Carnitine-acylcarnitine Translocase Deficiency

Mendelian MONDO:0008918 Pathograph 37 Fatty Acid Oxidation Disorder Inborn Error of Metabolism

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disorder of mitochondrial long-chain fatty acid oxidation caused by biallelic pathogenic variants in SLC25A20. CACT is a mitochondrial inner membrane transporter that facilitates the exchange of long-chain acylcarnitines for free carnitine across the inner mitochondrial membrane, a critical step in the carnitine shuttle required for long-chain fatty acid beta-oxidation. Loss of CACT function leads to impaired mitochondrial energy production during fasting or catabolic stress, accumulation of toxic long-chain acylcarnitines, and secondary free carnitine depletion. The severe neonatal-onset form presents within the first days of life with hypoketotic hypoglycemia, hyperammonemia, cardiac arrhythmia, cardiomyopathy, hepatic dysfunction, and high mortality (~65%) predominantly from cardiac causes. An attenuated form with later onset and milder symptoms allows better developmental outcomes with appropriate treatment.

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6
Pathophys.
1
Histopath.
15
Phenotypes
37
Pathograph
2
Genes
8
Treatments
1
References
1
Deep Research
⚙

Pathophysiology

6
SLC25A20 transporter molecular function deficiency
Biallelic SLC25A20 pathogenic variants reduce mitochondrial inner membrane carnitine-acylcarnitine translocase activity.
SLC25A20 link
carnitine transport link
mitochondrial inner membrane link
Downstream
Impaired mitochondrial long-chain fatty acid oxidation Defective acylcarnitine translocation limits matrix substrate delivery for long-chain FAO.
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity."
Supports SLC25A20/CACT transporter dysfunction as the initiating molecular event.
Impaired mitochondrial long-chain fatty acid oxidation
Impaired transport of long-chain acylcarnitines into the mitochondrial matrix blocks long-chain fatty acid beta-oxidation. This leads to inadequate ATP generation during fasting, birth, or illness, and impaired ketogenesis, shifting energy reliance to glucose until glycogen stores are depleted.
hepatocyte link cardiac muscle cell link
fatty acid beta-oxidation link ketone body metabolic process link
mitochondrion link
Downstream
Toxic acylcarnitine accumulation and secondary carnitine depletion Failure of long-chain fatty acid oxidation is reflected by long-chain acylcarnitine accumulation and reduced free carnitine.
Catabolic stress-triggered metabolic decompensation Fasting, illness, and the neonatal birth transition increase dependence on long-chain FAO, exposing the energy-generation block.
Hypoketotic hypoglycemia Impaired long-chain FAO reduces hepatic ketogenesis and forces glucose dependence during fasting or illness.
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity."
Supports impaired long-chain fatty acid oxidation downstream of CACT transporter dysfunction.
Toxic acylcarnitine accumulation and secondary carnitine depletion
Blocked transport of long-chain acylcarnitines results in their cytoplasmic accumulation and secondary depletion of free carnitine. Accumulated long-chain acylcarnitines and acyl-CoA derivatives cause biochemical toxicity in high-energy-demand tissues including heart, skeletal muscle, liver, and kidney, manifesting as lipid-laden microvesicular steatosis across multiple organs.
hepatocyte link cardiac muscle cell link epithelial cell of proximal tubule link skeletal muscle fiber link
carnitine shuttle link
mitochondrial inner membrane link
Downstream
Cardiac energy failure and arrhythmogenesis Long-chain acylcarnitine/lipid accumulation and reduced fatty-acid energy production injure cardiomyocytes.
Long-chain acylcarnitines (C16, C18, C18:1) Blocked acylcarnitine handling produces the characteristic elevated long-chain acylcarnitine profile.
Free carnitine (C0) Trapping of carnitine in acylcarnitine species can deplete circulating free carnitine.
Dicarboxylic aciduria Impaired mitochondrial long-chain FAO can shunt fatty acids toward omega-oxidation and urinary dicarboxylic acids.
Hepatomegaly Lipid accumulation and hepatic energy failure cause liver dysfunction with hepatomegaly.
Elevated circulating hepatic transaminase concentration Hepatocyte lipid accumulation and energy failure produce hepatocellular injury reflected by transaminitis.
Rhabdomyolysis Toxic lipid accumulation and energy failure in skeletal muscle predispose to muscle breakdown during stress.
Show evidence (2 references)
PMID:38628283 SUPPORT Human Clinical
"We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes."
Autopsy evidence of multi-organ lipid accumulation directly supports toxic acylcarnitine/lipid handling failure.
PMID:35862567 SUPPORT Human Clinical
"Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency."
Elevated long-chain acylcarnitines confirm acylcarnitine accumulation as a disease hallmark.
Catabolic stress-triggered metabolic decompensation
Birth transition, fasting, illness, or poor intake increase dependence on long-chain fatty acid oxidation. In CACT deficiency this exposes the transport and FAO block, producing acute systemic decompensation with poor feeding, lethargy, hypotonia, respiratory distress or apnea, and encephalopathy.
hepatocyte link cardiac muscle cell link skeletal muscle fiber link
response to starvation link generation of precursor metabolites and energy link
Downstream
Hyperammonemia during metabolic crises Acute FAO failure during catabolic crises contributes to hyperammonemia, which is prominent and difficult to treat in CACT deficiency.
Poor feeding Acute energy failure in neonatal and illness-triggered crises produces feeding difficulty.
Lethargy Acute systemic energy deficit during metabolic crises causes decreased alertness.
Muscular hypotonia Energy failure affecting skeletal muscle and CNS function contributes to hypotonia in the acute presentation.
Respiratory distress Severe neonatal metabolic decompensation can present with respiratory distress.
Encephalopathy Acute metabolic crisis and impaired energy supply can produce encephalopathy.
Apnea Severe neonatal metabolic decompensation can manifest with apnea.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy."
Review evidence links neonatal long-chain fatty-acid dependence to the severe systemic CACT deficiency presentation.
Cardiac energy failure and arrhythmogenesis
The heart is highly dependent on long-chain fatty acid oxidation for energy. CACT deficiency causes cardiac energy deficit and toxic lipid accumulation in cardiomyocytes, leading to hypertrophic cardiomyopathy and cardiac arrhythmias. Cardiac involvement is often the primary determinant of mortality.
cardiac muscle cell link
fatty acid beta-oxidation link
heart link
Downstream
Cardiac arrhythmia Cardiomyocyte energy failure and lipid toxicity increase arrhythmia risk in early-onset CACT deficiency.
Hypertrophic cardiomyopathy Energy failure and lipid accumulation in cardiomyocytes produce hypertrophic cardiomyopathy.
Show evidence (3 references)
PMID:35862567 SUPPORT Human Clinical
"Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest."
GeneReviews confirms cardiac arrhythmia and cardiac arrest as prominent early-onset features.
PMID:25614308 SUPPORT Human Clinical
"The mortality rate is high (65%), most in the first year of life due to myocardiopathy or sudden death."
Confirms cardiomyopathy and sudden death as primary causes of mortality.
PMID:33024728 SUPPORT Human Clinical
"Patients with a defect in the oxidation of long-chain FAs are at risk to develop cardiac and skeletal muscle abnormalities including cardiomyopathy and arrhythmias, which may progress into early death"
Review confirming cardiac and skeletal muscle vulnerability in long-chain fatty acid oxidation disorders.
Hyperammonemia during metabolic crises
Hyperammonemia is a prominent and difficult-to-treat feature of CACT deficiency, particularly during neonatal and acute metabolic crises. It is an important determinant of long-term neurocognitive outcome. Ammonia scavenger medications are of limited efficacy; high-rate dextrose infusion is the most effective intervention.
urea cycle link
Downstream
Hyperammonemia The metabolic-crisis mechanism is clinically measured as elevated blood ammonia.
Seizures Severe hypoglycemia and hyperammonemia during CACTD crises can be accompanied by seizures.
Global developmental delay Recurrent hyperammonemia and acute brain injury can lead to developmental delay or intellectual disability.
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome."
GeneReviews directly describes hyperammonemia as a key clinical challenge and prognostic factor.
PMID:25614308 SUPPORT Human Clinical
"the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress."
Literature review confirms hyperammonemia as one of the most frequent presenting symptoms.
✶

Histopathology

1
Multi-organ microvesicular steatosis
Autopsy pathology in CACT deficiency can be dominated by microvesicular steatosis involving hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes. This microscopic lipid accumulation reflects impaired long-chain fatty-acid handling across high-energy tissues.
Show evidence (1 reference)
PMID:38628283 SUPPORT Human Clinical
"We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes."
Autopsy case report directly documents the multi-organ microvesicular steatosis pattern.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Carnitine-acylcarnitine Translocase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Cardiovascular 2
Cardiac arrhythmia VERY_FREQUENT Arrhythmia (HP:0011675)
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest."
GeneReviews identifies cardiac arrhythmia as prominent in early-onset disease.
PMID:29502916 SUPPORT Human Clinical
"Fatty acid oxidation disorders (FAODs) and carnitine shuttling defects are inborn errors of energy metabolism with associated mortality and morbidity due to cardiomyopathy, exercise intolerance, rhabdomyolysis, and liver disease"
Review confirms cardiomyopathy and cardiac morbidity in fatty acid oxidation and carnitine shuttle disorders.
Hypertrophic cardiomyopathy FREQUENT Hypertrophic cardiomyopathy (HP:0001639)
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"Univentricular or biventricular hypertrophic cardiomyopathy, ranging from mild to severe, may respond to appropriate dietary and medical therapies."
GeneReviews describes hypertrophic cardiomyopathy as a recognized feature that may respond to treatment.
PMID:25614308 SUPPORT Human Clinical
"the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress."
Literature review identifies cardiomyopathy as among the most frequent presenting symptoms.
Digestive 2
Hepatomegaly FREQUENT Hepatomegaly (HP:0002240)
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
GeneReviews lists liver dysfunction with hepatomegaly as a typical clinical feature.
PMID:25614308 SUPPORT Human Clinical
"the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress."
Literature review confirms hepatomegaly as one of the most frequent presenting symptoms.
Poor feeding FREQUENT Feeding difficulties (HP:0011968)
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
GeneReviews lists poor feeding as a typical clinical feature.
Metabolism 3
Hypoketotic hypoglycemia VERY_FREQUENT Hypoketotic hypoglycemia (HP:0001985)
Show evidence (3 references)
PMID:35862567 SUPPORT Human Clinical
"Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
GeneReviews lists hypoketotic hypoglycemia as a typical clinical feature.
PMID:25614308 SUPPORT Human Clinical
"the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress."
Literature review confirms hypoketotic hypoglycemia as among the most frequent presenting symptoms.
PMID:33024728 SUPPORT Human Clinical
"A general characteristic of all mFAO disorders is hypoketotic hypoglycemia resulting from the enhanced reliance on glucose oxidation and the inability to synthesize ketone bodies from FAs."
Review confirms hypoketotic hypoglycemia as a general characteristic of all mitochondrial fatty acid oxidation disorders.
Hyperammonemia VERY_FREQUENT Hyperammonemia (HP:0001987)
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest."
GeneReviews identifies hyperammonemia as prominent in early-onset CACT deficiency.
PMID:25614308 SUPPORT Human Clinical
"the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress."
Literature review confirms hyperammonemia as one of the most frequent presenting symptoms.
Elevated circulating hepatic transaminase concentration FREQUENT Elevated circulating hepatic transaminase concentration (HP:0002910)
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
GeneReviews lists transaminitis as a typical clinical feature.
Musculoskeletal 2
Muscular hypotonia FREQUENT Hypotonia (HP:0001252)
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
GeneReviews lists hypotonia as a typical clinical feature of CACT deficiency.
Rhabdomyolysis OCCASIONAL Rhabdomyolysis (HP:0003201)
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
GeneReviews lists rhabdomyolysis as a typical clinical feature of long-chain fatty acid oxidation disorders.
PMID:29502916 SUPPORT Human Clinical
"Fatty acid oxidation disorders (FAODs) and carnitine shuttling defects are inborn errors of energy metabolism with associated mortality and morbidity due to cardiomyopathy, exercise intolerance, rhabdomyolysis, and liver disease"
Review confirms rhabdomyolysis as a source of morbidity in FAODs and carnitine shuttle defects.
Nervous System 4
Lethargy FREQUENT Lethargy (HP:0001254)
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
GeneReviews lists lethargy as a typical clinical feature.
Global developmental delay FREQUENT Global developmental delay (HP:0001263)
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Affected individuals with early-onset disease typically experience brain injury at presentation, and have recurrent hyperammonemia leading to developmental delay / intellectual disability."
GeneReviews directly states developmental delay as a consequence of early-onset disease.
Seizures OCCASIONAL Seizure (HP:0001250)
Show evidence (1 reference)
PMID:34449152 SUPPORT Human Clinical
"CACTD is characterized by severe episodes of hypoglycemia and hyperammonemia, seizures, cardiomyopathy, liver dysfunction, severe neurological damage, and muscle weakness."
CACTD case series directly supports seizures as part of the clinical spectrum.
Encephalopathy Encephalopathy (HP:0001298)
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy."
Review evidence lists encephalopathy among severe neonatal CACT deficiency manifestations.
Respiratory 2
Respiratory distress FREQUENT Respiratory distress (HP:0002098)
Show evidence (1 reference)
PMID:25614308 SUPPORT Human Clinical
"the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress."
Literature review identifies respiratory distress among the most frequent presenting symptoms.
Apnea Apnea (HP:0002104)
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy."
Review evidence lists apnea among severe neonatal CACT deficiency manifestations.
🧬

