Beta-Ketothiolase Deficiency

Mendelian MONDO:0008760 Pathograph 30 Organic Acidemia Inborn Error of Metabolism

Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in ACAT1, encoding mitochondrial acetoacetyl-CoA thiolase (T2). The enzyme is required for both isoleucine catabolism and ketone body metabolism. Loss of T2 activity blocks the terminal step of isoleucine degradation and impairs extrahepatic ketolysis, leading to accumulation of toxic organic acid intermediates. The disorder typically manifests in infancy or early childhood with recurrent episodes of ketoacidosis triggered by catabolic stressors such as infection, fasting, or ketogenic diet. Between episodes, patients are generally well. Characteristic biochemical markers include elevated urinary 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate. The frequency of ketoacidotic episodes tends to decrease with age and is rare after age 10. With appropriate management, the prognosis is generally favorable, although neurological sequelae including extrapyramidal signs can occur.

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Mappings

Definitions

Inheritance

Histopathology

Subtypes

Differentials

Datasets

Trials

Models

References

Deep Research

🏷

Classifications

Harrison's Chapter

⚙

Pathophysiology

ACAT1 molecular function deficiency

Biallelic ACAT1 pathogenic variants reduce mitochondrial acetoacetyl-CoA thiolase catalytic activity.

ACAT1 link

acetyl-CoA C-acetyltransferase activity link ↓ DECREASED

mitochondrion link

Downstream

Impaired isoleucine catabolism Reduced T2 activity blocks terminal isoleucine catabolic cleavage.

Impaired ketone body metabolism Reduced T2 activity impairs ketolysis and ketone body handling in extrahepatic tissues.

Show evidence (1 reference)

PMID:31268215 SUPPORT Human Clinical

"Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism."

Supports ACAT1/T2 molecular dysfunction as the proximal defect.

Impaired isoleucine catabolism

ACAT1/T2 catalyzes the thiolytic cleavage of 2-methyl-acetoacetyl-CoA into propionyl-CoA and acetyl-CoA, the terminal step in the isoleucine degradation pathway. Loss of T2 activity blocks this step, leading to accumulation of upstream isoleucine-derived metabolites including 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate, and tiglylglycine.

hepatocyte link cell of skeletal muscle link

isoleucine catabolic process link ↓ DECREASED branched-chain amino acid catabolic process link

Downstream

Isoleucine-derived organic acid accumulation Blocked terminal isoleucine catabolism causes buildup of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, tiglylglycine, and related acylcarnitines.

Show evidence (2 references)

PMID:38853254 SUPPORT Human Clinical

"Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive condition affecting isoleucine catabolism and ketone body metabolism."

Directly supports impaired isoleucine catabolism as a core feature of BKD.

PMID:31268215 SUPPORT Human Clinical

"Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism."

Comprehensive review confirming isoleucine metabolism disruption in T2 deficiency.

Impaired ketone body metabolism

T2 is involved in ketogenesis in the liver (synthesizing acetoacetyl-CoA from acetyl-CoA) and in the terminal step of ketolysis in extrahepatic tissues (cleaving acetoacetyl-CoA to two acetyl-CoAs). Loss of T2 activity impairs extrahepatic ketone body utilization, predisposing to ketosis and ketoacidosis under catabolic stress.

hepatocyte link neuron link cardiac muscle cell link cell of skeletal muscle link

ketone body metabolic process link ⚠ ABNORMAL

liver link

Downstream

Episodic metabolic decompensation Impaired ketone body utilization predisposes to recurrent ketoacidotic crises under catabolic stress.

Show evidence (2 references)

PMID:38853254 SUPPORT Human Clinical

"BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age."

Supports recurrent ketoacidosis due to impaired ketone body handling.

PMID:31268215 SUPPORT Human Clinical

"Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism."

Confirms ketone body metabolism disruption as core pathophysiology.

Isoleucine-derived organic acid accumulation

Failure to clear 2-methylacetoacetyl-CoA redirects upstream isoleucine intermediates into diagnostic organic acids and acylcarnitines, including 2-methyl-3-hydroxybutyrate, tiglylglycine, 2-methylacetoacetate, tiglylcarnitine, and 2-methyl-3-hydroxybutyrylcarnitine.

isoleucine catabolic process link ↓ DECREASED

Downstream

2-Methyl-3-hydroxybutyrate (2M3HB) 2-methyl-3-hydroxybutyrate accumulates in urine as a characteristic isoleucine-derived marker.

Tiglylglycine (TIG) Tiglylglycine accumulates in urine as a characteristic isoleucine-derived marker.

2-Methylacetoacetate (2MAA) 2-methylacetoacetate can be excreted in large amounts during acute crisis.

Tiglylcarnitine (C5:1) Tiglyl-CoA accumulation is reflected by elevated C5:1 tiglylcarnitine in blood acylcarnitine profiles.

2-Methyl-3-hydroxybutyrylcarnitine (C5-OH) 2-methyl-3-hydroxybutyryl-CoA accumulation is reflected by elevated C5-OH acylcarnitine.

Neurological complications and basal ganglia involvement Accumulated isoleucine-derived metabolites may contribute to neurologic injury through a crisis-independent neurotoxicity route.

Episodic metabolic decompensation Organic acid accumulation contributes to acidotic metabolic crises when catabolic stress increases pathway flux.

Show evidence (2 references)

PMID:40598206 SUPPORT Human Clinical

"T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia."

Patient cohort abstract describes accumulation of urine organic acid and blood acylcarnitine markers.

PMID:23958592 SUPPORT Human Clinical

"During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated and large amounts of 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate were excreted."

Documents simultaneous acylcarnitine elevation and urinary organic acid excretion during acute crisis.

Episodic metabolic decompensation

Under catabolic triggers such as infection, prolonged fasting, or ketogenic diet, increased reliance on ketone body flux and amino acid catabolism overwhelms the blocked T2 pathway. Accumulated organic acids produce high anion gap metabolic acidosis with ketosis and variable glycemia. Between crises, biochemical profiles may normalize, complicating detection. Episodes decrease in frequency with age, and are rare after age 10 in most patients.

response to starvation link cellular response to acidic pH link

Downstream

Episodic ketoacidosis Decompensation episodes manifest as recurrent ketoacidosis.

Metabolic acidosis Severe crises include metabolic acidosis.

Acute ketoacidotic crisis syndrome Severe ketoacidotic crises produce an acute syndrome with toxic encephalopathy, gastrointestinal symptoms, abnormal tone, and compensatory tachypnea.

Variable glycemic response during crisis Acute illness and impaired energy handling can be accompanied by stress hyperglycemia or hypoglycemia.

Respiratory failure Severe acidotic decompensation can progress to respiratory failure requiring intensive support.

Neurological complications and basal ganglia involvement Decompensation episodes can leave neurologic sequelae, while some neurologic complications may also appear without an obvious crisis.

Show evidence (2 references)

PMID:38853254 SUPPORT Human Clinical

"BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age."

Supports episodic nature and age-dependent reduction of decompensation episodes.

PMID:40598206 SUPPORT Human Clinical

"Ketoacidotic episodes were the predominant manifestations in all patients, and each episode was triggered by either acute gastroenteritis or upper respiratory infections."

Confirms infection-triggered ketoacidotic episodes as the predominant clinical pattern.

Acute ketoacidotic crisis syndrome

Severe ketoacidotic episodes can present with toxic metabolic encephalopathy and associated acute-crisis signs, including reduced arousal, vomiting, hypotonia, tachypnea, seizures, and coma.

neuron link

cellular response to acidic pH link

Downstream

Lethargy Toxic encephalopathy during crisis reduces arousal and activity.

Vomiting Vomiting occurs during the acute ketoacidotic crisis syndrome.

Muscular hypotonia Hypotonia can occur as part of the acute ketoacidotic crisis syndrome.

Tachypnea Tachypnea accompanies the acute ketoacidotic crisis syndrome and acidotic compensation.

Seizures Severe encephalopathic crises can include tonic-clonic seizures.

Coma Severe toxic encephalopathy can progress to coma.

Show evidence (2 references)

PMID:30026775 SUPPORT Human Clinical

"Clinical features characterized by intermittent keto acidotic episodes are associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients"

Directly supports an acute ketoacidotic syndrome with toxic encephalopathy and associated signs.

PMID:30026775 SUPPORT Human Clinical

"acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma"

Documents severe encephalopathic crisis with seizures and coma.

Variable glycemic response during crisis

During acute illness and metabolic crisis, BKD patients may show stress hyperglycemia, while other presentations include hypoglycemia together with the characteristic metabolite accumulation.

glucose homeostasis link ⚠ ABNORMAL

Downstream

Hyperglycemia Acute illness can produce short-lived stress hyperglycemia during BKD crises.

Hypoglycemia Some biochemical crisis presentations occur with hypoglycemia.

Show evidence (2 references)

PMID:38853254 SUPPORT Human Clinical

"Stress hyperglycemia is not uncommon when children with BKD are acutely unwell, with several pediatric case reports describing short-lived hyperglycemia but normal HbA1c measurements during metabolic crises"

Supports stress hyperglycemia during acute BKD crises.

PMID:40598206 SUPPORT Human Clinical

Supports hypoglycemia as a variable accompanying feature.

Neurological complications and basal ganglia involvement

BKD can produce neurologic complications, especially extrapyramidal manifestations and basal ganglia lesions, as sequelae of ketoacidotic episodes or occasionally without a recognized preceding crisis.

neuron link

basal ganglion link

Downstream

Abnormal basal ganglia morphology Basal ganglia involvement can manifest as bilateral basal ganglia lesions.

Psychomotor delay Neurologic involvement can include psychomotor developmental delay.

Show evidence (2 references)

PMID:40598206 SUPPORT Human Clinical

"Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis."

Supports neurologic complications as sequelae or crisis-independent manifestations.

PMID:23958592 SUPPORT Human Clinical

"Brain CT showed bilateral basal ganglia lesions."

Supports basal ganglia involvement in a patient with T2 deficiency.

⬡

Pathograph

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

●

Phenotypes

Digestive 1

Vomiting Vomiting (HP:0002013)

Show evidence (1 reference)

PMID:30026775 SUPPORT Human Clinical

"clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients"

Directly lists vomiting as a clinical sign during ketoacidotic episodes.

Metabolism 4

Episodic ketoacidosis Ketoacidosis (HP:0001993)

Show evidence (1 reference)

PMID:38853254 SUPPORT Human Clinical

"BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age."

Directly supports recurrent ketoacidosis as the hallmark phenotype.

Metabolic acidosis Metabolic acidosis (HP:0001942)

Show evidence (1 reference)

PMID:35850931 SUPPORT Human Clinical

"At the time of admission, the patient had acidosis, drowsiness, and respiratory failure."

Documents severe acidosis during acute BKD crisis in a pediatric patient.

Hyperglycemia Hyperglycemia (HP:0003074)

Show evidence (1 reference)

PMID:38853254 SUPPORT Human Clinical

Documents stress hyperglycemia during acute BKD episodes and the first report of persistent diabetes in an adult with BKD.

Hypoglycemia Hypoglycemia (HP:0001943)

Show evidence (1 reference)

PMID:40598206 SUPPORT Human Clinical

Documents hypoglycemia as a variable associated feature in T2 deficiency; "2methylacetoacetate" is verbatim from the source abstract [sic].

Musculoskeletal 1

Muscular hypotonia Hypotonia (HP:0001252)

Show evidence (1 reference)

PMID:40598206 SUPPORT Human Clinical

"One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward."

Documents hypotonia as an initial presenting feature preceding ketoacidosis.

Nervous System 5

Lethargy Lethargy (HP:0001254)

Show evidence (2 references)

PMID:30026775 SUPPORT Human Clinical

Directly lists lethargy as a clinical sign during ketoacidotic episodes.

PMID:35850931 SUPPORT Human Clinical

"At the time of admission, the patient had acidosis, drowsiness, and respiratory failure."

Documents drowsiness (altered consciousness) during acute decompensation.

Seizures Seizure (HP:0001250)

Show evidence (1 reference)

PMID:30026775 SUPPORT Human Clinical

"acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma"

Documents tonic-clonic seizures during acute metabolic crisis in BKD.

Coma Coma (HP:0001259)

Show evidence (1 reference)

PMID:30026775 SUPPORT Human Clinical

"clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients"

Directly lists coma as a clinical sign in severe presentations.

Abnormal basal ganglia morphology Abnormal basal ganglia morphology (HP:0002134)

Show evidence (2 references)

PMID:40598206 SUPPORT Human Clinical

"Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis."

Documents neurological complications including extrapyramidal signs in BKD.

PMID:23958592 SUPPORT Human Clinical

"Brain CT showed bilateral basal ganglia lesions."

Documents bilateral basal ganglia lesions on imaging in a BKD patient.

Psychomotor delay Global developmental delay (HP:0001263)

Show evidence (1 reference)

PMID:40598206 SUPPORT Human Clinical

"One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward."

Documents psychomotor delay as an early presentation in BKD.

Respiratory 2

Tachypnea Tachypnea (HP:0002789)

Show evidence (1 reference)

PMID:30026775 SUPPORT Human Clinical

"clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients"

Directly lists tachypnea as a clinical sign during ketoacidotic episodes.

Respiratory failure Respiratory failure (HP:0002878)

Show evidence (1 reference)

PMID:35850931 SUPPORT Human Clinical

"At the time of admission, the patient had acidosis, drowsiness, and respiratory failure."

Documents respiratory failure during acute severe BKD crisis in a 9-month-old.

🧬

Genetic Associations

ACAT1 pathogenic variants

Autosomal recessive

Show evidence (2 references)

PMID:31268215 SUPPORT Human Clinical

"To date, 105 ACAT1 variants have been reported in 149 T2-deficient patients."

Comprehensive mutation update cataloging all known ACAT1 variants.

CGGV:assertion_99bcab0a-de59-479d-8fe6-8b76cbce90ee-2018-05-22T160000.000Z SUPPORT Other

ClinGen classifies the ACAT1-beta-ketothiolase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

Avoidance of catabolic triggers

Action: supportive care MAXO:0000950

The cornerstone of chronic BKD management is avoidance of prolonged fasting, ketogenic diets, and prompt treatment of intercurrent illness to prevent catabolic stress and ketoacidotic episodes.

Show evidence (1 reference)

PMID:38853254 PARTIAL Human Clinical

"BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age."

Episodic nature triggered by catabolic stress supports the importance of trigger avoidance.

Dietary management

Action: dietary intervention MAXO:0000088

Mild protein restriction with avoidance of excess fat intake, regular carbohydrate intake to prevent ketosis, and sick-day glucose and electrolyte solutions. The dietary approach is less restrictive than for many other organic acidemias due to the generally favorable prognosis.

Acute crisis management with intravenous dextrose

Action: supportive care MAXO:0000950

During acute ketoacidotic episodes, intravenous dextrose infusion to suppress ketogenesis (even if euglycemic), along with intravenous fluids and electrolyte correction. Bicarbonate may be used for severe acidosis. Severe crises may require intensive care with ventilation and dialysis when needed.

Show evidence (1 reference)

PMID:35850931 PARTIAL Human Clinical

"At the time of admission, the patient had acidosis, drowsiness, and respiratory failure."

Documents the severity of acute crisis presentation requiring intensive care, but the abstract does not detail the treatment protocol itself.

Carnitine supplementation

Action: carnitine supplementation MAXO:0010006

L-carnitine supplementation may be considered if carnitine deficiency is documented, to support organic acid detoxification and excretion via acylcarnitine conjugation.

Newborn screening

Action: disease screening MAXO:0000124

BKD can be detected through expanded newborn screening using tandem mass spectrometry (MS/MS) via elevated C5:1 and C5-OH acylcarnitines. However, screening sensitivity is not 100 percent, and some affected patients may be missed. Second-tier genetic testing using NGS panels can reduce false positive rates.

Show evidence (1 reference)

PMID:38535123 SUPPORT Human Clinical

"The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed."

Documents implementation of NGS second-tier NBS including BKD, reducing false positives.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk (25%), and carrier testing for informative family members. Prenatal diagnosis is available through molecular analysis of ACAT1.

Show evidence (2 references)

PMID:40598206 SUPPORT Human Clinical

"By identifying haplotype blocks, founder mutations, and novel pathogenic variants, researchers can significantly improve diagnostic precision, enhance genetic counseling, and lay the groundwork for developing targeted therapies."

Supports the role of genetic counseling in BKD management and family planning.

PMID:30026775 SUPPORT Human Clinical

"We recommended carrier testing for all informative family members to recognize mutations in asymptomatic family members."

Directly recommends carrier testing as part of genetic counseling for BKD families.

HbA1c monitoring for dysglycemia

Action: biomarker analysis MAXO:0000018

Given the first reported case of persistent diabetes in an adult with BKD, checking HbA1c in people with BKD and hyperglycemia is recommended to uncover potential coexisting diabetes and facilitate timely management.

Show evidence (1 reference)

PMID:38853254 SUPPORT Human Clinical

"This case highlights the importance of checking HbA1c in people with BKD and hyperglycemia in order to uncover potential coexisting diabetes, facilitating timely management and preventing complications."

Directly supports HbA1c monitoring as a new clinical recommendation for BKD.

🔬

Biochemical Markers

2-Methyl-3-hydroxybutyrate (2M3HB) (INCREASED)

Context: Elevated urinary 2-methyl-3-hydroxybutyrate is the most sensitive biochemical marker of BKD, elevated in the large majority of patients during crisis. It is a characteristic isoleucine-derived metabolite accumulating due to the T2 enzyme block.

Pathograph Readouts

Readout Of Isoleucine-derived organic acid accumulation Positive Diagnostic

Increased urinary 2-methyl-3-hydroxybutyrate reports the accumulated isoleucine-derived organic acid pool.

Readout Of Impaired isoleucine catabolism Positive Diagnostic

Elevated 2-methyl-3-hydroxybutyrate reflects blocked terminal isoleucine catabolism.

Show evidence (2 references)

PMID:40598206 SUPPORT Human Clinical

"The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine."

Documents 2M3HB as the characteristic laboratory finding in all 12 patients.

PMID:31268215 SUPPORT Human Clinical

"The presence of isoleucine-derived metabolites is the key marker for biochemical diagnosis."

Confirms isoleucine-derived metabolites as key diagnostic markers in T2 deficiency.

Tiglylglycine (TIG) (INCREASED)

Context: Elevated urinary tiglylglycine is a characteristic organic acid marker of BKD. It is part of the diagnostic triad along with 2M3HB and 2MAA, though the full triad is not always present in all patients.

Pathograph Readouts

Readout Of Isoleucine-derived organic acid accumulation Positive Diagnostic

Increased urinary tiglylglycine reports the accumulated isoleucine-derived organic acid pool.

Readout Of Impaired isoleucine catabolism Positive Diagnostic

Elevated tiglylglycine reflects blocked isoleucine catabolic flux through the T2-dependent step.

Show evidence (1 reference)

PMID:40598206 SUPPORT Human Clinical

"The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine."

Documents tiglylglycine elevation as a characteristic finding in BKD patients.

2-Methylacetoacetate (2MAA) (INCREASED)

Context: Elevated urinary 2-methylacetoacetate is part of the classic diagnostic triad for BKD but is the least reliably detected of the three markers. 2MAA is unstable on filter paper and may degrade to 2-butanone, potentially causing underdetection in some testing modalities.

Pathograph Readouts

Readout Of Isoleucine-derived organic acid accumulation Positive Diagnostic

Increased urinary 2-methylacetoacetate reports the accumulated isoleucine-derived organic acid pool during crisis.

Readout Of Impaired isoleucine catabolism Positive Diagnostic

Elevated 2-methylacetoacetate reflects failure to clear the T2 substrate branch of isoleucine catabolism.

Show evidence (1 reference)

PMID:23958592 SUPPORT Human Clinical

"large amounts of 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate were excreted."

Documents 2-methylacetoacetate excretion during acute BKD crisis.

Tiglylcarnitine (C5:1) (INCREASED)

Context: Elevated C5:1 (tiglylcarnitine) on blood acylcarnitine analysis by MS/MS is used in newborn screening and diagnostic workup. However, sensitivity is not 100 percent and some patients may lack this elevation even during crisis.

