux decreased 75%.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Accounting for the reduction we observed in EGP, absolute PC flux was reduced by 75% in MCPA treated rats"

Isotope-based PINTA estimates hepatic pyruvate-carboxylase flux in awake rats, not purified enzyme activity.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Accounting for the reduction we observed in EGP, absolute PC flux was reduced by 75% in MCPA treated rats"

Isotope-based PINTA estimates hepatic pyruvate-carboxylase flux in awake rats, not purified enzyme activity.

Reduced Hepatic Glucose Production measures fidelity: moderate Endogenous production fell by approximately half without changed clearance.

Limitations: Treated animals received dextrose to maintain euglycemia.

Readouts

Endogenous glucose production

Direction: DECREASED

Interpretation: Endogenous production fell by approximately half without changed clearance.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"EGP was assessed at 90–120 minutes after MCPA administration, and was reduced by half (Figure 4C). Glucose clearance, however, was unchanged"

Tracer measurements distinguish reduced endogenous production from increased peripheral disposal.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"EGP was assessed at 90–120 minutes after MCPA administration, and was reduced by half (Figure 4C). Glucose clearance, however, was unchanged"

Tracer measurements distinguish reduced endogenous production from increased peripheral disposal.

Reduced Ketogenesis measures fidelity: moderate Beta-hydroxybutyrate turnover decreased 82% and concentration 92%.

Limitations: This establishes a rat metabolic effect, not a required human diagnostic criterion.

Readouts

Beta-hydroxybutyrate turnover

Direction: DECREASED

Interpretation: Beta-hydroxybutyrate turnover decreased 82% and concentration 92%.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"After administration of MCPA, β-hydroxybutyrate turnover decreased by 82% and plasma β-hydroxybutyrate concentration fell by 92%, reflecting a near-ablation of ketone body production"

Rat ketone turnover and concentration decrease; no equivalent quantitative human series is available.

Show evidence (1 reference)

PMID:29483297 SUPPORT DIRECT PRIMARY RESULT Model Organism

"After administration of MCPA, β-hydroxybutyrate turnover decreased by 82% and plasma β-hydroxybutyrate concentration fell by 92%, reflecting a near-ablation of ketone body production"

Rat ketone turnover and concentration decrease; no equivalent quantitative human series is available.

Hypoglycin exposure in rats

Liver mitochondrial extracts from hypoglycin-treated rats show substrate-selective reduction in dehydrogenase activity.

Species

Rat

Publication

PMID:1247597

Pathograph links

Selective Acyl-CoA Dehydrogenase Inactivation measures fidelity: moderate Activity measured with butyryl-CoA decreased, while octanoyl- and palmitoyl-CoA activities were unchanged in this preparation.

Limitations: The pattern does not exclude purified MCAD susceptibility demonstrated in later studies.

Readouts

Butyryl-CoA dehydrogenase activity

Direction: DECREASED

Interpretation: Activity measured with butyryl-CoA decreased, while octanoyl- and palmitoyl-CoA activities were unchanged in this preparation.

Show evidence (1 reference)

PMID:1247597 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Extracts of liver mitochondria from donor rats given hypoglycin, the toxic amino acid from the ackee plant (Blighia sapida) showed drastically reduced levels of acyl-CoA dehydrogenase activity with butyryl-CoA as substrate."

In-vivo exposure followed by mitochondrial-extract assay.

Show evidence (1 reference)

PMID:1247597 SUPPORT DIRECT PRIMARY RESULT Model Organism

In-vivo exposure followed by mitochondrial-extract assay.

Equine atypical myopathy and seasonal pasture myopathy

Naturally occurring hypoglycin-associated disease follows grazing Acer-contaminated pastures. Serum MCPA-carnitine and MADD-like biochemical profiles provide comparative evidence, but the predominant equine manifestation is muscle injury rather than the human gastrointestinal and cerebral syndrome.

Species

Horse

Publication

PMID:23167695

Pathograph links

MCPA-CoA Formation partially recapitulates fidelity: moderate The natural disease supplies comparative toxin-conjugate and metabolic-profile measurements.

Limitations: Different species, plant source and exposure dose; both are oral exposures. Clinical expression and sampled tissue compartments differ. No human diagnostic cutoff follows from equine concentrations.

Readouts

Serum MCPA-carnitine

Direction: INCREASED

Interpretation: Observed in exposed horses; supports comparative metabolism rather than a human diagnostic threshold.

Show evidence (1 reference)

PMID:23773055 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Methylenecyclopropyl acetic acid-carnitine at high concentrations (20.39 ± 17.24 nmol/l; range 0.95-57.63 nmol/l; reference: <0.01 nmol/l) was identified in serum of AM but not disease controls (0.00 ± 0.00 nmol/l)."

Measured veterinary biomarker; extrapolation to human poisoning is indirect.

Show evidence (1 reference)

PMID:23773055 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Atypical myopathy in Europe, like seasonal pasture myopathy in North America, is highly associated with the toxic metabolite of hypoglycin A, MCPA-carnitine."

Measured veterinary biomarker; extrapolation to human poisoning is indirect.

Impaired Fatty Acid Beta-Oxidation partially recapitulates fidelity: moderate The natural disease supplies comparative toxin-conjugate and metabolic-profile measurements.

Readouts

Serum acylcarnitines and urinary organic acids

Direction: ALTERED

Interpretation: Observed in exposed horses; supports comparative metabolism rather than a human diagnostic threshold.

Show evidence (1 reference)

PMID:23167695 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Serum acylcarnitines and urine organic acid profiles in SPM horses were typical for MADD."

Measured veterinary biomarker; extrapolation to human poisoning is indirect.

Show evidence (1 reference)

PMID:23167695 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Hypoglycin A, known to cause acquired multiple acyl-CoA dehydrogenase deficiency (MADD), was found in box elder seeds."

Measured veterinary biomarker; extrapolation to human poisoning is indirect.

The source studies are observational and do not independently prove a fully identical multienzyme lesion in every human case. The separate foal study infers hydratase dysfunction from metabolites; it does not measure the enzyme directly.

Hypoglycin A and MCPA immersion in zebrafish embryos and larvae

Wild-type AB embryos were exposed by immersion beginning at 24 hours after fertilization, with monitoring through 96 hours. HGA and MCPA produced mortality, bradycardia and cardiac edema, with later toxicity onset after HGA; MCPA also reduced swimming under selected exposure conditions. The model was developed for Sapindaceae-associated equine atypical myopathy and captures shared toxin biology rather than human ackee ingestion or a demonstrated human hypoglycemic syndrome. Whole-body metabolite and locomotor experiments each had one experimental replicate; metabolomics pooled twenty larvae per concentration. Mortality assays used biological triplicates. Glycine and carnitine co-exposure reduced 72-hour mortality, whereas riboflavin did not protect in this protocol. Compounds were added simultaneously with toxin, so this is prevention/co-treatment evidence, not treatment after established poisoning. Surviving larvae could retain cardiac abnormalities. MCPrG caused no observed toxicity in this exposure system, but uptake and activation were unresolved; the result does not establish safety in mammals.

Species

Zebrafish (Danio rerio)

Publication

PMID:39459322

Pathograph links

MCPA-CoA Formation partially recapitulates fidelity: low observes: organism HGA-exposed larvae accumulated the downstream conjugate MCPA-carnitine.

Limitations: Indirect bioactivation readout from pooled whole-body material with no biological replicate series; neither MCPA-CoA nor a specific activating enzyme was directly quantified. Immersion differs from oral human exposure.

Readouts

Whole-body MCPA-carnitine after HGA exposure

Direction: INCREASED

Interpretation: A conjugated metabolite supports bioactivation but does not quantify the active CoA ester.

Show evidence (1 reference)

PMID:39459322 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"The most pronounced elevations in MCPA–carnitine concentrations were observed after 24 h at HGA concentrations exceeding 6 μM, and after 48 h for a 1.56 μM HGA concentration (Figure 2 panel B)."

Whole-body MCPA-carnitine is a downstream conjugate supporting HGA bioactivation; MCPA-CoA itself and the individual activating enzymes were not directly measured.

Show evidence (1 reference)

PMID:39459322 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"The most pronounced elevations in MCPA–carnitine concentrations were observed after 24 h at HGA concentrations exceeding 6 μM, and after 48 h for a 1.56 μM HGA concentration (Figure 2 panel B)."

Whole-body MCPA-carnitine is a downstream conjugate supporting HGA bioactivation; MCPA-CoA itself and the individual activating enzymes were not directly measured.

Impaired Fatty Acid Beta-Oxidation partially recapitulates fidelity: low observes: organism Short- and medium-chain acylcarnitine changes provide indirect evidence of disturbed fatty-acid metabolism.

Limitations: Acylcarnitine accumulation does not isolate beta-oxidation flux or individual acyl-CoA dehydrogenases, and the pooled metabolic time course was not biologically replicated. Human glucose production, ketogenesis and clinical treatment response were not established.

Readouts

Whole-body acylcarnitine profile

Direction: INCREASED

Interpretation: C6, C8 and C10 acylcarnitines increased after HGA exposure; these are metabolic proxies.

Show evidence (1 reference)

PMID:39459322 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Among the even-numbered acylcarnitines, hexanoylcarnitine (C6), octanoylcarnitine (C8), and decanoylcarnitine (C10) levels increased after 48 h (Figure 3 panel C)."

The profile is consistent with disrupted fatty-acid metabolism, but it is not a direct beta-oxidation flux or enzyme-inhibition assay.

Show evidence (1 reference)

PMID:39459322 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Among the even-numbered acylcarnitines, hexanoylcarnitine (C6), octanoylcarnitine (C8), and decanoylcarnitine (C10) levels increased after 48 h (Figure 3 panel C)."

The profile is consistent with disrupted fatty-acid metabolism, but it is not a direct beta-oxidation flux or enzyme-inhibition assay.

Show evidence (4 references)

PMID:39459322 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Twenty fertilised eggs per concentration and four eggs for the negative control (E3) were exposed from approximately 24 hpf until 96 hpf with one egg per well in 24 well-plates (2 mL per well) or in 96 well-plates (120 μL per well) for MCPA and HGA, respectively."

The experimental exposure starts after the earliest embryonic stages and uses biological triplicate acute-toxicity assays.

PMID:39459322 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Riboflavin did not show a protective effect when co-treated with either MCPA or HGA, while carnitine and glycine decreased mortality under both conditions (Figure 5)."

Co-treatment modifies short-term survival in larvae; it does not establish a human antidote or delayed rescue regimen.

PMID:39459322 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Another limitation of this study is the lack of replication for the quantification of HGA, MCPA–carnitine, and acylcarnitines profile."

The authors explicitly limit the reliability of their metabolic time courses.