Genetic Associations

2
SLC25A20 pathogenic variants
Autosomal recessive
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"The diagnosis of CACT deficiency is confirmed by identification of biallelic pathogenic variants in SLC25A20"
GeneReviews confirms SLC25A20 as the causal gene with biallelic variants required for diagnosis.
PMID:36835358 SUPPORT Computational
"The Carnitine-Acylcarnitine Carrier is a member of the mitochondrial Solute Carrier Family 25 (SLC25), known as SLC25A20, involved in the electroneutral exchange of acylcarnitine and carnitine across the inner mitochondrial membrane."
Structural biology study confirming SLC25A20 function in acylcarnitine-carnitine exchange.
SLC25A20 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_95c9aece-49b5-496f-9547-f6d03dd69b4f-2018-05-22T160000.000Z SUPPORT Other
"SLC25A20 | HGNC:1421 | carnitine-acylcarnitine translocase deficiency | MONDO:0008918 | AR | Definitive"
ClinGen classifies the SLC25A20-carnitine-acylcarnitine translocase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
💊

Treatments

8
High-carbohydrate, long-chain fat-restricted diet
Action: dietary intervention MAXO:0000088
The mainstay of chronic therapy is a high-carbohydrate diet providing over 60% of total caloric intake, with restriction of long-chain dietary fat to less than 10% of total calories. Fasting is avoided or strictly limited. Essential fatty acid targets include linoleic acid at 3-4% and linolenic acid at 0.5-1% of total calories.
Mechanism Target:
BYPASSES Impaired mitochondrial long-chain fatty acid oxidation — High carbohydrate intake and long-chain fat restriction reduce dependence on the blocked long-chain FAO pathway and limit lipolysis.
Show evidence (1 reference)
PMID:39203843 SUPPORT Human Clinical
"It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible."
Nutritional management review explains the bypass rationale for glucose provision and fatty-acid fuel avoidance in FAODs.
INHIBITS Catabolic stress-triggered metabolic decompensation — Preventing fasting and maintaining uninterrupted calories reduces catabolic decompensation risk.
Show evidence (1 reference)
PMID:39203843 SUPPORT Human Clinical
"Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake."
Review supports diet as prevention of fasting-driven decompensation in FAODs.
Target Phenotypes: Hypoketotic hypoglycemia ↗ Hyperammonemia ↗
Show evidence (3 references)
PMID:35862567 SUPPORT Human Clinical
"The mainstay of therapy is a high-carbohydrate diet (>60% of total caloric intake) with restriction of long-chain dietary fat (to <10% of total calories)"
GeneReviews provides specific dietary guidelines for CACT deficiency management.
PMID:39203843 SUPPORT Human Clinical
"In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1%"
Review confirms LCT restriction targets and essential fatty acid requirements for long-chain FAODs.
PMID:25614308 SUPPORT Human Clinical
"Diagnosis before the occurrence of clinical symptoms by tandem MS-MS and very early therapeutic intervention together with good dietary compliance could lead to a better prognosis"
Supports importance of early dietary intervention for improved outcomes.
Triheptanoin therapy
Action: nutritional supplementation MAXO:0000106
Agent: triheptanoin ↗
Triheptanoin (UX007/Dojolvi), a synthetic medium odd-chain triglyceride, provides anaplerotic support by generating propionyl-CoA that replenishes TCA cycle intermediates via succinyl-CoA. Recommended at 25-35% of total calories. Has demonstrated rapid reversal of cardiogenic shock in a CACT deficiency case and significant reduction in hospitalizations compared with MCT oil in LC-FAOD patients.
Mechanism Target:
BYPASSES Impaired mitochondrial long-chain fatty acid oxidation — Triheptanoin provides a medium odd-chain triglyceride energy substrate and anaplerotic support when long-chain fatty acid oxidation is impaired.
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"The mainstay of therapy is a high-carbohydrate diet (>60% of total caloric intake) with restriction of long-chain dietary fat (to <10% of total calories) and treatment with the anaplerotic agent triheptanoin (to provide 25%-35% of total calories)."
GeneReviews identifies triheptanoin as an anaplerotic treatment for CACT deficiency.
INHIBITS Catabolic stress-triggered metabolic decompensation — Triheptanoin reduces catabolic and metabolic decompensation episodes in long-chain FAODs.
Show evidence (1 reference)
PMID:39375714 SUPPORT Human Clinical
"The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD."
Clinical cohort supports triheptanoin reducing decompensation burden in long-chain FAODs.
Target Phenotypes: Hypertrophic cardiomyopathy ↗ Cardiac arrhythmia ↗ Hyperammonemia ↗ Rhabdomyolysis ↗
Show evidence (1 reference)
PMID:39375714 SUPPORT Human Clinical
"The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014)"
Italian cohort study showing significant reduction in catabolic episodes and hospitalizations with triheptanoin versus MCT oil in LC-FAOD patients.
Medium-chain triglyceride supplementation
Action: dietary intervention MAXO:0000088
MCT oil (10-30% of total calories) provides alternative fuel that bypasses the long-chain fatty acid transport defect. MCT oil is used as a substitute when triheptanoin is not available.
Mechanism Target:
BYPASSES Impaired mitochondrial long-chain fatty acid oxidation — Medium-chain triglycerides provide calories that bypass the long-chain carnitine shuttle defect.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Formula should have reduced long-chain fat plus mediumchain triglyceride (MCT) supplementation."
Review supports MCT supplementation as a bypass dietary strategy for CACT deficiency.
Target Phenotypes: Hypoketotic hypoglycemia ↗ Hyperammonemia ↗
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"If triheptanoin is not available, medium-chain triglyceride (MCT) oil (10%-30% of total calories) could be used as a substitute."
GeneReviews recommends MCT oil as an alternative when triheptanoin is unavailable.
Carnitine supplementation
Action: carnitine supplementation MAXO:0010006
L-carnitine supplementation at approximately 100 mg/kg/day is recommended to replenish depleted free carnitine stores and support acylcarnitine excretion.
Mechanism Target:
MODULATES Toxic acylcarnitine accumulation and secondary carnitine depletion — Carnitine supplementation replenishes low free carnitine, although benefit is uncertain and use is guided by carnitine levels.
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Fasting is avoided or limited, and carnitine supplemented at ~100 mg/kg/day is recommended."
GeneReviews recommends carnitine supplementation as part of routine CACT deficiency management.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Carnitine supplementation may be helpful."
Review supports carnitine supplementation in long-chain fatty acid oxidation disorders.
Emergency metabolic crisis management
Action: supportive care MAXO:0000950
Acute management centers on reversal of catabolism with high-rate intravenous dextrose infusion (12-15 g/kg/day for infants, 10-12 g/kg/day for children). Ammonia scavenger medications are of limited efficacy. Cardiac arrhythmias, cardiomyopathy, rhabdomyolysis, and acute renal impairment are treated per standard of care, typically in the ICU. Triheptanoin should be considered for cardiogenic shock.
Mechanism Target:
INHIBITS Catabolic stress-triggered metabolic decompensation — High-dextrose fluids reverse catabolism and reduce endogenous lipolysis during acute crises.
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Administration of high-dextrose-containing fluids: oral/enteral carbohydrate polymer (at home) or intravenous dextrose (in the hospital)."
GeneReviews supports high-dextrose fluids as acute therapy for CACT deficiency crises.
INHIBITS Hyperammonemia during metabolic crises — High-rate dextrose infusion is the most effective acute intervention for CACT-associated hyperammonemia.
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Hyperammonemia is most sensitive to high rates of dextrose infusion (12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children age 1-6 years), while ammonia scavenging medications (sodium benzoate, sodium phenylbutyrate) are of limited efficacy."
GeneReviews directly identifies high-rate dextrose as the most effective hyperammonemia-directed acute intervention.
Target Phenotypes: Hyperammonemia ↗ Hypoketotic hypoglycemia ↗ Cardiac arrhythmia ↗ Hypertrophic cardiomyopathy ↗ Rhabdomyolysis ↗
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Hyperammonemia is most sensitive to high rates of dextrose infusion (12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children age 1-6 years), while ammonia scavenging medications (sodium benzoate, sodium phenylbutyrate) are of limited efficacy."
GeneReviews provides specific emergency management guidelines including dextrose infusion rates.
Newborn screening
Action: disease screening MAXO:0000124
CACT deficiency is detectable by newborn screening via tandem mass spectrometry using acylcarnitine profiling. Elevated long-chain acylcarnitines are the primary markers. Use of ratio indices improves discrimination and reduces false-positive rates. Because CACT deficiency often presents before routine screening collection timing, early clinical vigilance is also important.
Target Phenotypes: Hypoketotic hypoglycemia ↗ Hyperammonemia ↗ Cardiac arrhythmia ↗ Hypertrophic cardiomyopathy ↗ Global developmental delay ↗
Show evidence (2 references)
PMID:37305732 SUPPORT Human Clinical
"Newborn screening via tandem mass spectrometry (MS/MS) technology enables early diagnosis."
Confirms the role of MS/MS-based newborn screening for early CACT deficiency diagnosis.
PMID:37305732 SUPPORT Human Clinical
"The ratios of the primary markers (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 can facilitate the diagnosis of CACT deficiency, thereby increasing sensitivity and reducing false-positivity."
Demonstrates improved newborn screening performance with ratio-based markers.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling is recommended for affected families. Once SLC25A20 pathogenic variants are identified, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible. At-risk newborn siblings should be tested in parallel with newborn screening.
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Once the SLC25A20 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible."
GeneReviews confirms availability of carrier, prenatal, and preimplantation genetic testing.
Fasting avoidance and emergency planning
Action: supportive care MAXO:0000950
Prevention of metabolic crises through strict avoidance of prolonged fasting, provision of nocturnal feeding, and implementation of a home emergency plan for prompt illness management. Pre-procedure hospital management with IV dextrose is recommended for surgeries or sedation.
Mechanism Target:
INHIBITS Catabolic stress-triggered metabolic decompensation — Avoiding fasting and maintaining emergency plans reduce catabolic stress exposures that precipitate crises.
Show evidence (1 reference)
PMID:35862567 SUPPORT Human Clinical
"Agents/circumstances to avoid: Prolonged fasting, catabolic illness (fever, intercurrent infection), inadequate caloric provision during times of catabolic stress (including during fasting), prolonged strenuous physical activity, and prolonged administration of anesthetics containing high levels..."
GeneReviews lists fasting and catabolic illness as exposures to avoid in CACT deficiency.
Target Phenotypes: Hypoketotic hypoglycemia ↗ Hyperammonemia ↗ Encephalopathy ↗
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"A home emergency plan for prompt illness management should be provided to parents, primary care providers, teachers, and school staff."
GeneReviews emphasizes the importance of emergency planning and fasting avoidance.
PMID:39203843 SUPPORT Human Clinical
"Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis"
Review confirms the central importance of preventing lipolysis and managing catabolic states.
🔬