Pathograph Readouts

Readout Of Isoleucine-derived organic acid accumulation Positive Diagnostic

Elevated C5:1 tiglylcarnitine reports acylcarnitine conjugation of accumulated isoleucine-derived intermediates.

Readout Of Impaired isoleucine catabolism Positive Diagnostic

Elevated C5:1 tracks blocked isoleucine catabolic flux.

Show evidence (2 references)

PMID:23958592 SUPPORT Human Clinical

"During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated"

Documents elevated C5:1 acylcarnitine during acute BKD crisis.

PMID:31268215 SUPPORT Human Clinical

"The presence of isoleucine-derived metabolites is the key marker for biochemical diagnosis."

Supports acylcarnitine markers as part of the diagnostic workup.

2-Methyl-3-hydroxybutyrylcarnitine (C5-OH) (INCREASED)

Context: Elevated C5-OH (2-methyl-3-hydroxybutyrylcarnitine) on blood acylcarnitine profile is a diagnostic marker used in newborn screening and during acute crisis evaluation.

Pathograph Readouts

Readout Of Isoleucine-derived organic acid accumulation Positive Diagnostic

Elevated C5-OH reports acylcarnitine conjugation of accumulated 2-methyl-3-hydroxybutyryl intermediates.

Readout Of Impaired isoleucine catabolism Positive Diagnostic

Elevated 2-methyl-3-hydroxybutyrylcarnitine tracks blocked isoleucine catabolic flux.

Show evidence (1 reference)

PMID:23958592 SUPPORT Human Clinical

"During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated"

Documents elevated C5-OH acylcarnitine during acute BKD crisis.

{ }

Source YAML

click to show

name: Beta-Ketothiolase Deficiency
category: Mendelian
creation_date: '2025-06-12T20:16:27Z'
updated_date: '2026-05-20T08:20:05Z'
synonyms:
- T2 deficiency
- Mitochondrial acetoacetyl-CoA thiolase deficiency
- 3-oxothiolase deficiency
- Alpha-methylacetoaceticaciduria
- BKD
description: 'Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in ACAT1, encoding mitochondrial acetoacetyl-CoA thiolase (T2). The enzyme is required for both isoleucine catabolism and ketone body metabolism. Loss of T2 activity blocks the terminal step of isoleucine degradation and impairs extrahepatic ketolysis, leading to accumulation of toxic organic acid intermediates. The disorder typically manifests in infancy or early childhood with recurrent episodes of ketoacidosis triggered by catabolic stressors such as infection, fasting, or ketogenic diet. Between episodes, patients are generally well. Characteristic biochemical markers include elevated urinary 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate. The frequency of ketoacidotic episodes tends to decrease with age and is rare after age 10. With appropriate management, the prognosis is generally favorable, although neurological sequelae including extrapyramidal signs can occur.

  '
disease_term:
  preferred_term: beta-ketothiolase deficiency
  term:
    id: MONDO:0008760
    label: beta-ketothiolase deficiency
parents:
- Organic Acidemia
- Inborn Error of Metabolism
prevalence:
- population: Global
  percentage: Rare
  notes: 'BKD is rare. In a large Chinese newborn screening cohort of 206,977 neonates, the incidence was estimated at approximately 1:32,237, detected only in the Miao ethnic subgroup. To date, over 149 patients have been reported worldwide.

    '
progression:
- phase: Onset
  age_range: Infancy to early childhood
  notes: 'Typically presents between 6 months and 2 years with a first episode of ketoacidosis, often triggered by intercurrent illness.

    '
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: diagnosed between 7 months and 22 months of age at two tertiary care centers in Palestine.
    explanation: Documents typical age of diagnosis in a cohort of 12 BKD patients.
- phase: Recurrent episodic crises
  notes: 'Recurrent ketoacidotic episodes occur during early childhood, triggered by infection, fasting, or ketogenic diet. Frequency tends to decrease with age and episodes are rare after age 10.

    '
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age.
    explanation: Supports episodic nature and age-dependent reduction of decompensation.
- phase: Long-term outcome
  notes: 'The overall prognosis is generally favorable with appropriate management. Neurological complications, particularly extrapyramidal signs, may occur as sequelae of severe episodes or occasionally independent of recognized metabolic crises. Mortality occurs in a minority of patients during severe crises.

    '
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ten of the twelve patients had favorable outcomes, while two unfortunately passed away at the time of the study.
    explanation: Documents favorable long-term outcomes in the majority of BKD patients with some mortality.
pathophysiology:
- name: ACAT1 molecular function deficiency
  description: 'Biallelic ACAT1 pathogenic variants reduce mitochondrial acetoacetyl-CoA thiolase catalytic activity.

    '
  genes:
  - preferred_term: ACAT1
    term:
      id: hgnc:93
      label: ACAT1
  molecular_functions:
  - preferred_term: acetyl-CoA C-acetyltransferase activity
    term:
      id: GO:0003985
      label: acetyl-CoA C-acetyltransferase activity
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:31268215
    reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism.
    explanation: Supports ACAT1/T2 molecular dysfunction as the proximal defect.
  downstream:
  - target: Impaired isoleucine catabolism
    description: Reduced T2 activity blocks terminal isoleucine catabolic cleavage.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31268215
      reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism.
      explanation: Identifies ACAT1/T2 deficiency as the inherited defect disrupting isoleucine metabolism.
  - target: Impaired ketone body metabolism
    description: Reduced T2 activity impairs ketolysis and ketone body handling in extrahepatic tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31268215
      reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism.
      explanation: Identifies ACAT1/T2 deficiency as the inherited defect disrupting ketone body metabolism.
- name: Impaired isoleucine catabolism
  description: 'ACAT1/T2 catalyzes the thiolytic cleavage of 2-methyl-acetoacetyl-CoA into propionyl-CoA and acetyl-CoA, the terminal step in the isoleucine degradation pathway. Loss of T2 activity blocks this step, leading to accumulation of upstream isoleucine-derived metabolites including 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate, and tiglylglycine.

    '
  biological_processes:
  - preferred_term: isoleucine catabolic process
    term:
      id: GO:0006550
      label: L-isoleucine catabolic process
    modifier: DECREASED
  - preferred_term: branched-chain amino acid catabolic process
    term:
      id: GO:0009083
      label: branched-chain amino acid catabolic process
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: cell of skeletal muscle
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive condition affecting isoleucine catabolism and ketone body metabolism.
    explanation: Directly supports impaired isoleucine catabolism as a core feature of BKD.
  - reference: PMID:31268215
    reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism.
    explanation: Comprehensive review confirming isoleucine metabolism disruption in T2 deficiency.
  downstream:
  - target: Isoleucine-derived organic acid accumulation
    description: Blocked terminal isoleucine catabolism causes buildup of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, tiglylglycine, and related acylcarnitines.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia.
      explanation: Directly links T2 deficiency to accumulation of isoleucine-derived metabolites in patient samples.
- name: Impaired ketone body metabolism
  description: 'T2 is involved in ketogenesis in the liver (synthesizing acetoacetyl-CoA from acetyl-CoA) and in the terminal step of ketolysis in extrahepatic tissues (cleaving acetoacetyl-CoA to two acetyl-CoAs). Loss of T2 activity impairs extrahepatic ketone body utilization, predisposing to ketosis and ketoacidosis under catabolic stress.

    '
  biological_processes:
  - preferred_term: ketone body metabolic process
    term:
      id: GO:1902224
      label: ketone body metabolic process
    modifier: ABNORMAL
  chemical_entities:
  - preferred_term: ketone body
    term:
      id: CHEBI:73693
      label: ketone body
    modifier: INCREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: cell of skeletal muscle
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age.
    explanation: Supports recurrent ketoacidosis due to impaired ketone body handling.
  - reference: PMID:31268215
    reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism.
    explanation: Confirms ketone body metabolism disruption as core pathophysiology.
  downstream:
  - target: Episodic metabolic decompensation
    description: Impaired ketone body utilization predisposes to recurrent ketoacidotic crises under catabolic stress.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31268215
      reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: T2 deficiency causes episodic ketoacidosis.
      explanation: Supports ketoacidotic decompensation as the clinical consequence of the ketone-body metabolism defect.
- name: Isoleucine-derived organic acid accumulation
  description: 'Failure to clear 2-methylacetoacetyl-CoA redirects upstream isoleucine intermediates into diagnostic organic acids and acylcarnitines, including 2-methyl-3-hydroxybutyrate, tiglylglycine, 2-methylacetoacetate, tiglylcarnitine, and 2-methyl-3-hydroxybutyrylcarnitine.

    '
  biological_processes:
  - preferred_term: isoleucine catabolic process
    term:
      id: GO:0006550
      label: L-isoleucine catabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: 2-methyl-3-hydroxybutyrate
    term:
      id: CHEBI:78554
      label: 2-methyl-3-hydroxybutyrate
    modifier: INCREASED
  - preferred_term: tiglylglycine
    term:
      id: CHEBI:73018
      label: tiglylglycine
    modifier: INCREASED
  - preferred_term: 2-methylacetoacetate
    term:
      id: CHEBI:19680
      label: 2-methylacetoacetate
    modifier: INCREASED
  - preferred_term: tiglylcarnitine
    term:
      id: CHEBI:71179
      label: O-tiglylcarnitine
    modifier: INCREASED
  - preferred_term: 2-methyl-3-hydroxybutyrylcarnitine
    term:
      id: CHEBI:233719
      label: 2-methyl-3-hydroxybutyrylcarnitine
    modifier: INCREASED
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia.
    explanation: Patient cohort abstract describes accumulation of urine organic acid and blood acylcarnitine markers.
  - reference: PMID:23958592
    reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated and large amounts of 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate were excreted.
    explanation: Documents simultaneous acylcarnitine elevation and urinary organic acid excretion during acute crisis.
  downstream:
  - target: 2-Methyl-3-hydroxybutyrate (2M3HB)
    description: 2-methyl-3-hydroxybutyrate accumulates in urine as a characteristic isoleucine-derived marker.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine.
      explanation: Supports the edge from isoleucine-derived metabolite accumulation to increased 2M3HB.
  - target: Tiglylglycine (TIG)
    description: Tiglylglycine accumulates in urine as a characteristic isoleucine-derived marker.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine.
      explanation: Supports the edge from isoleucine-derived metabolite accumulation to increased TIG.
  - target: 2-Methylacetoacetate (2MAA)
    description: 2-methylacetoacetate can be excreted in large amounts during acute crisis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23958592
      reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: large amounts of 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate were excreted.
      explanation: Supports the edge from isoleucine-derived metabolite accumulation to increased 2MAA.
  - target: Tiglylcarnitine (C5:1)
    description: Tiglyl-CoA accumulation is reflected by elevated C5:1 tiglylcarnitine in blood acylcarnitine profiles.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23958592
      reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated
      explanation: Supports the edge from isoleucine-derived metabolite accumulation to elevated C5:1.
  - target: 2-Methyl-3-hydroxybutyrylcarnitine (C5-OH)
    description: 2-methyl-3-hydroxybutyryl-CoA accumulation is reflected by elevated C5-OH acylcarnitine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23958592
      reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated
      explanation: Supports the edge from isoleucine-derived metabolite accumulation to elevated C5-OH.
  - target: Neurological complications and basal ganglia involvement
    description: Accumulated isoleucine-derived metabolites may contribute to neurologic injury through a crisis-independent neurotoxicity route.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31268215
      reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: Several patients with T2 deficiency developed chronic neurological impairment, mainly extrapyramidal, independent of frank ketoacidosis (Buhaş et al., 2013; Fukao et al., 2018; Paquay et al., 2017).
      explanation: Human clinical observations support neurologic impairment that is not simply downstream of frank ketoacidosis.
    - reference: PMID:31268215
      reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: In vitro studies indicate that 2MAA and 2M3HB exert neurotoxic effects (Leipnitz et al., 2010; Rosa et al., 2005).
      explanation: Human mutation-update review summarizes prior neurotoxicity evidence supporting a plausible metabolite-to-neurologic component of this branch.
  - target: Episodic metabolic decompensation
    description: Organic acid accumulation contributes to acidotic metabolic crises when catabolic stress increases pathway flux.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Accumulated organic acids contribute to high-anion-gap acidemia during catabolic stress.
    evidence:
    - reference: PMID:30026775
      reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Bio chemical tests that suggested diagnose of beta ketothiolase deficiency were attacks of ketoacidosis with urinary exertion of 2-methyl-3-hydroxybutyric acid 2-methyl aceto acetic acid tiglylglycine.
      explanation: Links ketoacidotic attacks with excretion of isoleucine-derived organic acids in a molecularly confirmed case.
- name: Episodic metabolic decompensation
  description: 'Under catabolic triggers such as infection, prolonged fasting, or ketogenic diet, increased reliance on ketone body flux and amino acid catabolism overwhelms the blocked T2 pathway. Accumulated organic acids produce high anion gap metabolic acidosis with ketosis and variable glycemia. Between crises, biochemical profiles may normalize, complicating detection. Episodes decrease in frequency with age, and are rare after age 10 in most patients.

    '
  biological_processes:
  - preferred_term: response to starvation
    term:
      id: GO:0042594
      label: response to starvation
  - preferred_term: cellular response to acidic pH
    term:
      id: GO:0071468
      label: cellular response to acidic pH
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age.
    explanation: Supports episodic nature and age-dependent reduction of decompensation episodes.
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ketoacidotic episodes were the predominant manifestations in all patients, and each episode was triggered by either acute gastroenteritis or upper respiratory infections.
    explanation: Confirms infection-triggered ketoacidotic episodes as the predominant clinical pattern.
  downstream:
  - target: Episodic ketoacidosis
    description: Decompensation episodes manifest as recurrent ketoacidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38853254
      reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age.
      explanation: Supports ketoacidosis as the recurrent clinical expression of metabolic decompensation.
  - target: Metabolic acidosis
    description: Severe crises include metabolic acidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35850931
      reference_title: "Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: At the time of admission, the patient had acidosis, drowsiness, and respiratory failure.
      explanation: Supports acidosis during acute BKD decompensation.
  - target: Acute ketoacidotic crisis syndrome
    description: Severe ketoacidotic crises produce an acute syndrome with toxic encephalopathy, gastrointestinal symptoms, abnormal tone, and compensatory tachypnea.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Severe acidosis and toxic metabolite burden impair brain function during crisis.
    evidence:
    - reference: PMID:30026775
      reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Clinical features characterized by intermittent keto acidotic episodes are associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
      explanation: Links intermittent ketoacidotic episodes to the acute clinical syndrome including encephalopathy and crisis signs.
  - target: Variable glycemic response during crisis
    description: Acute illness and impaired energy handling can be accompanied by stress hyperglycemia or hypoglycemia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38853254
      reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Stress hyperglycemia is not uncommon when children with BKD are acutely unwell, with several pediatric case reports describing short-lived hyperglycemia but normal HbA1c measurements during metabolic crises
      explanation: Supports acute-illness hyperglycemia during BKD metabolic crises.
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia.
      explanation: Supports variable hypoglycemia accompanying the metabolic/biochemical crisis state.
  - target: Respiratory failure
    description: Severe acidotic decompensation can progress to respiratory failure requiring intensive support.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Severe acidosis and altered consciousness can compromise ventilation in acute crisis.
    evidence:
    - reference: PMID:35850931
      reference_title: "Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: At the time of admission, the patient had acidosis, drowsiness, and respiratory failure.
      explanation: Documents respiratory failure together with acidosis and drowsiness during acute presentation.
  - target: Neurological complications and basal ganglia involvement
    description: Decompensation episodes can leave neurologic sequelae, while some neurologic complications may also appear without an obvious crisis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis.
      explanation: Partially supports crisis-related neurologic sequelae; crisis-independent involvement is represented by the metabolite-to-neurologic edge.
- name: Acute ketoacidotic crisis syndrome
  description: 'Severe ketoacidotic episodes can present with toxic metabolic encephalopathy and associated acute-crisis signs, including reduced arousal, vomiting, hypotonia, tachypnea, seizures, and coma.

    '
  biological_processes:
  - preferred_term: cellular response to acidic pH
    term:
      id: GO:0071468
      label: cellular response to acidic pH
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:30026775
    reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical features characterized by intermittent keto acidotic episodes are associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
    explanation: Directly supports an acute ketoacidotic syndrome with toxic encephalopathy and associated signs.
  - reference: PMID:30026775
    reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma
    explanation: Documents severe encephalopathic crisis with seizures and coma.
  downstream:
  - target: Lethargy
    description: Toxic encephalopathy during crisis reduces arousal and activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30026775
      reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
      explanation: Lists lethargy among toxic encephalopathy signs.
  - target: Vomiting
    description: Vomiting occurs during the acute ketoacidotic crisis syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30026775
      reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
      explanation: Lists vomiting among toxic encephalopathy signs.
  - target: Muscular hypotonia
    description: Hypotonia can occur as part of the acute ketoacidotic crisis syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30026775
      reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
      explanation: Lists hypotonia among toxic encephalopathy signs.
  - target: Tachypnea
    description: Tachypnea accompanies the acute ketoacidotic crisis syndrome and acidotic compensation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30026775
      reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
      explanation: Lists tachypnea among crisis-associated toxic encephalopathy signs.
  - target: Seizures
    description: Severe encephalopathic crises can include tonic-clonic seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30026775
      reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma
      explanation: Documents tonic-clonic seizures in acute toxic encephalopathy.
  - target: Coma
    description: Severe toxic encephalopathy can progress to coma.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30026775
      reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma
      explanation: Documents coma following acute toxic encephalopathy.
- name: Variable glycemic response during crisis
  description: 'During acute illness and metabolic crisis, BKD patients may show stress hyperglycemia, while other presentations include hypoglycemia together with the characteristic metabolite accumulation.

    '
  biological_processes:
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Stress hyperglycemia is not uncommon when children with BKD are acutely unwell, with several pediatric case reports describing short-lived hyperglycemia but normal HbA1c measurements during metabolic crises
    explanation: Supports stress hyperglycemia during acute BKD crises.
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia.
    explanation: Supports hypoglycemia as a variable accompanying feature.
  downstream:
  - target: Hyperglycemia
    description: Acute illness can produce short-lived stress hyperglycemia during BKD crises.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38853254
      reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Stress hyperglycemia is not uncommon when children with BKD are acutely unwell, with several pediatric case reports describing short-lived hyperglycemia but normal HbA1c measurements during metabolic crises
      explanation: Directly supports crisis-associated hyperglycemia.
  - target: Hypoglycemia
    description: Some biochemical crisis presentations occur with hypoglycemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia.
      explanation: Directly supports hypoglycemia as a variable accompanying feature.
- name: Neurological complications and basal ganglia involvement
  description: 'BKD can produce neurologic complications, especially extrapyramidal manifestations and basal ganglia lesions, as sequelae of ketoacidotic episodes or occasionally without a recognized preceding crisis.

    '
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis.
    explanation: Supports neurologic complications as sequelae or crisis-independent manifestations.
  - reference: PMID:23958592
    reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain CT showed bilateral basal ganglia lesions.
    explanation: Supports basal ganglia involvement in a patient with T2 deficiency.
  downstream:
  - target: Abnormal basal ganglia morphology
    description: Basal ganglia involvement can manifest as bilateral basal ganglia lesions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23958592
      reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Brain CT showed bilateral basal ganglia lesions.
      explanation: Directly supports basal ganglia pathology in BKD.
  - target: Psychomotor delay
    description: Neurologic involvement can include psychomotor developmental delay.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward.
      explanation: Documents psychomotor delay as part of the neurologic presentation.
phenotypes:
- name: Episodic ketoacidosis
  description: 'Recurrent episodes of ketoacidosis are the hallmark manifestation. Episodes are triggered by catabolic stressors such as infection, fasting, or ketogenic diet, typically presenting in infancy or early childhood with high anion gap metabolic acidosis and ketonuria.

    '
  phenotype_term:
    preferred_term: Recurrent ketoacidosis
    term:
      id: HP:0001993
      label: Ketoacidosis
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age.
    explanation: Directly supports recurrent ketoacidosis as the hallmark phenotype.
- name: Metabolic acidosis
  description: 'High-anion-gap metabolic acidosis during metabolic decompensation episodes, which can be severe with pH as low as 6.99 in reported cases.