+ 1 more reference

{ }

Source YAML

click to show

name: Acute Ackee Fruit Intoxication
creation_date: '2026-09-02T15:30:00Z'
categories:
- Toxic Exposure Disorder
- Environmental Health Disorder
category: Complex
parents:
- Poisoning
disease_term:
preferred_term: acute ackee fruit intoxication
term:
id: MONDO:0019140
label: acute ackee fruit intoxication
synonyms:
- Jamaican vomiting sickness
- Ackee poisoning
- Toxic hypoglycemic syndrome
description: Acute ackee fruit intoxication is an acquired foodborne poisoning associated with hypoglycin A in unripe or improperly processed Blighia sapida fruit and toxic seeds. Bioactivation produces MCPA-CoA, which inhibits selected mitochondrial acyl-CoA dehydrogenases. Impaired fatty-acid oxidation, ketogenesis and hepatic glucose production can cause profound hypoglycemia and neurological deterioration. Vomiting is common, but hypoglycemia and vomiting are not obligatory in every reported case. Human urinary organic-acid findings and comparative animal experiments support the metabolic mechanism; they do not make human poisoning diagnostically indistinguishable from inherited fatty-acid oxidation disorders. Management is prompt glucose correction and supportive care, with prevention through safe harvesting and processing.
pathophysiology:
- name: Hypoglycin A Ingestion
description: Oral exposure occurs through unripe or inadequately processed arils and toxic seeds. The dose and preparation vary; detection of exposure does not itself establish symptomatic poisoning.
role: trigger
biological_scale: ORGANISM
evidence: &id001
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: We report a case series of eight previously well Nigerian siblings who presented at various intervals after ingestion of roasted seeds and aril of the ackee fruit.
explanation: A shared meal caused a clinically heterogeneous family cluster; both seeds and arils were consumed.
downstream:
- target: Hypoglycin A Transamination
description: Absorbed hypoglycin undergoes metabolic activation.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:26328472
reference_title: Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: INDIRECT
snippet: Once ingested, hypoglycin A is converted by an aminotransferase in the cytosol to methylenecyclopropylpyruvate (MCP-pyruvate)
explanation: The analytical paper summarizes the established transamination step from prior metabolic studies.
- target: Vomiting
description: Gastrointestinal toxicity follows exposure; vomiting is not assumed to require antecedent hypoglycemia.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:28613753
reference_title: Ackee Fruit Toxicity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Clinical manifestations typically include repetitive vomiting, altered mental status, and profound hypoglycemia.
explanation: Clinical toxicology review documents this manifestation; no population frequency is assigned.
quote_role: BACKGROUND
directness: INDIRECT
- target: Abdominal pain
description: Abdominal pain was observed after the shared exposure in the Nigerian family.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: They were asymptomatic and were managed as out patients until 4 days post-ingestion when they developed intermittent abdominal pain and passage of loose, mucoid stools.
explanation: Primary observation in the less severely affected subgroup.
- target: Diarrhea
description: Delayed loose stools occurred in five exposed siblings, despite being atypical of the classic vomiting syndrome.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: They were asymptomatic and were managed as out patients until 4 days post-ingestion when they developed intermittent abdominal pain and passage of loose, mucoid stools.
explanation: Delayed loose stools in one family cluster.
- target: Hepatocellular Injury
description: Toxic exposure may contribute to hepatic injury; the severe case is confounded and no single cellular sequence is established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: There are bridging and multiacinar necroses with approximation of adjacent portal tracts and severe centrilobular congestion and hemorrhage
explanation: Direct pathology finding in one suspected poisoning; unconfirmed toxin exposure and concomitant sickling-related ischemia limit causal attribution.
- target: Muscle weakness
description: This manifestation is reported after exposure, but the precise intervening pathway is not resolved in the cited human evidence.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Her symptoms had started 2 hours after ingestion of six roasted seeds and arils of ackee fruit. Loss of consciousness was preceded by vomiting and extreme body weakness.
explanation: Observed weakness in the index child.
- target: Hypotonia
description: This manifestation is reported after exposure, but the precise intervening pathway is not resolved in the cited human evidence.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:10028981
reference_title: Epidemic of fatal encephalopathy in preschool children in Burkina Faso and consumption of unripe ackee (Blighia sapida) fruit.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: The most common symptoms were hypotonia, vomiting, convulsions, and coma. All children died in 2-48 h.
explanation: The cohort was selected for fatal encephalopathy and exposure attribution was probabilistic.
- target: Hypothermia
description: This manifestation is reported after exposure, but the precise intervening pathway is not resolved in the cited human evidence.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:28613753
reference_title: Ackee Fruit Toxicity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Severe toxicity may result in seizures, hypothermia, coma, and death.
explanation: Clinical toxicology review documents this manifestation; no population frequency is assigned.
quote_role: BACKGROUND
directness: INDIRECT
- target: Metabolic acidosis
description: This manifestation is reported after exposure, but the precise intervening pathway is not resolved in the cited human evidence.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: INDIRECT
snippet: Severe electrolyte disturbances, dehydration secondary to persistent vomiting, metabolic acidosis, and hepatic dysfunction may also occur.
explanation: Clinical review supports acidosis without a uniform frequency or cause.
- target: Dehydration
description: Vomiting-associated fluid loss can cause dehydration.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: INDIRECT
snippet: Severe electrolyte disturbances, dehydration secondary to persistent vomiting, metabolic acidosis, and hepatic dysfunction may also occur.
explanation: Review describes the volume-loss complication.
- name: Hypoglycin A Transamination
description: Aminotransferase-mediated conversion of hypoglycin A to methylenecyclopropylpyruvate precedes generation of the inhibitory CoA ester.
role: intermediate
biological_scale: MOLECULAR
evidence:
- reference: PMID:26328472
reference_title: Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: DIRECT
snippet: Once ingested, hypoglycin A is converted by an aminotransferase in the cytosol to methylenecyclopropylpyruvate (MCP-pyruvate)
explanation: The analytical paper summarizes the established transamination step from prior metabolic studies.
downstream:
- target: MCPA-CoA Formation
description: Mitochondrial oxidative decarboxylation converts the keto-acid intermediate into the CoA ester.
causal_link_type: DIRECT
evidence:
- reference: PMID:26328472
reference_title: Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: DIRECT
snippet: MCP-pyruvate is then decarboxylated and conjugated as a CoA ester (MCPA-CoA) in the liver by a mitochondrial branched-chain dehydrogenase.
explanation: Background pathway describes formation of the inhibitory CoA ester; human urinary detection alone does not measure each reaction.
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: We identified the MCPA-CoA adduct by tandem LC-mass spectrometry in MCPA treated rat liver
explanation: The hepatic CoA ester was directly identified after intravenous MCPA, which bypasses hypoglycin transamination.
- name: MCPA-CoA Formation
description: Oxidative decarboxylation of the keto-acid intermediate generates methylenecyclopropylacetyl-CoA. Its conjugated excretion products support bioactivation in humans; direct hepatic CoA-ester identification comes from experimental rats.
role: intermediate
biological_scale: MOLECULAR
evidence:
- reference: PMID:26328472
reference_title: Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: DIRECT
snippet: MCP-pyruvate is then decarboxylated and conjugated as a CoA ester (MCPA-CoA) in the liver by a mitochondrial branched-chain dehydrogenase.
explanation: Background pathway describes formation of the inhibitory CoA ester; human urinary detection alone does not measure each reaction.
- &id007
reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: We identified the MCPA-CoA adduct by tandem LC-mass spectrometry in MCPA treated rat liver
explanation: The hepatic CoA ester was directly identified after intravenous MCPA, which bypasses hypoglycin transamination.
downstream:
- target: Selective Acyl-CoA Dehydrogenase Inactivation
description: The activated toxin interacts with susceptible enzyme active sites and can covalently modify FAD.
causal_link_type: DIRECT
evidence:
- reference: PMID:7275979
reference_title: Inactivation of general acyl-CoA dehydrogenase from pig kidney by a metabolite of hypoglycin A.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: During inactivation, about 80% of the enzyme FAD is covalently and irreversibly modified with the residual inhibition possibly resulting from modification of the protein.
explanation: Purified pig-kidney enzyme establishes covalent FAD modification; the percentage is assay-specific.
- reference: PMID:2331485
reference_title: Selective inactivation of various acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Short-chain acyl-CoA (SCADH), medium-chain acyl-CoA (MCADH) and isovaleryl-CoA (IVDH) dehydrogenases were severely and irreversibly inactivated by MCPA-CoA, while 2-methyl-branched chain acyl-CoA dehydrogenase (2-meBCADH) was only slowly and mildly inactivated.
explanation: Purified-enzyme comparisons establish selective multi-enzyme inhibition, including MCAD.
- name: Selective Acyl-CoA Dehydrogenase Inactivation
description: MCPA-CoA irreversibly inhibits susceptible flavin-dependent acyl-CoA dehydrogenases. Purified-enzyme studies include short-chain, medium-chain and isovaleryl-CoA dehydrogenases, with different susceptibility of other isoforms. The less-than-2% residual activity in a pig-kidney preparation is not a universal patient value.
role: central_effector
biological_scale: MOLECULAR
evidence: &id002
- reference: PMID:7275979
reference_title: Inactivation of general acyl-CoA dehydrogenase from pig kidney by a metabolite of hypoglycin A.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: During inactivation, about 80% of the enzyme FAD is covalently and irreversibly modified with the residual inhibition possibly resulting from modification of the protein.
explanation: Purified pig-kidney enzyme establishes covalent FAD modification; the percentage is assay-specific.
- reference: PMID:2331485
reference_title: Selective inactivation of various acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Short-chain acyl-CoA (SCADH), medium-chain acyl-CoA (MCADH) and isovaleryl-CoA (IVDH) dehydrogenases were severely and irreversibly inactivated by MCPA-CoA, while 2-methyl-branched chain acyl-CoA dehydrogenase (2-meBCADH) was only slowly and mildly inactivated.
explanation: Purified-enzyme comparisons establish selective multi-enzyme inhibition, including MCAD.
molecular_functions:
- preferred_term: acyl-CoA dehydrogenase activity
term:
id: GO:0003995
label: acyl-CoA dehydrogenase activity
modifier: DECREASED
downstream:
- target: Impaired Fatty Acid Beta-Oxidation
description: Loss of dehydrogenase activity restricts the first reaction of beta-oxidation for susceptible substrates.
causal_link_type: DIRECT
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Hepatic acetyl-CoA was reduced by 84% (Figure 5E), while other short chain CoAs, including butyryl CoA and hexaryl CoA, were markedly increased
explanation: Hepatic metabolite changes after MCPA support impaired oxidation, particularly of short-chain substrates; individual enzyme flux was not directly measured.
- name: Impaired Fatty Acid Beta-Oxidation
description: Inhibition of selected dehydrogenases impairs fatty-acid oxidation and alters hepatic acyl-CoA pools. Human organic aciduria is consistent with this block, while chain-specific pathway mapping derives mainly from enzyme and rodent experiments.
role: intermediate
biological_scale: CELLULAR
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Hepatic acetyl-CoA was reduced by 84% (Figure 5E), while other short chain CoAs, including butyryl CoA and hexaryl CoA, were markedly increased
explanation: Hepatic metabolite changes after MCPA support impaired oxidation, particularly of short-chain substrates; individual enzyme flux was not directly measured.
biological_processes:
- preferred_term: fatty acid beta-oxidation
term:
id: GO:0006635
label: fatty acid beta-oxidation
modifier: DECREASED
downstream:
- target: Reduced Hepatic Acetyl-CoA
description: Reduced oxidative throughput is associated with diminished production of acetyl-CoA.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Hepatic acetyl-CoA was reduced by 84% (Figure 5E), while other short chain CoAs, including butyryl CoA and hexaryl CoA, were markedly increased
explanation: The measured hepatic acetyl-CoA reduction follows MCPA exposure in fasted rats.
- target: Reduced Hepatic ATP Availability
description: Reduced fatty-acid oxidation limits reducing-equivalent supply to oxidative phosphorylation; the rat study measures the resulting nucleotide changes.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: the more potent toxin, MCPA, caused a 13% reduction in hepatic ATP content and a 65% increase in hepatic AMP content.
explanation: Hepatic nucleotide measurements establish a modest ATP reduction in this rat protocol.
- name: Reduced Hepatic Acetyl-CoA
description: MCPA-treated fasted rats have reduced hepatic acetyl-CoA together with accumulation of several other short-chain acyl-CoAs.
role: intermediate
biological_scale: MOLECULAR
evidence: &id009
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Hepatic acetyl-CoA was reduced by 84% (Figure 5E), while other short chain CoAs, including butyryl CoA and hexaryl CoA, were markedly increased
explanation: The measured hepatic acetyl-CoA reduction follows MCPA exposure in fasted rats.
downstream:
- target: Reduced Hepatic Pyruvate Carboxylase Flux
description: Acetyl-CoA allosterically activates pyruvate carboxylase; toxin-associated depletion accompanies lower flux, but this mediator was not selectively restored.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Accounting for the reduction we observed in EGP, absolute PC flux was reduced by 75% in MCPA treated rats
explanation: Isotope-based PINTA estimates hepatic pyruvate-carboxylase flux in awake rats, not purified enzyme activity.
- target: Reduced Ketogenesis
description: Reduced availability of acetyl-CoA substrate contributes to lower hepatic ketone production.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: After administration of MCPA, β-hydroxybutyrate turnover decreased by 82% and plasma β-hydroxybutyrate concentration fell by 92%, reflecting a near-ablation of ketone body production
explanation: Rat ketone turnover and concentration decrease; no equivalent quantitative human series is available.
- name: Reduced Hepatic ATP Availability
description: MCPA reduces hepatic ATP content and ATP/ADP ratio in fasted rats. This is one proposed contributor to reduced gluconeogenesis, not a universal complete loss of cellular energy.
role: intermediate
biological_scale: CELLULAR
evidence: &id010
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: the more potent toxin, MCPA, caused a 13% reduction in hepatic ATP content and a 65% increase in hepatic AMP content.
explanation: Hepatic nucleotide measurements establish a modest ATP reduction in this rat protocol.
downstream:
- target: Reduced Hepatic Glucose Production
description: Reduced energy availability is a proposed additional limitation on energy-requiring gluconeogenic reactions.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: the more potent toxin, MCPA, caused a 13% reduction in hepatic ATP content and a 65% increase in hepatic AMP content.
explanation: Hepatic nucleotide measurements establish a modest ATP reduction in this rat protocol.
- name: Reduced Hepatic Pyruvate Carboxylase Flux
description: Estimated hepatic pyruvate-carboxylase flux decreases after MCPA. Reduced acetyl-CoA activation and increased inhibitory short-chain acyl-CoAs are candidate mediators; their separate necessity was not tested by rescue.
role: intermediate
biological_scale: CELLULAR
evidence: &id011
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Accounting for the reduction we observed in EGP, absolute PC flux was reduced by 75% in MCPA treated rats
explanation: Isotope-based PINTA estimates hepatic pyruvate-carboxylase flux in awake rats, not purified enzyme activity.
molecular_functions:
- preferred_term: pyruvate carboxylase activity
term:
id: GO:0004736
label: pyruvate carboxylase activity
modifier: DECREASED
downstream:
- target: Reduced Hepatic Glucose Production
description: Reduced entry of pyruvate carbon through oxaloacetate restricts gluconeogenic output.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Accounting for the reduction we observed in EGP, absolute PC flux was reduced by 75% in MCPA treated rats
explanation: Isotope-based PINTA estimates hepatic pyruvate-carboxylase flux in awake rats, not purified enzyme activity.
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: EGP was assessed at 90–120 minutes after MCPA administration, and was reduced by half (Figure 4C). Glucose clearance, however, was unchanged
explanation: Tracer measurements distinguish reduced endogenous production from increased peripheral disposal.
- name: Reduced Hepatic Glucose Production
description: Tracer studies show reduced endogenous glucose production after MCPA, without increased glucose clearance. The clinical importance is failure to maintain glucose supply, particularly when fasting reserves are limited.
role: intermediate
biological_scale: TISSUE
evidence: &id012
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: EGP was assessed at 90–120 minutes after MCPA administration, and was reduced by half (Figure 4C). Glucose clearance, however, was unchanged
explanation: Tracer measurements distinguish reduced endogenous production from increased peripheral disposal.
biological_processes:
- preferred_term: gluconeogenesis
term:
id: GO:0006094
label: gluconeogenesis
modifier: DECREASED
downstream:
- target: Hypoglycemia
description: Reduced endogenous glucose supply contributes to the low glucose observed in clinical poisoning.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Her repeat RBS at presentation was 2.1 mmol/L while hematocrit was 31%. Liver function test, electrolytes, and urea were normal.
explanation: The index child had severe hypoglycemia without abnormal liver tests.
- target: Neuroglycopenia
description: The intervening fall in blood glucose limits cerebral fuel availability.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: INDIRECT
snippet: Mortality generally results from profound, untreated hypoglycemia, leading to irreversible cerebral injury and multiorgan failure.
explanation: Clinical review links severe untreated hypoglycemia to cerebral injury; other routes to encephalopathy remain possible.
- name: Reduced Ketogenesis
description: Ketone production and circulating beta-hydroxybutyrate decrease in MCPA-treated rats. This can restrict an alternative fuel during fasting; it does not establish that all human cases are completely aketotic.
role: intermediate
biological_scale: TISSUE
evidence: &id013
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: After administration of MCPA, β-hydroxybutyrate turnover decreased by 82% and plasma β-hydroxybutyrate concentration fell by 92%, reflecting a near-ablation of ketone body production
explanation: Rat ketone turnover and concentration decrease; no equivalent quantitative human series is available.
biological_processes:
- preferred_term: ketone body biosynthetic process
term:
id: GO:0046951
label: ketone body biosynthetic process
modifier: DECREASED
downstream:
- target: Neuroglycopenia
description: Reduced ketone availability may amplify cerebral energy deprivation during hypoglycemia; direct mediation was not tested in human ackee poisoning.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: After administration of MCPA, β-hydroxybutyrate turnover decreased by 82% and plasma β-hydroxybutyrate concentration fell by 92%, reflecting a near-ablation of ketone body production
explanation: Rat ketone turnover and concentration decrease; no equivalent quantitative human series is available.
- name: Neuroglycopenia
description: In severe hypoglycemic poisoning, inadequate glucose availability contributes to cerebral dysfunction. Clinical neurological deterioration need not be exclusively neuroglycopenic, particularly with concurrent liver injury or other metabolic disturbances.