Biochemical Markers

4
Long-chain acylcarnitines (C16, C18, C18:1) (INCREASED)
Context: Characteristic elevation of long-chain acylcarnitines C16 (palmitoylcarnitine), C18 (stearoylcarnitine), and C18:1 (oleoylcarnitine) on acylcarnitine profiling is the primary diagnostic marker. This profile overlaps with CPT II deficiency and requires genetic confirmation for discrimination.
Pathograph Readouts
Readout Of Toxic acylcarnitine accumulation and secondary carnitine depletion Positive Diagnostic
Elevated C16, C18, and C18:1 acylcarnitines report the long-chain acylcarnitine accumulation caused by defective CACT-mediated transport.
Show evidence (1 reference)
PMID:37305732 SUPPORT Human Clinical
"The acylcarnitine profiles from 15 patients were classified into three categories using C12, C14, C16, C18, C16:1, C18:1, and C18:2 as the primary diagnostic markers."
Patient newborn-screening profiles support C16, C18, C16:1, and C18:1 as primary diagnostic markers that report the long-chain acylcarnitine accumulation state.
Show evidence (2 references)
PMID:35862567 SUPPORT Human Clinical
"Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency."
GeneReviews confirms elevated C16, C18, and C18:1 as diagnostic markers.
PMID:37305732 SUPPORT Human Clinical
"The acylcarnitine profiles from 15 patients were classified into three categories using C12, C14, C16, C18, C16:1, C18:1, and C18:2 as the primary diagnostic markers."
Newborn screening study confirms long-chain acylcarnitines as primary diagnostic markers in genetically confirmed cases.
Free carnitine (C0) (DECREASED)
Context: Secondary free carnitine depletion results from sequestration in long-chain acylcarnitine esters that cannot be transported into mitochondria. Low free carnitine is a characteristic biochemical finding.
Pathograph Readouts
Readout Of Toxic acylcarnitine accumulation and secondary carnitine depletion Negative Diagnostic
Low free carnitine reports the secondary carnitine-depletion component of the CACT acylcarnitine trapping mechanism.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Free carnitine is low in blood, with marked elevations of C16, C18, and C18:1 carnitine species."
The review directly links low free carnitine with the marked long-chain acylcarnitine elevation pattern in CACT deficiency.
Show evidence (1 reference)
PMID:37305732 SUPPORT Human Clinical
"The second category for patients P7 and P8 showed a significant decrease in the C0 level and a normal concentration of long-chain acylcarnitines."
Directly demonstrates decreased free carnitine (C0) in confirmed CACT-deficient patients.
Acylcarnitine ratio indices (INCREASED)
Context: Acylcarnitine ratio indices including (C16+C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 improve diagnostic sensitivity and reduce false-positive rates in newborn screening compared with single acylcarnitine markers alone. False-positive rates with ratios were 0.02-0.08% versus 0.16-0.88% for single acylcarnitine indices.
Pathograph Readouts
Readout Of Toxic acylcarnitine accumulation and secondary carnitine depletion Positive Diagnostic
Increased long-chain acylcarnitine ratio indices report the abnormal acylcarnitine accumulation pattern caused by CACT deficiency and improve newborn-screening discrimination.
Show evidence (1 reference)
PMID:37305732 SUPPORT Human Clinical
"An acylcarnitine ratio analysis showed that C14/C3, C16/C2, C16/C3, C18/C3, C16:1/C3, and C16:1-OH/C3 were significantly increased in all 15 patients."
Ratio indices are increased in genetically confirmed CACT deficiency and therefore read out the acylcarnitine accumulation state.
Show evidence (1 reference)
PMID:37305732 SUPPORT Human Clinical
"The ratios of the primary markers (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 can facilitate the diagnosis of CACT deficiency, thereby increasing sensitivity and reducing false-positivity."
Study demonstrates improved diagnostic performance of ratio indices over single markers.
Dicarboxylic aciduria (INCREASED)
Context: Urinary dicarboxylic acid excretion can be seen when impaired mitochondrial long-chain fatty acid oxidation redirects substrates toward alternative oxidation pathways.
Pathograph Readouts
Readout Of Impaired mitochondrial long-chain fatty acid oxidation Positive Diagnostic
Dicarboxylic aciduria is a urinary organic-acid readout of impaired mitochondrial long-chain fatty acid oxidation and compensatory omega-oxidation.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Urine organic acids may show dicarboxylic aciduria."
The review supports dicarboxylic aciduria as an organic-acid finding in CACT deficiency, reflecting the long-chain FAO block.
Show evidence (1 reference)
PMID:29502916 SUPPORT Human Clinical
"Urine organic acids may show dicarboxylic aciduria."
Review evidence supports dicarboxylic aciduria as a urinary biochemical finding in CACT deficiency.
{ }

Source YAML

click to show 
name: Carnitine-acylcarnitine Translocase Deficiency
category: Mendelian
creation_date: '2026-02-23T00:00:00Z'
updated_date: '2026-05-21T04:48:31Z'
synonyms:
- CACT deficiency
- CACTD
- SLC25A20 deficiency
- Carnitine-acylcarnitine carrier deficiency
description: 'Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disorder of mitochondrial long-chain fatty acid oxidation caused by biallelic pathogenic variants in SLC25A20. CACT is a mitochondrial inner membrane transporter that facilitates the exchange of long-chain acylcarnitines for free carnitine across the inner mitochondrial membrane, a critical step in the carnitine shuttle required for long-chain fatty acid beta-oxidation. Loss of CACT function leads to impaired mitochondrial energy production during fasting or catabolic stress, accumulation of toxic long-chain acylcarnitines, and secondary free carnitine depletion. The severe neonatal-onset form presents within the first days of life with hypoketotic hypoglycemia, hyperammonemia, cardiac arrhythmia, cardiomyopathy, hepatic dysfunction, and high mortality (~65%) predominantly from cardiac causes. An attenuated form with later onset and milder symptoms allows better developmental outcomes with appropriate treatment.

  '
disease_term:
  preferred_term: carnitine-acylcarnitine translocase deficiency
  term:
    id: MONDO:0008918
    label: carnitine-acylcarnitine translocase deficiency
parents:
- Fatty Acid Oxidation Disorder
- Inborn Error of Metabolism
prevalence:
- population: Hong Kong newborns
  percentage: 1 in 30,448
  notes: >-
    In Hong Kong newborn screening, one CACT deficiency case was identified
    among 30,448 screened newborns. Retrospective biochemical ascertainment in
    Hong Kong also found that CACT deficiency was the predominant long-chain
    fatty acid oxidation defect locally, supporting population enrichment in
    southern Chinese populations despite the disease's global rarity.
  evidence:
  - reference: PMID:28862145
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six neonates were confirmed to have inborn errors of metabolism, including two cases of medium-chain acyl-coenzyme A dehydrogenase deficiency, one case of carnitine-acylcarnitine translocase deficiency, and three milder conditions."
    explanation: This Hong Kong newborn-screening cohort directly documents one CACT deficiency case among 30,448 screened newborns.
  - reference: PMID:21542954
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "8 cases (19%) of fatty acid oxidation defects (predominantly carnitine-acylcarnitine translocase deficiency)."
    explanation: This retrospective Hong Kong diagnostic series shows that CACT deficiency was the predominant fatty-acid oxidation defect in the local ascertained cohort, supporting relative enrichment.
progression:
- phase: neonatal onset
  notes: 'The severe neonatal-onset form accounts for approximately 82% of cases. Symptoms become evident within two days after birth, with acute metabolic decompensation triggered by the transition from placental energy supply to dependence on endogenous fatty acid oxidation. Hyperammonemia and cardiac arrhythmia are prominent, with high rates of cardiac arrest.

    '
  evidence:
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The onset of symptoms is predominantly neonatal in 82% and infantile in 18%.
    explanation: Quantifies neonatal onset frequency at 82%.
- phase: infantile onset
  notes: 'Attenuated cases presenting in the first months of life account for approximately 18% of cases. These patients have milder symptoms and are less likely to experience recurrent hyperammonemia, allowing better developmental outcomes.

    '
  evidence:
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The onset of symptoms is predominantly neonatal in 82% and infantile in 18%.
    explanation: Quantifies infantile onset frequency at 18%.
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected individuals with later-onset disease have milder symptoms and are less likely to experience recurrent hyperammonemia, allowing a better developmental outcome.
    explanation: GeneReviews confirms milder course and better outcomes in later-onset disease.
pathophysiology:
- name: SLC25A20 transporter molecular function deficiency
  description: 'Biallelic SLC25A20 pathogenic variants reduce mitochondrial inner membrane carnitine-acylcarnitine translocase activity.

    '
  genes:
  - preferred_term: SLC25A20
    term:
      id: hgnc:1421
      label: SLC25A20
  biological_processes:
  - preferred_term: carnitine transport
    term:
      id: GO:0015879
      label: carnitine transport
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity.
    explanation: Supports SLC25A20/CACT transporter dysfunction as the initiating molecular event.
  downstream:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    description: Defective acylcarnitine translocation limits matrix substrate delivery for long-chain FAO.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Carnitine-acylcarnitine translocase (CACT) is a critical component of the carnitine shuttle, which facilitates the transfer of long-chain fatty acylcarnitines across the inner mitochondrial membrane.
      explanation: GeneReviews identifies CACT as the inner-membrane carnitine-shuttle transporter required for long-chain acylcarnitine transfer, supporting this direct proximal edge.
- name: Impaired mitochondrial long-chain fatty acid oxidation
  description: 'Impaired transport of long-chain acylcarnitines into the mitochondrial matrix blocks long-chain fatty acid beta-oxidation. This leads to inadequate ATP generation during fasting, birth, or illness, and impaired ketogenesis, shifting energy reliance to glucose until glycogen stores are depleted.