    '
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:35850931
    reference_title: "Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the time of admission, the patient had acidosis, drowsiness, and respiratory failure.
    explanation: Documents severe acidosis during acute BKD crisis in a pediatric patient.
- name: Lethargy
  description: 'Reduced arousal and energy during decompensation events, ranging from drowsiness to altered consciousness in severe episodes.

    '
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:30026775
    reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical features characterized by intermittent keto acidotic episodes are associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
    explanation: Directly lists lethargy as a clinical sign during ketoacidotic episodes.
  - reference: PMID:35850931
    reference_title: "Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the time of admission, the patient had acidosis, drowsiness, and respiratory failure.
    explanation: Documents drowsiness (altered consciousness) during acute decompensation.
- name: Vomiting
  description: Recurrent vomiting during metabolic decompensation episodes.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:30026775
    reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
    explanation: Directly lists vomiting as a clinical sign during ketoacidotic episodes.
- name: Muscular hypotonia
  description: 'Hypotonia is observed during acute metabolic crises and may be a presenting feature in some patients even before the first recognized ketoacidotic episode.

    '
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward.
    explanation: Documents hypotonia as an initial presenting feature preceding ketoacidosis.
- name: Tachypnea
  description: 'Rapid breathing during metabolic acidosis episodes as compensatory respiratory response (Kussmaul breathing).

    '
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:30026775
    reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
    explanation: Directly lists tachypnea as a clinical sign during ketoacidotic episodes.
- name: Seizures
  description: 'Seizures may occur during severe metabolic crises, including tonic-clonic seizures as part of toxic metabolic encephalopathy.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30026775
    reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma
    explanation: Documents tonic-clonic seizures during acute metabolic crisis in BKD.
- name: Coma
  description: 'Coma may occur in severe pediatric presentations during metabolic decompensation, representing the severe end of metabolic encephalopathy.

    '
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:30026775
    reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients
    explanation: Directly lists coma as a clinical sign in severe presentations.
- name: Abnormal basal ganglia morphology
  description: 'Bilateral basal ganglia lesions may occur as a neurological complication, either as a sequela of severe ketoacidotic episodes or sometimes occurring without or before any apparent metabolic crisis.

    '
  phenotype_term:
    preferred_term: Abnormal basal ganglia morphology
    term:
      id: HP:0002134
      label: Abnormal basal ganglia morphology
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis.
    explanation: Documents neurological complications including extrapyramidal signs in BKD.
  - reference: PMID:23958592
    reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain CT showed bilateral basal ganglia lesions.
    explanation: Documents bilateral basal ganglia lesions on imaging in a BKD patient.
- name: Psychomotor delay
  description: 'Psychomotor delay may occur, either as a consequence of severe or recurrent metabolic crises or as an early presenting feature in some patients.

    '
  phenotype_term:
    preferred_term: Psychomotor developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward.
    explanation: Documents psychomotor delay as an early presentation in BKD.
- name: Hyperglycemia
  description: 'Stress hyperglycemia is not uncommon during acute ketoacidotic crises in children with BKD. Persistent dysglycemia with elevated HbA1c has been reported in an adult patient, suggesting potential coexisting diabetes.

    '
  phenotype_term:
    preferred_term: Hyperglycemia
    term:
      id: HP:0003074
      label: Hyperglycemia
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Stress hyperglycemia is not uncommon when children with BKD are acutely unwell, with several pediatric case reports describing short-lived hyperglycemia but normal HbA1c measurements during metabolic crises
    explanation: Documents stress hyperglycemia during acute BKD episodes and the first report of persistent diabetes in an adult with BKD.
- name: Hypoglycemia
  description: 'Hypoglycemia may occur during metabolic crises, reflecting impaired energy metabolism and variable glycemic responses.

    '
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia.
    explanation: Documents hypoglycemia as a variable associated feature in T2 deficiency; "2methylacetoacetate" is verbatim from the source abstract [sic].
- name: Respiratory failure
  description: 'Respiratory failure may occur in severe metabolic crises requiring intensive care support.

    '
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:35850931
    reference_title: "Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the time of admission, the patient had acidosis, drowsiness, and respiratory failure.
    explanation: Documents respiratory failure during acute severe BKD crisis in a 9-month-old.
biochemical:
- name: 2-Methyl-3-hydroxybutyrate (2M3HB)
  presence: INCREASED
  context: 'Elevated urinary 2-methyl-3-hydroxybutyrate is the most sensitive biochemical marker of BKD, elevated in the large majority of patients during crisis. It is a characteristic isoleucine-derived metabolite accumulating due to the T2 enzyme block.

    '
  biomarker_term:
    preferred_term: 2-methyl-3-hydroxybutyrate
    term:
      id: CHEBI:78554
      label: 2-methyl-3-hydroxybutyrate
  readouts:
  - target: Isoleucine-derived organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary 2-methyl-3-hydroxybutyrate reports the accumulated isoleucine-derived organic acid pool.
  - target: Impaired isoleucine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated 2-methyl-3-hydroxybutyrate reflects blocked terminal isoleucine catabolism.
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine.
    explanation: Documents 2M3HB as the characteristic laboratory finding in all 12 patients.
  - reference: PMID:31268215
    reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The presence of isoleucine-derived metabolites is the key marker for biochemical diagnosis.
    explanation: Confirms isoleucine-derived metabolites as key diagnostic markers in T2 deficiency.
- name: Tiglylglycine (TIG)
  presence: INCREASED
  context: 'Elevated urinary tiglylglycine is a characteristic organic acid marker of BKD. It is part of the diagnostic triad along with 2M3HB and 2MAA, though the full triad is not always present in all patients.

    '
  biomarker_term:
    preferred_term: tiglylglycine
    term:
      id: CHEBI:73018
      label: tiglylglycine
  readouts:
  - target: Isoleucine-derived organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary tiglylglycine reports the accumulated isoleucine-derived organic acid pool.
  - target: Impaired isoleucine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated tiglylglycine reflects blocked isoleucine catabolic flux through the T2-dependent step.
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine.
    explanation: Documents tiglylglycine elevation as a characteristic finding in BKD patients.
- name: 2-Methylacetoacetate (2MAA)
  presence: INCREASED
  context: 'Elevated urinary 2-methylacetoacetate is part of the classic diagnostic triad for BKD but is the least reliably detected of the three markers. 2MAA is unstable on filter paper and may degrade to 2-butanone, potentially causing underdetection in some testing modalities.

    '
  biomarker_term:
    preferred_term: 2-methylacetoacetate
    term:
      id: CHEBI:19680
      label: 2-methylacetoacetate
  readouts:
  - target: Isoleucine-derived organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary 2-methylacetoacetate reports the accumulated isoleucine-derived organic acid pool during crisis.
  - target: Impaired isoleucine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated 2-methylacetoacetate reflects failure to clear the T2 substrate branch of isoleucine catabolism.
  evidence:
  - reference: PMID:23958592
    reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: large amounts of 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate were excreted.
    explanation: Documents 2-methylacetoacetate excretion during acute BKD crisis.
- name: Tiglylcarnitine (C5:1)
  presence: INCREASED
  context: 'Elevated C5:1 (tiglylcarnitine) on blood acylcarnitine analysis by MS/MS is used in newborn screening and diagnostic workup. However, sensitivity is not 100 percent and some patients may lack this elevation even during crisis.

    '
  biomarker_term:
    preferred_term: tiglylcarnitine
    term:
      id: CHEBI:71179
      label: O-tiglylcarnitine
  readouts:
  - target: Isoleucine-derived organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated C5:1 tiglylcarnitine reports acylcarnitine conjugation of accumulated isoleucine-derived intermediates.
  - target: Impaired isoleucine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated C5:1 tracks blocked isoleucine catabolic flux.
  evidence:
  - reference: PMID:23958592
    reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated
    explanation: Documents elevated C5:1 acylcarnitine during acute BKD crisis.
  - reference: PMID:31268215
    reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The presence of isoleucine-derived metabolites is the key marker for biochemical diagnosis.
    explanation: Supports acylcarnitine markers as part of the diagnostic workup.
- name: 2-Methyl-3-hydroxybutyrylcarnitine (C5-OH)
  presence: INCREASED
  context: 'Elevated C5-OH (2-methyl-3-hydroxybutyrylcarnitine) on blood acylcarnitine profile is a diagnostic marker used in newborn screening and during acute crisis evaluation.

    '
  biomarker_term:
    preferred_term: 2-methyl-3-hydroxybutyrylcarnitine
    term:
      id: CHEBI:233719
      label: 2-methyl-3-hydroxybutyrylcarnitine
  readouts:
  - target: Isoleucine-derived organic acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated C5-OH reports acylcarnitine conjugation of accumulated 2-methyl-3-hydroxybutyryl intermediates.
  - target: Impaired isoleucine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated 2-methyl-3-hydroxybutyrylcarnitine tracks blocked isoleucine catabolic flux.
  evidence:
  - reference: PMID:23958592
    reference_title: "Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated
    explanation: Documents elevated C5-OH acylcarnitine during acute BKD crisis.
genetic:
- name: ACAT1 pathogenic variants
  gene_term:
    preferred_term: ACAT1
    term:
      id: hgnc:93
      label: ACAT1
  features: 'BKD is caused by biallelic pathogenic variants in the ACAT1 gene, which encodes mitochondrial acetoacetyl-CoA thiolase (T2). To date, 105 ACAT1 variants have been reported in 149 T2-deficient patients. The 56 disease-associated missense variants map to buried residues in the T2 crystal structure, likely causing deficiency through lower folding efficiency or stability. Residual T2 activity in vivo determines the severity of the biochemical phenotype, while clinical phenotype does not correlate well with genotype.

    '
  inheritance:
  - name: Autosomal recessive
    description: 'BKD follows autosomal recessive inheritance. All affected individuals carry biallelic (homozygous or compound heterozygous) pathogenic variants in ACAT1.

      '
    evidence:
    - reference: PMID:38853254
      reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive condition affecting isoleucine catabolism and ketone body metabolism.
      explanation: Directly states autosomal recessive inheritance for BKD.
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency (OMIM #203750, *607809) is an autosomal recessive disorder of isoleucine catabolism and ketone body utilization.'
      explanation: Confirms autosomal recessive inheritance with OMIM reference.
  variants:
  - name: Compound heterozygous ACAT1 variants
    description: 'Compound heterozygosity for two different ACAT1 pathogenic variants is a common genotype. For example, ACAT1 c.481T>C, p.(Tyr161His) was identified in compound heterozygosity in an adult patient presenting with diabetic ketoacidosis.

      '
    evidence:
    - reference: PMID:38853254
      reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: genetically confirmed compound heterozygosity for variants in ACAT1, including a novel ACAT1 c.481T>C, p.(Tyr161His) variant.
      explanation: Documents a specific novel ACAT1 variant in a BKD patient.
  - name: Founder mutations in consanguineous populations
    description: 'Founder mutations have been identified in specific populations. In a Palestinian cohort, a founder mutation was found in six patients from three families. All affected patients were offspring of consanguineous marriages, increasing the likelihood of homozygous pathogenic variants.

      '
    evidence:
    - reference: PMID:40598206
      reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a founder mutation was identified in six patients from three families.
      explanation: Documents a founder ACAT1 mutation in the Palestinian population.
  - name: Missense variants affecting buried residues
    description: 'Almost all of the 56 disease-associated missense ACAT1 variants affect residues that are completely or partially buried in the T2 structure, causing deficiency through lower in vivo T2 activity due to reduced folding efficiency or stability.

      '
    evidence:
    - reference: PMID:31268215
      reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Almost all these missense variants concern residues that are completely or partially buried in the T2 structure. Such variants are expected to cause T2 deficiency by having lower in vivo T2 activity because of lower folding efficiency and/or stability.
      explanation: Structural analysis of ACAT1 missense variants mapped onto T2 crystal structure.
  evidence:
  - reference: PMID:31268215
    reference_title: "Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To date, 105 ACAT1 variants have been reported in 149 T2-deficient patients.
    explanation: Comprehensive mutation update cataloging all known ACAT1 variants.
  - reference: CGGV:assertion_99bcab0a-de59-479d-8fe6-8b76cbce90ee-2018-05-22T160000.000Z
    reference_title: "ACAT1 / beta-ketothiolase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACAT1 | HGNC:93 | beta-ketothiolase deficiency | MONDO:0008760 | AR | Definitive"
    explanation: ClinGen classifies the ACAT1-beta-ketothiolase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Avoidance of catabolic triggers
  description: 'The cornerstone of chronic BKD management is avoidance of prolonged fasting, ketogenic diets, and prompt treatment of intercurrent illness to prevent catabolic stress and ketoacidotic episodes.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age.
    explanation: Episodic nature triggered by catabolic stress supports the importance of trigger avoidance.
- name: Dietary management
  description: 'Mild protein restriction with avoidance of excess fat intake, regular carbohydrate intake to prevent ketosis, and sick-day glucose and electrolyte solutions. The dietary approach is less restrictive than for many other organic acidemias due to the generally favorable prognosis.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  notes: Mild protein restriction and dietary management are standard of care but specific published evidence from the available abstracts is limited. The favorable natural history of BKD permits a less restrictive approach than other organic acidemias.
- name: Acute crisis management with intravenous dextrose
  description: 'During acute ketoacidotic episodes, intravenous dextrose infusion to suppress ketogenesis (even if euglycemic), along with intravenous fluids and electrolyte correction. Bicarbonate may be used for severe acidosis. Severe crises may require intensive care with ventilation and dialysis when needed.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:35850931
    reference_title: "Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: At the time of admission, the patient had acidosis, drowsiness, and respiratory failure.
    explanation: Documents the severity of acute crisis presentation requiring intensive care, but the abstract does not detail the treatment protocol itself.
- name: Carnitine supplementation
  description: 'L-carnitine supplementation may be considered if carnitine deficiency is documented, to support organic acid detoxification and excretion via acylcarnitine conjugation.

    '
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: MAXO:0010006
      label: carnitine supplementation
  notes: L-carnitine supplementation is a standard adjunctive therapy in organic acidemias but direct evidence specific to BKD efficacy is limited.
- name: Newborn screening
  description: 'BKD can be detected through expanded newborn screening using tandem mass spectrometry (MS/MS) via elevated C5:1 and C5-OH acylcarnitines. However, screening sensitivity is not 100 percent, and some affected patients may be missed. Second-tier genetic testing using NGS panels can reduce false positive rates.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
  evidence:
  - reference: PMID:38535123
    reference_title: "Harnessing Next-Generation Sequencing as a Timely and Accurate Second-Tier Screening Test for Newborn Screening of Inborn Errors of Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed.
    explanation: Documents implementation of NGS second-tier NBS including BKD, reducing false positives.
- name: Genetic counseling
  description: 'Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk (25%), and carrier testing for informative family members. Prenatal diagnosis is available through molecular analysis of ACAT1.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:40598206
    reference_title: "Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: By identifying haplotype blocks, founder mutations, and novel pathogenic variants, researchers can significantly improve diagnostic precision, enhance genetic counseling, and lay the groundwork for developing targeted therapies.
    explanation: Supports the role of genetic counseling in BKD management and family planning.
  - reference: PMID:30026775
    reference_title: "A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We recommended carrier testing for all informative family members to recognize mutations in asymptomatic family members.
    explanation: Directly recommends carrier testing as part of genetic counseling for BKD families.
- name: HbA1c monitoring for dysglycemia
  description: 'Given the first reported case of persistent diabetes in an adult with BKD, checking HbA1c in people with BKD and hyperglycemia is recommended to uncover potential coexisting diabetes and facilitate timely management.

    '
  treatment_term:
    preferred_term: biomarker analysis
    term:
      id: MAXO:0000018
      label: biomarker analysis
  evidence:
  - reference: PMID:38853254
    reference_title: "Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This case highlights the importance of checking HbA1c in people with BKD and hyperglycemia in order to uncover potential coexisting diabetes, facilitating timely management and preventing complications.
    explanation: Directly supports HbA1c monitoring as a new clinical recommendation for BKD.
notes: 'BKD can clinically mimic diabetic ketoacidosis, particularly in the pediatric setting. Atypical features such as persistent acidosis, fluctuating glucose, and normal HbA1c should prompt evaluation for inborn errors of metabolism. The biochemical triad (2M3HB, TIG, 2MAA) is not always complete, and MS/MS acylcarnitine screening does not ensure 100 percent sensitivity. Even patients with null mutations can show normal urine organic acids and blood acylcarnitines when clinically well.