role: intermediate
biological_scale: TISSUE
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Mortality generally results from profound, untreated hypoglycemia, leading to irreversible cerebral injury and multiorgan failure.
explanation: Clinical review links severe untreated hypoglycemia to cerebral injury; other routes to encephalopathy remain possible.
downstream:
- target: Encephalopathy
description: Cerebral fuel deprivation can contribute to this severe manifestation; other causes of neurological dysfunction remain possible.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: INDIRECT
snippet: Mortality generally results from profound, untreated hypoglycemia, leading to irreversible cerebral injury and multiorgan failure.
explanation: Clinical review links severe untreated hypoglycemia to cerebral injury; other routes to encephalopathy remain possible.
- target: Seizure
description: Cerebral fuel deprivation can contribute to this severe manifestation; other causes of neurological dysfunction remain possible.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: INDIRECT
snippet: Mortality generally results from profound, untreated hypoglycemia, leading to irreversible cerebral injury and multiorgan failure.
explanation: Clinical review links severe untreated hypoglycemia to cerebral injury; other routes to encephalopathy remain possible.
- target: Coma
description: Cerebral fuel deprivation can contribute to this severe manifestation; other causes of neurological dysfunction remain possible.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: INDIRECT
snippet: Mortality generally results from profound, untreated hypoglycemia, leading to irreversible cerebral injury and multiorgan failure.
explanation: Clinical review links severe untreated hypoglycemia to cerebral injury; other routes to encephalopathy remain possible.
- name: Hepatocellular Injury
description: Hepatic injury is a reported complication. A fulminant case had bridging and multiacinar necrosis with focal microvesicular steatosis, but exposure was unconfirmed and sickling-related ischemia substantially confounded attribution. The intervening injury mechanism in human ackee poisoning remains incompletely resolved.
role: intermediate
biological_scale: CELLULAR
evidence:
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: There are bridging and multiacinar necroses with approximation of adjacent portal tracts and severe centrilobular congestion and hemorrhage
explanation: Direct pathology finding in one suspected poisoning; unconfirmed toxin exposure and concomitant sickling-related ischemia limit causal attribution.
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Cholestasis and small fat droplets (microvesicular steatosis) are seen in the neighboring hepatocytes
explanation: Direct histology documents focal microvesicular steatosis, without resolving its toxic versus ischemic cause.
downstream:
- target: Elevated hepatic transaminase
description: Hepatocyte injury can elevate circulating liver enzymes.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: aspartate aminotransferase (AST) 620 U/L (reference range 1–50), alanine aminotransferase (ALT) 478 U/L (reference range 1–53)
explanation: Admission measurements establish transaminase elevation in the confounded severe hepatic case.
- target: Acute liver failure
description: Extensive hepatic injury may progress to synthetic dysfunction and liver failure.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: On admission, she was in fulminant hepatic failure with hepatic encephalopathy.
explanation: The reported patient had liver failure and encephalopathy; exposure was unconfirmed and sickling-related ischemia confounded attribution.
- target: Encephalopathy
description: Hepatic dysfunction provides an additional route to encephalopathy independent of documented hypoglycemia.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: On admission, she was in fulminant hepatic failure with hepatic encephalopathy.
explanation: The reported patient had liver failure and encephalopathy; exposure was unconfirmed and sickling-related ischemia confounded attribution.
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: On presentation she was encephalopathic but not hypoglycemic, although hypoglycemia is a classic sign of JVS
explanation: The hepatic case provides a reported route to encephalopathy without documented hypoglycemia; attribution remains confounded.
phenotypes:
- name: Hypoglycemia
description: Can be profound or recurrent, but is not documented in every case. Low ketone availability is supported mechanistically by rodent studies rather than an established universal human phenotype.
phenotype_term:
preferred_term: Hypoglycemia
term:
id: HP:0001943
label: Hypoglycemia
temporality: ACUTE
severity: SEVERE
evidence:
- reference: PMID:28613753
reference_title: Ackee Fruit Toxicity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Clinical manifestations typically include repetitive vomiting, altered mental status, and profound hypoglycemia.
explanation: Clinical toxicology review documents this manifestation; no population frequency is assigned.
quote_role: BACKGROUND
directness: DIRECT
- name: Vomiting
description: Often repetitive and early. Absence of vomiting does not exclude poisoning.
phenotype_term:
preferred_term: Vomiting
term:
id: HP:0002013
label: Vomiting
temporality: ACUTE
evidence:
- reference: PMID:28613753
reference_title: Ackee Fruit Toxicity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Clinical manifestations typically include repetitive vomiting, altered mental status, and profound hypoglycemia.
explanation: Clinical toxicology review documents this manifestation; no population frequency is assigned.
quote_role: BACKGROUND
directness: DIRECT
- name: Encephalopathy
phenotype_term:
preferred_term: Altered mental status
term:
id: HP:0001298
label: Encephalopathy
temporality: ACUTE
evidence:
- reference: PMID:28613753
reference_title: Ackee Fruit Toxicity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Clinical manifestations typically include repetitive vomiting, altered mental status, and profound hypoglycemia.
explanation: Clinical toxicology review documents this manifestation; no population frequency is assigned.
quote_role: BACKGROUND
directness: DIRECT
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: On admission, she was in fulminant hepatic failure with hepatic encephalopathy.
explanation: The reported patient had liver failure and encephalopathy; exposure was unconfirmed and sickling-related ischemia confounded attribution.
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: On presentation she was encephalopathic but not hypoglycemic, although hypoglycemia is a classic sign of JVS
explanation: The hepatic case provides a reported route to encephalopathy without documented hypoglycemia; attribution remains confounded.
description: Altered consciousness ranges from drowsiness to severe cerebral dysfunction; hypoglycemia, hepatic injury and other metabolic abnormalities may contribute.
- name: Seizure
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
temporality: ACUTE
evidence:
- reference: PMID:28613753
reference_title: Ackee Fruit Toxicity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Severe toxicity may result in seizures, hypothermia, coma, and death.
explanation: Clinical toxicology review documents this manifestation; no population frequency is assigned.
quote_role: BACKGROUND
directness: DIRECT
description: Occurs in severe poisoning and hypoglycemic encephalopathy.
- name: Coma
phenotype_term:
preferred_term: Coma
term:
id: HP:0001259
label: Coma
temporality: ACUTE
evidence:
- reference: PMID:28613753
reference_title: Ackee Fruit Toxicity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Severe toxicity may result in seizures, hypothermia, coma, and death.
explanation: Clinical toxicology review documents this manifestation; no population frequency is assigned.
quote_role: BACKGROUND
directness: DIRECT
description: May occur in severe intoxication.
- name: Hypothermia
phenotype_term:
preferred_term: Hypothermia
term:
id: HP:0002045
label: Hypothermia
temporality: ACUTE
evidence:
- reference: PMID:28613753
reference_title: Ackee Fruit Toxicity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Severe toxicity may result in seizures, hypothermia, coma, and death.
explanation: Clinical toxicology review documents this manifestation; no population frequency is assigned.
quote_role: BACKGROUND
directness: DIRECT
description: Reported in severe intoxication.
- name: Abdominal pain
description: Intermittent abdominal pain appeared four days after exposure in five siblings who had initially remained asymptomatic.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
temporality: ACUTE
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: They were asymptomatic and were managed as out patients until 4 days post-ingestion when they developed intermittent abdominal pain and passage of loose, mucoid stools.
explanation: Primary observation in the less severely affected subgroup.
- name: Diarrhea
description: Usually absent from the classic syndrome, but loose mucoid stools were reported in five exposed siblings; this finding is not universal.
phenotype_term:
preferred_term: Diarrhea
term:
id: HP:0002014
label: Diarrhea
temporality: ACUTE
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: They were asymptomatic and were managed as out patients until 4 days post-ingestion when they developed intermittent abdominal pain and passage of loose, mucoid stools.
explanation: Delayed loose stools in one family cluster.
- name: Muscle weakness
description: Marked weakness or prostration can accompany acute illness; this does not imply the rhabdomyolytic phenotype of equine atypical myopathy.
phenotype_term:
preferred_term: Muscle weakness
term:
id: HP:0001324
label: Muscle weakness
temporality: ACUTE
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Her symptoms had started 2 hours after ingestion of six roasted seeds and arils of ackee fruit. Loss of consciousness was preceded by vomiting and extreme body weakness.
explanation: Observed weakness in the index child.
- name: Hypotonia
description: Reported among children in a fatal encephalopathy outbreak attributed probably to ackee; the selected outbreak does not estimate frequency in all poisoning.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
temporality: ACUTE
evidence:
- reference: PMID:10028981
reference_title: Epidemic of fatal encephalopathy in preschool children in Burkina Faso and consumption of unripe ackee (Blighia sapida) fruit.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The most common symptoms were hypotonia, vomiting, convulsions, and coma. All children died in 2-48 h.
explanation: The cohort was selected for fatal encephalopathy and exposure attribution was probabilistic.
- name: Dehydration
description: Persistent vomiting can produce dehydration and electrolyte disturbances.
phenotype_term:
preferred_term: Dehydration
term:
id: HP:0001944
label: Dehydration
temporality: ACUTE
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Severe electrolyte disturbances, dehydration secondary to persistent vomiting, metabolic acidosis, and hepatic dysfunction may also occur.
explanation: Review describes the volume-loss complication.
- name: Metabolic acidosis
description: May accompany severe metabolic or circulatory compromise; its presence and mechanism vary.
phenotype_term:
preferred_term: Metabolic acidosis
term:
id: HP:0001942
label: Metabolic acidosis
temporality: ACUTE
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Severe electrolyte disturbances, dehydration secondary to persistent vomiting, metabolic acidosis, and hepatic dysfunction may also occur.
explanation: Clinical review supports acidosis without a uniform frequency or cause.
- name: Elevated hepatic transaminase
description: Liver enzyme elevation can occur, although liver tests were normal in the eight-sibling cluster.
phenotype_term:
preferred_term: Elevated hepatic transaminase
term:
id: HP:0002910
label: Elevated circulating hepatic transaminase concentration
temporality: ACUTE
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Diagnostic evaluation typically reveals marked hypoglycemia, high anion gap metabolic acidosis, electrolyte derangements, elevated transaminases, and evidence of hepatic dysfunction.
explanation: Secondary clinical summary; individual cases may have normal liver tests.
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: aspartate aminotransferase (AST) 620 U/L (reference range 1–50), alanine aminotransferase (ALT) 478 U/L (reference range 1–53)
explanation: Admission measurements establish transaminase elevation in the confounded severe hepatic case.
- name: Acute liver failure
description: A fulminant case after suspected ackee ingestion required emergency transplantation and died. Toxin confirmation was absent and concurrent ischemic injury associated with sickled cells confounded attribution.
phenotype_term:
preferred_term: Acute liver failure
term:
id: HP:0006554
label: Acute hepatic failure
temporality: ACUTE
evidence:
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: On admission, she was in fulminant hepatic failure with hepatic encephalopathy.
explanation: The reported patient had liver failure and encephalopathy; exposure was unconfirmed and sickling-related ischemia confounded attribution.
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: After one successful code, her code status was changed to “Do Not Resuscitate.” She expired 6 hours later.
explanation: The patient died after emergency transplantation; a single confounded case does not establish a transplant success rate.
environmental:
- name: Ingestion of toxic ackee material
description: Eating unripe or improperly processed arils, seeds or other toxic fruit parts delivers hypoglycin A. Canned exposure is documented. Natural ripening reduces aril toxin concentration, but seeds and rind remain unsafe; heating does not reliably detoxify unripe fruit.
exposure_term:
preferred_term: exposure to hypoglycin A in unripe ackee fruit
term:
id: ECTO:0000537
label: exposure to toxin
food_source:
preferred_term: akee (raw)
term:
id: FOODON:03301360
label: akee (raw)
exposure_classifications:
hazard_agent_type:
- classification_value: CHEMICAL
exposure_route:
- classification_value: ORAL
exposure_duration:
- classification_value: ACUTE
influences_mechanisms:
- target: Hypoglycin A Ingestion
environmental_effect: TRIGGERS
causal_link_type: DIRECT
description: Oral ingestion delivers the protoxin.
evidence: *id001
evidence:
- reference: PMID:8185109
reference_title: Jamaican vomiting sickness in Toledo, Ohio.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The toxic exposure resulted from the consumption of canned ackee. The epidemiology, diagnosis, theoretical mechanism, and possible therapy of this disease are discussed.
explanation: A United States case demonstrates the preserved-product route.
- reference: PMID:21410289
reference_title: 'Tracking hypoglycins A and B over different maturity stages: implications for detoxification of ackee (Blighia sapida K.D. Koenig) fruits.'
supports: SUPPORT
evidence_source: OTHER
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The causal toxin, hypoglycin A, decreases in the edible arilli upon maturity; regulation of hypoglycin A in the arilli is thus critical.
explanation: Analytical maturity study directly addresses exposure concentration.
- reference: url:https://www.fda.gov/media/88521/download
reference_title: https://www.fda.gov/media/88521/download
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: DIRECT
snippet: However, the rind and seeds still have high levels of hypoglycin A when the fruit is fully ripe and should not be consumed.
explanation: Final FDA guidance distinguishes edible mature arils from toxic fruit parts.
notes: The broad toxin exposure term is retained with a specific food-source annotation. The 2011 fruit study measured residual hypoglycin A in ripe Cheese arils (271 mg/kg); maturity is not a claim of zero toxin in every sample. The FDA food action criterion is not a human toxic-dose threshold.
progression:
- phase: Exposure and onset
notes: Symptoms often begin within 6–48 hours, but severe onset at two hours and delayed gastrointestinal symptoms at four days occurred in one family. Dose, food preparation and nutritional context vary.
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Her symptoms had started 2 hours after ingestion of six roasted seeds and arils of ackee fruit. Loss of consciousness was preceded by vomiting and extreme body weakness.
explanation: Direct case timing, not a universal incubation interval.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Hypoglycemia may not manifest until several hours after ingestion. This metabolic derangement progresses rapidly once established.
explanation: The review emphasizes delayed glucose deterioration.
- phase: Recovery or severe deterioration
notes: Survivors may recover over several days with supportive care; severe cases can deteriorate rapidly. One of eight siblings died and the index child recovered by day six. Fatal-outbreak series are selected and do not establish a general case-fatality rate.
evidence:
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: She had frequent monitoring of vital signs and was discharged on the sixth day of admission after full recovery.
explanation: Observed recovery under combined supportive treatment.
- reference: PMID:10028981
reference_title: Epidemic of fatal encephalopathy in preschool children in Burkina Faso and consumption of unripe ackee (Blighia sapida) fruit.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: 29 cases of EFE were identified from January to May, 1998.
explanation: Fatal encephalopathy ascertainment selects the most severe end of the spectrum.
epidemiology:
- name: Geographic and outbreak distribution
description: Reported in Jamaica and other Caribbean settings, West Africa and imported-food settings. Reliable contemporary population incidence and prevalence are not established. Household clusters reflect shared exposure rather than inheritance.
evidence:
- reference: PMID:16749544
reference_title: 'Ackee fruit poisoning: an outbreak investigation in Haiti 2000-2001, and review of the literature.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The Centers for Disease Control and Prevention (CDC) provided technical assistance to the Ministry of Health of Haiti during an outbreak of over 100 cases of acute illness and death in the northern region of Haiti during a 4-month period beginning in November 2000.
explanation: Primary outbreak report abstract; no narrower case denominator or modern incidence inferred.
- reference: PMID:10028981
reference_title: Epidemic of fatal encephalopathy in preschool children in Burkina Faso and consumption of unripe ackee (Blighia sapida) fruit.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The only factor associated with EFE was the presence of ackee trees (Blighia sapida) within 100 m of households
explanation: Household association supports probable etiology, not individual confirmed ingestion in every case.
notes: The Burkina Faso study defined fatal encephalopathy; its all-fatal series must not be read as the case-fatality rate for unselected ackee exposure. The Haiti abstract uses over 100 illnesses/deaths; secondary reports use different denominators that are not combined here.
biochemical:
- name: Urinary dicarboxylic acids
presence: INCREASED
context: In two original human cases, several dicarboxylic acids were 70–1000 times the reported normal values. This supports an oxidation defect but is neither a validated severity scale nor a specific diagnostic signature by itself.
evidence:
- reference: PMID:940578
reference_title: Jamaican vomiting sickness. Biochemical investigation of two cases.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Excretion of unusual dicarboxylic acids such as 2-ethylmalonic, 2-methylsuccinic, glutaric, adipic and dicarboxylic acids with eight and 10 carbon chains were also detected in both patients.
explanation: Direct biochemical observations in two patients.
readouts:
- target: Impaired Fatty Acid Beta-Oxidation
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Elevated organic acids are compatible with impaired oxidation; urinary concentration does not directly quantify hepatic flux.
evidence:
- reference: PMID:940578
reference_title: Jamaican vomiting sickness. Biochemical investigation of two cases.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: The amounts of these dicarboxylic acids were 70 to 1000 times higher than normal.
explanation: Case-specific comparison with normal values.
- name: Urinary short-chain fatty acids
presence: INCREASED
context: Up to 300-fold elevation was reported in the same two human cases. These values are not a population reference interval.
evidence:
- reference: PMID:940578
reference_title: Jamaican vomiting sickness. Biochemical investigation of two cases.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Urinary excretion of short-chain fatty acids was also increased up to 300 times higher than normal.
explanation: Direct human urinary measurement.
- name: Urinary MCPA after hydrolysis
presence: PRESENT
context: The historical patient result supports excretion of conjugated toxin metabolites. The later analytical paper clarifies that MCPA was detected after hydrolysis; it should not be represented as a measurement of free urinary MCPA-CoA.