    '
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  - preferred_term: ketone body metabolic process
    term:
      id: GO:1902224
      label: ketone body metabolic process
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity.
    explanation: Supports impaired long-chain fatty acid oxidation downstream of CACT transporter dysfunction.
  downstream:
  - target: Toxic acylcarnitine accumulation and secondary carnitine depletion
    description: Failure of long-chain fatty acid oxidation is reflected by long-chain acylcarnitine accumulation and reduced free carnitine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency.
      explanation: The characteristic diagnostic profile supports long-chain acylcarnitine accumulation downstream of impaired CACT-mediated long-chain FAO.
  - target: Catabolic stress-triggered metabolic decompensation
    description: Fasting, illness, and the neonatal birth transition increase dependence on long-chain FAO, exposing the energy-generation block.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased reliance on long-chain fatty acids during fasting, illness, and early neonatal adaptation.
    - Reduced acetyl-CoA, reducing-equivalent, ATP, and ketone-body generation.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.
      explanation: The review links neonatal reliance on long-chain fatty acids to the severe acute CACT deficiency presentation.
  - target: Hypoketotic hypoglycemia
    description: Impaired long-chain FAO reduces hepatic ketogenesis and forces glucose dependence during fasting or illness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced mitochondrial acetyl-CoA production from long-chain fatty acids.
    - Impaired ketone-body synthesis with enhanced reliance on glucose oxidation.
    evidence:
    - reference: PMID:33024728
      reference_title: "Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A general characteristic of all mFAO disorders is hypoketotic hypoglycemia resulting from the enhanced reliance on glucose oxidation and the inability to synthesize ketone bodies from FAs.
      explanation: Review evidence supports hypoketotic hypoglycemia as the downstream biochemical-clinical consequence of mitochondrial FAO failure.
- name: Toxic acylcarnitine accumulation and secondary carnitine depletion
  description: 'Blocked transport of long-chain acylcarnitines results in their cytoplasmic accumulation and secondary depletion of free carnitine. Accumulated long-chain acylcarnitines and acyl-CoA derivatives cause biochemical toxicity in high-energy-demand tissues including heart, skeletal muscle, liver, and kidney, manifesting as lipid-laden microvesicular steatosis across multiple organs.

    '
  biological_processes:
  - preferred_term: carnitine shuttle
    term:
      id: GO:0006853
      label: carnitine shuttle
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:38628283
    reference_title: "Carnitine-acylcarnitine translocase deficiency: a case report with autopsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes.
    explanation: Autopsy evidence of multi-organ lipid accumulation directly supports toxic acylcarnitine/lipid handling failure.
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency.
    explanation: Elevated long-chain acylcarnitines confirm acylcarnitine accumulation as a disease hallmark.
  downstream:
  - target: Cardiac energy failure and arrhythmogenesis
    description: Long-chain acylcarnitine/lipid accumulation and reduced fatty-acid energy production injure cardiomyocytes.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cardiomyocyte energy deficit during reliance on long-chain fatty acids.
    - Lipid-laden microvesicular steatosis in cardiac myocytes.
    evidence:
    - reference: PMID:38628283
      reference_title: "Carnitine-acylcarnitine translocase deficiency: a case report with autopsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes.
      explanation: Autopsy pathology documents lipid accumulation in cardiac myocytes, supporting the tissue-level cardiac mechanism.
  - target: Long-chain acylcarnitines (C16, C18, C18:1)
    description: Blocked acylcarnitine handling produces the characteristic elevated long-chain acylcarnitine profile.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency.
      explanation: GeneReviews directly supports elevated C16, C18, and C18:1 as the biochemical consequence represented by this edge.
  - target: Free carnitine (C0)
    description: Trapping of carnitine in acylcarnitine species can deplete circulating free carnitine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Free carnitine is low in blood, with marked elevations of C16, C18, and C18:1 carnitine species.
      explanation: Review evidence directly supports low free carnitine with marked long-chain acylcarnitine elevation in CACT deficiency.
  - target: Dicarboxylic aciduria
    description: Impaired mitochondrial long-chain FAO can shunt fatty acids toward omega-oxidation and urinary dicarboxylic acids.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mitochondrial long-chain FAO block.
    - Compensatory omega-oxidation and urinary organic acid excretion.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Urine organic acids may show dicarboxylic aciduria.
      explanation: Review evidence supports dicarboxylic aciduria as a downstream biochemical finding in CACT deficiency.
  - target: Hepatomegaly
    description: Lipid accumulation and hepatic energy failure cause liver dysfunction with hepatomegaly.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatocyte microvesicular steatosis.
    - Hepatic dysfunction during metabolic decompensation.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
      explanation: GeneReviews supports hepatic dysfunction with hepatomegaly among the downstream clinical features of long-chain FAO failure.
  - target: Elevated circulating hepatic transaminase concentration
    description: Hepatocyte lipid accumulation and energy failure produce hepatocellular injury reflected by transaminitis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatocyte microvesicular steatosis.
    - Hepatic dysfunction during long-chain FAO crises.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
      explanation: GeneReviews lists transaminitis as a typical downstream feature of the long-chain FAO disorder phenotype.
  - target: Rhabdomyolysis
    description: Toxic lipid accumulation and energy failure in skeletal muscle predispose to muscle breakdown during stress.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Rhabdomyocyte microvesicular steatosis.
    - Skeletal muscle energy deficit during physiologic stress.
    evidence:
    - reference: PMID:38628283
      reference_title: "Carnitine-acylcarnitine translocase deficiency: a case report with autopsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes.
      explanation: Autopsy evidence of rhabdomyocyte lipid accumulation supports skeletal muscle vulnerability downstream of CACT deficiency.
- name: Catabolic stress-triggered metabolic decompensation
  description: 'Birth transition, fasting, illness, or poor intake increase dependence on long-chain fatty acid oxidation. In CACT deficiency this exposes the transport and FAO block, producing acute systemic decompensation with poor feeding, lethargy, hypotonia, respiratory distress or apnea, and encephalopathy.

    '
  biological_processes:
  - preferred_term: response to starvation
    term:
      id: GO:0042594
      label: response to starvation
  - preferred_term: generation of precursor metabolites and energy
    term:
      id: GO:0006091
      label: generation of precursor metabolites and energy
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.
    explanation: Review evidence links neonatal long-chain fatty-acid dependence to the severe systemic CACT deficiency presentation.
  downstream:
  - target: Hyperammonemia during metabolic crises
    description: Acute FAO failure during catabolic crises contributes to hyperammonemia, which is prominent and difficult to treat in CACT deficiency.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acute hepatic energy deficit during catabolism.
    - Secondary disruption of nitrogen disposal during metabolic crises.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome.
      explanation: GeneReviews supports hyperammonemia as a key downstream crisis mechanism in CACT deficiency.
  - target: Poor feeding
    description: Acute energy failure in neonatal and illness-triggered crises produces feeding difficulty.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acute systemic energy deficit during metabolic decompensation.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
      explanation: GeneReviews lists poor feeding among the typical clinical features of long-chain FAO-related CACT deficiency.
  - target: Lethargy
    description: Acute systemic energy deficit during metabolic crises causes decreased alertness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acute systemic energy deficit during metabolic decompensation.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
      explanation: GeneReviews lists lethargy among the typical clinical features of CACT deficiency.
  - target: Muscular hypotonia
    description: Energy failure affecting skeletal muscle and CNS function contributes to hypotonia in the acute presentation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Skeletal muscle energy deficit.
    - Systemic neonatal metabolic decompensation.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis."
      explanation: GeneReviews lists hypotonia among the typical clinical features of CACT deficiency.
  - target: Respiratory distress
    description: Severe neonatal metabolic decompensation can present with respiratory distress.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acute systemic metabolic crisis.
    - Cardiac, hepatic, neurologic, or respiratory muscle involvement during decompensation.
    evidence:
    - reference: PMID:25614308
      reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress.
      explanation: Literature review identifies respiratory distress as a frequent presenting feature of CACT deficiency.
  - target: Encephalopathy
    description: Acute metabolic crisis and impaired energy supply can produce encephalopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acute systemic metabolic decompensation.
    - Hyperammonemia, hypoglycemia, and impaired cerebral energy supply.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.
      explanation: Review evidence lists encephalopathy as part of severe neonatal CACT deficiency presentation.
  - target: Apnea
    description: Severe neonatal metabolic decompensation can manifest with apnea.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acute systemic metabolic decompensation.
    - Neurologic and respiratory instability during severe neonatal disease.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.
      explanation: Review evidence lists apnea as part of severe neonatal CACT deficiency presentation.
- name: Cardiac energy failure and arrhythmogenesis
  description: 'The heart is highly dependent on long-chain fatty acid oxidation for energy. CACT deficiency causes cardiac energy deficit and toxic lipid accumulation in cardiomyocytes, leading to hypertrophic cardiomyopathy and cardiac arrhythmias. Cardiac involvement is often the primary determinant of mortality.

    '
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest.
    explanation: GeneReviews confirms cardiac arrhythmia and cardiac arrest as prominent early-onset features.
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The mortality rate is high (65%), most in the first year of life due to myocardiopathy or sudden death.
    explanation: Confirms cardiomyopathy and sudden death as primary causes of mortality.
  - reference: PMID:33024728
    reference_title: "Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with a defect in the oxidation of long-chain FAs are at risk to develop cardiac and skeletal muscle abnormalities including cardiomyopathy and arrhythmias, which may progress into early death
    explanation: Review confirming cardiac and skeletal muscle vulnerability in long-chain fatty acid oxidation disorders.
  downstream:
  - target: Cardiac arrhythmia
    description: Cardiomyocyte energy failure and lipid toxicity increase arrhythmia risk in early-onset CACT deficiency.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest.
      explanation: GeneReviews supports cardiac arrhythmia as a prominent downstream feature of the cardiac disease mechanism.
  - target: Hypertrophic cardiomyopathy
    description: Energy failure and lipid accumulation in cardiomyocytes produce hypertrophic cardiomyopathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Univentricular or biventricular hypertrophic cardiomyopathy, ranging from mild to severe, may respond to appropriate dietary and medical therapies.
      explanation: GeneReviews directly supports hypertrophic cardiomyopathy as a downstream cardiac manifestation.
- name: Hyperammonemia during metabolic crises
  description: 'Hyperammonemia is a prominent and difficult-to-treat feature of CACT deficiency, particularly during neonatal and acute metabolic crises. It is an important determinant of long-term neurocognitive outcome. Ammonia scavenger medications are of limited efficacy; high-rate dextrose infusion is the most effective intervention.

    '
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome.
    explanation: GeneReviews directly describes hyperammonemia as a key clinical challenge and prognostic factor.
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress.
    explanation: Literature review confirms hyperammonemia as one of the most frequent presenting symptoms.
  downstream:
  - target: Hyperammonemia
    description: The metabolic-crisis mechanism is clinically measured as elevated blood ammonia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest.
      explanation: GeneReviews supports hyperammonemia as a prominent early-onset clinical manifestation.
  - target: Seizures
    description: Severe hypoglycemia and hyperammonemia during CACTD crises can be accompanied by seizures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acute metabolic decompensation with hypoglycemia and hyperammonemia.
    - Cerebral energy failure and hyperammonemic neurotoxicity.
    evidence:
    - reference: PMID:34449152
      reference_title: "Clinical and molecular characteristics of carnitineacylcarnitine translocase deficiency with c.270delC and a novel c.408C>A variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: CACTD is characterized by severe episodes of hypoglycemia and hyperammonemia, seizures, cardiomyopathy, liver dysfunction, severe neurological damage, and muscle weakness.
      explanation: CACTD case series directly lists seizures with severe hypoglycemia and hyperammonemia.
  - target: Global developmental delay
    description: Recurrent hyperammonemia and acute brain injury can lead to developmental delay or intellectual disability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hyperammonemic brain injury during early-onset crises.
    - Recurrent hyperammonemia after presentation.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Affected individuals with early-onset disease typically experience brain injury at presentation, and have recurrent hyperammonemia leading to developmental delay / intellectual disability.
      explanation: GeneReviews directly links brain injury and recurrent hyperammonemia to developmental delay/intellectual disability.
phenotypes:
- name: Hypoketotic hypoglycemia
  frequency: VERY_FREQUENT
  description: 'Fasting intolerance with low ketone production and hypoglycemia is a hallmark of CACT deficiency, resulting from the inability to oxidize long-chain fatty acids for ketogenesis.