  '
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
references:
- reference: DOI:10.25259/jped_9_2023
  title: A rare case of β-ketothiolase deficiency presenting as mimicker of diabetic ketoacidosis
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-falcon.md
  findings:
  - statement: β-ketothiolase (3-oxothiolase, BKT), also called mitochondrial acetoacetyl-coenzyme-A thiolase (T2), is a mitochondrial enzyme involved in isoleucine catabolism and ketone metabolism.
    supporting_text: β-ketothiolase (3-oxothiolase, BKT), also called mitochondrial acetoacetyl-coenzyme-A thiolase (T2), is a mitochondrial enzyme involved in isoleucine catabolism and ketone metabolism.
    evidence:
    - reference: DOI:10.25259/jped_9_2023
      reference_title: A rare case of β-ketothiolase deficiency presenting as mimicker of diabetic ketoacidosis
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: β-ketothiolase (3-oxothiolase, BKT), also called mitochondrial acetoacetyl-coenzyme-A thiolase (T2), is a mitochondrial enzyme involved in isoleucine catabolism and ketone metabolism.
      explanation: Human clinical case report summarizes the enzyme and pathway context for beta-ketothiolase deficiency.
- reference: DOI:10.3389/fgene.2024.1387423
  title: 206,977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in Huaihua, China
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-falcon.md
  findings:
  - statement: Inborn errors of metabolism (IEMs) are rare diseases caused by inherited defects in various biochemical pathways that strongly correlate with early neonatal mortality and stunting.
    supporting_text: Inborn errors of metabolism (IEMs) are rare diseases caused by inherited defects in various biochemical pathways that strongly correlate with early neonatal mortality and stunting.
    evidence:
    - reference: DOI:10.3389/fgene.2024.1387423
      reference_title: 206,977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in Huaihua, China
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Inborn errors of metabolism (IEMs) are rare diseases caused by inherited defects in various biochemical pathways that strongly correlate with early neonatal mortality and stunting.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: DOI:10.52852/tcncyh.v171i10.2016
  title: Đặc điểm hóa sinh của bệnh nhân thiếu beta-ketothiolase
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-falcon.md
  findings:
  - statement: Bệnh thiếu hụt enzym beta-ketothiolase là một bệnh rối loạn chuyển hóa do đột biến gen ACAT1 (gen T2) nằm trên nhiễm sắc thể số 11 (11q22.3-q23).
    supporting_text: Bệnh thiếu hụt enzym beta-ketothiolase là một bệnh rối loạn chuyển hóa do đột biến gen ACAT1 (gen T2) nằm trên nhiễm sắc thể số 11 (11q22.3-q23).
    evidence:
    - reference: DOI:10.52852/tcncyh.v171i10.2016
      reference_title: Đặc điểm hóa sinh của bệnh nhân thiếu beta-ketothiolase
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Bệnh thiếu hụt enzym beta-ketothiolase là một bệnh rối loạn chuyển hóa do đột biến gen ACAT1 (gen T2) nằm trên nhiễm sắc thể số 11 (11q22.3-q23).
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: DOI:10.1186/s40842-024-00174-9
  title: 'Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant: first report of established diabetes in BKD and a review of the literature'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-falcon.md
  findings:
  - statement: Persistent dysglycemia can coexist with beta-ketothiolase deficiency and complicate ketoacidosis presentation in adulthood.
    supporting_text: This is the first report of diabetic ketoacidosis in an adult with BKD, with an elevated HbA1c consistent with persistent hyperglycemia.
    evidence:
    - reference: DOI:10.1186/s40842-024-00174-9
      reference_title: 'Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant: first report of established diabetes in BKD and a review of the literature'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: This is the first report of diabetic ketoacidosis in an adult with BKD, with an elevated HbA1c consistent with persistent hyperglycemia.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: DOI:10.3390/ijns10010019
  title: Harnessing Next-Generation Sequencing as a Timely and Accurate Second-Tier Screening Test for Newborn Screening of Inborn Errors of Metabolism
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-falcon.md
  findings:
  - statement: A second-tier NGS panel included beta-ketothiolase deficiency among screened inborn errors of metabolism and reduced false positives.
    supporting_text: The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed.
    evidence:
    - reference: DOI:10.3390/ijns10010019
      reference_title: Harnessing Next-Generation Sequencing as a Timely and Accurate Second-Tier Screening Test for Newborn Screening of Inborn Errors of Metabolism
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:31268215
  title: Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: ACAT1 genotype does not correlate with the clinical phenotype in mitochondrial acetoacetyl-CoA thiolase deficiency.
    supporting_text: In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype.
    evidence:
    - reference: PMID:31268215
      reference_title: Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:35850931
  title: Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy.
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: Whole-exome sequencing identified novel compound heterozygous ACAT1 variants in a child with beta-ketothiolase deficiency.
    supporting_text: Novel compound heterozygous variant (c.871G>C and c.1016_1017del) in the ACAT1 gene were detected in the proband by WES and verified through direct sequencing.
    evidence:
    - reference: PMID:35850931
      reference_title: Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Novel compound heterozygous variant (c.871G>C and c.1016_1017del) in the ACAT1 gene were detected in the proband by WES and verified through direct sequencing.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:40598206
  title: 'Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: A Palestinian beta-ketothiolase deficiency cohort identified two novel ACAT1 variants and a founder mutation.
    supporting_text: Molecular genetic analysis of the ACAT1 gene was conducted on nine patients from six families, revealing four different variants, two of which were novel.
    evidence:
    - reference: PMID:40598206
      reference_title: 'Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Molecular genetic analysis of the ACAT1 gene was conducted on nine patients from six families, revealing four different variants, two of which were novel.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:15128923
  title: 'Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency: T2-deficient patients with "mild" mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2004 Jul;56(1):60-4. doi: 10.1203/01.PDR.0000129657.48122.52.'
    supporting_text: '2004 Jul;56(1):60-4. doi: 10.1203/01.PDR.0000129657.48122.52.'
    evidence:
    - reference: PMID:15128923
      reference_title: 'Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency: T2-deficient patients with "mild" mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2004 Jul;56(1):60-4. doi: 10.1203/01.PDR.0000129657.48122.52.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:17236799
  title: 'Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): identification of a Km mutant and an analysis of the mutational sites in the structure.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2007 Apr;90(4):370-8. doi: 10.1016/j.ymgme.2006.12.002.'
    supporting_text: '2007 Apr;90(4):370-8. doi: 10.1016/j.ymgme.2006.12.002.'
    evidence:
    - reference: PMID:17236799
      reference_title: 'Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): identification of a Km mutant and an analysis of the mutational sites in the structure.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2007 Apr;90(4):370-8. doi: 10.1016/j.ymgme.2006.12.002.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:20157782
  title: 'The first case of mitochondrial acetoacetyl-CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2010 Dec;33 Suppl 3(Suppl 3):S91-4. doi: 10.1007/s10545-009-9028-3.'
    supporting_text: '2010 Dec;33 Suppl 3(Suppl 3):S91-4. doi: 10.1007/s10545-009-9028-3.'
    evidence:
    - reference: PMID:20157782
      reference_title: 'The first case of mitochondrial acetoacetyl-CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2010 Dec;33 Suppl 3(Suppl 3):S91-4. doi: 10.1007/s10545-009-9028-3.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:23430882
  title: 'Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1 : Subtle Abnormality in Urinary Organic Acid Analysis and Blood Acylcarnitine Analysis Using Tandem Mass Spectrometry.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2012;3:107-15. doi: 10.1007/8904_2011_72.'
    supporting_text: '2012;3:107-15. doi: 10.1007/8904_2011_72.'
    evidence:
    - reference: PMID:23430882
      reference_title: 'Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1 : Subtle Abnormality in Urinary Organic Acid Analysis and Blood Acylcarnitine Analysis Using Tandem Mass Spectrometry.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2012;3:107-15. doi: 10.1007/8904_2011_72.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:26790708
  title: 'Inborn errors of metabolism detectable by tandem mass spectrometry in Egypt: The first newborn screening pilot study.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2016 Sep;23(3):124-9. doi: 10.1177/0969141315618229.'
    supporting_text: '2016 Sep;23(3):124-9. doi: 10.1177/0969141315618229.'
    evidence:
    - reference: PMID:26790708
      reference_title: 'Inborn errors of metabolism detectable by tandem mass spectrometry in Egypt: The first newborn screening pilot study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2016 Sep;23(3):124-9. doi: 10.1177/0969141315618229.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:28689740
  title: Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency.
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2017 Sep;122(1-2):67-75. doi: 10.1016/j.ymgme.2017.06.012.'
    supporting_text: '2017 Sep;122(1-2):67-75. doi: 10.1016/j.ymgme.2017.06.012.'
    evidence:
    - reference: PMID:28689740
      reference_title: Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2017 Sep;122(1-2):67-75. doi: 10.1016/j.ymgme.2017.06.012.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:28726122
  title: Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals.
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2018;39:45-54. doi: 10.1007/8904_2017_45.'
    supporting_text: '2018;39:45-54. doi: 10.1007/8904_2017_45.'
    evidence:
    - reference: PMID:28726122
      reference_title: Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2018;39:45-54. doi: 10.1007/8904_2017_45.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:28875337
  title: 'Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2017 Dec;32(6):2063-2071. doi: 10.1007/s11011-017-0097-y.'
    supporting_text: '2017 Dec;32(6):2063-2071. doi: 10.1007/s11011-017-0097-y.'
    evidence:
    - reference: PMID:28875337
      reference_title: 'Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2017 Dec;32(6):2063-2071. doi: 10.1007/s11011-017-0097-y.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:29039164
  title: '[Screening for newborn organic aciduria in Zhejiang province:prevalence, outcome and follow-up].'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: Zhejiang newborn screening identified beta-ketothiolase deficiency among confirmed organic acidurias.
    supporting_text: 1 had 3-hydroxy-3-methylglutaric aciduria (1:1 861 300), 2 had β-ketothiolase deficiency (1:960 600), and 3 had biotinidase deficiency/holocarboxylase synthetase deficiency (1:620 400).
    evidence:
    - reference: PMID:29039164
      reference_title: '[Screening for newborn organic aciduria in Zhejiang province:prevalence, outcome and follow-up].'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 1 had 3-hydroxy-3-methylglutaric aciduria (1:1 861 300), 2 had β-ketothiolase deficiency (1:960 600), and 3 had biotinidase deficiency/holocarboxylase synthetase deficiency (1:620 400).
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:32345314
  title: '2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways'
    supporting_text: 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetyl-coenzyme A thiolase T2/ "beta-ketothiolase") is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1.
    evidence:
    - reference: PMID:32345314
      reference_title: '2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetyl-coenzyme A thiolase T2/ "beta-ketothiolase") is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:32880084
  title: 'Brief Report: Delayed Diagnosis of Treatable Inborn Errors of Metabolism in Children with Autism and Other Neurodevelopmental Disorders.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2021 Jun;51(6):2124-2131. doi: 10.1007/s10803-020-04682-2.'
    supporting_text: '2021 Jun;51(6):2124-2131. doi: 10.1007/s10803-020-04682-2.'
    evidence:
    - reference: PMID:32880084
      reference_title: 'Brief Report: Delayed Diagnosis of Treatable Inborn Errors of Metabolism in Children with Autism and Other Neurodevelopmental Disorders.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '2021 Jun;51(6):2124-2131. doi: 10.1007/s10803-020-04682-2.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:33708533
  title: 'Ketoacidotic crisis after vaccination in a girl with beta-ketothiolase deficiency: a case report.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2021 Feb;10(2):459-463. doi: 10.21037/tp-20-265.'
    supporting_text: '2021 Feb;10(2):459-463. doi: 10.21037/tp-20-265.'
    evidence:
    - reference: PMID:33708533
      reference_title: 'Ketoacidotic crisis after vaccination in a girl with beta-ketothiolase deficiency: a case report.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '2021 Feb;10(2):459-463. doi: 10.21037/tp-20-265.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:34001203
  title: C4OH is a potential newborn screening marker-a multicenter retrospective study of patients with beta-ketothiolase deficiency in China.
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis.
    supporting_text: Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis.
    evidence:
    - reference: PMID:34001203
      reference_title: C4OH is a potential newborn screening marker-a multicenter retrospective study of patients with beta-ketothiolase deficiency in China.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:38684297
  title: '[Clinical analysis and genetic diagnosis of three children with Isoleucine metabolic disorders due to variants of HSD17B10 and ACAT1 genes].'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: BKD and HSD17B10 deficiency can be clinically difficult to distinguish, making genetic testing important.
    supporting_text: Both the HSD17B10 deficiency and BKD can lead to Isoleucine metabolism disorders, which may be difficult to distinguish clinically. Genetic testing can further confirm the diagnosis.
    evidence:
    - reference: PMID:38684297
      reference_title: '[Clinical analysis and genetic diagnosis of three children with Isoleucine metabolic disorders due to variants of HSD17B10 and ACAT1 genes].'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both the HSD17B10 deficiency and BKD can lead to Isoleucine metabolism disorders, which may be difficult to distinguish clinically. Genetic testing can further confirm the diagnosis.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:40981306
  title: 'Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Three New Cases Detected by Newborn Screening Confirming the Significance of C4OH Elevation.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2025 Sep 6;11(3):76. doi: 10.3390/ijns11030076.'
    supporting_text: '2025 Sep 6;11(3):76. doi: 10.3390/ijns11030076.'
    evidence:
    - reference: PMID:40981306
      reference_title: 'Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Three New Cases Detected by Newborn Screening Confirming the Significance of C4OH Elevation.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '2025 Sep 6;11(3):76. doi: 10.3390/ijns11030076.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:41180774
  title: 'Beta-ketothiolase deficiency with neurological impairment: a case report.'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '2025 Sep 30;87(11):7739-7744. doi: 10.1097/MS9.0000000000003958. eCollection 2025 Nov.'
    supporting_text: '2025 Sep 30;87(11):7739-7744. doi: 10.1097/MS9.0000000000003958. eCollection 2025 Nov.'
    evidence:
    - reference: PMID:41180774
      reference_title: 'Beta-ketothiolase deficiency with neurological impairment: a case report.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '2025 Sep 30;87(11):7739-7744. doi: 10.1097/MS9.0000000000003958. eCollection 2025 Nov.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:7726385
  title: Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism.
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: '1994 Nov;16 Suppl:81-5. doi: 10.1016/0387-7604(94)90100-7.'
    supporting_text: '1994 Nov;16 Suppl:81-5. doi: 10.1016/0387-7604(94)90100-7.'
    evidence:
    - reference: PMID:7726385
      reference_title: Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '1994 Nov;16 Suppl:81-5. doi: 10.1016/0387-7604(94)90100-7.'
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.
- reference: PMID:8218125
  title: '[Pathomorpholigical findings in ketothiolase deficiency].'
  found_in:
  - Beta-Ketothiolase_Deficiency-deep-research-openscientist.md
  findings:
  - statement: Autopsy findings in ketothiolase deficiency included cardiac and brain pathology.
    supporting_text: Autopsy revealed cardiac hypertrophy and brain pathology in both children.
    evidence:
    - reference: PMID:8218125
      reference_title: '[Pathomorpholigical findings in ketothiolase deficiency].'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Autopsy revealed cardiac hypertrophy and brain pathology in both children.
      explanation: Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

📚

References & Deep Research

References

DOI:10.25259/jped_9_2023

A rare case of β-ketothiolase deficiency presenting as mimicker of diabetic ketoacidosis

1 finding

β-ketothiolase (3-oxothiolase, BKT), also called mitochondrial acetoacetyl-coenzyme-A thiolase (T2), is a mitochondrial enzyme involved in isoleucine catabolism and ketone metabolism.

"β-ketothiolase (3-oxothiolase, BKT), also called mitochondrial acetoacetyl-coenzyme-A thiolase (T2), is a mitochondrial enzyme involved in isoleucine catabolism and ketone metabolism."

Show evidence (1 reference)

DOI:10.25259/jped_9_2023 SUPPORT Human Clinical

"β-ketothiolase (3-oxothiolase, BKT), also called mitochondrial acetoacetyl-coenzyme-A thiolase (T2), is a mitochondrial enzyme involved in isoleucine catabolism and ketone metabolism."

Human clinical case report summarizes the enzyme and pathway context for beta-ketothiolase deficiency.

DOI:10.3389/fgene.2024.1387423

206,977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in Huaihua, China

1 finding

Inborn errors of metabolism (IEMs) are rare diseases caused by inherited defects in various biochemical pathways that strongly correlate with early neonatal mortality and stunting.

"Inborn errors of metabolism (IEMs) are rare diseases caused by inherited defects in various biochemical pathways that strongly correlate with early neonatal mortality and stunting."

Show evidence (1 reference)

DOI:10.3389/fgene.2024.1387423 SUPPORT Human Clinical

"Inborn errors of metabolism (IEMs) are rare diseases caused by inherited defects in various biochemical pathways that strongly correlate with early neonatal mortality and stunting."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

DOI:10.52852/tcncyh.v171i10.2016

Đặc điểm hóa sinh của bệnh nhân thiếu beta-ketothiolase

1 finding

Bệnh thiếu hụt enzym beta-ketothiolase là một bệnh rối loạn chuyển hóa do đột biến gen ACAT1 (gen T2) nằm trên nhiễm sắc thể số 11 (11q22.3-q23).

"Bệnh thiếu hụt enzym beta-ketothiolase là một bệnh rối loạn chuyển hóa do đột biến gen ACAT1 (gen T2) nằm trên nhiễm sắc thể số 11 (11q22.3-q23)."

Show evidence (1 reference)

DOI:10.52852/tcncyh.v171i10.2016 SUPPORT Other

"Bệnh thiếu hụt enzym beta-ketothiolase là một bệnh rối loạn chuyển hóa do đột biến gen ACAT1 (gen T2) nằm trên nhiễm sắc thể số 11 (11q22.3-q23)."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

DOI:10.1186/s40842-024-00174-9

Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant: first report of established diabetes in BKD and a review of the literature

1 finding

Persistent dysglycemia can coexist with beta-ketothiolase deficiency and complicate ketoacidosis presentation in adulthood.

"This is the first report of diabetic ketoacidosis in an adult with BKD, with an elevated HbA1c consistent with persistent hyperglycemia."

Show evidence (1 reference)

DOI:10.1186/s40842-024-00174-9 SUPPORT Human Clinical

"This is the first report of diabetic ketoacidosis in an adult with BKD, with an elevated HbA1c consistent with persistent hyperglycemia."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

DOI:10.3390/ijns10010019

Harnessing Next-Generation Sequencing as a Timely and Accurate Second-Tier Screening Test for Newborn Screening of Inborn Errors of Metabolism

1 finding

A second-tier NGS panel included beta-ketothiolase deficiency among screened inborn errors of metabolism and reduced false positives.

Show evidence (1 reference)

DOI:10.3390/ijns10010019 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:31268215

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.

1 finding

ACAT1 genotype does not correlate with the clinical phenotype in mitochondrial acetoacetyl-CoA thiolase deficiency.

"In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype."

Show evidence (1 reference)

PMID:31268215 SUPPORT Human Clinical

"In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:35850931

Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy.

1 finding

Whole-exome sequencing identified novel compound heterozygous ACAT1 variants in a child with beta-ketothiolase deficiency.

"Novel compound heterozygous variant (c.871G>C and c.1016_1017del) in the ACAT1 gene were detected in the proband by WES and verified through direct sequencing."

Show evidence (1 reference)

PMID:35850931 SUPPORT Human Clinical

"Novel compound heterozygous variant (c.871G>C and c.1016_1017del) in the ACAT1 gene were detected in the proband by WES and verified through direct sequencing."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:40598206

Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene.

1 finding

A Palestinian beta-ketothiolase deficiency cohort identified two novel ACAT1 variants and a founder mutation.

"Molecular genetic analysis of the ACAT1 gene was conducted on nine patients from six families, revealing four different variants, two of which were novel."

Show evidence (1 reference)

PMID:40598206 SUPPORT Human Clinical

"Molecular genetic analysis of the ACAT1 gene was conducted on nine patients from six families, revealing four different variants, two of which were novel."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:15128923

Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency: T2-deficient patients with "mild" mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA.

1 finding

2004 Jul;56(1):60-4. doi: 10.1203/01.PDR.0000129657.48122.52.

"2004 Jul;56(1):60-4. doi: 10.1203/01.PDR.0000129657.48122.52."

Show evidence (1 reference)

PMID:15128923 SUPPORT Human Clinical

"2004 Jul;56(1):60-4. doi: 10.1203/01.PDR.0000129657.48122.52."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:17236799

Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): identification of a Km mutant and an analysis of the mutational sites in the structure.

1 finding

2007 Apr;90(4):370-8. doi: 10.1016/j.ymgme.2006.12.002.

"2007 Apr;90(4):370-8. doi: 10.1016/j.ymgme.2006.12.002."

Show evidence (1 reference)

PMID:17236799 SUPPORT Human Clinical

"2007 Apr;90(4):370-8. doi: 10.1016/j.ymgme.2006.12.002."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:20157782

The first case of mitochondrial acetoacetyl-CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach.

1 finding

2010 Dec;33 Suppl 3(Suppl 3):S91-4. doi: 10.1007/s10545-009-9028-3.

"2010 Dec;33 Suppl 3(Suppl 3):S91-4. doi: 10.1007/s10545-009-9028-3."

Show evidence (1 reference)

PMID:20157782 SUPPORT Human Clinical

"2010 Dec;33 Suppl 3(Suppl 3):S91-4. doi: 10.1007/s10545-009-9028-3."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:23430882

Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1 : Subtle Abnormality in Urinary Organic Acid Analysis and Blood Acylcarnitine Analysis Using Tandem Mass Spectrometry.

1 finding

2012;3:107-15. doi: 10.1007/8904_2011_72.

"2012;3:107-15. doi: 10.1007/8904_2011_72."

Show evidence (1 reference)

PMID:23430882 SUPPORT Human Clinical

"2012;3:107-15. doi: 10.1007/8904_2011_72."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:26790708

Inborn errors of metabolism detectable by tandem mass spectrometry in Egypt: The first newborn screening pilot study.

1 finding

2016 Sep;23(3):124-9. doi: 10.1177/0969141315618229.

"2016 Sep;23(3):124-9. doi: 10.1177/0969141315618229."

Show evidence (1 reference)

PMID:26790708 SUPPORT Human Clinical

"2016 Sep;23(3):124-9. doi: 10.1177/0969141315618229."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:28689740

Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency.

1 finding

2017 Sep;122(1-2):67-75. doi: 10.1016/j.ymgme.2017.06.012.

"2017 Sep;122(1-2):67-75. doi: 10.1016/j.ymgme.2017.06.012."

Show evidence (1 reference)

PMID:28689740 SUPPORT Human Clinical

"2017 Sep;122(1-2):67-75. doi: 10.1016/j.ymgme.2017.06.012."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:28726122

Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals.

1 finding

2018;39:45-54. doi: 10.1007/8904_2017_45.

"2018;39:45-54. doi: 10.1007/8904_2017_45."

Show evidence (1 reference)

PMID:28726122 SUPPORT Human Clinical

"2018;39:45-54. doi: 10.1007/8904_2017_45."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:28875337

Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene.

1 finding

2017 Dec;32(6):2063-2071. doi: 10.1007/s11011-017-0097-y.

"2017 Dec;32(6):2063-2071. doi: 10.1007/s11011-017-0097-y."

Show evidence (1 reference)

PMID:28875337 SUPPORT Human Clinical

"2017 Dec;32(6):2063-2071. doi: 10.1007/s11011-017-0097-y."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:29039164

[Screening for newborn organic aciduria in Zhejiang province:prevalence, outcome and follow-up].

1 finding

Zhejiang newborn screening identified beta-ketothiolase deficiency among confirmed organic acidurias.

"1 had 3-hydroxy-3-methylglutaric aciduria (1:1 861 300), 2 had β-ketothiolase deficiency (1:960 600), and 3 had biotinidase deficiency/holocarboxylase synthetase deficiency (1:620 400)."

Show evidence (1 reference)

PMID:29039164 SUPPORT Human Clinical

"1 had 3-hydroxy-3-methylglutaric aciduria (1:1 861 300), 2 had β-ketothiolase deficiency (1:960 600), and 3 had biotinidase deficiency/holocarboxylase synthetase deficiency (1:620 400)."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:32345314

2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways.