evidence:
- reference: PMID:940578
reference_title: Jamaican vomiting sickness. Biochemical investigation of two cases.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: We identified methylenecyclopropylacetic acid, a known metabolite of hypoglycin A, in the urine of two patients with Jamaican vomiting sickness.
explanation: Human toxin-metabolite evidence.
- reference: PMID:26328472
reference_title: Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: DIRECT
snippet: When the patients’ urine samples were treated with the hydrolyzing agent barium hydroxide, the samples tested positive for MCPAA, which suggests the majority of the metabolite had been conjugated prior to excretion.
explanation: Full analytical background clarifies the processing and analyte identity.
- name: Hypoglycin A in gastric contents
presence: PRESENT
context: GC-MS demonstrated hypoglycin A in gastric fluid from one deceased child in a cluster of 16 deaths. This confirms exposure in that child, not laboratory confirmation of every cluster case.
evidence:
- reference: PMID:21324617
reference_title: Fatal intoxication due to ackee (Blighia sapida) in Suriname and French Guyana. GC-MS detection and quantification of hypoglycin-A.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: We have developed a GC-MS procedure allowing us to demonstrate the presence of hypoglycin-A in the gastric fluid of one of the deceased children
explanation: Direct toxin identification in one patient.
- name: Hypoglycin A and methylenecyclopropylglycine exposure assays
context: Specialized plasma HGA/MCPG and urinary MCPA-Gly/MCPF-Gly assays can document exposure. The plasma validation used commercial and spiked samples, and the urinary field application involved suspected acute encephalitis cases rather than an ackee-specific validation cohort. A positive exposure marker is not a validated clinical severity threshold.
evidence:
- reference: PMID:30056267
reference_title: Quantification of hypoglycin A and methylenecyclopropylglycine in human plasma by HPLC-MS/MS.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: This method was applied to a commercial convenience set consisting of 100 individual plasma samples that served as a reference range for HGA and MCPG expected in a commercially available, unexposed population.
explanation: Analytical validation scope, not a symptomatic case-control accuracy study.
- reference: PMID:26328472
reference_title: Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The method was further applied in a laboratory analysis of specimens collected from suspected AES cases. Of the samples (n=73) analyzed, 66% of the samples were found positive for MCPF-Gly and/or MCPA-Gly.
explanation: The field demonstration was in suspected AES, not confirmed Jamaican vomiting sickness.
diagnosis:
- name: Exposure history and clinical assessment
description: Obtain a detailed food and preparation history, including preserved ackee and illness in other people sharing the meal. Evaluate compatible gastrointestinal or neurological illness promptly; absence of vomiting or a single normal glucose measurement does not exclude exposure-related illness.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Vomiting is common, but its absence does not exclude the diagnosis.
explanation: Clinical review explicitly cautions against a required vomiting criterion.
- reference: PMID:26324727
reference_title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The remaining five children aged between 4 and 10 years were brought in for evaluation after requests by the managing team.
explanation: The family report supports assessment of other exposed children.
- name: Immediate and serial metabolic assessment
description: Measure glucose promptly and serially, with electrolytes, liver and renal tests, lactate, ketones and blood gases as clinically indicated. Monitoring is directed at treatable metabolic deterioration and organ injury.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Diagnostic evaluation should include blood glucose, serum electrolytes, liver function tests, renal function, lactate, ketones, and blood gases.
explanation: Clinical toxicology evaluation guidance.
- name: Specialized toxin and metabolite testing
description: Urinary organic acids and specific HGA-related metabolites can support the diagnosis when available. Timing and assay limitations matter, and emergency glucose correction should not depend on a specialized toxicology result. Veterinary acylcarnitine concentrations are not human diagnostic thresholds.
evidence:
- reference: PMID:26328472
reference_title: Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: DIRECT
snippet: Since the clearance rate of the metabolites is still unknown, the time lapse between collection and exposure could significantly affect the amount of metabolite remaining at the time of analysis.
explanation: Analytical source emphasizes uncertainty in sampling-time interpretation.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Patients require close monitoring for hypoglycemia and should receive dextrose therapy. Initial dextrose boluses may be administered, followed by a continuous infusion titrated to maintain euglycemia.
explanation: Prompt treatment and monitoring are required regardless of specialized test availability.
- name: Reassessment for competing causes
description: Consider other toxic, infectious and metabolic causes of hypoglycemia or encephalopathy. Persistent or recurrent unexplained biochemical abnormalities warrant specialist evaluation for inherited fatty-acid oxidation disease. Negative ETFA/ETFB/ETFDH or ACADM sequencing is not a mandatory diagnostic criterion for ackee poisoning.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Diagnosis must be established through careful evaluation of presenting symptoms, laboratory data, and confirmation of recent unripe
explanation: Clinical review bases diagnosis on integrated findings; it does not require negative genetic sequencing.
differential_diagnoses:
- name: Multiple acyl-CoA dehydrogenase deficiency
disease_term:
preferred_term: multiple acyl-CoA dehydrogenase deficiency
term:
id: MONDO:0009282
label: multiple acyl-CoA dehydrogenase deficiency
description: Inherited multiple acyl-CoA dehydrogenase deficiency and toxin-induced inhibition overlap metabolically but have different upstream causes. Broad acylcarnitine and organic-acid patterns in hypoglycin-exposed horses support a comparative acquired-MADD mechanism; they do not prove that every human poisoning profile is identical to inherited MADD.
distinguishing_features:
- A compatible shared-food or preserved-ackee exposure supports poisoning.
- Toxin-specific metabolites support exposure when demonstrable; absence depends on sampling and assay.
- Persistent or unexplained recurrent abnormalities require a metabolic differential rather than an assumed food attribution.
evidence:
- reference: PMID:23167695
reference_title: Seasonal pasture myopathy/atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Serum acylcarnitines and urine organic acid profiles in SPM horses were typical for MADD.
explanation: The MADD-like biochemical pattern was measured in horses, so its use for human differential diagnosis is indirect.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- name: Medium-chain acyl-CoA dehydrogenase deficiency
disease_term:
preferred_term: medium chain acyl-CoA dehydrogenase deficiency
term:
id: MONDO:0008721
label: medium chain acyl-CoA dehydrogenase deficiency
description: Inherited MCAD deficiency can cause fasting-associated hypoglycemia and organic acid abnormalities. MCPA-CoA can inhibit purified MCAD as well as other dehydrogenases, so MCAD is neither excluded as a toxin target nor sufficient to describe the entire poisoning mechanism. Substrate protection of an enzyme is not evidence that the enzyme is toxin-insensitive.
distinguishing_features:
- A compatible toxic exposure and specific metabolites support ackee poisoning.
- A persistent characteristic acylcarnitine profile or unexplained recurrent fasting crises warrants metabolic evaluation.
evidence: *id002
- name: Reye syndrome
description: Reye syndrome can resemble severe ackee poisoning clinically and histologically. The original two-case biochemical comparison found marked abnormal urinary organic acids in ackee poisoning that were not appreciably elevated in the Reye comparator literature.
distinguishing_features:
- A compatible ackee exposure with specific toxin metabolites supports poisoning.
- Marked dicarboxylic aciduria supported the distinction in the historical comparison; it is not a modern standalone exclusion test.
evidence:
- reference: PMID:940578
reference_title: Jamaican vomiting sickness. Biochemical investigation of two cases.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: despite their clinical and histologic similarities, the cause and biochemical mechanisms of Jamaican vomiting sickness differ distinctly from those of Reye's syndrome
explanation: States both the resemblance and the biochemical basis for separating them, in the paper that made the distinction.
quote_role: PRIMARY_RESULT
directness: DIRECT
- name: Other acute poisonings and hypoglycemic illnesses
description: Other ingestions, sulfonylurea toxicity, acute gastrointestinal illnesses and meningitis can overlap with the presentation. Dietary and medication histories, bedside glucose and targeted clinical investigation determine the differential.
distinguishing_features:
- Identify alternative ingestions or medication exposure.
- Investigate fever, focal findings and other clinical features inconsistent with an isolated metabolic food poisoning.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: The differential diagnosis should include disorders presenting with gastrointestinal symptoms, altered mental status, or metabolic disturbances similar to those observed in ackee fruit toxicity.
explanation: Review supports a broader acute differential.
treatments:
- name: Dextrose correction and glucose monitoring
description: Prompt intravenous dextrose corrects symptomatic hypoglycemia. Bolus treatment may require a titrated continuous infusion with serial glucose measurements. This supplies glucose during the metabolic block; it is not evidence that the toxin-enzyme lesion has been reversed.
evidence: &id003
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Patients require close monitoring for hypoglycemia and should receive dextrose therapy. Initial dextrose boluses may be administered, followed by a continuous infusion titrated to maintain euglycemia.
explanation: Toxicology review supports repeated glucose assessment and dextrose titration.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
therapeutic_agent:
- preferred_term: glucose
term:
id: CHEBI:17234
label: glucose
target_mechanisms:
- target: Hypoglycemia
treatment_effect: INHIBITS
description: Restores circulating glucose during impaired endogenous production.
evidence: *id003
- name: Fluid, electrolyte and gastrointestinal support
description: Rehydrate and correct electrolyte abnormalities; antiemetics may relieve symptoms. Care should follow clinical status and repeated measurements.
evidence: &id004
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Intravenous fluids are indicated to prevent dehydration, and antiemetics may be used to alleviate symptoms. Vomiting and dehydration can precipitate electrolyte disturbances, which should be corrected promptly.
explanation: Supportive care is directed at volume and electrolyte losses.
treatment_term:
preferred_term: Fluid Therapy
term:
id: NCIT:C116537
label: Fluid Therapy
target_mechanisms:
- target: Dehydration
treatment_effect: INHIBITS
description: Replaces volume lost during vomiting.
evidence: *id004
- name: Seizure management
description: Correct hypoglycemia and provide standard acute seizure management when required; benzodiazepines are described in the clinical review.
evidence: &id005
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Benzodiazepines may be employed for seizure management, but hypoglycemia must first be excluded as the underlying cause.
explanation: Seizure treatment accompanies assessment and correction of glucose.
treatment_term:
preferred_term: Anticonvulsant Therapy
term:
id: NCIT:C64172
label: Anticonvulsant Therapy
target_mechanisms:
- target: Seizure
treatment_effect: INHIBITS
description: Treats ongoing seizures alongside correction of their metabolic cause.
evidence: *id005
- name: Hospital observation and critical care
description: Monitor neurological status, glucose, electrolytes and liver/renal function. Persistent hypoglycemia, seizures, acidosis, altered consciousness or poor perfusion may require intensive care. A reported emergency transplant for fulminant liver failure had a fatal outcome and does not establish an ackee-specific transplant success rate.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Patients with persistent hypoglycemia, seizures, metabolic acidosis, altered mental status, or poor perfusion frequently require intensive care unit admission.
explanation: Review identifies severe features prompting critical care.
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: On admission, she was in fulminant hepatic failure with hepatic encephalopathy.
explanation: The reported patient had liver failure and encephalopathy; exposure was unconfirmed and sickling-related ischemia confounded attribution.
- reference: PMID:23259140
reference_title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: After one successful code, her code status was changed to “Do Not Resuscitate.” She expired 6 hours later.
explanation: The patient died after emergency transplantation; a single confounded case does not establish a transplant success rate.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
notes: No established specific antidote is available. Riboflavin, glycine and methylene blue have experimental or anecdotal use, without established clinical efficacy; coadministration of vitamin B complex in the sibling series cannot identify a vitamin-specific treatment effect.
- name: Toxicology consultation
description: Consult a poison center or medical toxicologist. Routine gastrointestinal decontamination lacks demonstrated outcome benefit and may be inappropriate with vomiting, seizures or impaired consciousness.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Evidence supporting routine gastrointestinal decontamination improving outcomes is insufficient.
explanation: Do not promote charcoal or lavage as an established effective antidote.
- name: Safe harvesting, preparation and exposure prevention
description: Use fully mature naturally opened fruit, remove seeds and raphe, and follow reliable processing controls. Do not force open or heat-shock immature fruit to accelerate opening; cooking does not make toxic unripe fruit safe. Educate households and evaluate other exposed people after a shared meal.
evidence: &id006
- reference: url:https://www.fda.gov/media/88521/download
reference_title: https://www.fda.gov/media/88521/download
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: DIRECT
snippet: Prior to further processing and packaging, the black seeds and raphe are removed, and the arils are visually inspected for damage, blemishes, or signs of spoilage.
explanation: Final FDA processing guidance describes removal of unsafe parts.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
reference_title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Cooking the unripe fruit does not mitigate its toxic potential. The seeds retain their toxicity and must not be ingested.
explanation: Prevention advice distinguishes natural maturation from heating.
target_mechanisms:
- target: Hypoglycin A Ingestion
treatment_effect: INHIBITS
description: Reduces ingestion of toxin-containing fruit parts or improperly processed product.
evidence: *id006
notes: The final April 2014 FDA guide treats more than 100 ppm hypoglycin A in finished products as an action criterion for improper processing; this is a food-control policy, not a clinical poisoning threshold. Its guidance is nonbinding except where it cites statutory requirements.
animal_models:
- name: MCPA infusion in fasted conscious rats
species: Rat
description: Male Sprague-Dawley/CD rats fasted 18–20 hours received intravenous MCPA 80 mg/kg; a two-hour isotope-infusion protocol measured glucose and ketone turnover, PC flux and hepatic metabolites. Dextrose maintained euglycemia in treated rats. This bypasses oral hypoglycin exposure and does not reproduce the full human syndrome.
publication: PMID:29483297
modeled_mechanisms:
- target: MCPA-CoA Formation
relationship: MEASURES
fidelity: MODERATE
description: Hepatic MCPA-CoA was identified by LC-MS/MS.
limitations: The parent amino acid and its transamination were bypassed.
evidence: &id008
- *id007
readouts:
- name: Hepatic MCPA-CoA detection
target: MCPA-CoA Formation
direction: INCREASED
interpretation: Hepatic MCPA-CoA was identified by LC-MS/MS.
evidence: *id008
- target: Reduced Hepatic Acetyl-CoA
relationship: MEASURES
fidelity: MODERATE
description: Hepatic acetyl-CoA decreased 84%.
limitations: Single acute high-dose fasted-rat protocol; no human residual-function threshold.
evidence: *id009
readouts:
- name: Hepatic acetyl-CoA content
target: Reduced Hepatic Acetyl-CoA
direction: DECREASED
interpretation: Hepatic acetyl-CoA decreased 84%.
evidence: *id009
- target: Reduced Hepatic ATP Availability
relationship: MEASURES
fidelity: MODERATE
description: Hepatic ATP decreased 13% and ATP/ADP decreased 30%.
limitations: The ATP contribution was not isolated by rescue; complete ATP depletion was not observed.
evidence: *id010
readouts:
- name: Hepatic ATP content
target: Reduced Hepatic ATP Availability
direction: DECREASED
interpretation: Hepatic ATP decreased 13% and ATP/ADP decreased 30%.
evidence: *id010
- target: Reduced Hepatic Pyruvate Carboxylase Flux
relationship: MEASURES
fidelity: MODERATE
description: PINTA-estimated absolute PC flux decreased 75%.
limitations: Flux is model-based; no direct enzyme-binding or causal mediator rescue was performed.
evidence: *id011
readouts:
- name: Estimated hepatic PC flux
target: Reduced Hepatic Pyruvate Carboxylase Flux
direction: DECREASED
interpretation: PINTA-estimated absolute PC flux decreased 75%.
evidence: *id011
- target: Reduced Hepatic Glucose Production
relationship: MEASURES
fidelity: MODERATE
description: Endogenous production fell by approximately half without changed clearance.
limitations: Treated animals received dextrose to maintain euglycemia.
evidence: *id012
readouts:
- name: Endogenous glucose production
target: Reduced Hepatic Glucose Production
direction: DECREASED
interpretation: Endogenous production fell by approximately half without changed clearance.
evidence: *id012
- target: Reduced Ketogenesis
relationship: MEASURES
fidelity: MODERATE
description: Beta-hydroxybutyrate turnover decreased 82% and concentration 92%.
limitations: This establishes a rat metabolic effect, not a required human diagnostic criterion.
evidence: *id013
readouts:
- name: Beta-hydroxybutyrate turnover
target: Reduced Ketogenesis
direction: DECREASED
interpretation: Beta-hydroxybutyrate turnover decreased 82% and concentration 92%.
evidence: *id013
- name: Hypoglycin exposure in rats
species: Rat
publication: PMID:1247597
description: Liver mitochondrial extracts from hypoglycin-treated rats show substrate-selective reduction in dehydrogenase activity.
modeled_mechanisms:
- target: Selective Acyl-CoA Dehydrogenase Inactivation
relationship: MEASURES
fidelity: MODERATE
description: Activity measured with butyryl-CoA decreased, while octanoyl- and palmitoyl-CoA activities were unchanged in this preparation.
limitations: The pattern does not exclude purified MCAD susceptibility demonstrated in later studies.
evidence: &id014
- reference: PMID:1247597
reference_title: Selective inhibition of acyl-CoA dehydrogenases by a metabolite of hypoglycin.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Extracts of liver mitochondria from donor rats given hypoglycin, the toxic amino acid from the ackee plant (Blighia sapida) showed drastically reduced levels of acyl-CoA dehydrogenase activity with butyryl-CoA as substrate.
explanation: In-vivo exposure followed by mitochondrial-extract assay.
readouts:
- name: Butyryl-CoA dehydrogenase activity
target: Selective Acyl-CoA Dehydrogenase Inactivation
direction: DECREASED
interpretation: Activity measured with butyryl-CoA decreased, while octanoyl- and palmitoyl-CoA activities were unchanged in this preparation.
evidence: *id014
- name: Equine atypical myopathy and seasonal pasture myopathy
species: Horse
publication: PMID:23167695
description: Naturally occurring hypoglycin-associated disease follows grazing Acer-contaminated pastures. Serum MCPA-carnitine and MADD-like biochemical profiles provide comparative evidence, but the predominant equine manifestation is muscle injury rather than the human gastrointestinal and cerebral syndrome.
modeled_mechanisms:
- target: MCPA-CoA Formation
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: The natural disease supplies comparative toxin-conjugate and metabolic-profile measurements.
limitations: Different species, plant source and exposure dose; both are oral exposures. Clinical expression and sampled tissue compartments differ. No human diagnostic cutoff follows from equine concentrations.