    '
  phenotype_term:
    preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis.'
    explanation: GeneReviews lists hypoketotic hypoglycemia as a typical clinical feature.
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress.
    explanation: Literature review confirms hypoketotic hypoglycemia as among the most frequent presenting symptoms.
  - reference: PMID:33024728
    reference_title: "Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A general characteristic of all mFAO disorders is hypoketotic hypoglycemia resulting from the enhanced reliance on glucose oxidation and the inability to synthesize ketone bodies from FAs.
    explanation: Review confirms hypoketotic hypoglycemia as a general characteristic of all mitochondrial fatty acid oxidation disorders.
- name: Hyperammonemia
  frequency: VERY_FREQUENT
  description: 'Elevated ammonia is a prominent and difficult-to-treat feature, particularly in early-onset disease. It is an important determinant of neurocognitive outcome.

    '
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest.
    explanation: GeneReviews identifies hyperammonemia as prominent in early-onset CACT deficiency.
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress.
    explanation: Literature review confirms hyperammonemia as one of the most frequent presenting symptoms.
- name: Cardiac arrhythmia
  frequency: VERY_FREQUENT
  description: 'Cardiac arrhythmias are prominent in early-onset disease and are associated with high rates of cardiac arrest. Arrhythmia is a major contributor to early mortality.

    '
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest.
    explanation: GeneReviews identifies cardiac arrhythmia as prominent in early-onset disease.
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fatty acid oxidation disorders (FAODs) and carnitine shuttling defects are inborn errors of energy metabolism with associated mortality and morbidity due to cardiomyopathy, exercise intolerance, rhabdomyolysis, and liver disease
    explanation: Review confirms cardiomyopathy and cardiac morbidity in fatty acid oxidation and carnitine shuttle disorders.
- name: Hypertrophic cardiomyopathy
  frequency: FREQUENT
  description: 'Univentricular or biventricular hypertrophic cardiomyopathy, ranging from mild to severe, is a common feature. Cardiac involvement may respond to dietary and medical therapies but is a frequent cause of death.

    '
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Univentricular or biventricular hypertrophic cardiomyopathy, ranging from mild to severe, may respond to appropriate dietary and medical therapies.
    explanation: GeneReviews describes hypertrophic cardiomyopathy as a recognized feature that may respond to treatment.
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress.
    explanation: Literature review identifies cardiomyopathy as among the most frequent presenting symptoms.
- name: Hepatomegaly
  frequency: FREQUENT
  description: 'Liver enlargement with hepatic dysfunction, transaminitis, and microvesicular steatosis reflecting impaired mitochondrial fat handling and lipid accumulation in hepatocytes.

    '
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis.'
    explanation: GeneReviews lists liver dysfunction with hepatomegaly as a typical clinical feature.
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress.
    explanation: Literature review confirms hepatomegaly as one of the most frequent presenting symptoms.
- name: Muscular hypotonia
  frequency: FREQUENT
  description: 'Hypotonia is a typical feature of CACT deficiency, reflecting impaired skeletal muscle energy metabolism.

    '
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis.'
    explanation: GeneReviews lists hypotonia as a typical clinical feature of CACT deficiency.
- name: Rhabdomyolysis
  frequency: OCCASIONAL
  description: 'Skeletal muscle breakdown due to impaired muscle energy metabolism and toxic metabolite accumulation. Rhabdomyolysis can occur during metabolic decompensation episodes.

    '
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis.'
    explanation: GeneReviews lists rhabdomyolysis as a typical clinical feature of long-chain fatty acid oxidation disorders.
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fatty acid oxidation disorders (FAODs) and carnitine shuttling defects are inborn errors of energy metabolism with associated mortality and morbidity due to cardiomyopathy, exercise intolerance, rhabdomyolysis, and liver disease
    explanation: Review confirms rhabdomyolysis as a source of morbidity in FAODs and carnitine shuttle defects.
- name: Lethargy
  frequency: FREQUENT
  description: 'Decreased alertness and lethargy during acute metabolic decompensation episodes, reflecting systemic energy failure.

    '
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis.'
    explanation: GeneReviews lists lethargy as a typical clinical feature.
- name: Poor feeding
  frequency: FREQUENT
  description: 'Feeding difficulties are common, particularly in neonatal-onset disease. Feeding tube placement and/or feeding therapy may be required.

    '
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis.'
    explanation: GeneReviews lists poor feeding as a typical clinical feature.
- name: Global developmental delay
  frequency: FREQUENT
  description: 'Affected individuals with early-onset disease typically experience brain injury at presentation and recurrent hyperammonemia, leading to developmental delay and intellectual disability. Later-onset cases have better developmental outcomes.

    '
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected individuals with early-onset disease typically experience brain injury at presentation, and have recurrent hyperammonemia leading to developmental delay / intellectual disability.
    explanation: GeneReviews directly states developmental delay as a consequence of early-onset disease.
- name: Respiratory distress
  frequency: FREQUENT
  description: 'Respiratory distress is a frequent presenting symptom in neonatal-onset CACT deficiency.

    '
  phenotype_term:
    preferred_term: Respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  evidence:
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress.
    explanation: Literature review identifies respiratory distress among the most frequent presenting symptoms.
- name: Seizures
  frequency: OCCASIONAL
  description: 'Seizures may occur in the context of metabolic decompensation, energy failure, and encephalopathy.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34449152
    reference_title: "Clinical and molecular characteristics of carnitineacylcarnitine translocase deficiency with c.270delC and a novel c.408C>A variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CACTD is characterized by severe episodes of hypoglycemia and hyperammonemia, seizures, cardiomyopathy, liver dysfunction, severe neurological damage, and muscle weakness.
    explanation: CACTD case series directly supports seizures as part of the clinical spectrum.
- name: Encephalopathy
  description: 'Severe neonatal metabolic decompensation can include encephalopathy due to combined energy failure, hypoglycemia, and hyperammonemia.

    '
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.
    explanation: Review evidence lists encephalopathy among severe neonatal CACT deficiency manifestations.
- name: Apnea
  description: 'Severe neonatal presentations can include apnea as part of respiratory and neurologic instability during metabolic crisis.

    '
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Because neonates depend largely on metabolism of long-chain fatty acids for energy, neonatal presentation is typically severe, with hypoketotic hypoglycemia, hyperammonemia, hypertrophic cardiomyopathy and/or arrhythmia, apnea, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.
    explanation: Review evidence lists apnea among severe neonatal CACT deficiency manifestations.
- name: Elevated circulating hepatic transaminase concentration
  frequency: FREQUENT
  description: 'Transaminitis reflecting hepatocellular injury and hepatic dysfunction is a typical feature of CACT deficiency.

    '
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis.'
    explanation: GeneReviews lists transaminitis as a typical clinical feature.
biochemical:
- name: Long-chain acylcarnitines (C16, C18, C18:1)
  presence: INCREASED
  context: 'Characteristic elevation of long-chain acylcarnitines C16 (palmitoylcarnitine), C18 (stearoylcarnitine), and C18:1 (oleoylcarnitine) on acylcarnitine profiling is the primary diagnostic marker. This profile overlaps with CPT II deficiency and requires genetic confirmation for discrimination.

    '
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency.
    explanation: GeneReviews confirms elevated C16, C18, and C18:1 as diagnostic markers.
  - reference: PMID:37305732
    reference_title: "Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The acylcarnitine profiles from 15 patients were classified into three categories using C12, C14, C16, C18, C16:1, C18:1, and C18:2 as the primary diagnostic markers.
    explanation: Newborn screening study confirms long-chain acylcarnitines as primary diagnostic markers in genetically confirmed cases.
  readouts:
  - target: Toxic acylcarnitine accumulation and secondary carnitine depletion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated C16, C18, and C18:1 acylcarnitines report the long-chain acylcarnitine accumulation caused by defective CACT-mediated transport.
    evidence:
    - reference: PMID:37305732
      reference_title: "Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The acylcarnitine profiles from 15 patients were classified into three categories using C12, C14, C16, C18, C16:1, C18:1, and C18:2 as the primary diagnostic markers.
      explanation: Patient newborn-screening profiles support C16, C18, C16:1, and C18:1 as primary diagnostic markers that report the long-chain acylcarnitine accumulation state.
- name: Free carnitine (C0)
  presence: DECREASED
  context: 'Secondary free carnitine depletion results from sequestration in long-chain acylcarnitine esters that cannot be transported into mitochondria. Low free carnitine is a characteristic biochemical finding.

    '
  evidence:
  - reference: PMID:37305732
    reference_title: "Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The second category for patients P7 and P8 showed a significant decrease in the C0 level and a normal concentration of long-chain acylcarnitines.
    explanation: Directly demonstrates decreased free carnitine (C0) in confirmed CACT-deficient patients.
  readouts:
  - target: Toxic acylcarnitine accumulation and secondary carnitine depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low free carnitine reports the secondary carnitine-depletion component of the CACT acylcarnitine trapping mechanism.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Free carnitine is low in blood, with marked elevations of C16, C18, and C18:1 carnitine species.
      explanation: The review directly links low free carnitine with the marked long-chain acylcarnitine elevation pattern in CACT deficiency.
- name: Acylcarnitine ratio indices
  presence: INCREASED
  context: 'Acylcarnitine ratio indices including (C16+C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 improve diagnostic sensitivity and reduce false-positive rates in newborn screening compared with single acylcarnitine markers alone. False-positive rates with ratios were 0.02-0.08% versus 0.16-0.88% for single acylcarnitine indices.

    '
  evidence:
  - reference: PMID:37305732
    reference_title: "Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ratios of the primary markers (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 can facilitate the diagnosis of CACT deficiency, thereby increasing sensitivity and reducing false-positivity.
    explanation: Study demonstrates improved diagnostic performance of ratio indices over single markers.
  readouts:
  - target: Toxic acylcarnitine accumulation and secondary carnitine depletion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased long-chain acylcarnitine ratio indices report the abnormal acylcarnitine accumulation pattern caused by CACT deficiency and improve newborn-screening discrimination.
    evidence:
    - reference: PMID:37305732
      reference_title: "Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: An acylcarnitine ratio analysis showed that C14/C3, C16/C2, C16/C3, C18/C3, C16:1/C3, and C16:1-OH/C3 were significantly increased in all 15 patients.
      explanation: Ratio indices are increased in genetically confirmed CACT deficiency and therefore read out the acylcarnitine accumulation state.
- name: Dicarboxylic aciduria
  presence: INCREASED
  context: 'Urinary dicarboxylic acid excretion can be seen when impaired mitochondrial long-chain fatty acid oxidation redirects substrates toward alternative oxidation pathways.

    '
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Urine organic acids may show dicarboxylic aciduria.
    explanation: Review evidence supports dicarboxylic aciduria as a urinary biochemical finding in CACT deficiency.
  readouts:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Dicarboxylic aciduria is a urinary organic-acid readout of impaired mitochondrial long-chain fatty acid oxidation and compensatory omega-oxidation.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Urine organic acids may show dicarboxylic aciduria.
      explanation: The review supports dicarboxylic aciduria as an organic-acid finding in CACT deficiency, reflecting the long-chain FAO block.
histopathology:
- name: Multi-organ microvesicular steatosis
  finding_term:
    preferred_term: Microvesicular steatosis
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  description: 'Autopsy pathology in CACT deficiency can be dominated by microvesicular steatosis involving hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes. This microscopic lipid accumulation reflects impaired long-chain fatty-acid handling across high-energy tissues.