1 finding

2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways

"2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetyl-coenzyme A thiolase T2/ "beta-ketothiolase") is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1."

Show evidence (1 reference)

PMID:32345314 SUPPORT Other

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:32880084

Brief Report: Delayed Diagnosis of Treatable Inborn Errors of Metabolism in Children with Autism and Other Neurodevelopmental Disorders.

1 finding

2021 Jun;51(6):2124-2131. doi: 10.1007/s10803-020-04682-2.

"2021 Jun;51(6):2124-2131. doi: 10.1007/s10803-020-04682-2."

Show evidence (1 reference)

PMID:32880084 SUPPORT Human Clinical

"2021 Jun;51(6):2124-2131. doi: 10.1007/s10803-020-04682-2."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:33708533

Ketoacidotic crisis after vaccination in a girl with beta-ketothiolase deficiency: a case report.

1 finding

2021 Feb;10(2):459-463. doi: 10.21037/tp-20-265.

"2021 Feb;10(2):459-463. doi: 10.21037/tp-20-265."

Show evidence (1 reference)

PMID:33708533 SUPPORT Other

"2021 Feb;10(2):459-463. doi: 10.21037/tp-20-265."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:34001203

C4OH is a potential newborn screening marker-a multicenter retrospective study of patients with beta-ketothiolase deficiency in China.

1 finding

Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis.

"Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis."

Show evidence (1 reference)

PMID:34001203 SUPPORT Other

"Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:38684297

[Clinical analysis and genetic diagnosis of three children with Isoleucine metabolic disorders due to variants of HSD17B10 and ACAT1 genes].

1 finding

BKD and HSD17B10 deficiency can be clinically difficult to distinguish, making genetic testing important.

"Both the HSD17B10 deficiency and BKD can lead to Isoleucine metabolism disorders, which may be difficult to distinguish clinically. Genetic testing can further confirm the diagnosis."

Show evidence (1 reference)

PMID:38684297 SUPPORT Human Clinical

"Both the HSD17B10 deficiency and BKD can lead to Isoleucine metabolism disorders, which may be difficult to distinguish clinically. Genetic testing can further confirm the diagnosis."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:40981306

Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Three New Cases Detected by Newborn Screening Confirming the Significance of C4OH Elevation.

1 finding

2025 Sep 6;11(3):76. doi: 10.3390/ijns11030076.

"2025 Sep 6;11(3):76. doi: 10.3390/ijns11030076."

Show evidence (1 reference)

PMID:40981306 SUPPORT Other

"2025 Sep 6;11(3):76. doi: 10.3390/ijns11030076."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:41180774

Beta-ketothiolase deficiency with neurological impairment: a case report.

1 finding

2025 Sep 30;87(11):7739-7744. doi: 10.1097/MS9.0000000000003958. eCollection 2025 Nov.

"2025 Sep 30;87(11):7739-7744. doi: 10.1097/MS9.0000000000003958. eCollection 2025 Nov."

Show evidence (1 reference)

PMID:41180774 SUPPORT Other

"2025 Sep 30;87(11):7739-7744. doi: 10.1097/MS9.0000000000003958. eCollection 2025 Nov."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:7726385

Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism.

1 finding

1994 Nov;16 Suppl:81-5. doi: 10.1016/0387-7604(94)90100-7.

"1994 Nov;16 Suppl:81-5. doi: 10.1016/0387-7604(94)90100-7."

Show evidence (1 reference)

PMID:7726385 SUPPORT Other

"1994 Nov;16 Suppl:81-5. doi: 10.1016/0387-7604(94)90100-7."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

PMID:8218125

[Pathomorpholigical findings in ketothiolase deficiency].

1 finding

Autopsy findings in ketothiolase deficiency included cardiac and brain pathology.

"Autopsy revealed cardiac hypertrophy and brain pathology in both children."

Show evidence (1 reference)

PMID:8218125 SUPPORT Human Clinical

"Autopsy revealed cardiac hypertrophy and brain pathology in both children."

Deep research cited this publication as relevant literature for Beta-Ketothiolase Deficiency.

Deep Research

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 20 citations 2026-02-23T23:40:37.564783

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

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

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

Disease Pathophysiology Research Template

Target Disease

Disease Name: Beta-ketothiolase Deficiency
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Beta-ketothiolase Deficiency. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

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

2. Key Molecular Players

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

3. Biological Processes (for GO annotation)

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

4. Cellular Components

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

5. Disease Progression

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

6. Phenotypic Manifestations

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

Citation Requirements

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

Output Format

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

Comprehensive Research Report: Pathophysiology of Beta-ketothiolase Deficiency (BKD)

Publication focus: molecular/cellular mechanisms underlying disease progression, with emphasis on recent (2023–2024) primary/clinical literature and implementation studies.

Disease definition and core concepts

1.1 Nomenclature and disease concept Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in ACAT1, the gene encoding mitochondrial acetoacetyl‑CoA thiolase (also called β-ketothiolase, 3‑oxothiolase, or T2). The disorder affects both ketone body metabolism and isoleucine catabolism. (zhen2024diabeticketoacidosisin pages 1-3, patra2023ararecase pages 1-2)

Recent definitional statements (verbatim/near-verbatim from sources): - “Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive condition affecting isoleucine catabolism and ketone body metabolism.” (Zhen et al., 2024; https://doi.org/10.1186/s40842-024-00174-9; published June 2024) (zhen2024diabeticketoacidosisin pages 1-3) - “BKT (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency is a rare metabolic disorder that affects the metabolism of ketone bodies and catabolism of amino acid isoleucine.” (Patra et al., 2023; https://doi.org/10.25259/jped_9_2023; published September 2023) (patra2023ararecase pages 2-3)

1.2 Core biochemical role of ACAT1/T2 (current understanding) ACAT1/T2 catalyzes key thiolase steps at the interface of: - Ketone body handling: it “synthesizes acetoacetyl-CoA from acetyl-CoA in the liver (ketogenesis) and catalyzes acetoacetyl-CoA to acetyl-CoAs in the last step of ketolysis in extrahepatic tissue.” (Patra et al., 2023) (patra2023ararecase pages 2-3) - Isoleucine catabolism: ACAT1/T2 is described as “the only known enzyme that catalyzes the last step in the isoleucine degradation,” cleaving 2‑methyl‑acetoacetyl‑CoA into propionyl‑CoA and acetyl‑CoA. (Patra et al., 2023) (patra2023ararecase pages 2-3)

A 2024 pathway diagram (Figure 1) in Zhen et al. visually places β‑ketothiolase action sites within both isoleucine catabolism and ketone metabolism and explicitly notes “The short red bar denotes the site of action of beta-ketothiolase.” (https://doi.org/10.1186/s40842-024-00174-9; June 2024) (zhen2024diabeticketoacidosisin media 3ab27e16)

Core pathophysiology (molecular and cellular mechanisms)

2.1 Primary pathophysiological mechanisms The primary pathophysiology arises from loss or reduction of mitochondrial ACAT1/T2 activity, which produces: 1) Impaired terminal step of isoleucine catabolism → accumulation of upstream reactive/acidic intermediates. (patra2023ararecase pages 2-3, zhen2024diabeticketoacidosisin media 3ab27e16) 2) Impaired ketolysis (extrahepatic utilization of ketone bodies) and altered ketone handling → propensity to ketosis/ketoacidosis, especially under catabolic stress. (patra2023ararecase pages 2-3, zhen2024diabeticketoacidosisin pages 1-3)

Clinically, BKD “most commonly manifests as recurrent ketoacidosis episodes” with episodes “usually triggered by infection, prolonged fasting, or consumption of a ketogenic diet.” (Zhen et al., 2024; June 2024) (zhen2024diabeticketoacidosisin pages 1-3)

2.2 Dysregulated molecular pathways Based on clinical-biochemical evidence, the dysregulated pathways include: - Isoleucine degradation (branched-chain amino acid catabolic pathway segment specific to isoleucine) with block at 2‑methyl‑acetoacetyl‑CoA cleavage by ACAT1/T2. (patra2023ararecase pages 2-3, zhen2024diabeticketoacidosisin media 3ab27e16) - Ketone body metabolism including the reversible acetoacetyl‑CoA ↔ acetyl‑CoA step and ketolysis in extrahepatic tissues. (patra2023ararecase pages 2-3, zhen2024diabeticketoacidosisin media 3ab27e16)

2.3 Cellular processes affected At the cellular level, the principal affected processes are mitochondrial intermediary metabolism and redox/energy homeostasis during fasting or illness, when reliance on ketone body production/utilization and amino-acid-derived acetyl‑CoA flux increases. This is reflected clinically as episodic metabolic decompensation with high anion gap metabolic acidosis and ketosis/ketoacidosis. (zhen2024diabeticketoacidosisin pages 1-3, patra2023ararecase pages 2-3)

Key molecular players

3.1 Genes/Proteins (HGNC) - ACAT1 (acetyl‑CoA acetyltransferase 1; mitochondrial acetoacetyl‑CoA thiolase/T2/β‑ketothiolase) is the causal gene. (zhen2024diabeticketoacidosisin pages 1-3, patra2023ararecase pages 2-3)

Genotype–phenotype considerations supported by recent clinical series: residual T2 function is associated with milder/less distinctive biochemical abnormalities, whereas loss-of-function genotypes more often show “characteristic” organic acid/acylcarnitine abnormalities. (Anh et al., 2023; https://doi.org/10.52852/tcncyh.v171i10.2016; published Dec 2023) (anh2023đặcđiểmhóa pages 6-8)

3.2 Chemical entities / metabolites (CHEBI-oriented list) Characteristic metabolites (used diagnostically and mechanistically linked to pathway blockade): Urine organic acids: - 2‑methyl‑3‑hydroxybutyrate (2M3HB) (zhen2024diabeticketoacidosisin pages 1-3, anh2023đặcđiểmhóa pages 6-8) - 2‑methylacetoacetate (2MAA) (zhen2024diabeticketoacidosisin pages 1-3, anh2023đặcđiểmhóa pages 6-8) - Tiglylglycine (TIG) (zhen2024diabeticketoacidosisin pages 1-3, anh2023đặcđiểmhóa pages 6-8) Blood acylcarnitines: - Tiglylcarnitine (C5:1) and 2‑methyl‑3‑hydroxybutyryl‑carnitine (often aligned with C5:OH patterns in screening contexts) (zhen2024diabeticketoacidosisin pages 1-3, anh2023đặcđiểmhóa pages 8-8) Additional crisis-associated ketone-related molecules: - Acetoacetate and β‑hydroxybutyrate are reported among urinary elevations in crisis contexts. (patra2023ararecase pages 2-3)

Stability/measurement caveat (important for interpreting biochemical data): 2MAA can be missed because “2MAA is unstable on filter paper” (degrading to 2‑butanone), so dried urine spots may under-detect this metabolite. (Anh et al., 2023; Dec 2023) (anh2023đặcđiểmhóa pages 6-8)

3.3 Cell types (CL terms; inferred from clinical physiology) Direct cell-type-specific mechanistic studies were not available in the retrieved 2023–2024 BKD-focused texts. However, clinical physiology and the cited mechanistic hypotheses indicate particular relevance of: - Hepatocytes (liver ketogenesis context) and extrahepatic oxidative tissues that perform ketolysis. (patra2023ararecase pages 2-3) - Pancreatic endocrine cells (β-cells) are implicated indirectly through observed dysglycemia/hyperglycemia in decompensations and hypothesized effects of organic acid accumulation on pancreatic function. (zhen2024diabeticketoacidosisin pages 3-5)

3.4 Anatomical locations (UBERON terms) - Liver: implicated through ketogenesis (“in the liver (ketogenesis)”). (patra2023ararecase pages 2-3) - Extrahepatic tissues: ketolysis impairment occurs “in extrahepatic tissue.” (patra2023ararecase pages 2-3) - Pancreas: hypothesized vulnerability—Zhen et al. cite a postulate that “accumulation of organic acids in the pancreas may predispose to diabetes by impairing the structure and normal functionality of the pancreas.” (Zhen et al., 2024; June 2024) (zhen2024diabeticketoacidosisin pages 3-5)

Biological processes (GO annotation candidates) The following GO biological process concepts are supported by evidence from the retrieved sources:
Branched-chain amino acid catabolic process / isoleucine catabolic process (pathway block at 2‑methyl‑acetoacetyl‑CoA processing) (patra2023ararecase pages 2-3, zhen2024diabeticketoacidosisin media 3ab27e16)
Ketone body metabolic process (ketogenesis and ketolysis-related steps; recurrent ketoacidosis phenotype) (patra2023ararecase pages 2-3, zhen2024diabeticketoacidosisin pages 1-3)
Response to starvation/fasting (clinical triggers: prolonged fasting; crisis prevention includes fasting avoidance) (zhen2024diabeticketoacidosisin pages 1-3, patra2023ararecase pages 1-2)
Organic acid metabolic process / cellular acid-base homeostasis (clinical biochemical phenotype: high anion gap metabolic acidosis) (patra2023ararecase pages 2-3, patra2023ararecase pages 1-2)
Cellular components (GO cellular component candidates)
Mitochondrion (mitochondrial enzyme; explicitly described as “mitochondrial acetoacetyl‑CoA thiolase”) (patra2023ararecase pages 2-3)
Mitochondrial matrix (not explicitly quoted in the BKD-specific recent papers retrieved; however, the enzyme is consistently described as mitochondrial, and related mitochondrial metabolic context is shown in pathway diagrams) (patra2023ararecase pages 2-3, zhen2024diabeticketoacidosisin media 3ab27e16)
Disease progression model (trigger → molecular events → clinical crisis)

6.1 Triggering conditions Acute crises are commonly triggered by catabolic stressors: infection, prolonged fasting, or ketogenic diets. (Zhen et al., 2024; June 2024) (zhen2024diabeticketoacidosisin pages 1-3)

6.2 Sequence of events (mechanistic-to-clinical) 1) Trigger increases reliance on ketone body flux and amino acid catabolism. 2) ACAT1/T2 functional block causes accumulation of characteristic isoleucine-catabolic/ketone-related organic acids (2M3HB, TIG, 2MAA) and related acylcarnitines. (zhen2024diabeticketoacidosisin pages 1-3, zhen2024diabeticketoacidosisin media 3ab27e16) 3) Accumulated organic acids contribute to high anion gap metabolic acidosis with ketosis/ketoacidosis and may be associated with fluctuating glucose (hypo-/hyperglycemia). (patra2023ararecase pages 2-3, patra2023ararecase pages 1-2) 4) Clinical decompensation presents as episodic ketoacidosis, often in infancy/early childhood, with intervals of relative wellness; episodes tend to reduce in frequency with age and are reported as rare after age 10 in classic descriptions. (zhen2024diabeticketoacidosisin pages 1-3, anh2023đặcđiểmhóa pages 8-8)

6.3 Stages/phases - Intercritical/asymptomatic phase: may have normal metabolic testing; even individuals with null mutations can show normal urine organic acids and blood acylcarnitines when clinically well, and variants with residual function may be difficult to detect even during crisis. (zhen2024diabeticketoacidosisin pages 1-3) - Acute decompensation phase: ketoacidosis episodes with characteristic metabolite patterns, but with documented variability in marker presence/intensity across patients. (anh2023đặcđiểmhóa pages 6-8, anh2023đặcđiểmhóa pages 8-8)

Phenotypic manifestations and mechanistic links

7.1 Core clinical phenotypes (HP-oriented) - Episodic ketoacidosis / acute metabolic decompensation: “recurrent episodes of ketoacidosis” (Zhen et al., 2024) and “episodes of acute ketoacidosis” with well intervals (Anh et al., 2023). (zhen2024diabeticketoacidosisin pages 1-3, anh2023đặcđiểmhóa pages 8-8) - High anion gap metabolic acidosis, potentially severe (e.g., pH 6.99 in an infant case). (patra2023ararecase pages 2-3) - Seizures, coma, shock may occur in severe pediatric presentations, consistent with metabolic encephalopathy/critical illness physiology. (patra2023ararecase pages 1-2) - Glucose dysregulation: episodes may mimic diabetic ketoacidosis with hyperglycemia; Zhen et al. report the first adult case of diabetes presenting with DKA in BKD and emphasize HbA1c evaluation for persistent dysglycemia. (zhen2024diabeticketoacidosisin pages 1-3)

7.2 Diagnostic pitfalls as phenotypic modifiers - Dipstick ketone testing may be negative early in presentation despite severe acidosis; later ketonuria can appear, creating diagnostic confusion with diabetic ketoacidosis. (patra2023ararecase pages 1-2) - Biomarker sensitivity limitations: MS/MS blood acylcarnitine screening is not 100% sensitive, and the full urine organic acid “triad” may be absent; this may delay diagnosis and affect outcomes. (anh2023đặcđiểmhóa pages 8-8, anh2023đặcđiểmhóa pages 6-8)

Recent developments and latest research (2023–2024)

8.1 Adult presentations and dysglycemia: expanding phenotype spectrum (2024) Zhen et al. (June 2024) report the first described adult case of diabetes presenting as DKA in BKD and propose practice changes: “importance of checking HbA1c in people with BKD and hyperglycemia” to detect coexisting diabetes. (https://doi.org/10.1186/s40842-024-00174-9; June 2024) (zhen2024diabeticketoacidosisin pages 1-3)

Mechanistic hypothesis raised: organic acids may accumulate and potentially impair pancreatic structure/function (“postulated … accumulation of organic acids in the pancreas may predispose to diabetes”). (zhen2024diabeticketoacidosisin pages 3-5)

8.2 Newborn screening (NBS) epidemiology and BKD incidence estimates (2024) A large MS/MS newborn screening cohort (Huaihua, China; 206,977 newborns screened 2015–2021) reported: - 5,578 initial positives (2.69%), 4,085 recalls (73.23% of positives), 297 referred for diagnostic testing, and 69 confirmed IEM cases (overall incidence ~1:3,000). (Frontiers in Genetics; https://doi.org/10.3389/fgene.2024.1387423; May 2024) (xiao2024206977newbornscreening pages 5-7) - Within FAODs, beta‑ketothiolase deficiency incidence was reported as 1:32,237, observed only in the Miao ethnic subgroup in that cohort. (xiao2024206977newbornscreening pages 5-7) These are actionable statistics for population-level planning and for assessing inclusion in expanded NBS panels. (xiao2024206977newbornscreening pages 5-7)

8.3 Implementing genetic second-tier testing to reduce NBS false positives (2024) A Hong Kong program implemented an amplicon-based NGS second-tier panel including BKD among six IEMs (screening period 1 Sept 2021–31 Aug 2022). Key operational outcomes: - Second-tier genetic testing was performed for 1.8% of 22,883 NBS samples. - The overall false-positive rate across those six conditions after NGS second-tier testing was 0.017%, with “no false negatives reported.” (International Journal of Neonatal Screening; https://doi.org/10.3390/ijns10010019; published 5 March 2024) (chan2024harnessingnextgenerationsequencing pages 1-2) While BKD-specific yields were not detailed in the excerpt, this represents a real-world implementation approach relevant to improving BKD detection while minimizing unnecessary recalls. (chan2024harnessingnextgenerationsequencing pages 1-2)

Current applications and real-world implementations

9.1 Diagnostics in clinical practice Evidence-supported diagnostic workflow: - During acute episodes: urine organic acids (GC/MS) plus blood acylcarnitines (MS/MS) can be “confirmatory” in pediatric presentations and are emphasized as hallmark tools. (patra2023ararecase pages 1-2) - Confirmatory testing: ACAT1 gene sequencing and/or enzyme activity assays in patient cells. (zhen2024diabeticketoacidosisin pages 1-3, patra2023ararecase pages 2-3)

Real-world diagnostic performance limitations: - Vietnamese case-series data show biochemical screening variability: in 23 symptomatic patients screened by blood acylcarnitines, 2/23 had neither C5:1 nor C5:OH elevation, indicating incomplete sensitivity. (Anh et al., Dec 2023) (anh2023đặcđiểmhóa pages 8-8) - Urine organic acids also vary: 2M3HB elevated in 23/26, TIG 13/26, and 2MAA 6/26, with the classic triad not universal. (anh2023đặcđiểmhóa pages 6-8)