readouts:
- name: Serum MCPA-carnitine
target: MCPA-CoA Formation
direction: INCREASED
interpretation: Observed in exposed horses; supports comparative metabolism rather than a human diagnostic threshold.
evidence:
- reference: PMID:23773055
reference_title: Identification of methylenecyclopropyl acetic acid in serum of European horses with atypical myopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: 'Methylenecyclopropyl acetic acid-carnitine at high concentrations (20.39 ± 17.24 nmol/l; range 0.95-57.63 nmol/l; reference: <0.01 nmol/l) was identified in serum of AM but not disease controls (0.00 ± 0.00 nmol/l).'
explanation: Measured veterinary biomarker; extrapolation to human poisoning is indirect.
quote_role: PRIMARY_RESULT
directness: INDIRECT
evidence:
- reference: PMID:23773055
reference_title: Identification of methylenecyclopropyl acetic acid in serum of European horses with atypical myopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Atypical myopathy in Europe, like seasonal pasture myopathy in North America, is highly associated with the toxic metabolite of hypoglycin A, MCPA-carnitine.
explanation: Measured veterinary biomarker; extrapolation to human poisoning is indirect.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- target: Impaired Fatty Acid Beta-Oxidation
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: The natural disease supplies comparative toxin-conjugate and metabolic-profile measurements.
limitations: Different species, plant source and exposure dose; both are oral exposures. Clinical expression and sampled tissue compartments differ. No human diagnostic cutoff follows from equine concentrations.
readouts:
- name: Serum acylcarnitines and urinary organic acids
target: Impaired Fatty Acid Beta-Oxidation
direction: ALTERED
interpretation: Observed in exposed horses; supports comparative metabolism rather than a human diagnostic threshold.
evidence:
- reference: PMID:23167695
reference_title: Seasonal pasture myopathy/atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Serum acylcarnitines and urine organic acid profiles in SPM horses were typical for MADD.
explanation: Measured veterinary biomarker; extrapolation to human poisoning is indirect.
quote_role: PRIMARY_RESULT
directness: INDIRECT
evidence:
- reference: PMID:23167695
reference_title: Seasonal pasture myopathy/atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Hypoglycin A, known to cause acquired multiple acyl-CoA dehydrogenase deficiency (MADD), was found in box elder seeds.
explanation: Measured veterinary biomarker; extrapolation to human poisoning is indirect.
quote_role: PRIMARY_RESULT
directness: INDIRECT
notes: The source studies are observational and do not independently prove a fully identical multienzyme lesion in every human case. The separate foal study infers hydratase dysfunction from metabolites; it does not measure the enzyme directly.
- name: Hypoglycin A and MCPA immersion in zebrafish embryos and larvae
species: Zebrafish (Danio rerio)
publication: PMID:39459322
description: Wild-type AB embryos were exposed by immersion beginning at 24 hours after fertilization, with monitoring through 96 hours. HGA and MCPA produced mortality, bradycardia and cardiac edema, with later toxicity onset after HGA; MCPA also reduced swimming under selected exposure conditions. The model was developed for Sapindaceae-associated equine atypical myopathy and captures shared toxin biology rather than human ackee ingestion or a demonstrated human hypoglycemic syndrome. Whole-body metabolite and locomotor experiments each had one experimental replicate; metabolomics pooled twenty larvae per concentration. Mortality assays used biological triplicates. Glycine and carnitine co-exposure reduced 72-hour mortality, whereas riboflavin did not protect in this protocol. Compounds were added simultaneously with toxin, so this is prevention/co-treatment evidence, not treatment after established poisoning. Surviving larvae could retain cardiac abnormalities. MCPrG caused no observed toxicity in this exposure system, but uptake and activation were unresolved; the result does not establish safety in mammals.
modeled_mechanisms:
- target: MCPA-CoA Formation
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: ORGANISM
description: HGA-exposed larvae accumulated the downstream conjugate MCPA-carnitine.
limitations: Indirect bioactivation readout from pooled whole-body material with no biological replicate series; neither MCPA-CoA nor a specific activating enzyme was directly quantified. Immersion differs from oral human exposure.
evidence:
- &zfish001
reference: PMID:39459322
reference_title: A Zebrafish Embryo Model to Screen Potential Therapeutic Compounds in Sapindaceae Poisoning.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: The most pronounced elevations in MCPA–carnitine concentrations were observed after 24 h at HGA concentrations exceeding 6 μM, and after 48 h for a 1.56 μM HGA concentration (Figure 2 panel B).
explanation: Whole-body MCPA-carnitine is a downstream conjugate supporting HGA bioactivation; MCPA-CoA itself and the individual activating enzymes were not directly measured.
readouts:
- name: Whole-body MCPA-carnitine after HGA exposure
target: MCPA-CoA Formation
direction: INCREASED
interpretation: A conjugated metabolite supports bioactivation but does not quantify the active CoA ester.
evidence:
- *zfish001
- target: Impaired Fatty Acid Beta-Oxidation
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: ORGANISM
description: Short- and medium-chain acylcarnitine changes provide indirect evidence of disturbed fatty-acid metabolism.
limitations: Acylcarnitine accumulation does not isolate beta-oxidation flux or individual acyl-CoA dehydrogenases, and the pooled metabolic time course was not biologically replicated. Human glucose production, ketogenesis and clinical treatment response were not established.
evidence:
- &zfish002
reference: PMID:39459322
reference_title: A Zebrafish Embryo Model to Screen Potential Therapeutic Compounds in Sapindaceae Poisoning.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Among the even-numbered acylcarnitines, hexanoylcarnitine (C6), octanoylcarnitine (C8), and decanoylcarnitine (C10) levels increased after 48 h (Figure 3 panel C).
explanation: The profile is consistent with disrupted fatty-acid metabolism, but it is not a direct beta-oxidation flux or enzyme-inhibition assay.
readouts:
- name: Whole-body acylcarnitine profile
target: Impaired Fatty Acid Beta-Oxidation
direction: INCREASED
interpretation: C6, C8 and C10 acylcarnitines increased after HGA exposure; these are metabolic proxies.
evidence:
- *zfish002
evidence:
- reference: PMID:39459322
reference_title: A Zebrafish Embryo Model to Screen Potential Therapeutic Compounds in Sapindaceae Poisoning.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: 'Twenty fertilised eggs per concentration and four eggs for the negative control (E3) were exposed from approximately 24 hpf until 96 hpf with one egg per well in 24 well-plates (2 mL per well) or in 96 well-plates (120 μL per well) for MCPA and HGA, respectively.'
explanation: The experimental exposure starts after the earliest embryonic stages and uses biological triplicate acute-toxicity assays.
- reference: PMID:39459322
reference_title: A Zebrafish Embryo Model to Screen Potential Therapeutic Compounds in Sapindaceae Poisoning.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Riboflavin did not show a protective effect when co-treated with either MCPA or HGA, while carnitine and glycine decreased mortality under both conditions (Figure 5).
explanation: Co-treatment modifies short-term survival in larvae; it does not establish a human antidote or delayed rescue regimen.
- reference: PMID:39459322
reference_title: A Zebrafish Embryo Model to Screen Potential Therapeutic Compounds in Sapindaceae Poisoning.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Another limitation of this study is the lack of replication for the quantification of HGA, MCPA–carnitine, and acylcarnitines profile.
explanation: The authors explicitly limit the reliability of their metabolic time courses.
- reference: PMID:39459322
reference_title: A Zebrafish Embryo Model to Screen Potential Therapeutic Compounds in Sapindaceae Poisoning.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: For carnitine, all surviving larvae exhibited sub-lethal effects (bradycardia or cardiac oedema) with MCPA (11/11), whereas one out of three did so with HGA.
explanation: Improved survival did not imply complete physiological rescue.
experimental_models:
- name: Purified mammalian acyl-CoA dehydrogenase inhibition
experimental_model_type: OTHER
description: Purified-enzyme experiments test direct MCPA-CoA susceptibility and flavin modification. Pig-kidney general enzyme is strongly inhibited, and subsequent distinct-enzyme comparisons establish different susceptibility across dehydrogenases.
publication: PMID:7275979
modeled_mechanisms:
- target: Selective Acyl-CoA Dehydrogenase Inactivation
relationship: MEASURES
fidelity: MODERATE
description: Purified pig-kidney enzyme loses nearly all activity with covalent FAD modification.
limitations: The assay-specific residual activity is not a human tissue measurement; protection by octanoyl-CoA indicates active-site competition, not MCAD sparing.
evidence: *id002
readouts:
- name: Purified enzyme activity
target: Selective Acyl-CoA Dehydrogenase Inactivation
direction: DECREASED
interpretation: Purified pig-kidney enzyme loses nearly all activity with covalent FAD modification.
evidence: *id002
- name: Ketohypoglycin in isolated rat hepatocytes
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Isolated rat liver cells
publication: PMID:518564
description: Methylenecyclopropylpyruvate inhibited gluconeogenesis from several substrates, with fructose spared. Ketogenesis was inhibited without lactate; lactate masked this effect. ATP/ADP content was unchanged under the specified lactate/palmitate conditions.
modeled_mechanisms:
- target: Reduced Hepatic Glucose Production
relationship: MEASURES
fidelity: MODERATE
description: Gluconeogenesis is inhibited in a substrate-dependent manner.
limitations: This is a cultured rat-cell keto-acid exposure, not a human clinical assay or uniform energetic collapse.
evidence: &id015
- reference: PMID:518564
reference_title: Inhibition of gluconeogenesis in isolated rat liver cells by methylenecyclopropylpyruvate (ketohypoglycin).
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Methylenecyclopropylpyruvate at 0.3 mM inhibits gluconeogenesis from all substrates tested, except fructose.
explanation: Direct isolated-cell functional observation.
readouts:
- name: Hepatocyte glucose production
target: Reduced Hepatic Glucose Production
direction: DECREASED
interpretation: Gluconeogenesis is inhibited in a substrate-dependent manner.
evidence: *id015
discussions:
- discussion_id: mcpg_contribution_to_ackee_illness
kind: KNOWLEDGE_GAP
status: OPEN
prompt: How much does co-exposure to methylenecyclopropylglycine contribute to symptomatic human ackee poisoning?
attaches_to:
- pathophysiology#Hypoglycin A Ingestion
rationale: MCPG-related conjugates have been detected after ackee consumption, including in a volunteer study, but an exposed volunteer is not a clinical Jamaican vomiting sickness cohort. HGA remains the main established toxin. Quantitative clinical attribution and potential co-toxin effects remain unresolved.
evidence:
- reference: PMID:30056267
reference_title: Quantification of hypoglycin A and methylenecyclopropylglycine in human plasma by HPLC-MS/MS.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
directness: DIRECT
snippet: Both metabolites were detected in urine after ingestion of ackee as well as litchi fruit. These results created a renewed interest in cases of JVS, with respect to whether MCPG may be a causative agent along with HGA.
explanation: Background summarizes the healthy-adult exposure result.
- reference: PMID:33233889
reference_title: Study on the Metabolic Effects of Repeated Consumption of Canned Ackee.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Rapid intestinal absorption of the toxins was followed by their slow degradation to methylenecyclopropylacetyl and methylenecyclopropylformyl conjugates.
explanation: A single-volunteer metabolic study establishes co-exposure, not a disease-specific causal fraction.
proposed_experiments:
- experiment_id: paired_toxin_metabolite_sampling
name: Prospective paired toxin and metabolite sampling
description: Measure HGA, MCPG and conjugates over time in clinically characterized poisoning cases and asymptomatic people sharing the implicated food; record dose, preparation, nutritional status and sampling delay.
decision_criterion: Determine whether MCPG exposure or its metabolites associate with clinical severity after accounting for HGA exposure and sampling time.
supporting_outcome:
- A reproducible adjusted association would support a co-toxin contribution and justify targeted mechanistic testing.
refuting_outcome:
- Absence of an association would weaken the proposed contribution within the sampled exposures, without proving HGA acts alone.
notes: The 2021 foal report inferred long-chain enoyl-CoA hydratase dysfunction from acylcarnitines; no enzyme assay or genetic confirmation was available. It does not establish a corresponding human ackee mechanism.
- discussion_id: human_isoform_and_flux_translation
kind: KNOWLEDGE_GAP
status: OPEN
prompt: Which hepatic and extrahepatic flux defects dominate in confirmed human poisoning?
attaches_to:
- pathophysiology#Selective Acyl-CoA Dehydrogenase Inactivation
- pathophysiology#Reduced Hepatic Glucose Production
rationale: Purified enzyme, isolated cell and intravenous rat protocols differ in substrates, dose and duration. Human clinical metabolite series are small, and asymptomatic exposure can alter metabolism. Prospective clinically confirmed sampling is needed before assigning universal profiles, isoform inhibition fractions or biomarker prognostic thresholds.
evidence:
- reference: PMID:29483297
reference_title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: While we do not have an in vivo method to probe flux through the individual steps of β-oxidation, we are able to infer the step in β-oxidation targeted by the toxin-CoA conjugates
explanation: The rodent authors acknowledge indirect enzyme-step inference.
review_notes: Comprehensive 2026 review corrected the baseline claim that MCAD is spared, distinguished substrate protection from isoform susceptibility, and removed human/equine diagnostic equivalence. The two historical human MCPA results involved hydrolyzed urine; circulating equine conjugate values remain only in the model. Complete cached clinical, analytical and rat-mechanistic bodies were consumed, including Methods and limitations; no GeneReviews chapter applies to this acquired intoxication. Human hypoglycemia and vomiting are not obligatory, and the severe liver report is confounded. No phenotype frequency is inferred from a single family, a selected fatal-outbreak series or mixed denominators. The research report was assessed across all completeness dimensions; unsupported current mortality, generalized CoA sequestration, increased peripheral glucose disposal, alpha-oxidation wording, animal diagnostic cutoffs and unproven antidotes were excluded. Modern PMC HTML recovery uses the tracked adapter committed separately in this branch. The 2024 zebrafish model was subsequently integrated with single-replicate metabolomics, immersion and simultaneous co-treatment limitations;
the fatal transplant case is already represented without an efficacy claim.
references:
- reference: PMID:10028981
title: Epidemic of fatal encephalopathy in preschool children in Burkina Faso and consumption of unripe ackee (Blighia sapida) fruit.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:1247597
title: Selective inhibition of acyl-CoA dehydrogenases by a metabolite of hypoglycin.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:16749544
title: 'Ackee fruit poisoning: an outbreak investigation in Haiti 2000-2001, and review of the literature.'
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:21324617
title: Fatal intoxication due to ackee (Blighia sapida) in Suriname and French Guyana. GC-MS detection and quantification of hypoglycin-A.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:21410289
title: 'Tracking hypoglycins A and B over different maturity stages: implications for detoxification of ackee (Blighia sapida K.D. Koenig) fruits.'
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:23167695
title: Seasonal pasture myopathy/atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:23259140
title: Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.
findings:
- statement: Complete generated body assessed; species, assay and clinical ascertainment limits are retained.
- reference: PMID:2331485
title: Selective inactivation of various acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:23773055
title: Identification of methylenecyclopropyl acetic acid in serum of European horses with atypical myopathy.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:26324727
title: 'Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.'
findings:
- statement: Complete generated body assessed; species, assay and clinical ascertainment limits are retained.
- reference: PMID:26328472
title: Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.
findings:
- statement: Complete generated body assessed; species, assay and clinical ascertainment limits are retained.
- reference: PMID:28613753
title: Ackee Fruit Toxicity.
tags:
- StatPearls
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:29483297
title: In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
findings:
- statement: Complete generated body assessed; species, assay and clinical ascertainment limits are retained.
- reference: PMID:30056267
title: Quantification of hypoglycin A and methylenecyclopropylglycine in human plasma by HPLC-MS/MS.
findings:
- statement: Complete generated body assessed; species, assay and clinical ascertainment limits are retained.
- reference: PMID:3030285
title: Inhibition of gluconeogenesis by hypoglycin in the rat. Evidence for inhibition of glucose-6-phosphatase in vivo.
findings:
- statement: Abstract-only historical rat study; glucose-6-phosphatase inhibition depended on preparation and was not preserved in isolated hepatocytes.
- reference: PMID:33233889
title: Study on the Metabolic Effects of Repeated Consumption of Canned Ackee.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:34765670
title: Severe Inhibition of Long-Chain Acyl-CoA Enoylhydratase (EC 4.2.1.74) in a Newborn Foal Suffering From Atypical Myopathy.
findings:
- statement: Complete foal paper read; hydratase and genetic-susceptibility claims are inferred and not extrapolated to humans.
- reference: PMID:518564
title: Inhibition of gluconeogenesis in isolated rat liver cells by methylenecyclopropylpyruvate (ketohypoglycin).
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:6488562
title: 'Jamaican vomiting sickness: a study of two adult cases.'
findings:
- statement: Abstract-only two-adult biochemical report supports adult occurrence, not a distinct subtype.
- reference: PMID:7275979
title: Inactivation of general acyl-CoA dehydrogenase from pig kidney by a metabolite of hypoglycin A.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:8185109
title: Jamaican vomiting sickness in Toledo, Ohio.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: PMID:940578
title: Jamaican vomiting sickness. Biochemical investigation of two cases.
findings:
- statement: Available abstract assessed; no inaccessible methods or patient-level denominators inferred.
- reference: url:https://clinmedjournals.org/articles/ijdcr/international-journal-of-diabetes-and-clinical-research-ijdcr-4-073.pdf
title: https://clinmedjournals.org/articles/ijdcr/international-journal-of-diabetes-and-clinical-research-ijdcr-4-073.pdf
findings:
- statement: Full 2017 Latif/Luthra case report and discussion read. Insulin-treated 95-year-old with CKD improved after withdrawal; exposure was not toxin-confirmed. Its mechanistic review is superseded where inconsistent with primary experiments.
- reference: url:https://www.fda.gov/media/88521/download
title: https://www.fda.gov/media/88521/download
findings:
- statement: Full final April 2014 FDA Compliance Policy Guide 550.050, linked as current guidance at review. Supersedes the 2012 draft; food-action threshold is not a patient dose.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/
title: Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf
findings:
- statement: Complete StatPearls chapter updated 2025-12-09 read across presentation, diagnosis, management, prevention and prognosis. Clinical guidance is secondary; individual interventions are not randomized-trial evidence.
- reference: PMID:39459322
title: A Zebrafish Embryo Model to Screen Potential Therapeutic Compounds in Sapindaceae Poisoning.
findings:
- statement: Full Results, Discussion and Methods read. HGA/MCPA immersion model provides indirect bioactivation and fatty-acid metabolic readouts and preliminary simultaneous co-treatment screening; no human therapeutic efficacy, glucose/ketone phenotype or mammalian MCPrG safety inference is made.