    '
  evidence:
  - reference: PMID:38628283
    reference_title: "Carnitine-acylcarnitine translocase deficiency: a case report with autopsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes.
    explanation: Autopsy case report directly documents the multi-organ microvesicular steatosis pattern.
genetic:
- name: SLC25A20 pathogenic variants
  gene_term:
    preferred_term: SLC25A20
    term:
      id: hgnc:1421
      label: SLC25A20
  features: 'CACT deficiency is caused by biallelic pathogenic variants in SLC25A20, encoding the mitochondrial inner membrane carnitine-acylcarnitine translocase. The protein functions via an alternating-access mechanism with asymmetric conformational changes. Over 30 pathogenic variants have been described. The acylcarnitine profile overlaps with CPT II deficiency, requiring SLC25A20 sequencing or functional assays for definitive diagnosis.

    '
  inheritance:
  - name: Autosomal recessive
    description: 'CACT deficiency is inherited in an autosomal recessive manner. Each sibling of an affected individual has a 25% chance of being affected, 50% chance of being a carrier, and 25% chance of being unaffected. Heterozygous carriers are asymptomatic.

      '
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: CACT deficiency is inherited in an autosomal recessive manner.
      explanation: GeneReviews directly states autosomal recessive inheritance.
  variants:
  - name: c.199-10T>G splice variant in SLC25A20
    description: 'A recurrent splice variant common in a Chinese cohort (14/15 patients homozygous), associated with severe early-onset disease.

      '
    gene:
      preferred_term: SLC25A20
      term:
        id: hgnc:1421
        label: SLC25A20
  - name: p.Gly20Asp (c.59G>A) variant
    description: 'Novel variant identified in a Spanish patient with severe neonatal-onset disease and fatal outcome during intercurrent infection in the first year.

      '
    gene:
      preferred_term: SLC25A20
      term:
        id: hgnc:1421
        label: SLC25A20
    evidence:
    - reference: PMID:25614308
      reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Two cases with neonatal onset, carrying in homozygosity the novel variant sequences p.Gly20Asp (c.59G>A) and p.Arg179Gly (c.536A>G), died during an intercurrent infectious process in the first year of life
      explanation: Spanish case series reporting novel pathogenic variants with clinical outcomes.
  - name: Asp231His and Ala281Val pathogenic mutations
    description: 'In silico structural modeling demonstrates that Asp231His disrupts the matrix salt-bridge network and Ala281Val impairs helix packing and conformational transitions required for substrate transport.

      '
    gene:
      preferred_term: SLC25A20
      term:
        id: hgnc:1421
        label: SLC25A20
    evidence:
    - reference: PMID:36835358
      reference_title: "In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: analysis of the MD simulations' trajectories of the apo-protein in the two conformational states allowed for a better understanding of the role of SLC25A20 Asp231His and Ala281Val pathogenic mutations, which are at the basis of Carnitine-Acylcarnitine Translocase Deficiency.
      explanation: In silico study providing structural mechanistic insight into pathogenic variants.
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The diagnosis of CACT deficiency is confirmed by identification of biallelic pathogenic variants in SLC25A20
    explanation: GeneReviews confirms SLC25A20 as the causal gene with biallelic variants required for diagnosis.
  - reference: PMID:36835358
    reference_title: "In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: The Carnitine-Acylcarnitine Carrier is a member of the mitochondrial Solute Carrier Family 25 (SLC25), known as SLC25A20, involved in the electroneutral exchange of acylcarnitine and carnitine across the inner mitochondrial membrane.
    explanation: Structural biology study confirming SLC25A20 function in acylcarnitine-carnitine exchange.
- name: SLC25A20
  gene_term:
    preferred_term: SLC25A20
    term:
      id: hgnc:1421
      label: SLC25A20
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_95c9aece-49b5-496f-9547-f6d03dd69b4f-2018-05-22T160000.000Z
    reference_title: "SLC25A20 / carnitine-acylcarnitine translocase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC25A20 | HGNC:1421 | carnitine-acylcarnitine translocase deficiency | MONDO:0008918 | AR | Definitive"
    explanation: ClinGen classifies the SLC25A20-carnitine-acylcarnitine translocase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: High-carbohydrate, long-chain fat-restricted diet
  description: 'The mainstay of chronic therapy is a high-carbohydrate diet providing over 60% of total caloric intake, with restriction of long-chain dietary fat to less than 10% of total calories. Fasting is avoided or strictly limited. Essential fatty acid targets include linoleic acid at 3-4% and linolenic acid at 0.5-1% of total calories.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: BYPASSES
    description: High carbohydrate intake and long-chain fat restriction reduce dependence on the blocked long-chain FAO pathway and limit lipolysis.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible.
      explanation: Nutritional management review explains the bypass rationale for glucose provision and fatty-acid fuel avoidance in FAODs.
  - target: Catabolic stress-triggered metabolic decompensation
    treatment_effect: INHIBITS
    description: Preventing fasting and maintaining uninterrupted calories reduces catabolic decompensation risk.
    evidence:
    - reference: PMID:39203843
      reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake.
      explanation: Review supports diet as prevention of fasting-driven decompensation in FAODs.
  target_phenotypes:
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The mainstay of therapy is a high-carbohydrate diet (>60% of total caloric intake) with restriction of long-chain dietary fat (to <10% of total calories)
    explanation: GeneReviews provides specific dietary guidelines for CACT deficiency management.
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1%
    explanation: Review confirms LCT restriction targets and essential fatty acid requirements for long-chain FAODs.
  - reference: PMID:25614308
    reference_title: "Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diagnosis before the occurrence of clinical symptoms by tandem MS-MS and very early therapeutic intervention together with good dietary compliance could lead to a better prognosis
    explanation: Supports importance of early dietary intervention for improved outcomes.
- name: Triheptanoin therapy
  description: 'Triheptanoin (UX007/Dojolvi), a synthetic medium odd-chain triglyceride, provides anaplerotic support by generating propionyl-CoA that replenishes TCA cycle intermediates via succinyl-CoA. Recommended at 25-35% of total calories. Has demonstrated rapid reversal of cardiogenic shock in a CACT deficiency case and significant reduction in hospitalizations compared with MCT oil in LC-FAOD patients.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
    therapeutic_agent:
    - preferred_term: triheptanoin
      term:
        id: CHEBI:17855
        label: triglyceride
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: BYPASSES
    description: Triheptanoin provides a medium odd-chain triglyceride energy substrate and anaplerotic support when long-chain fatty acid oxidation is impaired.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The mainstay of therapy is a high-carbohydrate diet (>60% of total caloric intake) with restriction of long-chain dietary fat (to <10% of total calories) and treatment with the anaplerotic agent triheptanoin (to provide 25%-35% of total calories).
      explanation: GeneReviews identifies triheptanoin as an anaplerotic treatment for CACT deficiency.
  - target: Catabolic stress-triggered metabolic decompensation
    treatment_effect: INHIBITS
    description: Triheptanoin reduces catabolic and metabolic decompensation episodes in long-chain FAODs.
    evidence:
    - reference: PMID:39375714
      reference_title: "Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD.
      explanation: Clinical cohort supports triheptanoin reducing decompensation burden in long-chain FAODs.
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  - preferred_term: Cardiac arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:39375714
    reference_title: "Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014)'
    explanation: Italian cohort study showing significant reduction in catabolic episodes and hospitalizations with triheptanoin versus MCT oil in LC-FAOD patients.
- name: Medium-chain triglyceride supplementation
  description: 'MCT oil (10-30% of total calories) provides alternative fuel that bypasses the long-chain fatty acid transport defect. MCT oil is used as a substitute when triheptanoin is not available.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: BYPASSES
    description: Medium-chain triglycerides provide calories that bypass the long-chain carnitine shuttle defect.
    evidence:
    - reference: PMID:29502916
      reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Formula should have reduced long-chain fat plus mediumchain triglyceride (MCT) supplementation.
      explanation: Review supports MCT supplementation as a bypass dietary strategy for CACT deficiency.
  target_phenotypes:
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: If triheptanoin is not available, medium-chain triglyceride (MCT) oil (10%-30% of total calories) could be used as a substitute.
    explanation: GeneReviews recommends MCT oil as an alternative when triheptanoin is unavailable.
- name: Carnitine supplementation
  description: 'L-carnitine supplementation at approximately 100 mg/kg/day is recommended to replenish depleted free carnitine stores and support acylcarnitine excretion.

    '
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: MAXO:0010006
      label: carnitine supplementation
  target_mechanisms:
  - target: Toxic acylcarnitine accumulation and secondary carnitine depletion
    treatment_effect: MODULATES
    description: Carnitine supplementation replenishes low free carnitine, although benefit is uncertain and use is guided by carnitine levels.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fasting is avoided or limited, and carnitine supplemented at ~100 mg/kg/day is recommended.
      explanation: GeneReviews recommends carnitine supplementation as part of routine CACT deficiency management.
  evidence:
  - reference: PMID:29502916
    reference_title: "Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Carnitine supplementation may be helpful.
    explanation: Review supports carnitine supplementation in long-chain fatty acid oxidation disorders.
- name: Emergency metabolic crisis management
  description: 'Acute management centers on reversal of catabolism with high-rate intravenous dextrose infusion (12-15 g/kg/day for infants, 10-12 g/kg/day for children). Ammonia scavenger medications are of limited efficacy. Cardiac arrhythmias, cardiomyopathy, rhabdomyolysis, and acute renal impairment are treated per standard of care, typically in the ICU. Triheptanoin should be considered for cardiogenic shock.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Catabolic stress-triggered metabolic decompensation
    treatment_effect: INHIBITS
    description: High-dextrose fluids reverse catabolism and reduce endogenous lipolysis during acute crises.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Administration of high-dextrose-containing fluids: oral/enteral carbohydrate polymer (at home) or intravenous dextrose (in the hospital)."
      explanation: GeneReviews supports high-dextrose fluids as acute therapy for CACT deficiency crises.
  - target: Hyperammonemia during metabolic crises
    treatment_effect: INHIBITS
    description: High-rate dextrose infusion is the most effective acute intervention for CACT-associated hyperammonemia.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hyperammonemia is most sensitive to high rates of dextrose infusion (12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children age 1-6 years), while ammonia scavenging medications (sodium benzoate, sodium phenylbutyrate) are of limited efficacy.
      explanation: GeneReviews directly identifies high-rate dextrose as the most effective hyperammonemia-directed acute intervention.
  target_phenotypes:
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Cardiac arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hyperammonemia is most sensitive to high rates of dextrose infusion (12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children age 1-6 years), while ammonia scavenging medications (sodium benzoate, sodium phenylbutyrate) are of limited efficacy.
    explanation: GeneReviews provides specific emergency management guidelines including dextrose infusion rates.
- name: Newborn screening
  description: 'CACT deficiency is detectable by newborn screening via tandem mass spectrometry using acylcarnitine profiling. Elevated long-chain acylcarnitines are the primary markers. Use of ratio indices improves discrimination and reduces false-positive rates. Because CACT deficiency often presents before routine screening collection timing, early clinical vigilance is also important.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
  target_phenotypes:
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  - preferred_term: Cardiac arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37305732
    reference_title: "Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Newborn screening via tandem mass spectrometry (MS/MS) technology enables early diagnosis.
    explanation: Confirms the role of MS/MS-based newborn screening for early CACT deficiency diagnosis.
  - reference: PMID:37305732
    reference_title: "Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ratios of the primary markers (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 can facilitate the diagnosis of CACT deficiency, thereby increasing sensitivity and reducing false-positivity.
    explanation: Demonstrates improved newborn screening performance with ratio-based markers.
- name: Genetic counseling
  description: 'Genetic counseling is recommended for affected families. Once SLC25A20 pathogenic variants are identified, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible. At-risk newborn siblings should be tested in parallel with newborn screening.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Once the SLC25A20 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
    explanation: GeneReviews confirms availability of carrier, prenatal, and preimplantation genetic testing.
- name: Fasting avoidance and emergency planning
  description: 'Prevention of metabolic crises through strict avoidance of prolonged fasting, provision of nocturnal feeding, and implementation of a home emergency plan for prompt illness management. Pre-procedure hospital management with IV dextrose is recommended for surgeries or sedation.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Catabolic stress-triggered metabolic decompensation
    treatment_effect: INHIBITS
    description: Avoiding fasting and maintaining emergency plans reduce catabolic stress exposures that precipitate crises.
    evidence:
    - reference: PMID:35862567
      reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Prolonged fasting, catabolic illness (fever, intercurrent infection), inadequate caloric provision during times of catabolic stress (including during fasting), prolonged strenuous physical activity, and prolonged administration of anesthetics containing high levels of long-chain fatty acids (e.g., propofol)."
      explanation: GeneReviews lists fasting and catabolic illness as exposures to avoid in CACT deficiency.
  target_phenotypes:
  - preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  - preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:35862567
    reference_title: "Carnitine-Acylcarnitine Translocase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A home emergency plan for prompt illness management should be provided to parents, primary care providers, teachers, and school staff.
    explanation: GeneReviews emphasizes the importance of emergency planning and fasting avoidance.
  - reference: PMID:39203843
    reference_title: "Nutritional Management of Patients with Fatty Acid Oxidation Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis
    explanation: Review confirms the central importance of preventing lipolysis and managing catabolic states.
notes: 'Outcomes correlate strongly with cardiac involvement and residual long-chain fatty acid oxidation capacity rather than a single enzyme activity metric. The acylcarnitine profile of CACT deficiency is indistinguishable from CPT II deficiency, requiring SLC25A20 sequencing and/or functional assays for definitive diagnosis. CACT deficiency often presents before routine newborn screening collection timing (e.g., 72-hour DBS sampling), creating a structural limitation for prevention of the earliest crises. Agents and circumstances to avoid include prolonged fasting, catabolic illness, prolonged strenuous physical activity, and anesthetics containing high levels of long-chain fatty acids (e.g., propofol).