9.2 Acute management (“sick-day” and crisis treatment) Recent expert recommendations converge on: - Acute crisis: intravenous dextrose “to suppress ketogenesis (even if euglycemic),” plus fluids/electrolytes/supportive care. (Zhen et al., June 2024) (zhen2024diabeticketoacidosisin pages 1-3) - Pediatric severe crises may require insulin infusion (for DKA-like states), bicarbonate correction, and intensive supportive care, including ventilation/dialysis when required. (Patra et al., 2023) (patra2023ararecase pages 2-3)

9.3 Chronic management and prevention - Avoid fasting; ensure regular carbohydrate intake; avoid ketogenic diets. (zhen2024diabeticketoacidosisin pages 1-3) - Consider carnitine supplementation if deficient. (zhen2024diabeticketoacidosisin pages 1-3) - Dietary approach in one recent pediatric report includes “mild protein restriction” with avoidance of excess fat intake and sick-day glucose/electrolyte solutions. (patra2023ararecase pages 2-3)

Expert opinions and analysis (authoritative sources, 2023–2024)

10.1 Diagnostic caution: BKD can mimic DKA Patra et al. (2023) emphasize that BKD can clinically mimic diabetic ketoacidosis and that atypical features (e.g., persistent acidosis, fluctuating glucose, normal HbA1c/C-peptide) should prompt evaluation for inborn errors of metabolism, to prevent “death or permanent neurological complications.” (patra2023ararecase pages 2-3)

10.2 Surveillance for persistent dysglycemia in BKD Zhen et al. (2024) highlight the practice implication that HbA1c should be checked in BKD patients with hyperglycemia to uncover coexisting diabetes and prevent complications. (zhen2024diabeticketoacidosisin pages 1-3)

10.3 Screening strategy interpretation Anh et al. (2023) explicitly state MS/MS acylcarnitine screening “không đảm bảo độ nhạy 100%” (does not ensure 100% sensitivity), and recommend urine organic acid analysis to confirm diagnosis even when screening is normal but clinical suspicion persists. (anh2023đặcđiểmhóa pages 6-8)

Relevant statistics and data (recent studies)

11.1 Biomarker frequencies in a 2017–2023 clinical cohort (Vietnam; published Dec 2023) In 26 patients with BKD, urine GC/MS showed: - 2M3HB elevated: 23/26 - TIG elevated: 13/26 - 2MAA elevated: 6/26 (Anh et al., 2023) (anh2023đặcđiểmhóa pages 6-8)

In 23 patients screened by blood acylcarnitines (MS/MS): - C5:1 elevated: 19/23 - C5:OH elevated: 20/23 - Both elevated: 18/23 - Neither elevated: 2/23 (Anh et al., 2023) (anh2023đặcđiểmhóa pages 8-8)

11.2 NBS incidence estimate in a large Chinese cohort (published May 2024) In 206,977 newborns screened by MS/MS: - BKD incidence was reported as 1:32,237 in this cohort (detected only in Miao subgroup). (xiao2024206977newbornscreening pages 5-7)

11.3 NGS second-tier testing operational metrics (published March 2024) In 22,883 screened newborns, NGS second-tier testing applied to 1.8% of samples yielded an overall false-positive rate of 0.017% across six IEMs and “no false negatives reported.” (chan2024harnessingnextgenerationsequencing pages 1-2)

Knowledge-base-style annotations (ontology-oriented)

12.1 Pathophysiology summary (knowledge-base narrative) Biallelic ACAT1 pathogenic variants reduce mitochondrial acetoacetyl‑CoA thiolase (T2/β‑ketothiolase) activity. This blocks the terminal step of isoleucine degradation (2‑methyl‑acetoacetyl‑CoA → propionyl‑CoA + acetyl‑CoA) and disrupts ketone body metabolism, including ketolysis in extrahepatic tissues. Under catabolic triggers (infection, fasting, ketogenic diets), toxic organic acids and ketone-related intermediates accumulate, producing episodic high anion gap metabolic acidosis with ketosis/ketoacidosis and variable glycemia; between crises, biochemical profiles may normalize, complicating detection. (patra2023ararecase pages 2-3, zhen2024diabeticketoacidosisin pages 1-3)

12.2 Gene/protein annotations - ACAT1 (HGNC: acetyl‑CoA acetyltransferase 1) — causal gene; encodes mitochondrial acetoacetyl‑CoA thiolase (T2). (zhen2024diabeticketoacidosisin pages 1-3, patra2023ararecase pages 2-3)

12.3 GO terms (candidate list; evidence-backed) - Ketone body metabolic process (supported by explicit ketogenesis/ketolysis role and ketoacidosis phenotype) (patra2023ararecase pages 2-3) - Isoleucine catabolic process / branched-chain amino acid catabolic process (supported by explicit statement of terminal isoleucine degradation step) (patra2023ararecase pages 2-3) - Mitochondrial metabolic process (enzyme is mitochondrial; crisis pathophysiology is mitochondrial intermediary metabolism under catabolic stress) (patra2023ararecase pages 2-3)

12.4 Cellular components - Mitochondrion (explicitly “mitochondrial acetoacetyl‑CoA thiolase”) (patra2023ararecase pages 2-3)

12.5 Cell types (candidate list; inferential) - Hepatocyte (ketogenesis context in liver) (patra2023ararecase pages 2-3) - Ketolytic extrahepatic oxidative cell types (e.g., muscle cells, renal cortex) — not directly specified in retrieved texts; supported only at the level of “extrahepatic tissue” ketolysis wording. (patra2023ararecase pages 2-3) - Pancreatic endocrine cell (β-cell) — implicated by dysglycemia observations/hypothesis but not directly studied in retrieved evidence. (zhen2024diabeticketoacidosisin pages 3-5)

12.6 Anatomical locations - Liver (ketogenesis role) (patra2023ararecase pages 2-3) - Extrahepatic tissues (ketolysis role) (patra2023ararecase pages 2-3) - Pancreas (hypothesized organic-acid accumulation affecting function; adult dysglycemia context) (zhen2024diabeticketoacidosisin pages 3-5)

12.7 Chemical entities (CHEBI; key biomarkers) - Tiglylglycine (TIG) (zhen2024diabeticketoacidosisin pages 1-3) - 2‑methyl‑3‑hydroxybutyrate (2M3HB) (zhen2024diabeticketoacidosisin pages 1-3) - 2‑methylacetoacetate (2MAA) (zhen2024diabeticketoacidosisin pages 1-3) - Tiglylcarnitine (C5:1) and 2‑methyl‑3‑hydroxybutyryl‑carnitine / C5:OH pattern (zhen2024diabeticketoacidosisin pages 1-3, anh2023đặcđiểmhóa pages 8-8)

Evidence items (PMID notes) The retrieved evidence set contained DOIs and URLs, but PMIDs were not provided in the extracted text segments. Key 2023–2024 sources used here:
Zhen et al., Clinical Diabetes and Endocrinology (June 2024). DOI: 10.1186/s40842-024-00174-9. URL: https://doi.org/10.1186/s40842-024-00174-9 (zhen2024diabeticketoacidosisin pages 1-3)
Patra et al., Journal of Pediatric Endocrinology and Diabetes (Sept 2023). DOI: 10.25259/jped_9_2023. URL: https://doi.org/10.25259/jped_9_2023 (patra2023ararecase pages 1-2)
Anh et al., Tạp chí Nghiên cứu Y học (Dec 2023). DOI: 10.52852/tcncyh.v171i10.2016. URL: https://doi.org/10.52852/tcncyh.v171i10.2016 (anh2023đặcđiểmhóa pages 6-8)
Xiao et al., Frontiers in Genetics (May 2024). DOI: 10.3389/fgene.2024.1387423. URL: https://doi.org/10.3389/fgene.2024.1387423 (xiao2024206977newbornscreening pages 5-7)
Chan et al., International Journal of Neonatal Screening (published 5 March 2024). DOI: 10.3390/ijns10010019. URL: https://doi.org/10.3390/ijns10010019 (chan2024harnessingnextgenerationsequencing pages 1-2)

Limitations of this report - MONDO ID, OMIM/Orphanet IDs, and PMIDs were not retrievable from the available tool outputs in this run; the report therefore relies on DOI-based identification for the 2023–2024 sources. - Cell-type-resolved molecular mechanisms (e.g., direct mitochondrial stress signaling, ROS, or organ-specific pathology beyond metabolic decompensation physiology) were not present in the retrieved 2023–2024 BKD-focused evidence; additional basic-science literature would be needed for deeper cellular mechanism granularity.

References

(zhen2024diabeticketoacidosisin pages 1-3): Xi May Zhen, Stephen M. Twigg, Ted Wu, Eddy Tabet, Margaret J. McGill, Maria Constantino, Amali Mallawaarachchi, Connie Luo, Senthil Thillainadesan, Yusof Rahman, and Jencia Wong. Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (bkd) involving a novel acat1 variant : first report of established diabetes in bkd and a review of the literature. Clinical Diabetes and Endocrinology, Jun 2024. URL: https://doi.org/10.1186/s40842-024-00174-9, doi:10.1186/s40842-024-00174-9. This article has 5 citations and is from a peer-reviewed journal.
(patra2023ararecase pages 1-2): Bijoy Patra, Shamitha Rangrajan, Sayeeksha Kotekar, and Vishal Malhotra. A rare case of β-ketothiolase deficiency presenting as mimicker of diabetic ketoacidosis. Journal of Pediatric Endocrinology and Diabetes, 3:78-81, Sep 2023. URL: https://doi.org/10.25259/jped_9_2023, doi:10.25259/jped_9_2023. This article has 5 citations.
(patra2023ararecase pages 2-3): Bijoy Patra, Shamitha Rangrajan, Sayeeksha Kotekar, and Vishal Malhotra. A rare case of β-ketothiolase deficiency presenting as mimicker of diabetic ketoacidosis. Journal of Pediatric Endocrinology and Diabetes, 3:78-81, Sep 2023. URL: https://doi.org/10.25259/jped_9_2023, doi:10.25259/jped_9_2023. This article has 5 citations.
(zhen2024diabeticketoacidosisin media 3ab27e16): Xi May Zhen, Stephen M. Twigg, Ted Wu, Eddy Tabet, Margaret J. McGill, Maria Constantino, Amali Mallawaarachchi, Connie Luo, Senthil Thillainadesan, Yusof Rahman, and Jencia Wong. Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (bkd) involving a novel acat1 variant : first report of established diabetes in bkd and a review of the literature. Clinical Diabetes and Endocrinology, Jun 2024. URL: https://doi.org/10.1186/s40842-024-00174-9, doi:10.1186/s40842-024-00174-9. This article has 5 citations and is from a peer-reviewed journal.
(anh2023đặcđiểmhóa pages 6-8): Mai Quỳnh Anh, Trần Thị Thu Mai, Nguyễn Thị Phương Thùy, and Nguyễn Thị Kim Đông. Đặc điểm hóa sinh của bệnh nhân thiếu beta-ketothiolase. Tạp chí Nghiên cứu Y học, 171:150-157, Dec 2023. URL: https://doi.org/10.52852/tcncyh.v171i10.2016, doi:10.52852/tcncyh.v171i10.2016. This article has 0 citations.
(anh2023đặcđiểmhóa pages 8-8): Mai Quỳnh Anh, Trần Thị Thu Mai, Nguyễn Thị Phương Thùy, and Nguyễn Thị Kim Đông. Đặc điểm hóa sinh của bệnh nhân thiếu beta-ketothiolase. Tạp chí Nghiên cứu Y học, 171:150-157, Dec 2023. URL: https://doi.org/10.52852/tcncyh.v171i10.2016, doi:10.52852/tcncyh.v171i10.2016. This article has 0 citations.
(zhen2024diabeticketoacidosisin pages 3-5): Xi May Zhen, Stephen M. Twigg, Ted Wu, Eddy Tabet, Margaret J. McGill, Maria Constantino, Amali Mallawaarachchi, Connie Luo, Senthil Thillainadesan, Yusof Rahman, and Jencia Wong. Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (bkd) involving a novel acat1 variant : first report of established diabetes in bkd and a review of the literature. Clinical Diabetes and Endocrinology, Jun 2024. URL: https://doi.org/10.1186/s40842-024-00174-9, doi:10.1186/s40842-024-00174-9. This article has 5 citations and is from a peer-reviewed journal.
(xiao2024206977newbornscreening pages 5-7): Gang Xiao, Zonghui Feng, Chaochao Xu, Xuzhen Huang, Maosheng Chen, Min Zhao, Yanbin Li, Yang Gao, Shulin Wu, Yuyan Shen, and Ying Peng. 206,977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in huaihua, china. Frontiers in Genetics, May 2024. URL: https://doi.org/10.3389/fgene.2024.1387423, doi:10.3389/fgene.2024.1387423. This article has 1 citations and is from a peer-reviewed journal.
(chan2024harnessingnextgenerationsequencing pages 1-2): Toby Chun Hei Chan, Chloe Miu Mak, Matthew Chun Wing Yeung, Eric Chun-Yiu Law, Jana Cheung, Tsz Ki Wong, Vincent Wing-Sang Cheng, Jacky Kwan Ho Lee, Jimmy Chi Lap Wong, Cheuk Wing Fung, Kiran Moti Belaramani, Anne Mei Kwun Kwok, and Kwok Yeung Tsang. Harnessing next-generation sequencing as a timely and accurate second-tier screening test for newborn screening of inborn errors of metabolism. International Journal of Neonatal Screening, 10:19, Mar 2024. URL: https://doi.org/10.3390/ijns10010019, doi:10.3390/ijns10010019. This article has 8 citations.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 21 citations 2026-05-06T00:20:22.120831+00:00

1. Disease Information

Overview

Beta-ketothiolase deficiency (BKTD) is a rare inherited metabolic disorder affecting two interconnected metabolic pathways: the catabolism of the branched-chain amino acid isoleucine and the utilization of ketone bodies. The disease results from deficiency of the mitochondrial enzyme acetoacetyl-CoA thiolase (T2), which catalyzes the thiolytic cleavage of 2-methylacetoacetyl-CoA (in isoleucine degradation) and acetoacetyl-CoA (in ketolysis). The hallmark of the disease is episodic ketoacidotic crisis, often precipitated by intercurrent illness, fasting, or metabolic stress (PMID: 32345314).

Key Identifiers

Database	Identifier
MONDO	MONDO:0008760
OMIM (disease)	203750
OMIM (gene)	607809
Orphanet	ORPHA:134
ICD-10	E71.1 (Other disorders of branched-chain amino-acid metabolism)
ICD-11	5C50.0Y (Other specified disorders of branched-chain amino acid metabolism)
MeSH	C536438 (2-alpha-methyl-3-alpha-hydroxybutyric aciduria)
Gene (HGNC)	HGNC:93 (ACAT1)

Synonyms and Alternative Names

Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency
2-Methylacetoacetyl-CoA thiolase (MAT) deficiency
Alpha-methylacetoaceticaciduria
3-Oxothiolase deficiency
2-Methyl-3-hydroxybutyric acidemia
3-Ketothiolase deficiency
T2 deficiency
ACAT1 deficiency

Information Sources

The information in this report is derived from aggregated disease-level resources including OMIM, Orphanet, ClinVar, and GeneReviews, as well as primary literature comprising case reports, case series, multicenter cohort studies, and systematic literature reviews. The largest aggregated dataset comes from a systematic literature review of 244 patients (PMID: 32345314).

2. Etiology

Disease Causal Factors

BKTD is exclusively genetic in origin, caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in the ACAT1 gene. There are no known environmental, infectious, or non-genetic causes. The disease follows autosomal recessive inheritance.

Risk Factors

Genetic Risk Factors: - Biallelic pathogenic variants in ACAT1 are the sole causal factor - Consanguinity significantly increases risk, as demonstrated in multiple studies. All 12 patients from Palestine were offspring of consanguineous marriages (PMID: 40598206) - Founder mutations have been identified in certain populations (e.g., a founder mutation was identified in six Palestinian patients from three families) (PMID: 40598206) - Carrier status: being heterozygous for a pathogenic ACAT1 variant (carriers are clinically unaffected due to sufficient residual enzyme activity)

Environmental Risk Factors (triggers for metabolic crises, not disease causation): - Intercurrent infections (gastroenteritis, upper respiratory infections) - Prolonged fasting - High-protein or high-fat dietary intake - Febrile illness - Vaccination (documented case of ketoacidotic crisis following Japanese encephalitis vaccination) (PMID: 33708533) - Metabolic stress of any kind

Protective Factors

Genetic Protective Factors: - "Mild" mutations that retain some residual T2 enzyme activity may confer relative protection against severe metabolic crises, though they can lead to diagnostic challenges (PMID: 15128923; PMID: 23430882) - Temperature-sensitive mutations (e.g., E252del) show higher protein stability at lower temperatures, potentially modulating disease severity (PMID: 17236799)

Environmental Protective Factors: - Avoidance of fasting and catabolic states - Prompt treatment of intercurrent infections - Protein-restricted diet (particularly limiting isoleucine intake) - L-carnitine supplementation - Established sick-day management protocols - Early diagnosis through newborn screening

Gene-Environment Interactions

The clinical expression of BKTD represents a classic gene-environment interaction: while the genetic defect is constant, clinical crises are invariably triggered by environmental/physiological stressors. Patients with identical genotypes may have vastly different clinical courses depending on exposure to catabolic triggers and the timing/quality of medical intervention. As noted by Fukao et al., "the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype" (PMID: 31268215), suggesting that environmental factors and modifier genes play substantial roles in determining clinical outcomes.