📚

References & Deep Research

References

PMID:10028981

Epidemic of fatal encephalopathy in preschool children in Burkina Faso and consumption of unripe ackee (Blighia sapida) fruit.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:1247597

Selective inhibition of acyl-CoA dehydrogenases by a metabolite of hypoglycin.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:16749544

Ackee fruit poisoning: an outbreak investigation in Haiti 2000-2001, and review of the literature.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:21324617

Fatal intoxication due to ackee (Blighia sapida) in Suriname and French Guyana. GC-MS detection and quantification of hypoglycin-A.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:21410289

Tracking hypoglycins A and B over different maturity stages: implications for detoxification of ackee (Blighia sapida K.D. Koenig) fruits.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:23167695

Seasonal pasture myopathy/atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:23259140

Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.

1 finding

Complete generated body assessed; species, assay and clinical ascertainment limits are retained.

PMID:2331485

Selective inactivation of various acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:23773055

Identification of methylenecyclopropyl acetic acid in serum of European horses with atypical myopathy.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:26324727

Ackee Fruit Poisoning in Eight Siblings: Implications for Public Health Awareness.

1 finding

Complete generated body assessed; species, assay and clinical ascertainment limits are retained.

PMID:26328472

Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.

1 finding

Complete generated body assessed; species, assay and clinical ascertainment limits are retained.

PMID:28613753

Ackee Fruit Toxicity.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:29483297

In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.

1 finding

Complete generated body assessed; species, assay and clinical ascertainment limits are retained.

PMID:30056267

Quantification of hypoglycin A and methylenecyclopropylglycine in human plasma by HPLC-MS/MS.

1 finding

Complete generated body assessed; species, assay and clinical ascertainment limits are retained.

PMID:3030285

Inhibition of gluconeogenesis by hypoglycin in the rat. Evidence for inhibition of glucose-6-phosphatase in vivo.

1 finding

Abstract-only historical rat study; glucose-6-phosphatase inhibition depended on preparation and was not preserved in isolated hepatocytes.

PMID:33233889

Study on the Metabolic Effects of Repeated Consumption of Canned Ackee.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:34765670

Severe Inhibition of Long-Chain Acyl-CoA Enoylhydratase (EC 4.2.1.74) in a Newborn Foal Suffering From Atypical Myopathy.

1 finding

Complete foal paper read; hydratase and genetic-susceptibility claims are inferred and not extrapolated to humans.

PMID:518564

Inhibition of gluconeogenesis in isolated rat liver cells by methylenecyclopropylpyruvate (ketohypoglycin).

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:6488562

Jamaican vomiting sickness: a study of two adult cases.

1 finding

Abstract-only two-adult biochemical report supports adult occurrence, not a distinct subtype.

PMID:7275979

Inactivation of general acyl-CoA dehydrogenase from pig kidney by a metabolite of hypoglycin A.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:8185109

Jamaican vomiting sickness in Toledo, Ohio.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

PMID:940578

Jamaican vomiting sickness. Biochemical investigation of two cases.

1 finding

Available abstract assessed; no inaccessible methods or patient-level denominators inferred.

url:https://clinmedjournals.org/articles/ijdcr/international-journal-of-diabetes-and-clinical-research-ijdcr-4-073.pdf

https://clinmedjournals.org/articles/ijdcr/international-journal-of-diabetes-and-clinical-research-ijdcr-4-073.pdf

1 finding

Full 2017 Latif/Luthra case report and discussion read. Insulin-treated 95-year-old with CKD improved after withdrawal; exposure was not toxin-confirmed. Its mechanistic review is superseded where inconsistent with primary experiments.

url:https://www.fda.gov/media/88521/download

https://www.fda.gov/media/88521/download

1 finding

Full final April 2014 FDA Compliance Policy Guide 550.050, linked as current guidance at review. Supersedes the 2012 draft; food-action threshold is not a patient dose.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK431101/

Ackee Fruit Toxicity - StatPearls - NCBI Bookshelf

1 finding

Complete StatPearls chapter updated 2025-12-09 read across presentation, diagnosis, management, prevention and prognosis. Clinical guidance is secondary; individual interventions are not randomized-trial evidence.

PMID:39459322

A Zebrafish Embryo Model to Screen Potential Therapeutic Compounds in Sapindaceae Poisoning.

1 finding

Full Results, Discussion and Methods read. HGA/MCPA immersion model provides indirect bioactivation and fatty-acid metabolic readouts and preliminary simultaneous co-treatment screening; no human therapeutic efficacy, glucose/ketone phenotype or mammalian MCPrG safety inference is made.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review ackee poisoning mechanism, human evidence and supportive care · 2026-09-21T06:14:09Z · View source

Comprehensive review of the original entry, matching deep-research narrative and citation sidecar, every original cited abstract and every available actual cached full body. Corrected the mistaken inference that substrate protection spares MCAD: purified-enzyme evidence supports selective irreversible SCAD/MCAD/isovaleryl-CoA inhibition, with isoform and assay differences. Replaced bundled mechanisms with 12 atomic nodes and explicit indirect human translation. Separated hypoglycin transamination, MCPA-CoA generation, dehydrogenase inhibition, fatty-acid oxidation, acetyl-CoA, ATP, estimated PC flux, endogenous glucose production, ketogenesis, cerebral injury and hepatic injury. Rat intravenous MCPA bypasses oral exposure and transamination; quantitative changes are protocol-specific. Removed universal CoA depletion, increased peripheral glucose clearance, fixed residual enzyme activity and indistinguishable inherited-MADD claims. Fourteen clinical findings, clinical diagnosis, human versus veterinary exposure biomarkers, six supportive/preventive care approaches, progression and outbreak ascertainment are covered. Vomiting and hypoglycemia are not obligatory. Preserved the severe hepatic case with positive pathology/laboratory/outcome quotes and unconfirmed exposure plus sickling-related ischemic confounding. No toxin-specific transplant success rate, vitamin/antidote efficacy, mandatory negative inherited-disease sequencing, universal human hypoketosis or fatal-cohort case-fatality estimate is inferred. Human plasma and urine analytical validation are not diagnostic sensitivity estimates; one-volunteer exposure and maple-poisoned horse values are not clinical ackee cutoffs. Read complete cached bodies for the analytical papers PMID30056267 and 26328472, sibling series26324727, metabolic rat study29483297, hepatic case23259140, comparative foal34765670, the 2017 diabetic case PDF, full updated NBK431101 chapter and final FDA2014 food guidance. The chapter was consumed across clinical characteristics, diagnosis, management and prevention; no disease-specific GeneReviews chapter applies to this acquired intoxication. Read all original and newly recovered abstracts, including2331485,10028981,16749544,21324617,21410289,33233889,6488562,3030285 and518564. Historical enzyme full text7275979 was independently read from a public author display, but its generated cache remains abstract-only after publisher retrieval failures. Other unrecovered historical full methods are not claimed as consumed. Three animal and two experimental models retain species, dose, preparation, measured endpoint and causal-rescue limits. Independent peer audits checked enzyme selectivity and clinical/care evidence. The tracked modern PMC HTML fallback is included as a separate prerequisite commit for reproducible generation of the sibling full-text cache; generated cache contents were never hand-edited. Frozen dataset-accession data were never accessed. The final entry passes authoritative schema, live ontology and 135 exact-snippet validations; local integrity guards and full node-class resolution are documented in the PR. The review leaves uncertainties explicit in knowledge gaps instead of treating speculative MCPG contribution, maternal transfer or human modifier genotypes as established.

Create: Acute Ackee Fruit Intoxication · 2026-09-02T16:11:21Z · View source

New entry for acute ackee fruit intoxication (MONDO:0019140), Jamaican vomiting sickness. Selected from a shared Toxicologic Phenocopy Atlas of 48 exposure-gene pairs as the one case that could actually be curated here: it has a specific MONDO term, it was absent from the KB, and both of its Mendelian mimics were already curated (MCAD_Deficiency, Multiple_Acyl-CoA_Dehydrogenase_Deficiency), so the differentials resolve rather than dangle. Mechanism: hypoglycin A is a protoxin. Metabolism converts it to methylenecyclopropylacetyl-CoA, which is a suicide substrate that covalently modifies the flavin of acyl-CoA dehydrogenases and takes activity below 2 percent. Beta-oxidation stops, ketogenesis and gluconeogenesis fail together, and the hypoglycaemia that follows is profound and recurrent. Pathograph: 8 nodes, fully connected, all five phenotypes wired. 4 conforms_to against metabolic_intoxication_decompensation. THE ATLAS CLAIM WAS NOT CURATED AS GIVEN. The atlas calls this a Tier 1 phenocopy of MCAD deficiency and states the shared lesion as MCPA-CoA inhibiting the MEDIUM-chain acyl-CoA dehydrogenase. The two primary enzyme papers say the opposite for that substrate: PMID:1247597 found octanoyl-CoA and palmitoyl-CoA activity unaffected in hypoglycin-dosed rat liver mitochondria while butyryl-CoA activity was drastically reduced, and PMID:7275979 found octanoyl-CoA affords strong protection against the inactivation. Octanoyl-CoA is MCAD's substrate. What the clinical and veterinary literature supports is the broader claim, and it has a name: PMID:23167695 calls hypoglycin A a cause of ACQUIRED multiple acyl-CoA dehydrogenase deficiency, with acylcarnitine and organic acid profiles typical for MADD. This entry therefore curates a multi-enzyme block, names MADD as the closer phenocopy, and keeps MCAD deficiency as a differential with the octanoyl-CoA evidence attached to explain why the resemblance is clinical rather than enzyme-level. The node notes state the disagreement, name the 1976 and 1981 dates and species, and say plainly that those results are enough to decline naming the medium-chain enzyme but not enough to settle it. The phenocopy is more precise than the atlas allows in one further respect. Genetic MADD is ETFDH, ETFA and ETFB, which is the electron acceptor. Hypoglycin destroys the dehydrogenases that feed it. The lesions sit one rung apart on the same electron path and the downstream biochemistry does not separate them, which is recorded in the MADD differential. Reye syndrome is curated as a third differential, with the sentence from PMID:940578 that historically separated them. Evidence: 43 items over 9 references, every snippet pre-verified against the local cache before writing. Human anchors are PMID:28613753 (clinical syndrome), PMID:940578 (MCPA in the urine of two patients, dicarboxylic acids 70 to 1000 times normal, and the Reye distinction), PMID:8185109 (canned-product case outside the endemic area) and PMID:30056267. Enzyme mechanism from PMID:1247597 and PMID:7275979. The acquired-MADD framing from PMID:23167695 and PMID:23773055, both equine, cited for the toxin rather than for the species and graded MODEL_ORGANISM. FOODON:03301360 akee (raw) bound on the environmental food_source slot, following the pattern already used in Gout and Celiac_Disease. Raw rather than canned because the toxin is in unripe fruit; the canned route is documented in the Toledo case and noted, and the slot takes a single term. Deep research: three falcon reports via Edison. Two were the same trajectory returned twice and the duplicate was deleted rather than committed. The third (c8f13af1) differed substantively and is the reason this entry has a knowledge gap. Run one named MCAD and IVD among the inhibited enzymes; run three said "multiple acyl-CoA dehydrogenases" and named neither. Two runs of the same provider on the same question disagreeing on exactly the disputed point is better support for declining to name the enzyme than either run alone. Run three also presented a dual-target mechanism as established for this disease: hypoglycin A to MCPA-CoA blocking the dehydrogenases at step one, and MCPG to MCPF-CoA blocking the enoyl-CoA hydratases at step two. The framework is real and PMID:34765670 states it for the maple toxins in a foal. For ackee it is not established. PMID:30056267 says outright that MCPG exposure has not been evaluated in cases of Jamaican vomiting sickness. It is curated as a KNOWLEDGE_GAP discussion attached to the central node, with two proposed experiments, and the discussion notes record that the report did not carry the distinction. PMID:30056267 also closed two gaps this entry had recorded against itself: the unripe-fruit claim and the US import regulation behind the canned route. NEC preflight returned SKIP (MONDO records no causal gene for a poisoning) and was cleared manually: top gene mentions were MADD, ACADM and IVD. Falcon token note: two token copies on disk (dismech and deep-research-client) both returned 403 on a live probe; a replacement provided during the session authenticated. The plain `providers` listing reports Available on presence of the variable alone, so `providers --check` is the one that tells the truth. Validation: just validate-disorders (the batched sweep CI runs) passed; 43/43 snippets verified; check-folded-hyphens, check-duplicate-keys, check-title-snippets, check-environmental-evidence and check-entity-refs all clean. All reference_title values generated programmatically from the cache. Review round 1 (ai4c-reviewer, CHANGES_REQUESTED) raised four items. All four addressed. The reviewer confirmed the MCAD/MADD refusal and the MCPG quarantine as correct; the items were coverage gaps rather than errors. 1. No biochemical: section, and it carried the entry's own thesis. The description leads with the dicarboxylic aciduria and the MADD-like acylcarnitine profile, and both were prose only. Four biochemical entries added with readouts joining them to the mechanism nodes, following the pattern in Multiple_Acyl-CoA_Dehydrogenase_Deficiency.yaml: urinary dicarboxylic acids with the named analytes, urinary short-chain fatty acids, the MADD-typical acylcarnitine profile, and MCPA-carnitine. Two carry notes recording that the acylcarnitine profile and the carnitine conjugate are demonstrated in horses while the human evidence is the urinary organic acids. 2. Coma was in a snippet already quoted twice and never modelled. Added as a phenotype with a downstream edge from the encephalopathy node. 3. THE ONE THAT MATTERS. The Reye differential asserted that both diseases "show microvesicular steatosis on biopsy" while the entry curated no histology and the attached snippet supports only generic "clinical and histologic similarities". This is the same defect the reviewer caught on the isoniazid entry, where prose asserted what the evidence did not carry, and where I said I would read description against evidence before pushing. I did not extend that check to differential_diagnoses prose. The claim is removed; the resemblance is now stated at the level the source states it, with the entry saying plainly that it does not curate the histology. 4. No animal_models: despite three mechanistic claims resting on equine data. Equine atypical myopathy added with modeled_mechanisms on the activation node (RECAPITULATES, HIGH) and the beta-oxidation node (PARTIALLY_RECAPITULATES, MODERATE), the limitations line carrying the muscle-versus-CNS divergence, and readouts on both. The foal hydratase paper is deliberately left in the knowledge-gap discussion rather than moved here, since a single animal with a suspected additional sensitivity is not a property of the model. Two suggestions taken: dextrose bound to CHEBI:17234 as therapeutic_agent, and the PMID:1247597 whole-study conclusion regraded from IN_VITRO to OTHER because it spans both the rat and the enzyme-preparation arms. One suggestion declined with reason: HP:0001985 Hypoketotic hypoglycemia is the more specific binding and would strengthen the phenocopy claim, but the cited source says only "profound hypoglycemia". The binding stays at HP:0001943 until a source supports the hypoketotic qualifier.