  '
references:
- reference: PMID:35862567
  title: "Carnitine-Acylcarnitine Translocase Deficiency."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:35862567
Carnitine-Acylcarnitine Translocase Deficiency.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Pathophysiology Research Template
Edison Scientific Literature 40 citations 2026-02-23T23:44:15.030624

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: Carnitine-acylcarnitine Translocase Deficiency
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Carnitine-acylcarnitine Translocase 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

Title: Pathophysiology Research Report — Carnitine‑acylcarnitine Translocase Deficiency (CACTD; SLC25A20 deficiency)

Target disease - Disease: Carnitine‑acylcarnitine translocase deficiency (CACTD) - MONDO ID: MONDO:0008918 (as indexed in Open Targets disease–target association output for “carnitine‑acylcarnitine translocase deficiency”) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2) - Category: Genetic (autosomal recessive) long‑chain fatty‑acid oxidation disorder (LC‑FAOD) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8)

1) Key concepts and definitions (current understanding)

1.1 Definition CACTD is caused by biallelic pathogenic variants in SLC25A20, encoding the mitochondrial inner membrane carnitine‑acylcarnitine translocase (CACT), a solute carrier family 25 transporter required for the carnitine shuttle (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6).

A concise mechanistic definition from a 2024 autopsy case report: CACT is “responsible for the unidirectional transport of acylcarnitine across the inner mitochondrial membrane” and is “a crucial role in the oxidation of fatty acids” (Thunga et al., 2024-04; https://doi.org/10.4322/acr.2024.483) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5).

1.2 Carnitine shuttle context (molecular concept) Physiologic long‑chain fatty acid (LCFA) β‑oxidation requires: (i) CPT1 (outer mitochondrial membrane) to form long‑chain acylcarnitines, (ii) CACT/SLC25A20 (inner membrane) to exchange acylcarnitine for carnitine across the inner membrane, and (iii) CPT2 (matrix side) to regenerate long‑chain acyl‑CoA for β‑oxidation (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6). A schematic pathway depiction of CACT’s role in LCFA entry into the mitochondrial matrix is shown in Thunga et al. 2024 (Figure 4) (thunga2024carnitineacylcarnitinetranslocasedeficiency media a9332e20).

1.3 Core biochemical/clinical pattern Because newborns and fasting/stress states rely heavily on LCFA oxidation, CACTD classically presents with acute energy failure: hypoketotic hypoglycemia and hyperammonemia, with frequent cardiomyopathy/arrhythmia, hepatic dysfunction/hepatomegaly, skeletal myopathy/rhabdomyolysis, and encephalopathy; sudden unexpected death has been reported (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2).

2) Core pathophysiology (molecular and cellular mechanisms)

2.1 Primary pathophysiological mechanisms Mechanistic chain (canonical): 1) SLC25A20 loss‑of‑function → impaired transport of long‑chain acylcarnitines into the mitochondrial matrix (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5, elgharbawy2018inbornerrorsof pages 4-6). 2) Blocked LCFA β‑oxidation → inadequate ATP generation during fasting/birth/illness and impaired ketogenesis (hypoketosis), shifting reliance to glucose until glycogen is depleted (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8). 3) Accumulation of long‑chain acylcarnitines/acyl‑CoA derivatives and secondary free carnitine depletion → biochemical toxicity and organ dysfunction, particularly in high‑energy tissues (heart, skeletal muscle, liver, kidney) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2).

2.2 Dysregulated pathways - Mitochondrial long‑chain fatty‑acid β‑oxidation and associated ketone body production (energy metabolism pathway failure) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6). - Mitochondrial carnitine cycle / carnitine shuttle transport across the inner mitochondrial membrane (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5, thunga2024carnitineacylcarnitinetranslocasedeficiency media a9332e20). - Secondary metabolic responses: hypoketotic hypoglycemia, hyperammonemia, dicarboxylic aciduria (reflecting ω‑oxidation and incomplete oxidation) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, kheirandish2024theroleof pages 8-8).

2.3 Cellular processes affected - Mitochondrial substrate transport and matrix substrate availability (acylcarnitine ↔ carnitine exchange) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5, pasquadibisceglie2023insilicoanalysis pages 1-2). - Oxidative energy production under catabolic stress (fasting/illness) leading to cellular energy deficit (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2). - Lipid handling and storage: microvesicular steatosis in multiple cell types (hepatocytes, myocytes, renal proximal tubule epithelium) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6).

3) Key molecular players

3.1 Genes/proteins (HGNC) - SLC25A20 (solute carrier family 25 member 20; CACT/CAC): causal gene; mitochondrial inner membrane transporter (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5). - CPT1/CPT2: upstream/downstream carnitine shuttle enzymes; CACTD biochemically overlaps with CPT2 deficiency on acylcarnitine profiling, requiring genetic/enzymatic confirmation for discrimination (elgharbawy2018inbornerrorsof pages 4-6).

3.2 2023 structural/mechanistic insights on SLC25A20 A 2023 in silico study modeled SLC25A20 conformational cycling consistent with an alternating‑access mechanism and reported “a significant asymmetry in the conformational changes leading to the transition from the c- to the m-state,” with H6–H1–H2 moving more than H3–H4–H5 (Pasquadibisceglie et al., 2023-02; https://doi.org/10.3390/ijms24043946) (pasquadibisceglie2023insilicoanalysis pages 1-2, pasquadibisceglie2023insilicoanalysis pages 4-7). The same work used MD/docking to analyze pathogenic variants and proposed mechanisms by which Asp231His (matrix salt‑bridge network disruption) and Ala281Val (helix packing/conformational transition impairment) could destabilize transport function (pasquadibisceglie2023insilicoanalysis pages 18-19, pasquadibisceglie2023insilicoanalysis pages 2-4, pasquadibisceglie2023insilicoanalysis pages 4-7).

3.3 Chemical entities (metabolites/drugs; CHEBI names provided) Disease‑relevant metabolites/biomarkers (plasma/DBS): - Free carnitine (C0) (decreased) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6) - Long‑chain acylcarnitines: C16 (palmitoylcarnitine), C18, C18:1 (oleoylcarnitine) (elevated) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6) - Dicarboxylic acids in urine (reflecting alternative oxidation routes) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, kheirandish2024theroleof pages 8-8)

Therapeutically relevant chemicals: - Medium‑chain triglycerides (MCT oil; octanoate/decanoate mixtures) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, penaquintana2024nutritionalmanagementof pages 5-6) - Triheptanoin (C7 triglyceride; UX007/Dojolvi): anaplerotic odd‑chain triglyceride used in LC‑FAOD, including CACTD (mahapatra2018triheptanoinarescue pages 1-2, wanders2020mitochondrialfattyacid pages 12-13, NCT03773770 chunk 1).

3.4 Cell types and anatomical locations (CL/UBERON names provided) Primary vulnerable tissues/cell types (consistent across clinical/pathology reports): - Cardiomyocytes / heart (arrhythmia, cardiomyopathy; lipid accumulation) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2) - Skeletal muscle fibers / skeletal muscle (weakness, rhabdomyolysis; lipid accumulation) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, elgharbawy2018inbornerrorsof pages 4-6) - Hepatocytes / liver (microvesicular steatosis, hepatomegaly, dysfunction) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6) - Renal proximal tubular epithelial cells / kidney cortex (fatty change; energy failure) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2) - Central nervous system/brain involvement (encephalopathy, seizures) (kheirandish2024theroleof pages 7-8, elgharbawy2018inbornerrorsof pages 4-6)

4) Biological processes disrupted (GO-style process names) GO‑relevant disrupted processes (process names; suitable for GO annotation workflows): - Long‑chain fatty acid metabolic process / mitochondrial fatty acid β‑oxidation (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6) - Acylcarnitine transmembrane transport / mitochondrial inner membrane transport (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5, pasquadibisceglie2023insilicoanalysis pages 1-2) - Ketone body metabolic process (impaired ketogenesis; hypoketosis) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2) - Response to fasting / energy homeostasis during catabolic stress (clinical decompensation with fasting/illness) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2) - Lipid storage and triglyceride metabolic process (microvesicular steatosis across organs) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6)

5) Cellular components (GO-style component names) Key cellular components implicated: - Mitochondrial inner membrane (site of SLC25A20/CACT) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5, pasquadibisceglie2023insilicoanalysis pages 1-2) - Mitochondrial matrix (destination for acyl groups for β‑oxidation) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5) - Cytosol (site of fatty‑acid mobilization and carnitine ester formation prior to import) (mahapatra2018triheptanoinarescue pages 1-2) - Lipid droplets / cytoplasmic lipid inclusions (histologic correlate of steatosis) (thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6)

6) Disease progression (sequence of events and phases)

6.1 Trigger-to-crisis sequence A commonly described sequence is: catabolic trigger (birth transition, fasting, infection/illness) → increased reliance on LCFA oxidation → inability to import/oxidize long‑chain acylcarnitines → hypoketotic hypoglycemia (may be refractory), hyperammonemia, and rapid multi‑organ dysfunction (cardiac, hepatic, renal, muscle) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2).

6.2 Pathological tissue evolution Multi‑organ lipid accumulation is a key cellular pathology. In a 2024 autopsy case, diffuse microvesicular steatosis was reported in hepatocytes, cardiac myocytes, renal proximal tubular epithelium, skeletal muscle, and pancreatic acini (Thunga et al., 2024-04; https://doi.org/10.4322/acr.2024.483) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2). Representative liver histology showing microvesicular fat is shown in Thunga et al. 2024 (Figure 3) (thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6).