3. Phenotypes

Acute Metabolic Crises (Episodic Ketoacidosis)

Phenotype type: Clinical sign / laboratory abnormality
HPO terms: HP:0001942 (Metabolic acidosis), HP:0001985 (Ketoacidosis), HP:0001944 (Dehydration)
Age of onset: Median 12 months (range: 2 days to 8 years); >82% present in first 2 years of life; neonatal onset is rare (3.4%)
Severity: Moderate to severe; can be life-threatening if untreated
Progression: Episodic; patients are typically asymptomatic between episodes
Frequency: 89.6% of patients experience at least one acute metabolic decompensation (PMID: 32345314)
Quality of life impact: Severe during acute episodes; requires emergency medical care; between episodes, patients may be entirely normal

Neurological Manifestations

Phenotype type: Clinical signs / symptoms
HPO terms: HP:0001257 (Spasticity), HP:0001332 (Dystonia), HP:0002071 (Extrapyramidal dyskinesia), HP:0002134 (Abnormality of the basal ganglia), HP:0001250 (Seizures), HP:0001249 (Intellectual disability), HP:0001263 (Global developmental delay)
Age of onset: Typically following severe metabolic crisis in childhood
Severity: Variable; ranges from absent (77% of patients normal) to severe (7% major mental disability)
Progression: Neurological damage from metabolic stroke is typically non-progressive after the acute event; may improve partially with rehabilitation
Frequency: 23% develop some degree of neurological impairment; ~7% develop major mental disability (PMID: 32345314)
Specific findings:
Bilateral basal ganglia involvement (pallidal stroke) (PMID: 28726122)
Extrapyramidal dyskinesia and spasticity
Cerebellar abnormalities (PMID: 41180774)
Loss of consciousness during acute crises
Generalized muscle rigidity and limb spasticity

Metabolic/Laboratory Abnormalities

Phenotype type: Laboratory abnormalities
HPO terms: HP:6000603 (Elevated urinary tiglylglycine), HP:0001987 (Hyperammonemia), HP:0003128 (Elevated 2-methylacetoacetate), HP:0003231 (Elevated 2-methyl-3-hydroxybutyrate)
Characteristics:
Elevated urinary 2-methyl-3-hydroxybutyrate and tiglylglycine (present in virtually all patients)
Elevated urinary 2-methylacetoacetate (may be absent due to instability of this beta-ketoacid) (PMID: 20157782)
Elevated blood acylcarnitines: C4OH (3-hydroxybutyrylcarnitine), C5:1 (tiglylcarnitine), C5-OH (3-hydroxyisovalerylcarnitine)
Hyperammonemia during crises
Severe metabolic acidosis during crises
Note: Hypoglycemia is notably absent in BKTD, distinguishing it from many other organic acidemias (PMID: 7726385)

Gastrointestinal Symptoms

Phenotype type: Symptoms
HPO terms: HP:0002013 (Vomiting), HP:0002014 (Diarrhea)
Characteristics: Vomiting and poor feeding often precede or accompany metabolic crises
Frequency: Common during acute episodes

Respiratory Manifestations

Phenotype type: Clinical signs
HPO terms: HP:0002883 (Tachypnea / Kussmaul breathing)
Characteristics: Deep, rapid breathing (Kussmaul respiration) as compensation for metabolic acidosis during crises

Renal Manifestations

Phenotype type: Laboratory abnormality
HPO terms: HP:0001919 (Acute kidney injury)
Characteristics: Acute kidney injury can occur during severe metabolic crises (PMID: 41180774)

Cardiac Findings

Phenotype type: Pathological finding
HPO terms: HP:0001714 (Cardiac hypertrophy)
Characteristics: Cardiac hypertrophy documented at autopsy in fatal cases (PMID: 8218125)

Neurodevelopmental Associations

Phenotype type: Behavioral changes
HPO terms: HP:0000729 (Autistic behavior), HP:0001249 (Intellectual disability), HP:0007018 (Attention deficit hyperactivity disorder)
Characteristics: BKTD has been identified in children with autism spectrum disorder (ASD), intellectual disability, and ADHD (PMID: 32880084)
Frequency: Rare; relationship to underlying metabolic defect versus acquired brain injury not fully delineated

4. Genetic/Molecular Information

Causal Gene

Feature	Detail
Gene symbol	ACAT1
HGNC ID	HGNC:93
OMIM (gene)	607809
Chromosomal location	11q22.3
Protein	Mitochondrial acetoacetyl-CoA thiolase (T2)
EC number	2.3.1.9
Protein structure	Homotetramer of 427 amino acid subunits
UniProt	P24752

Pathogenic Variants

Variant Spectrum: As of 2019, 105 ACAT1 variants have been reported in 149 T2-deficient patients (PMID: 31268215). The variant types include:

Variant Type	Characteristics
Missense	56 disease-associated missense variants mapped to T2 crystal structure; almost all affect residues that are completely or partially buried in the T2 structure
Splice-site/Intronic	More than one-third of identified mutations are intronic, expected to disturb splicing (PMID: 28689740)
Frameshift	Including insertions and deletions (e.g., c.52-53insC, c.83_84delAT, c.1016_1017del)
Nonsense	Premature stop codons leading to truncated, nonfunctional protein

ClinVar Data: - 288 pathogenic/likely pathogenic entries for ACAT1 - 853 total variant entries

Population Allele Frequencies (gnomAD constraint metrics): - pLI = 0.00001 (loss-of-function tolerated in heterozygotes, consistent with AR inheritance) - Observed/expected loss-of-function ratio (oe_lof) = 0.59 - Loss-of-function Z-score (lof_z) = 2.38

Notable Variants: - p.Cys126Ser and p.Tyr219His: Active-site variants that retain wild-type stability but are catalytically inactive (PMID: 31268215) - E252del: Temperature-sensitive Km mutant with twofold Km elevation for both CoA and acetoacetyl-CoA substrates (PMID: 17236799) - c.431A>C (H144P): Shared among Japanese patients with subtle biochemical profiles (PMID: 23430882) - p.A111P (c.331G>C): Novel likely pathogenic variant identified in Chinese patient (PMID: 38684297) - Founder mutations identified in Palestinian populations (PMID: 40598206)

Germline vs. Somatic Origin: All pathogenic ACAT1 variants in BKTD are germline. Somatic mutations are not relevant to this disease.

Functional Consequences: All pathogenic variants result in loss of function through various mechanisms: - Reduced protein folding efficiency/stability (most missense variants affecting buried residues) - Abolished catalytic activity (active-site variants) - Reduced substrate affinity (Km mutants) - Absent protein expression (frameshift, nonsense) - Aberrant splicing (intronic variants)

Genotype-Phenotype Correlation

A critical finding is the dissociation between genotype and clinical phenotype: "the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype. This could be related to variable remaining residual T2 activity in vivo and has important clinical implications concerning disease management and newborn screening" (PMID: 31268215). This has been independently confirmed: "no clear genotype-phenotype correlation could be found" (PMID: 28689740).

Patients with "mild" mutations retaining residual enzyme activity may present with subtle biochemical profiles that can be missed by some screening and diagnostic methods (PMID: 15128923; PMID: 23430882).

Modifier Genes

No specific modifier genes have been definitively identified for BKTD. However, the marked variability in clinical outcomes among patients with identical genotypes suggests the involvement of genetic modifiers, potentially including genes involved in: - Alternative ketone body metabolism pathways - Mitochondrial function - Stress response and metabolic compensation

Epigenetic Information

No specific epigenetic modifications have been reported for the ACAT1 gene in the context of BKTD. This represents a knowledge gap.

Chromosomal Abnormalities

BKTD is not associated with large-scale chromosomal abnormalities. The disease is exclusively caused by point mutations, small insertions/deletions, and splice-site variants within ACAT1.

5. Environmental Information

Environmental Factors

BKTD is a purely genetic disease; no environmental toxins, radiation, pollution, or occupational exposures contribute to its development. However, environmental stressors are the primary triggers for acute metabolic decompensation episodes.

Lifestyle Factors

While lifestyle factors do not cause BKTD, they are critical in disease management: - Diet: High-protein and high-fat diets increase the risk of metabolic crises - Fasting: Prolonged fasting is a major trigger for ketoacidotic episodes - Exercise: Excessive physical exertion may precipitate metabolic stress - Illness management: Prompt treatment of intercurrent infections is essential

Infectious Agents

No infectious agents cause BKTD, but infections are the most common trigger for metabolic crises. Gastroenteritis and upper respiratory tract infections are the most frequently reported precipitants (PMID: 40598206).

6. Mechanism / Pathophysiology

Molecular Pathways

The T2 enzyme (ACAT1) operates at the intersection of two critical metabolic pathways:

1. Isoleucine Catabolism Pathway:

Isoleucine → ... → 2-Methylacetoacetyl-CoA --[T2]--> Propionyl-CoA + Acetyl-CoA
                                ↑
                          BLOCKED IN BKTD

When T2 is deficient, 2-methylacetoacetyl-CoA accumulates and is converted to the characteristic metabolites 2-methylacetoacetate and 2-methyl-3-hydroxybutyrate. Tiglylglycine also accumulates from the upstream metabolite tiglyl-CoA.

2. Ketone Body Utilization (Ketolysis) Pathway:

Acetoacetate → Acetoacetyl-CoA --[T2]--> 2 Acetyl-CoA → TCA Cycle
                    ↑
              BLOCKED IN BKTD

Impaired ketolysis prevents extrahepatic tissues (brain, muscle, kidney) from effectively utilizing ketone bodies as an alternative fuel source during fasting or metabolic stress.

Relevant pathway identifiers: - KEGG: hsa00280 (Valine, leucine and isoleucine degradation) - KEGG: hsa00072 (Synthesis and degradation of ketone bodies) - Reactome: R-HSA-71032 (Branched-chain amino acid catabolism) - GO:0006552 (Leucine catabolic process — related) - GO:0046952 (Ketone body catabolic process)

Cellular Processes

Mitochondrial energy metabolism dysfunction: T2 deficiency impairs the ability of cells to utilize ketone bodies for energy, leading to energy failure in extrahepatic tissues during ketogenic stress
Metabolic acidosis: Accumulation of organic acids overwhelms buffering capacity
Toxic metabolite accumulation: 2-methylacetoacetate and related metabolites may have direct neurotoxic effects
GO terms: GO:0006635 (Fatty acid beta-oxidation), GO:0006094 (Gluconeogenesis — compensatory)

Protein Dysfunction

The T2 protein is a homotetramer. Pathogenic variants cause dysfunction through several mechanisms: 1. Protein misfolding/instability: Most missense variants affect buried residues, reducing folding efficiency and thermodynamic stability. Many show temperature-sensitive expression (PMID: 17236799) 2. Catalytic inactivation: Active-site variants (p.Cys126Ser, p.Tyr219His) fold normally but cannot catalyze the reaction 3. Substrate binding defects: Km mutants (e.g., E252del) have reduced affinity for substrates 4. Absent protein: Null mutations (frameshift, nonsense, severe splice-site) produce no detectable protein

Structural biology: - The human T2 crystal structure has been solved, enabling mapping of all 56 disease-associated missense variants (PMID: 31268215) - PDB entries available for human T2 homotetramer - UniProt: P24752

Metabolic Changes

Metabolite	Change	Pathway	CHEBI
2-Methylacetoacetate	Elevated	Isoleucine catabolism	CHEBI:17622
2-Methyl-3-hydroxybutyrate	Elevated	Isoleucine catabolism	CHEBI:19396
Tiglylglycine	Elevated	Isoleucine catabolism	CHEBI:71179
Acetoacetate	Elevated	Ketolysis	CHEBI:13705
3-Hydroxybutyrate	Elevated	Ketolysis	CHEBI:37054
C4OH (3-hydroxybutyrylcarnitine)	Elevated (blood)	Acylcarnitine profile	—
C5:1 (tiglylcarnitine)	Elevated (blood)	Acylcarnitine profile	—
C5-OH (3-hydroxyisovalerylcarnitine)	Elevated (blood)	Acylcarnitine profile	—

Notably, 2-methylacetoacetate is unstable and undergoes spontaneous decarboxylation to 2-butanone, making it difficult to detect and potentially absent in asymptomatic patients (PMID: 20157782).

Tissue Damage Mechanisms

Neuropathological findings from autopsy studies reveal: - Loss of neurons in putamen, caudate nucleus, and claustrum - Spongiosis and slight reactive astrocytosis - Damage to parasagittal areas of parietal and occipital cortex, including visual cortex - Demyelination

"Autopsy revealed cardiac hypertrophy and brain pathology in both children. The latter consisted of loss of neurons, spongiosis and slight reactive astrocytosis affecting parasagittal areas of the parietal and occipital cortex, visual cortex, putamen, caput nuclei caudati and claustrum" (PMID: 8218125).

The mechanism of brain injury likely involves: 1. Metabolic stroke: Acute energy failure in metabolically active brain regions (basal ganglia) during severe ketoacidosis (PMID: 28726122) 2. Toxic metabolite accumulation: Direct neurotoxicity of accumulated organic acids 3. Impaired ketone body utilization: Brain cannot use ketones as alternative fuel during metabolic stress

Causal Chain: From Genetic Defect to Clinical Manifestation

ACAT1 biallelic mutations
|
v
T2 enzyme deficiency/dysfunction
|
v
   +----------------+-------------------+
   |                |                   |
   v                v                   v
Impaired         Impaired           Metabolite
isoleucine       ketolysis          accumulation
catabolism                          (2-MA, 2-M3HB,
   |                |               tiglylglycine)
   |          Energy failure             |
   |          in extrahepatic       Direct tissue
   |          tissues (brain)       toxicity
   |                |                   |
   +----------------+-------------------+
    |
    v
   CATABOLIC TRIGGER
(infection, fasting, fever)
    |
    v
 Acute ketoacidotic crisis
    |
 +---------+-----------+
 |                     |
 v                     v
  Metabolic acidosis    Neurological injury
  Hyperammonemia        (basal ganglia,
  Dehydration            cortex)
 |                     |
    If untreated:        If severe:
    Multi-organ failure  Permanent neurological
    Death (rare)         sequelae (dystonia,
         spasticity, ID)

Biochemical Abnormalities

Enzyme deficiency: Mitochondrial acetoacetyl-CoA thiolase (T2, EC 2.3.1.9) — reduced or absent activity
Dual pathway involvement: Unlike many IEMs that affect a single pathway, BKTD disrupts both isoleucine catabolism and ketolysis simultaneously, creating a "one disease — two pathways" paradigm (PMID: 32345314)

Molecular Profiling

Metabolomics signatures: Well-characterized: elevated 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, tiglylglycine (urine); elevated C4OH, C5:1, C5-OH (blood acylcarnitines)
Transcriptomics/proteomics: No disease-specific transcriptomic or proteomic studies published for BKTD
Single-cell analysis, spatial transcriptomics, multi-omics integration: Not available for this rare disease

7. Anatomical Structures Affected

Organ Level

Primary organs: - Brain (UBERON:0000955) — most critically affected during acute crises; basal ganglia particularly vulnerable - Liver (UBERON:0002107) — site of ketogenesis; metabolic derangement during crises - Kidney (UBERON:0002113) — acute kidney injury during severe crises

Secondary organ involvement: - Heart (UBERON:0000948) — cardiac hypertrophy documented at autopsy (PMID: 8218125) - Skeletal muscle (UBERON:0001134) — impaired ketone body utilization for energy

Body systems involved: - Central nervous system (primary target of metabolic injury) - Metabolic/endocrine system - Renal system (during crises) - Cardiovascular system (in severe cases)

Tissue and Cell Level

Neurons (CL:0000540) — particularly in basal ganglia (putamen, caudate) and cortex
Astrocytes (CL:0000127) — reactive astrocytosis documented at autopsy
Hepatocytes (CL:0000182) — high expression of T2 enzyme; site of metabolic perturbation
Renal tubular cells (CL:1000507) — affected in acute kidney injury
Cardiomyocytes (CL:0000746) — cardiac hypertrophy at autopsy
Oligodendrocytes (CL:0000128) — demyelination observed in neuropathology

Subcellular Level

Mitochondria (GO:0005739) — T2 enzyme is localized in the mitochondrial matrix; this is the primary subcellular compartment affected
Mitochondrial matrix (GO:0005759) — specific location of T2 enzyme activity

Localization

Specific anatomical sites affected in brain: - Putamen (UBERON:0001874) - Caudate nucleus (UBERON:0001873) - Globus pallidus (UBERON:0001875) — site of "pallidal stroke" (PMID: 28726122) - Parietal cortex (UBERON:0001872) - Occipital cortex / visual cortex (UBERON:0002021) - Cerebellum (UBERON:0002037) — abnormalities documented (PMID: 41180774) - Claustrum (UBERON:0002023)

Lateralization: Bilateral involvement of basal ganglia is typical; lesions are generally symmetric.

8. Temporal Development

Onset

Typical age of onset: Median 12 months; range 2 days to 8 years
Age distribution: >82% present in first 2 years of life; neonatal presentation rare (3.4%); only 63% present clinically (remainder identified by NBS or family studies) (PMID: 32345314)
Onset pattern: Acute — sudden onset of ketoacidotic crisis, typically during or following an intercurrent illness

Progression

Disease stages: Not formally staged; classified as:
Pre-symptomatic (identified by NBS)
First metabolic crisis
Recurrent crises
Stable (well-managed between crises)
Post-neurological injury (if permanent damage occurs)
Progression rate: Variable; the disease itself does not progress, but cumulative neurological injury from repeated severe crises can occur
Disease course pattern: Episodic — acute metabolic crises interspersed with asymptomatic intervals. Patients are clinically normal between episodes
Disease duration: Chronic lifelong; metabolic vulnerability persists throughout life, though crisis frequency often decreases with age as metabolic management improves and patient/family awareness increases

Patterns

Remission patterns: No true remission (genetic defect is permanent), but patients are clinically well between episodes with appropriate management
Critical periods:
Infancy and early childhood (6-24 months): period of highest vulnerability to first metabolic crisis
Any intercurrent illness throughout life
Perioperative period
Pregnancy (theoretical risk, limited data)

9. Inheritance and Population

Epidemiology

Metric	Value	Source
Estimated incidence	~1 per 1,000,000 newborns	China NBS data (PMID: 34001203)
Incidence (Zhejiang, China)	~1:960,600	NBS of 1,861,262 newborns (PMID: 29039164)
Incidence (Egypt)	~1:25,000 (pilot)	Pilot NBS of 25,276 newborns (PMID: 26790708)
Total reported patients	244 (up to 2020)	Systematic literature review (PMID: 32345314)

The Egyptian pilot study reported a notably higher incidence (1:25,000), though this was based on a small sample and may reflect regional consanguinity rates or ascertainment differences.

Genetic Characteristics

Feature	Detail
Inheritance pattern	Autosomal recessive (AR)
Penetrance	Variable; some individuals with biallelic mutations remain asymptomatic (identified through family screening or NBS)
Expressivity	Highly variable — from asymptomatic to life-threatening crises
Genetic anticipation	Not applicable (not a repeat expansion disorder)
Germline mosaicism	Not specifically reported
Consanguinity role	Significant; increases risk in populations with high consanguinity rates
Carrier frequency	Not precisely established; extremely low given disease rarity

Population Demographics

Affected populations: Reported worldwide; higher frequency in populations with consanguinity (Middle East, North Africa, South Asia)
Geographic distribution: Cases reported from Europe, Middle East, East Asia, South/Southeast Asia, North Africa, North America, Latin America
Founder effects: A founder mutation was identified in Palestinian patients (PMID: 40598206)
Sex ratio: Approximately 1:1 male:female (autosomal inheritance); the Palestinian series had 6 females and 6 males (PMID: 40598206)
Age distribution: Predominantly pediatric diagnosis (median 12 months), though adult patients exist and continue to require management

10. Diagnostics

Clinical Tests

Laboratory Tests:

Test	Finding	Utility
Urinary organic acids (GC-MS)	Elevated 2-methyl-3-hydroxybutyrate, tiglylglycine, +/- 2-methylacetoacetate	Gold standard confirmatory test
Blood acylcarnitines (MS/MS)	Elevated C4OH (94% sensitivity), C5:1, C5-OH	NBS and diagnostic marker
Blood gas analysis	Metabolic acidosis (low pH, low bicarbonate, increased anion gap)	During acute crises
Serum ammonia	Hyperammonemia	During acute crises
Blood glucose	Usually normal (distinguishing feature from other organic acidemias)	(PMID: 7726385)
Enzyme assay	Reduced T2 activity in cultured fibroblasts (HP:4000204)	Confirmatory; specialized laboratories only

Key diagnostic biomarker: C4OH (3-hydroxybutyrylcarnitine) has been identified as the most reliable newborn screening marker: "almost all patients (15/16, 94%) showed elevated 3-hydroxybutyrylcarnitine (C4OH) levels" (PMID: 34001203).

Important diagnostic caveat: The absence of 2-methylacetoacetic acid in urine may be attributed to "(i) the instability of this beta-ketoacid because it undergoes spontaneous decarboxylation to 2-butanone, which is highly volatile and thus difficult to detect, and (ii) the good health of the patient in the first days of life" (PMID: 20157782).

Imaging studies: - Brain MRI: May show bilateral basal ganglia lesions (pallidal, putaminal involvement), cortical abnormalities, and cerebellar changes during or after severe metabolic crises (PMID: 41180774; PMID: 28726122)

Genetic Testing

Recommended approach: Molecular genetic testing of the ACAT1 gene is the definitive diagnostic test
Single gene testing: Direct sequencing of ACAT1 (11 exons + flanking intronic sequences); detects the vast majority of pathogenic variants
WES/WGS utility: Useful when clinical presentation is atypical or when other diagnoses are being considered simultaneously; WES identified novel variants in multiple reports (PMID: 35850931)
Gene panels: ACAT1 is included in organic acidemia/inborn errors of metabolism gene panels, as well as broader metabolic disorder panels
CMA/Karyotyping/FISH: Not applicable (disease caused by small sequence variants, not structural chromosomal changes)
Mitochondrial DNA testing: Not applicable (ACAT1 is a nuclear gene)

Diagnostic Challenges

Patients with "mild" mutations present a significant diagnostic challenge. Fukao et al. demonstrated that "T2-deficient patients with 'mild' mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA" (PMID: 15128923). Similarly, "even during severe crises, C5-OH and C5:1 were within normal ranges in their blood acylcarnitine profiles and trace amounts of tiglylglycine and small amounts of 2-methyl-3-hydroxybutyrate were detected in their urinary organic acid profiles" for patients with certain mild mutations (PMID: 23430882).