Falcon ▸

Acute Ackee Fruit Intoxication: Disease-Characteristics Report

Edison Scientific Literature 17 citations 2026-09-02T11:55:12.584780

Acute Ackee Fruit Intoxication: Disease-Characteristics Report

Executive summary

Acute ackee fruit intoxication—classically Jamaican vomiting sickness—is an acquired, potentially fatal foodborne metabolic poisoning caused mainly by hypoglycin A (HGA) in immature Blighia sapida fruit. It produces an acquired multiple-acyl-CoA-dehydrogenase-deficiency phenotype: impaired mitochondrial fatty-acid oxidation deprives fasting patients of ketones and gluconeogenic energy, causing recurrent vomiting, profound hypoketotic hypoglycemia, encephalopathy, seizures, coma, hepatic steatosis/injury, and sometimes death. Children and undernourished or fasting persons are especially vulnerable. The evidence base is unusual: landmark human observations are old, modern human cohorts are scarce, and much current mechanistic, biomarker, and therapeutic evidence comes from rats, mice, and naturally poisoned horses. Accordingly, animal values below must not be used as human reference intervals.

domain	strongest finding	evidence type/species	key quantitative datum	source/date/DOI
Human clinical syndrome	Acute ackee intoxication follows ingestion of unripe ackee and presents with vomiting, hypoglycemia, and CNS depression; severe cases may progress to seizures, coma, and death	Human clinical case/report	Onset reported within 6–48 h; death in severe cases may occur within 48 h; unripe fruit reported to contain hypoglycin A at about 100-fold higher concentration than ripe fruit	Latif & Luthra, 2017, DOI: 10.23937/2377-3634/1410073 (latif2017newdevelopmentof pages 2-3, latif2017newdevelopmentof pages 1-2)
Human historical pathology	Fatal human cases show multi-organ fatty degeneration, especially liver, with renal, pancreatic, cardiac, and pulmonary involvement	Human historical autopsy series	Severe cases described with onset within about 2 h; historical mortality estimates 80–90% in early reports	Scott, 1916, DOI: 10.1080/00034983.1916.11684104 (scott1916onthevomiting pages 56-58, scott1916onthevomiting pages 58-62)
Mechanism	Hypoglycin A is metabolized to MCPA-CoA, causing an acquired multiple acyl-CoA dehydrogenase deficiency and impaired fatty-acid oxidation/gluconeogenesis	Mixed evidence: human biochemical inference plus extrapolative rat/horse data	Extrapolative horse biomarker data: serum HGA 387.8–8493.8 μg/L; urine HGA 143.8–926.4 μg/L; controls less than 10 μg/L	Bochnia et al., 2015, DOI: 10.1371/journal.pone.0136785; Boemer et al., 2017, DOI: 10.1371/journal.pone.0182761 (bochnia2015hypoglycinacontent pages 1-2, boemer2017acylcarnitinesprofilebest pages 15-16, boemer2017acylcarnitinesprofilebest pages 16-16)
Analytical diagnostics	Exposure can be supported by measuring hypoglycin A and downstream metabolites or conjugates; acylcarnitine and organic-acid profiling are informative	Human analytical mention plus extrapolative horse biomarker data	Extrapolative horse MCPA-carnitine data: serum 0.17–0.65 mmol/L vs controls less than 0.01; urine 0.34–2.05 μmol/mmol vs controls less than 0.001	Bochnia et al., 2015, DOI: 10.1371/journal.pone.0136785; Latif & Luthra, 2017, DOI: 10.23937/2377-3634/1410073 (latif2017newdevelopmentof pages 2-3, bochnia2015hypoglycinacontent pages 1-2)
2023 development	A derivatization-free UPLC-MS/MS method was validated for hypoglycin A, methylenecyclopropylglycine, and metabolites in milk and urine, improving surveillance capability	Extrapolative analytical method development	HGA limit of quantification in milk 1.12 μg/L; 68 milk samples from 35 farms showed no quantifiable toxin or metabolites	El-Khatib et al., 2023, DOI: 10.1007/s00216-023-04607-9 (medina2018detectionofequine pages 10-11)
Treatment evidence	Best-supported management is early dextrose plus supportive care, including fluids, electrolyte correction, and monitoring of glucose, liver, and kidney injury	Human case evidence plus extrapolative mouse/rat evidence	Recovery may occur within about 1 week in nonfatal cases; no validated antidote identified	Latif & Luthra, 2017, DOI: 10.23937/2377-3634/1410073 (latif2017newdevelopmentof pages 3-4)
Treatment limitations	Glycine, methylene blue, and carnitine have experimental rationale, but clinical efficacy in humans remains unproven	Mixed evidence; mouse/rat/horse evidence extrapolative	No controlled human trial identified; no ackee-specific interventional trial found in retrieved trial search	Latif & Luthra, 2017, DOI: 10.23937/2377-3634/1410073 (latif2017newdevelopmentof pages 3-4)
Epidemiology and outbreaks	Disease clusters seasonally where ackee is consumed, with children disproportionately affected; modern epidemiologic data are sparse	Human historical evidence plus outbreak review snippets	Haiti 2000–2001 outbreak reported as 60 intoxication cases; older reports emphasize child predominance	Scott, 1916, DOI: 10.1080/00034983.1916.11684104 (scott1916onthevomiting pages 58-62, scott1916onthevomiting pages 56-58)
Food safety and prevention	Prevention depends on avoiding unripe or unopened ackee, removing seeds and membrane, and using regulated low-hypoglycin products	Human public-health and food-safety evidence	FDA import standard cited as hypoglycin A limit of 100 ppm for regulated products	Latif & Luthra, 2017, DOI: 10.23937/2377-3634/1410073 (latif2017newdevelopmentof pages 2-3, latif2017newdevelopmentof pages 1-2)
Animal models	Rat, mouse, horse, and related Sapindaceae toxin studies support mechanism and biomarker development, but remain extrapolative for human disease	Extrapolative animal evidence	Rat dose-response model exists; horse disease shows strong biomarker association with HGA exposure	Bochnia et al., 2015, DOI: 10.1371/journal.pone.0136785; Boemer et al., 2017, DOI: 10.1371/journal.pone.0182761 (bochnia2015hypoglycinacontent pages 1-2, boemer2017acylcarnitinesprofilebest pages 15-16)

Table: This table summarizes the strongest available evidence for acute ackee fruit intoxication across clinical, mechanistic, diagnostic, epidemiologic, preventive, and animal-model domains. It prioritizes direct human evidence and clearly labels extrapolations from horse, rat, mouse, and other comparative studies.

1. Disease information

Definition and synonyms

The disorder is an acute exogenous intoxication, not a Mendelian disease. Synonyms include ackee poisoning, ackee fruit poisoning, acute ackee intoxication, hypoglycin A poisoning, toxic hypoglycemic syndrome, and Jamaican vomiting sickness. The classic syndrome consists of gastrointestinal illness, severe hypoglycemia, and central nervous-system depression after consumption of unripe ackee; severe disease includes seizures, coma, and death. Mature arils from fruit that has opened naturally are ordinarily consumed safely. (latif2017newdevelopmentof pages 2-3, latif2017newdevelopmentof pages 1-2)

Identifiers and coding

MONDO: no disease-specific MONDO identifier was substantiated in the retrieved sources; do not assign one without checking the current MONDO release.
OMIM/Orphanet: not applicable as disease-specific inherited-disorder identifiers; no dedicated entry was substantiated.
MeSH: best represented under broad concepts such as plant poisoning, foodborne intoxication, hypoglycemia, and hypoglycins; a dedicated descriptor was not substantiated.
ICD: coding is generally under toxic effects of ingested berries/other noxious food substances or plant poisoning, with intent and encounter extensions where required. The precise ICD-10-CM/ICD-11 code should be validated against the jurisdiction and release rather than inferred from literature.

The report is assembled from aggregated disease-level literature, human case reports and autopsies, outbreak investigations, analytical-method studies, and animal experiments—not individual EHR data.

2. Etiology, risk, and protective factors

Cause

The initiating exposure is ingestion of toxic ackee material, especially an immature, forcibly opened, damaged, or improperly prepared fruit. HGA occurs in arils and seeds; hypoglycin B is a less potent γ-glutamyl conjugate concentrated in seeds. One clinical review reports approximately 100-fold more HGA in unripe than ripe fruit, although toxin concentration varies with maturity and processing. (latif2017newdevelopmentof pages 2-3, latif2017newdevelopmentof pages 1-2)

Suggested chemical annotations are hypoglycin A, hypoglycin B, methylenecyclopropylpyruvate, methylenecyclopropylacetate/MCPA, MCPA-CoA, MCPA-carnitine, and MCPA-glycine; exact ChEBI identifiers should be release-validated.

Risk factors

Environmental/dietary: unripe or unopened ackee, seeds or attached membrane, contaminated cooking liquid, inadequate washing, and unregulated processing.
Physiological: childhood, low body mass, overnight fasting, malnutrition, depleted glycogen, and delayed glucose treatment plausibly increase vulnerability. Historical disease was strongly seasonal and concentrated in children when other foods were scarce. (scott1916onthevomiting pages 56-58, scott1916onthevomiting pages 58-62)
Clustering: multiple members of a household may become ill after sharing fruit. (scott1916onthevomiting pages 56-58)
Sex: historical work found no clear sex preference. (scott1916onthevomiting pages 56-58)

Historical ethnic differences are more parsimoniously explained by dietary access and exposure than inherited susceptibility. No reproducible human susceptibility locus or pharmacogenomic association has been established.

Protective factors

Primary protection consists of eating only fruit that has opened naturally, discarding seeds and the attached pink/red membrane, washing arils thoroughly, using validated processing controls, and avoiding prolonged fasting—particularly in children. Regulated products and hazard-analysis systems reduce exposure; a clinical review cites an FDA import/HACCP ceiling of 100 ppm HGA. (latif2017newdevelopmentof pages 1-2)

No genetic protective variant is known. Gene–environment interaction remains hypothetical: variants affecting fatty-acid oxidation or toxin disposition could modify severity, but this has not been demonstrated in human ackee poisoning.

3. Phenotypes

Percentages are unavailable from modern, adequately sized cohorts; frequencies therefore remain qualitative.

Phenotype	Type and characteristics	Suggested HPO term
Recurrent severe vomiting	Cardinal early symptom; episodes may alternate with quiescent intervals	Vomiting, HP:0002013
Hypoglycemia, usually hypoketotic	Cardinal laboratory abnormality; may be profound or refractory	Hypoglycemia, HP:0001943; Hypoketotic hypoglycemia, HP:0001985
Encephalopathy/CNS depression	Variable from lethargy to coma; downstream of energy failure and possibly direct toxicity	Encephalopathy, HP:0001298; Coma, HP:0001259
Seizures	Severe manifestation, often accompanying marked hypoglycemia	Seizure, HP:0001250
Metabolic acidosis/organic aciduria	Laboratory manifestation of blocked oxidation and alternative ω-oxidation	Metabolic acidosis, HP:0001942; Organic aciduria, HP:0001992
Hepatic steatosis/injury	Transaminase elevation to fulminant injury; historical autopsies show diffuse fatty change	Hepatic steatosis, HP:0001397; Elevated hepatic transaminase, HP:0002910
Renal injury	Creatinine elevation or tubular injury in severe disease	Acute kidney injury, HP:0001919
Weakness/hypotonia	Reported during hypoglycemic crisis and recovery	Muscle weakness, HP:0001324; Hypotonia, HP:0001252

Symptoms generally begin within 6–48 hours, although historical fulminant cases began near two hours after exposure. Severe cases may die within 48 hours; survivors commonly improve over days and may recover within approximately one week. (latif2017newdevelopmentof pages 2-3, scott1916onthevomiting pages 56-58, scott1916onthevomiting pages 58-62)

Quality-of-life instruments such as EQ-5D or SF-36 have not been studied. Acute impact is nevertheless major: inability to eat or function, emergency hospitalization, seizures, ventilation/critical care, and risk of neurologic injury or death.

4. Genetic and molecular information

There is no established causal gene, pathogenic germline or somatic variant, inheritance pattern, chromosomal lesion, penetrance estimate, modifier gene, or disease-specific epigenetic abnormality. WES, WGS, panels, CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine diagnostic tests.

Mechanistically relevant human proteins include mitochondrial acyl-CoA dehydrogenases—especially ACADM/MCAD and IVD—and electron-transfer flavoprotein pathways. These are inhibited by toxin metabolites rather than altered genetically. Thus, intoxication phenocopies inherited MADD/glutaric acidemia type II but must not be represented as an ETF-pathway genetic disorder. Comparative work supports inhibition of multiple acyl-CoA dehydrogenases and consequent abnormal acylcarnitines and organic acids. (bochnia2015hypoglycinacontent pages 1-2, boemer2017acylcarnitinesprofilebest pages 15-16, boemer2017acylcarnitinesprofilebest pages 16-16)

5. Environmental information

The disease is entirely exposure driven. Blighia sapida is the relevant plant; unripe fruit is the principal source. Diet, food scarcity, harvesting before natural opening, and unsafe preparation govern risk. There is no infectious agent, person-to-person transmission, radiation association, or conventional occupational syndrome, although harvesters, processors, and food inspectors have exposure-control responsibilities.

6. Mechanism and pathophysiology

Ordered causal chain

Ingestion of immature/improperly prepared ackee leads to absorption of HGA and related methylenecyclopropyl compounds.
HGA metabolism leads to methylenecyclopropyl intermediates and MCPA-CoA, the active inhibitory metabolite.
MCPA-CoA leads to irreversible or functionally sustained inhibition of several mitochondrial acyl-CoA dehydrogenases, including MCAD and IVD, producing acquired MADD. (bochnia2015hypoglycinacontent pages 1-2, boemer2017acylcarnitinesprofilebest pages 15-16, boemer2017acylcarnitinesprofilebest pages 16-16)
Blocked β-oxidation leads to reduced acetyl-CoA, reducing equivalents, ATP, and ketogenesis, while accumulating acyl-CoAs.
Energy/cofactor depletion leads to impaired hepatic gluconeogenesis and depleted glucose availability, producing hypoketotic hypoglycemia. (latif2017newdevelopmentof pages 2-3, latif2017newdevelopmentof pages 3-4)
Accumulated acyl-CoAs branch into acylcarnitines/acylglycines and ω-oxidation, resulting in characteristic acylcarnitinemia, dicarboxylic aciduria, and metabolic acidosis. Rat studies identify glutaric, adipic, unsaturated dicarboxylic acids, MCPA-glycine, and isovalerylglycine; their diagnostic interpretation in humans is partly extrapolative. (boemer2017acylcarnitinesprofilebest pages 15-16)
Hepatic lipid oxidation failure leads to triglyceride accumulation and hepatocellular energy failure, resulting in micro-/macrovesicular fatty change and potentially acute liver injury.
Neuroglycopenia leads to vomiting-associated lethargy, seizures, encephalopathy, and coma; a separate direct neurotoxic contribution is reported but less firmly resolved in humans. (latif2017newdevelopmentof pages 2-3, latif2017newdevelopmentof pages 3-4)
Severe systemic energy failure branches to renal, pancreatic, cardiac, and pulmonary injury, resulting in multiorgan failure and death in fulminant cases. (scott1916onthevomiting pages 56-58)

Upstream processes are exposure, toxin bioactivation, and enzyme inhibition; downstream processes are metabolic energy failure, alternative metabolite formation, steatosis, neuroglycopenia, and organ injury.

Suggested GO annotations include fatty-acid beta-oxidation (GO:0006635), mitochondrial fatty-acid beta-oxidation (GO:0006635 with mitochondrial context), gluconeogenesis (GO:0006094), ketone-body biosynthetic process (GO:0046951), cellular response to hypoglycemia, and lipid-storage process. Principal cells are hepatocytes (CL:0000182), neurons (CL:0000540), renal tubular epithelial cells, pancreatic acinar cells, and cardiomyocytes (CL:0000746). Principal compartment: mitochondrion (GO:0005739), especially mitochondrial matrix (GO:0005759).

No ackee-specific human transcriptomic, proteomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or multi-omics dataset was substantiated. Targeted metabolomics is currently the relevant molecular-profiling modality.

7. Anatomical structures affected

The liver is the principal metabolic organ; the brain is the principal clinically vulnerable organ. Historical fatal pathology demonstrated diffuse fatty liver, renal tubular fatty degeneration/nephritis, pancreatic necrobiosis, myocardial fat droplets, and pulmonary/visceral congestion. (scott1916onthevomiting pages 56-58)

Suggested anatomy annotations include liver (UBERON:0002107), brain (UBERON:0000955), kidney (UBERON:0002113), pancreas (UBERON:0001264), heart (UBERON:0000948), and lung (UBERON:0002048). At cell level, hepatocytes and renal tubular epithelial cells are central. At subcellular level, mitochondria are primary; cytosolic lipid droplets are secondary. Lateralization is not relevant.

8. Temporal development

The disease is acute and monophasic after a discrete meal. A useful clinical staging scheme is:

Latent/early phase: hours after ingestion; nausea, malaise, vomiting.
Metabolic phase: recurrent vomiting, hypoglycemia, low ketones, aciduria/acidosis.
Neurologic/organ-injury phase: altered consciousness, seizures, rising aminotransferases/creatinine.
Recovery or fulminant phase: improvement over several days after glucose/support, or coma, multiorgan failure, and death—often within 48 hours in severe cases. (latif2017newdevelopmentof pages 2-3, latif2017newdevelopmentof pages 3-4)

There is no chronic relapsing course unless exposure recurs. The crucial therapeutic window is before prolonged neuroglycopenia and hepatic energy failure; glucose should not await confirmatory toxicology.

9. Inheritance and population epidemiology

Inheritance, anticipation, mosaicism, founder effects, consanguinity, carrier frequency, and penetrance are not applicable.

Reliable contemporary incidence and prevalence per 100,000 are unavailable. Historical Jamaican reports described seasonality, household clusters, disproportionate pediatric disease, and mortality estimates as high as 80–90%, but these figures predate modern critical care and should not be treated as current case-fatality rates. (scott1916onthevomiting pages 58-62)

A secondary retrieved source reports 60 intoxications in Haiti during 2000–2001; the primary outbreak report should be consulted before database ingestion. Disease is concentrated where ackee grows or is imported, particularly Jamaica, Haiti, and parts of West Africa. Historical racial/ethnic patterns likely reflected food practices and poverty rather than proven biology. No current sex ratio is established.

10. Diagnostics

Clinical diagnosis

Diagnosis is based on compatible exposure plus acute vomiting and hypoketotic hypoglycemia, with neurologic or hepatic abnormalities. Immediate tests should include serial bedside glucose, blood gas, electrolytes, bicarbonate/anion gap, lactate, serum/urine ketones, AST/ALT, bilirubin, INR, creatinine, urea, ammonia, CK, urinalysis, ECG, and continuous neurologic monitoring where severe.

Specific and omics-based tests

Confirmation can use LC-MS/MS or GC-MS measurement of HGA, MCPA-glycine, MCPA-carnitine, related acylcarnitines, acylglycines, and urinary organic acids. The clinical report describes urinary MCPAA detection by GC-MS and HGA/metabolite measurement in blood and urine. (latif2017newdevelopmentof pages 2-3)

Horse data demonstrate the principle but not human cutoffs: affected horses had serum HGA 387.8–8,493.8 μg/L and urine HGA 143.8–926.4 μg/L, versus controls below 10 μg/L; serum MCPA-carnitine was 0.17–0.65 mmol/L, versus below 0.01 in controls. (bochnia2015hypoglycinacontent pages 1-2)

A 2023 derivatization-free UPLC-MS/MS method achieved an HGA quantification limit of 1.12 μg/L in milk, 85–106% recovery across milk/urine, and ≤20% precision; none of 68 samples from 35 German dairy farms contained quantifiable analytes. This is an exposure-surveillance advance, not a validated human diagnostic threshold. The authors’ abstract states: “The determination of HGA, MCPrG, and their glycine and carnitine metabolites in blood and urine is a useful tool for screening for potential exposure to these toxins.” DOI: https://doi.org/10.1007/s00216-023-04607-9, published March 2023.

Differential diagnosis

Important alternatives are inherited fatty-acid-oxidation disorders/MADD, Reye syndrome, sepsis, malaria or meningoencephalitis in endemic settings, insulin/sulfonylurea exposure, starvation, alcohol-related hypoglycemia, adrenal insufficiency, inborn organic acidemias, acetaminophen or other hepatotoxic poisoning, and litchi-associated MCPG/HGA encephalopathy. Historical cases were mistaken for meningitis or yellow fever. (scott1916onthevomiting pages 58-62)

Imaging, EEG, biopsy, and genetic testing are not routine; use them for complications or unresolved alternatives. There is no asymptomatic population screening program.

11. Outcome and prognosis

Outcome depends on dose, maturity of fruit, age/body mass, nutritional state, depth/duration of hypoglycemia, hepatic injury, and speed of glucose administration. Nonfatal cases can recover rapidly or within approximately one week; prolonged seizures, coma, acute liver failure, renal injury, aspiration, and death are principal complications. (latif2017newdevelopmentof pages 2-3, latif2017newdevelopmentof pages 3-4)

Historical 80–90% mortality estimates represent selected early severe outbreaks and are not generalizable to current treated patients. No validated human prognostic score, long-term survival curve, disability estimate, or quality-of-life dataset exists. Serial glucose, neurologic status, pH/lactate, INR, aminotransferases, creatinine, and ammonia are practical severity markers, but none is a validated ackee-specific prognostic biomarker.

12. Treatment

Immediate clinical algorithm

Stabilize airway, breathing, and circulation; check glucose immediately.
Administer IV dextrose promptly for symptomatic or documented hypoglycemia, then continue glucose-containing fluids/titrated infusion with frequent checks; recurrent hypoglycemia is expected.
Correct dehydration, electrolytes, acid–base disturbance, and temperature; stop fasting and provide carbohydrate when safe.
Treat seizures conventionally while correcting glucose; protect the airway if consciousness is impaired.
Monitor liver enzymes, bilirubin, INR, ammonia, creatinine, urine output, CK, ECG, and neurologic status; transfer severe cases to intensive care or a liver-capable center.
Contact a poison center/medical toxicologist and retain food, blood, and urine for targeted testing.

Human evidence supports early dextrose and supportive care; one review characterizes IV dextrose as extremely effective when administered early. (latif2017newdevelopmentof pages 3-4)

Suggested NCIt intervention concepts are dextrose administration, intravenous fluid therapy, electrolyte replacement, anticonvulsant therapy, mechanical ventilation, intensive-care management, and liver transplantation when fulminant failure meets standard criteria.

Unproven therapies

Glycine, methylene blue, and carnitine have experimental rationales. Mouse studies support early glucose and methylene blue; rat-hepatocyte experiments did not establish carnitine as an antidote. No controlled human efficacy data support these agents, and they should not replace dextrose/supportive care. (latif2017newdevelopmentof pages 3-4)

No ackee-specific gene, cell, RNA, immunologic, targeted, or surgical therapy exists. A ClinicalTrials.gov search retrieved no relevant ackee/HGA interventional trial. Pharmacogenomic guidance and response-rate estimates are unavailable.

13. Prevention

Primary: consume only naturally opened, fully mature fruit; never force open immature pods; discard seeds and membrane; wash arils; use approved processors and validated HACCP controls. (latif2017newdevelopmentof pages 1-2)
Secondary: recognize household clusters rapidly, test glucose in every exposed symptomatic person, and treat before encephalopathy. Assess children who shared the meal even if symptoms are initially mild.
Tertiary: prevent recurrent hypoglycemia, aspiration, seizures, cerebral injury, liver failure, and renal failure through monitoring and critical care.
Public health: trace and withdraw implicated lots, communicate safe harvesting/preparation practices, train clinicians in endemic regions, and maintain analytical capacity for HGA/MCPA compounds.

Vaccination, antimicrobial prophylaxis, genetic counseling, prenatal testing, carrier screening, and newborn screening are not applicable.

14. Other species and natural disease

HGA-containing Acer seeds/seedlings cause equine atypical myopathy, a naturally occurring, often fatal acquired MADD in horses. This is a mechanistically strong analogue but differs clinically: horses predominantly develop severe rhabdomyolysis, whereas human ackee intoxication is dominated by vomiting, hypoglycemia, encephalopathy, and liver injury. Horse exposure studies show that clinically normal co-grazers can contain HGA, demonstrating that exposure does not equal disease. (bochnia2015hypoglycinacontent pages 1-2)

A 2023 dairy study addressed possible carry-over into milk; its 68 field samples from 35 farms were negative at the assay’s quantification limits. This does not exclude exposure under different conditions. No zoonotic transmission occurs; susceptibility reflects shared plant toxins, not infection.

Suggested taxonomy annotations include Homo sapiens (NCBI Taxon 9606), Equus caballus (9796), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955). Breed-specific susceptibility is not established.

15. Model organisms and recent research

Established models

Rat: HGA dose-response and hepatocyte systems reproduce hypoglycemia, abnormal fatty-acid oxidation, dicarboxylic aciduria, and enzyme inhibition. They are valuable for mechanism and antidote testing but incompletely model human vomiting/encephalopathy.
Mouse: unripe-ackee exposure models have tested early glucose and methylene blue; timing and dosing limit translation.
Horse natural model: provides abundant blood/urine metabolomics and tissue pathology for acquired MADD. It strongly supports HGA causality and MCPA-conjugate biomarkers, but its muscle-dominant phenotype differs from human disease. In one study, HGA and MCPA conjugates clearly separated diseased horses, exposed healthy co-grazers, and unexposed controls. (bochnia2015hypoglycinacontent pages 1-2)
Zebrafish embryo: a 2024 study developed a Sapindaceae-poisoning platform to screen therapeutic compounds (Wouters et al., Molecules, October 2024; DOI: https://doi.org/10.3390/molecules29204954). This is a preclinical screening system, not evidence of human efficacy.
Historical guinea-pig/rabbit experiments: results were inconclusive because of limited extracts, solvent effects, and species selection. (scott1916onthevomiting pages 40-43)

No standardized knockout, knock-in, humanized mouse, organoid, or patient-derived iPSC model specific to ackee intoxication was identified. Genetic ETF/ETFDH/ACADM models may illuminate downstream energy failure but model inherited enzyme defects rather than toxin bioactivation.

Evidence interpretation and research gaps

The most authoritative conclusion is that acute ackee intoxication is a preventable exposure-induced mitochondrial energy crisis requiring immediate glucose and supportive care. The major gaps are contemporary prospective human cohorts, validated human toxin/metabolite reference ranges, dose–response data, standardized diagnostic criteria, controlled antidote trials, long-term neurodevelopmental follow-up, and modern incidence/case-fatality surveillance. Recent work has advanced sensitive mass-spectrometric exposure measurement and preclinical screening rather than changing clinical management.

Representative exact abstract quotation from the 2018 analytical/model literature is: “Hypoglycin A (HGA) toxicity, following ingestion of material from certain plants, is linked to an acquired multiple acyl-CoA dehydrogenase deficiency.” DOI: https://doi.org/10.1371/journal.pone.0199521, published July 2018. (medina2018detectionofequine pages 10-11)

Where PMIDs were not verified in the retrieved records, DOI URLs are provided rather than risking incorrect PMID assignment.

References

(latif2017newdevelopmentof pages 2-3): Summaya Abdul Latif and Pooja Luthra. New development of hypoglycemia in a previously poorly-controlled type 2 diabetic: ackee fruit-induced hypoglycemia. International Journal of Diabetes and Clinical Research, Dec 2017. URL: https://doi.org/10.23937/2377-3634/1410073, doi:10.23937/2377-3634/1410073. This article has 2 citations.
(latif2017newdevelopmentof pages 1-2): Summaya Abdul Latif and Pooja Luthra. New development of hypoglycemia in a previously poorly-controlled type 2 diabetic: ackee fruit-induced hypoglycemia. International Journal of Diabetes and Clinical Research, Dec 2017. URL: https://doi.org/10.23937/2377-3634/1410073, doi:10.23937/2377-3634/1410073. This article has 2 citations.
(scott1916onthevomiting pages 56-58): H. Harold Scott. On the 'vomiting sickness' of jamaica. Annals of Tropical Medicine and Parasitology, 10:1-78, Apr 1916. URL: https://doi.org/10.1080/00034983.1916.11684104, doi:10.1080/00034983.1916.11684104. This article has 54 citations.
(scott1916onthevomiting pages 58-62): H. Harold Scott. On the 'vomiting sickness' of jamaica. Annals of Tropical Medicine and Parasitology, 10:1-78, Apr 1916. URL: https://doi.org/10.1080/00034983.1916.11684104, doi:10.1080/00034983.1916.11684104. This article has 54 citations.
(bochnia2015hypoglycinacontent pages 1-2): M. Bochnia, J. Ziegler, J. Sander, A. Uhlig, S. Schaefer, S. Vollstedt, M. Glatter, Steffen Abel, S. Recknagel, G. Schusser, M. Wensch-Dorendorf, and A. Zeyner. Hypoglycin a content in blood and urine discriminates horses with atypical myopathy from clinically normal horses grazing on the same pasture. PLoS ONE, 10:e0136785, Sep 2015. URL: https://doi.org/10.1371/journal.pone.0136785, doi:10.1371/journal.pone.0136785. This article has 75 citations and is from a peer-reviewed journal.
(boemer2017acylcarnitinesprofilebest pages 15-16): François Boemer, Johann Detilleux, Christophe Cello, Hélène Amory, Christel Marcillaud-Pitel, Eric Richard, Gaby van Galen, Gunther van Loon, Laurence Lefère, and Dominique-Marie Votion. Acylcarnitines profile best predicts survival in horses with atypical myopathy. PLoS ONE, 12:e0182761, Aug 2017. URL: https://doi.org/10.1371/journal.pone.0182761, doi:10.1371/journal.pone.0182761. This article has 36 citations and is from a peer-reviewed journal.
(boemer2017acylcarnitinesprofilebest pages 16-16): François Boemer, Johann Detilleux, Christophe Cello, Hélène Amory, Christel Marcillaud-Pitel, Eric Richard, Gaby van Galen, Gunther van Loon, Laurence Lefère, and Dominique-Marie Votion. Acylcarnitines profile best predicts survival in horses with atypical myopathy. PLoS ONE, 12:e0182761, Aug 2017. URL: https://doi.org/10.1371/journal.pone.0182761, doi:10.1371/journal.pone.0182761. This article has 36 citations and is from a peer-reviewed journal.
(medina2018detectionofequine pages 10-11): Sonia González Medina, Carolyne Hyde, Imogen Lovera, and Richard J. Piercy. Detection of equine atypical myopathy-associated hypoglycin a in plant material: optimisation and validation of a novel lc-ms based method without derivatisation. PLoS ONE, 13:e0199521, Jul 2018. URL: https://doi.org/10.1371/journal.pone.0199521, doi:10.1371/journal.pone.0199521. This article has 24 citations and is from a peer-reviewed journal.
(latif2017newdevelopmentof pages 3-4): Summaya Abdul Latif and Pooja Luthra. New development of hypoglycemia in a previously poorly-controlled type 2 diabetic: ackee fruit-induced hypoglycemia. International Journal of Diabetes and Clinical Research, Dec 2017. URL: https://doi.org/10.23937/2377-3634/1410073, doi:10.23937/2377-3634/1410073. This article has 2 citations.
(scott1916onthevomiting pages 40-43): H. Harold Scott. On the 'vomiting sickness' of jamaica. Annals of Tropical Medicine and Parasitology, 10:1-78, Apr 1916. URL: https://doi.org/10.1080/00034983.1916.11684104, doi:10.1080/00034983.1916.11684104. This article has 54 citations.

Artifacts

Edison artifact artifact-00

Ask OpenScientist

OpenScientist Report

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Progression

Epidemiology

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Acute Ackee Fruit Intoxication: Disease-Characteristics Report

Executive summary

1. Disease information

Definition and synonyms

Identifiers and coding

2. Etiology, risk, and protective factors

Cause

Risk factors

Protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population epidemiology

10. Diagnostics

Clinical diagnosis

Specific and omics-based tests

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Immediate clinical algorithm

Unproven therapies

13. Prevention

14. Other species and natural disease

15. Model organisms and recent research

Established models

Evidence interpretation and research gaps

Artifacts