Clinical Criteria

Diagnostic criteria: 1. Clinical presentation: episodic ketoacidotic crisis in an infant/young child 2. Biochemical: characteristic urinary organic acid and/or blood acylcarnitine profile 3. Confirmatory: ACAT1 molecular testing and/or T2 enzyme assay in fibroblasts

Differential diagnosis:

Condition	Distinguishing Feature
HSD10 disease (HSD17B10 deficiency)	Similar urinary metabolites but more severe prognosis; distinguished by molecular testing (PMID: 28875337)
SCOT deficiency	Another ketolysis defect; different enzyme and gene involved
Propionic acidemia	Different organic acid profile; elevated propionylcarnitine
Methylmalonic acidemia	Different organic acid profile; elevated methylmalonic acid
Diabetic ketoacidosis	Hyperglycemia present; no elevated isoleucine metabolites

Newborn Screening

BKTD is included in expanded newborn screening (NBS) panels in several countries using tandem mass spectrometry (MS/MS): - Primary marker: Elevated C4OH (3-hydroxybutyrylcarnitine) — 94% sensitivity - Secondary markers: C5:1, C5-OH - Confirmation: Urinary organic acids, ACAT1 gene sequencing - BKTD is included in the Italian NBS panel (PMID: 40981306) and Chinese NBS programs (PMID: 34001203) - MAXO term: MAXO:0000127 (Newborn screening)

11. Outcome/Prognosis

Survival and Mortality

BKTD has a relatively favorable prognosis compared to other organic acidurias:

Outcome Metric	Value	Source
Normal psychomotor development	77.0% (157/204 patients)	PMID: 32345314
Any metabolic decompensation	89.6%	PMID: 32345314
Major mental disability	~7%	PMID: 32345314
Death (Chinese NBS cohort)	3 of 29 (10.3%)	PMID: 34001203
Death (Palestinian cohort)	2 of 12 (16.7%)	PMID: 40598206
Favorable outcomes (Palestinian)	10 of 12 (83.3%)	PMID: 40598206

Life expectancy is generally normal with appropriate management, though individual outcomes depend heavily on the frequency and severity of metabolic crises and the quality of acute management.

Morbidity and Function

Neurological morbidity: The main source of long-term disability; basal ganglia injury from metabolic stroke can cause permanent extrapyramidal symptoms (dystonia, spasticity, dyskinesia)
Cognitive outcomes: Most patients (77%) maintain normal cognitive function; those with neurological injury may have intellectual disability ranging from mild to severe
Quality of life: Limited formal QoL studies; likely impacts include dietary restrictions, need for emergency protocols, anxiety about metabolic crises, and potential neurocognitive impairments in affected individuals

Complications

Metabolic stroke with basal ganglia injury
Permanent movement disorders (dystonia, spasticity, dyskinesia)
Intellectual disability
Acute kidney injury (during severe crises)
Cardiac hypertrophy (rare, documented at autopsy)
Death (rare with appropriate management)

Prognostic Factors

Favorable prognostic factors: Early diagnosis (especially via NBS), prompt treatment of crises, good metabolic control, absence of severe neurological injury
Unfavorable prognostic factors: Delayed diagnosis, severe or prolonged metabolic crises, neurological complications (especially basal ganglia injury), limited access to metabolic specialty care
Notably, genotype is NOT a reliable prognostic indicator for clinical outcomes (PMID: 31268215)

12. Treatment

Acute Management of Metabolic Crises

Intravenous fluids: Dextrose-containing IV fluids to suppress catabolism and provide energy (MAXO:0001298 — Fluid therapy)
Bicarbonate therapy: Sodium bicarbonate to correct metabolic acidosis (MAXO:0010033 — Bicarbonate therapy)
Protein restriction: Temporary cessation of protein intake during acute crisis
Electrolyte correction: Management of hyperkalemia, hyponatremia, or other electrolyte derangements
Treatment of underlying trigger: Antibiotics for infection, antipyretics for fever
Monitoring: ICU-level care for severe crises with monitoring of blood gases, electrolytes, ammonia, glucose

Long-term Management

Dietary therapy (MAXO:0000016 — Diet therapy): - Mild protein restriction (particularly isoleucine restriction), typically 1.5-2.0 g/kg/day adjusted by age - Avoidance of prolonged fasting - Adequate caloric intake to prevent catabolism - Some patients tolerate a normal or near-normal diet between crises

Pharmacotherapy: - L-carnitine supplementation (CHEBI:16347): To enhance excretion of accumulated organic acids as carnitine conjugates and prevent secondary carnitine deficiency (MAXO:0001258 — Carnitine supplementation) - Typical dose: 50-100 mg/kg/day orally, divided into 2-3 doses

Sick-day management protocols (MAXO:0000127 — Disease management): - Emergency protocol cards for families - Increased caloric intake (glucose polymers, simple carbohydrates) - More frequent meals - Early medical evaluation for intercurrent illness - Low threshold for IV glucose/fluids - Avoidance of fasting >4-6 hours (age-dependent)

Advanced Therapeutics

Gene therapy: No gene therapy is currently available or in clinical trials for BKTD
Cell therapy: Not applicable
RNA-based therapies: Not available
Enzyme replacement therapy: Not available (mitochondrial enzyme; delivery challenges)

Supportive and Rehabilitative Care

Developmental assessment and early intervention for patients with neurological sequelae
Physical therapy and occupational therapy for motor impairments (MAXO:0000011 — Physical therapy)
Speech therapy if needed
Neuropsychological support
Genetic counseling for families (MAXO:0000079 — Genetic counseling)

Treatment Outcomes

"Approximately two-thirds of patients had favorable outcomes, one showed a developmental delay and three died" from the largest Chinese NBS cohort (PMID: 34001203). In the global systematic review, 77% of patients demonstrated normal psychomotor development (PMID: 32345314).

Treatment Strategy

The treatment approach follows a two-tier strategy: 1. Chronic maintenance: Mild protein restriction + L-carnitine supplementation + avoidance of fasting + sick-day education 2. Acute crisis management: Emergency IV dextrose + bicarbonate correction + protein restriction + ICU monitoring

There are no pharmacogenomic considerations specific to BKTD treatment, as the primary interventions are dietary and supportive rather than pharmacological.

13. Prevention

Primary Prevention

Genetic counseling: For families with known carriers or affected individuals (MAXO:0000079)
Carrier testing: Available for at-risk family members via ACAT1 sequencing
Prenatal diagnosis: Possible via chorionic villus sampling or amniocentesis with molecular testing of ACAT1
Preimplantation genetic diagnosis (PGD): Available for families with known pathogenic variants

Secondary Prevention (Early Detection)

Newborn screening: Tandem mass spectrometry (MS/MS) screening for elevated C4OH, C5:1, and C5-OH in dried blood spots (MAXO:0000127)
Cascade screening: Testing siblings and family members of affected individuals
Early intervention: Prompt initiation of dietary management and carnitine supplementation upon diagnosis

Tertiary Prevention (Preventing Complications)

Metabolic crisis prevention: Sick-day protocols, avoidance of fasting, prompt treatment of infections
Vaccination planning: Standard childhood vaccinations are recommended, but caregivers should be aware of the potential for post-vaccination metabolic stress (PMID: 33708533); consider administering vaccines during metabolically stable periods with close monitoring
Regular metabolic follow-up: Monitoring of metabolic parameters, growth, and development
Emergency preparedness: Families should carry emergency letters/protocol cards; medical alert identification recommended

Genetic Counseling

Autosomal recessive inheritance: 25% recurrence risk for each pregnancy of carrier parents
Importance of cascade testing in consanguineous families
Discussion of reproductive options including PGD and prenatal diagnosis

Public Health Considerations

Expansion of newborn screening programs to include BKTD in countries where it is not currently screened
Awareness campaigns among pediatricians regarding metabolic emergencies
Development of standardized emergency protocols for metabolic crisis management
The importance of metabolic screening in children with unexplained neurodevelopmental disorders has been highlighted: screening of Mexican children with NDD identified BKTD in one patient, indicating "the need to perform a minimum metabolic screening as part of the diagnostic approach" (PMID: 32880084)

14. Other Species / Natural Disease

Taxonomy and Comparative Biology

The ACAT1 gene is highly conserved across vertebrate species. Orthologs exist in:

Species	Gene	NCBI Gene ID
Homo sapiens (human)	ACAT1	38
Mus musculus (mouse)	Acat1	110446
Rattus norvegicus (rat)	Acat1	25014
Danio rerio (zebrafish)	acat1	30585

Natural Disease in Other Species

No naturally occurring BKTD has been definitively described in domestic animals or wildlife. This may reflect: - The rarity of the condition - Under-diagnosis in veterinary medicine - Potential embryonic lethality in some species - Different metabolic adaptations in non-human species

OMIA (Online Mendelian Inheritance in Animals) does not list a specific entry for beta-ketothiolase deficiency in animals.

Evolutionary Conservation

The mitochondrial acetoacetyl-CoA thiolase enzyme is highly conserved across eukaryotes, reflecting its fundamental role in both amino acid catabolism and ketone body metabolism. The conservation of disease-associated residues (as mapped to the crystal structure) across species supports the use of model organisms for studying disease mechanisms.

Zoonotic Potential and Transmission

Not applicable — BKTD is a non-communicable genetic disease with no zoonotic or infectious component.

15. Model Organisms

Mouse Models

Acat1 knockout mice: The International Mouse Phenotyping Consortium (IMPC) has generated Acat1 targeted alleles
Homozygous knockout may be embryonic lethal or have metabolic phenotypes that recapitulate the human disease
Detailed phenotyping data are limited in the published literature specifically for BKTD mouse models

In Vitro Models

Patient-derived fibroblasts: The most widely used model system for studying T2 deficiency
Used for enzyme activity assays (T2 activity measurement)
Used for expression analysis of mutant proteins
Temperature-sensitivity studies performed at 30 degrees C, 37 degrees C, and 40 degrees C (PMID: 17236799)
Transient expression systems: Mutant ACAT1 cDNAs expressed in cell lines for functional characterization of variants
Enables measurement of residual enzyme activity, protein stability, and kinetic parameters
Critical for classifying variants as "null" versus "mild" (PMID: 15128923)

Model Limitations

Mouse models may not fully recapitulate the episodic nature of human disease
In vitro enzyme assays may not reflect in vivo residual activity
The coupled assay with tiglyl-CoA has been shown to miss patients with "mild" mutations, highlighting limitations of some functional assays (PMID: 15128923)
No validated large-animal model exists

Research Applications

Understanding structure-function relationships of T2 using crystal structure and mutagenesis
Characterizing novel variants for pathogenicity classification
Studying temperature-sensitive folding mutants as potential therapeutic targets (pharmacological chaperones)
Developing improved diagnostic assays

Evidence Base

Key Literature

Citation	Contribution
PMID: 32345314 — Grünert et al., 2020	Landmark systematic review: Largest cohort (244 patients); established key outcome statistics (77% normal development, 89.6% had crises, median onset 12 months); defined "one disease — two pathways" concept
PMID: 31268215 — Fukao et al., 2019	Comprehensive mutation update: 105 variants in 149 patients; structural mapping of missense variants; established genotype-biochemical phenotype correlation and genotype-clinical phenotype dissociation
PMID: 34001203 — Chinese multicenter study, 2021	Largest NBS cohort: 16 million newborns screened; incidence estimate of 1:1,000,000; identified C4OH as most sensitive NBS marker (94%)
PMID: 28689740 — Paquay et al., 2017	Multicenter clinical series: 32 patients; confirmed lack of genotype-phenotype correlation; characterized intronic mutation burden
PMID: 8218125 — Autopsy study, 1993	Only neuropathological study: First documentation of brain and cardiac pathology in fatal BKTD cases
PMID: 28726122 — Metabolic stroke report, 2017	Novel presentation: Documented metabolic stroke with pallidal involvement after normal NBS
PMID: 17236799 — Kinetic studies, 2007	Functional characterization: Temperature-sensitive mutants; first Km mutant identified; structure-function analysis
PMID: 15128923 — Enzyme assay limitations, 2004	Diagnostic insight: Demonstrated that mild mutations can be missed by traditional coupled assay
PMID: 23430882 — Japanese patients, 2013	Subtle biochemistry: Showed that mild mutations produce near-normal acylcarnitine profiles even during crises
PMID: 20157782 — Italian NBS case, 2010	Marker instability: Explained why 2-methylacetoacetate may be absent in urine
PMID: 40598206 — Palestinian cohort, 2025	Population genetics: 12 patients from consanguineous families; two novel variants; founder mutation identified
PMID: 33708533 — Post-vaccination crisis, 2021	Novel trigger: First documented ketoacidotic crisis following vaccination
PMID: 41180774 — Neurological case, 2025	Neurological presentation: Detailed case with basal ganglia and cerebellar involvement
PMID: 28875337 — HSD10 vs. BKTD, 2017	Differential diagnosis: Distinguished BKTD from HSD10 deficiency clinically and molecularly
PMID: 32880084 — NDD screening, 2020	Undiagnosed IEM: Identified BKTD in children with neurodevelopmental disorders

Limitations and Knowledge Gaps

Small total patient cohort: With only ~244 patients reported worldwide, many aspects of the natural history remain poorly characterized, and robust statistical analyses are challenging.
Genotype-phenotype dissociation: The lack of correlation between genotype and clinical phenotype, combined with significant correlation with biochemical phenotype, remains mechanistically unexplained. The role of modifier genes, epigenetic factors, and stochastic events is unknown.
Limited neuropathological data: Only one autopsy study (PMID: 8218125) has characterized the histopathological basis of neurological injury. The precise mechanisms of selective basal ganglia vulnerability and cortical damage need further investigation.
No formal QoL studies: Quality of life assessments using validated instruments (EQ-5D, SF-36, PedsQL) have not been published for BKTD patients.
Incomplete NBS sensitivity: Patients with "mild" mutations may have subtle biochemical profiles that fall below NBS cutoffs, leading to missed diagnoses (PMID: 23430882; PMID: 15128923).
No long-term adult outcome data: Most published data concern pediatric patients; the long-term natural history into adulthood, including adult metabolic crisis risk, reproductive outcomes, and aging-related complications, is poorly documented.
Limited animal model characterization: No well-characterized animal model exists for studying BKTD pathophysiology or testing therapies in vivo.
No specific therapies beyond supportive care: There is no enzyme replacement, gene therapy, pharmacological chaperone, or other targeted therapy available for BKTD.
Incidence data variability: The incidence estimate (1:1,000,000) is based primarily on Chinese NBS data; true global incidence may vary substantially across populations with different consanguinity rates.
Epigenetic and modifier gene data absent: No studies have investigated DNA methylation, histone modifications, or modifier genes in BKTD.

Proposed Follow-up Experiments/Actions

Clinical Research

International BKTD registry: Establish a prospective international registry to systematically collect longitudinal clinical, biochemical, genetic, and outcome data on all diagnosed patients.
Adult outcome study: Conduct a multicenter study of adult BKTD patients to characterize long-term neurological, cognitive, metabolic, and psychosocial outcomes.
QoL assessment: Implement validated quality of life instruments (PedsQL for children, SF-36/EQ-5D for adults) in BKTD patient cohorts.
Optimized NBS protocols: Develop and validate improved newborn screening algorithms incorporating C4OH, C5:1, and second-tier molecular testing to reduce false negatives, particularly for patients with mild mutations.

Basic Science Research

Animal model development: Generate and characterize conditional Acat1 knockout mouse models to study disease pathophysiology, tissue-specific effects, and test therapeutic interventions.
Neuropathology studies: Use advanced neuroimaging (diffusion tensor imaging, MR spectroscopy) and, where tissue is available, neuropathological studies to delineate the mechanisms of selective basal ganglia vulnerability.
Pharmacological chaperone screening: Given that many pathogenic variants cause protein misfolding with temperature sensitivity, screen for small molecules that stabilize mutant T2 protein as potential therapeutic agents.
Modifier gene identification: Perform whole-exome/genome sequencing of discordant siblings or genotype-matched patients with different clinical outcomes to identify genetic modifiers.
Metabolomics profiling: Conduct comprehensive metabolomics on BKTD patient samples (plasma, urine, CSF) to identify novel biomarkers and better understand systemic metabolic perturbation.

Translational Research

Gene therapy development: Investigate AAV-mediated ACAT1 gene replacement therapy, leveraging liver-directed approaches given the hepatic expression of T2.
mRNA therapy exploration: Evaluate lipid nanoparticle-encapsulated ACAT1 mRNA as a potential therapeutic approach.

Ontology Term Summary

Disease

MONDO: MONDO:0008760 (Beta-ketothiolase deficiency)

Phenotypes (HPO)

HP:0001942 (Metabolic acidosis)
HP:0001985 (Ketoacidosis)
HP:0001944 (Dehydration)
HP:0001987 (Hyperammonemia)
HP:0001257 (Spasticity)
HP:0001332 (Dystonia)
HP:0002071 (Extrapyramidal dyskinesia)
HP:0002134 (Abnormality of the basal ganglia)
HP:0001250 (Seizures)
HP:0001249 (Intellectual disability)
HP:0001263 (Global developmental delay)
HP:0002013 (Vomiting)
HP:0002883 (Tachypnea)
HP:0001919 (Acute kidney injury)
HP:0001714 (Cardiac hypertrophy)
HP:6000603 (Elevated urinary tiglylglycine)
HP:0003128 (Elevated 2-methylacetoacetate)
HP:0003231 (Elevated 2-methyl-3-hydroxybutyrate)
HP:4000204 (Reduced acetyl-CoA acetyltransferase activity)
HP:0000729 (Autistic behavior)
HP:0007018 (Attention deficit hyperactivity disorder)
HP:0002014 (Diarrhea)

Gene Ontology (GO)

GO:0005739 (Mitochondrion)
GO:0005759 (Mitochondrial matrix)
GO:0046952 (Ketone body catabolic process)
GO:0006552 (Leucine catabolic process)
GO:0006635 (Fatty acid beta-oxidation)
GO:0006094 (Gluconeogenesis)

Cell Types (CL)

CL:0000540 (Neuron)
CL:0000127 (Astrocyte)
CL:0000182 (Hepatocyte)
CL:0000746 (Cardiomyocyte)
CL:0000128 (Oligodendrocyte)
CL:1000507 (Renal tubular cell)

Anatomy (UBERON)

UBERON:0000955 (Brain)
UBERON:0002107 (Liver)
UBERON:0002113 (Kidney)
UBERON:0000948 (Heart)
UBERON:0001134 (Skeletal muscle)
UBERON:0001874 (Putamen)
UBERON:0001873 (Caudate nucleus)
UBERON:0001875 (Globus pallidus)
UBERON:0001872 (Parietal cortex)
UBERON:0002021 (Occipital cortex)
UBERON:0002037 (Cerebellum)
UBERON:0002023 (Claustrum)

Chemical Entities (CHEBI)

CHEBI:17622 (2-Methylacetoacetate)
CHEBI:19396 (2-Methyl-3-hydroxybutyrate)
CHEBI:71179 (Tiglylglycine)
CHEBI:13705 (Acetoacetate)
CHEBI:37054 (3-Hydroxybutyrate)
CHEBI:16347 (L-carnitine)

Medical Actions (MAXO)

MAXO:0000127 (Newborn screening)
MAXO:0000016 (Diet therapy)
MAXO:0001258 (Carnitine supplementation)
MAXO:0001298 (Fluid therapy)
MAXO:0010033 (Bicarbonate therapy)
MAXO:0000079 (Genetic counseling)
MAXO:0000011 (Physical therapy)

Report generated: 2026-05-05 Based on systematic analysis of 30 peer-reviewed publications and disease database resources 4 confirmed findings from iterative investigation

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Target Disease

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Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format

1. Disease Information

Overview

Key Identifiers

Synonyms and Alternative Names

Information Sources

2. Etiology

Disease Causal Factors

Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Acute Metabolic Crises (Episodic Ketoacidosis)

Neurological Manifestations

Metabolic/Laboratory Abnormalities

Gastrointestinal Symptoms

Respiratory Manifestations

Renal Manifestations

Cardiac Findings

Neurodevelopmental Associations

4. Genetic/Molecular Information

Causal Gene

Pathogenic Variants

Genotype-Phenotype Correlation

Modifier Genes

Epigenetic Information

Chromosomal Abnormalities

5. Environmental Information

Environmental Factors

Lifestyle Factors

Infectious Agents

6. Mechanism / Pathophysiology

Molecular Pathways

Cellular Processes

Protein Dysfunction

Metabolic Changes

Tissue Damage Mechanisms

Causal Chain: From Genetic Defect to Clinical Manifestation

Biochemical Abnormalities

Molecular Profiling

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

Subcellular Level

Localization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Genetic Characteristics

Population Demographics

10. Diagnostics

Clinical Tests

Genetic Testing