7) Phenotypic manifestations (clinical phenotypes and mechanistic links)

7.1 Key phenotypes (HPO-style names) - Hypoketotic hypoglycemia / non‑ketotic hypoglycemia: mechanistically from failure of fatty‑acid–derived ketone production and ATP generation (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2). - Hyperammonemia: frequently observed during crises; in one autopsy case ammonia rose from 249 μmol/L to 433.5 μmol/L (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2). - Cardiomyopathy and cardiac arrhythmia: due to heart’s reliance on LCFA oxidation and toxicity/energy deficit; often a determinant of mortality (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6). - Hepatomegaly / hepatic dysfunction and microvesicular steatosis: consistent with impaired mitochondrial fat handling and secondary lipid accumulation (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6). - Rhabdomyolysis / myopathy (in surviving/older presentations): impaired muscle energy metabolism and toxic metabolite accumulation (elgharbawy2018inbornerrorsof pages 4-6). - Encephalopathy / seizures / coma: secondary to systemic metabolic decompensation and energy failure (kheirandish2024theroleof pages 7-8, elgharbawy2018inbornerrorsof pages 4-6).

7.2 Mortality and epidemiologic notes A 2015 literature review/series reported that CACTD typically presents neonatally (~82%) or in infancy (~18%) and has high mortality (~65%), often within the first year, frequently related to cardiomyopathy or sudden death (Vitoria et al., 2015-01; https://doi.org/10.1007/8904_2014_382) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2). A 2024 autopsy case report similarly cites first‑year mortality “up to 65%” and notes FAOD as a contributor to sudden unexpected death in infancy (SUDI) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8).

8) Recent developments (prioritizing 2023–2024)

8.1 Newborn screening: improved marker strategy (2023) A 2023 study addressed misclassification risk when relying only on single long‑chain acylcarnitines (C12–C18 series) in tandem MS/MS newborn screening and proposed ratio indices to improve discrimination (Shi et al., 2023-05; https://doi.org/10.21037/tp-22-468) (shi2023increasedacylcarnitineratio pages 1-2, shi2023increasedacylcarnitineratio pages 8-10).

Key ratio markers highlighted as elevated in all 15 genetically confirmed cases included: - (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1‑OH/C3 (shi2023increasedacylcarnitineratio pages 1-2, shi2023increasedacylcarnitineratio pages 2-3).

Performance/statistics from their validation dataset: - In 28,261 screened newborns, ratio false‑positive rates (except (C16 + C18)/C0) were lower than single acylcarnitine indices: 0.02–0.08% vs 0.16–0.88% (shi2023increasedacylcarnitineratio pages 1-2, shi2023increasedacylcarnitineratio pages 8-10). - Example single‑marker false‑positive rates: C16 0.46% and C18 0.55% (shi2023increasedacylcarnitineratio pages 8-10).

Genotype note relevant to screening interpretation: - A recurrent splice variant c.199‑10T>G in SLC25A20 was common in this cohort (14/15 patients homozygous) and associated with severe early onset; the authors discuss that carriers may have normal long‑chain acylcarnitine concentrations (shi2023increasedacylcarnitineratio pages 8-10, shi2023increasedacylcarnitineratio pages 2-3).

8.2 SLC25A20 mechanistic biology: structure–function (2023) Pasquadibisceglie et al. (2023) used AlphaFold‑based modeling, MD, and docking to refine understanding of SLC25A20 substrate recognition and conformational gating, supporting an alternating‑access model with asymmetric helix motion and multi‑step substrate recognition (pasquadibisceglie2023insilicoanalysis pages 1-2, pasquadibisceglie2023insilicoanalysis pages 4-7). This provides a contemporary mechanistic framework for interpreting pathogenic variants, including Asp231His and Ala281Val (pasquadibisceglie2023insilicoanalysis pages 18-19, pasquadibisceglie2023insilicoanalysis pages 2-4).

8.3 Nutritional management updates (2024) A 2024 Nutrients review on FAOD dietary management (including long‑chain disorders such as CACTD) emphasizes: - Avoidance of fasting (with strategies such as nocturnal feeding) (penaquintana2024nutritionalmanagementof pages 5-6). - Long‑chain triglyceride restriction to ~10% of total energy to normalize plasma acylcarnitines while avoiding essential fatty‑acid deficiency (penaquintana2024nutritionalmanagementof pages 5-6). - Essential fatty‑acid intake targets (linoleic 3–4%; linolenic 0.5–1% of total calories) and MCT supplementation 10–25% of total energy (minimum effective ~10%) (Peña‑Quintana & Correcher‑Medina, 2024-08; https://doi.org/10.3390/nu16162707) (penaquintana2024nutritionalmanagementof pages 5-6).

8.4 Triheptanoin: real‑world effectiveness data (2024) A 2024 nationwide Italian retrospective cohort evaluated nine LC‑FAOD patients switching from MCT oil to triheptanoin (Porta et al., 2024-10; https://doi.org/10.1186/s13052-024-01782-y) (porta2024triheptanoininpatients pages 2-4, porta2024triheptanoininpatients pages 1-2).

Quantitative outcomes after switching to triheptanoin: - Mean triheptanoin dose: 1.5 ± 0.9 g/kg/day, ~24 ± 9% of total daily calories, divided into 4 daily administrations (porta2024triheptanoininpatients pages 2-4). - Intercurrent catabolic episodes: 4.3 ± 5.3 (triheptanoin) vs 22.0 ± 22.2 (MCT), p=0.034 (porta2024triheptanoininpatients pages 2-4). - Hospitalizations for metabolic decompensation: 2.0 ± 2.5 (triheptanoin) vs 18.3 ± 17.7 (MCT), p=0.014 (porta2024triheptanoininpatients pages 2-4). - Annualized hospitalizations: 0.7 ± 0.8 vs 3.1 ± 3.0 per year, p=0.03; mean days per hospitalization: 3.6 ± 3.4 vs 10.5 ± 5.0, p=0.004 (porta2024triheptanoininpatients pages 2-4). - ICU admissions: 0 on triheptanoin vs 4 ICU admissions among 3 patients on MCT (porta2024triheptanoininpatients pages 2-4). - Adverse effects were mainly gastrointestinal (epigastric pain, diarrhea), similar to MCT (porta2024triheptanoininpatients pages 1-2, porta2024triheptanoininpatients pages 4-6).

Note: This cohort was heterogeneous (primarily MTPD/CPT2D/VLCADD), but the paper describes triheptanoin’s availability/usage in LC‑FAOD broadly, including CACTD in its reported diagnostic spectrum (porta2024triheptanoininpatients pages 1-2).

9) Current applications and real‑world implementations

9.1 Newborn screening (MS/MS) and confirmatory testing CACTD is screened via acylcarnitine profiling in dried blood spots using tandem mass spectrometry (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, shi2023increasedacylcarnitineratio pages 1-2). Because CACTD acylcarnitine profiles can overlap with CPT2 deficiency, confirmatory testing commonly requires SLC25A20 sequencing and/or functional assays (elgharbawy2018inbornerrorsof pages 4-6, vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2).

Practical screening enhancement (real‑world algorithm update): Shi et al. (2023) supports adding ratio indices such as (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1‑OH/C3 to improve sensitivity and reduce false positives relative to single long‑chain acylcarnitines (shi2023increasedacylcarnitineratio pages 1-2, shi2023increasedacylcarnitineratio pages 8-10).

9.2 Acute crisis management (implementation themes) Clinical reports/reviews emphasize emergency reversal of catabolism: intravenous glucose, avoidance of fasting, and dietary strategies that reduce reliance on LCFA oxidation (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2). These strategies are consistent with FAOD diet guidance (LCT restriction, carbohydrate support, MCT supplementation) in recent nutrition guidance (penaquintana2024nutritionalmanagementof pages 5-6).

9.3 Triheptanoin as an anaplerotic energy therapy Mechanistic rationale: triheptanoin is metabolized to heptanoate, producing acetyl‑CoA and propionyl‑CoA; propionyl‑CoA replenishes TCA intermediates (anaplerosis) via succinyl‑CoA, potentially mitigating energy deficiency in LC‑FAOD (wanders2020mitochondrialfattyacid pages 12-13).

CACTD‑specific clinical implementation evidence: a 2018 case report of an infant with genetically confirmed CACTD in cardiogenic shock described rapid recovery of cardiac function after triheptanoin initiation: ejection fraction increased from 24.9 to 73.7% within 72 hours and vasoactives were weaned, followed by discharge; the child remained on triheptanoin long‑term though later died at age 3 during an intercurrent illness (Mahapatra et al., 2018-01; https://doi.org/10.1007/8904_2017_36) (mahapatra2018triheptanoinarescue pages 2-4, mahapatra2018triheptanoinarescue pages 1-2).

Expanded access implementation: ClinicalTrials.gov lists an Expanded Access program for triheptanoin (UX007/Dojolvi) for LC‑FAOD explicitly including CACT/SLC25A20 deficiency (NCT03773770; https://clinicaltrials.gov/study/NCT03773770) (NCT03773770 chunk 1).

10) Expert opinion and interpretive analysis (authoritative synthesis)

10.1 Prognostic determinants A major interpretive theme from the CACTD literature is that outcomes correlate strongly with cardiac involvement and residual LCFA oxidation capacity rather than with a single enzyme activity metric alone (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2). This is consistent with high myocardial reliance on LCFA oxidation and the frequent lethal arrhythmia/cardiomyopathy phenotype (elgharbawy2018inbornerrorsof pages 4-6, vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2).

10.2 Screening limitations and the “early‑onset before sample” problem Shi et al. (2023) emphasize that CACTD often presents before routine newborn screening collection (e.g., routine 72-hour DBS timing in some systems), creating a structural limitation for prevention of the earliest crises; thus, improving discrimination (ratios) reduces false positives, but timing constraints still matter for clinical impact (shi2023increasedacylcarnitineratio pages 8-10).

10.3 Treatment landscape: diet + anaplerosis Recent nutritional guidance frames dietary management as a metabolic “catabolism avoidance” strategy (high carbohydrate availability, LCT restriction, essential fatty acids, and MCT/triheptanoin as alternative fuels) (penaquintana2024nutritionalmanagementof pages 5-6). Triheptanoin is increasingly treated as a pragmatic escalation for patients with ongoing episodes despite standard therapy, supported by real‑world data showing reduction in hospitalizations and catabolic episodes (porta2024triheptanoininpatients pages 2-4, porta2024triheptanoininpatients pages 6-9).

11) Evidence items (knowledge‑base ready; with identifiers and sources)

11.1 Gene/protein annotations - SLC25A20 (CACT/CAC): causal; mitochondrial inner membrane acylcarnitine/carnitine exchanger essential for LCFA β‑oxidation (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5). - Mechanistic/structure evidence: alternating access; asymmetric helix motion; pathogenic variant interpretation (Asp231His, Ala281Val) via MD/docking (pasquadibisceglie2023insilicoanalysis pages 1-2, pasquadibisceglie2023insilicoanalysis pages 18-19).

11.2 Ontology-style mappings (names) - GO biological processes (names): mitochondrial long‑chain fatty acid β‑oxidation; acylcarnitine transmembrane transport; ketone body metabolic process; response to fasting; lipid storage (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8). - GO cellular components (names): mitochondrial inner membrane; mitochondrial matrix; lipid droplet (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5, thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6). - HPO phenotype terms (names): hypoketotic hypoglycemia; hyperammonemia; cardiomyopathy; cardiac arrhythmia; hepatomegaly; microvesicular steatosis; rhabdomyolysis; seizures/encephalopathy; sudden death (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, elgharbawy2018inbornerrorsof pages 4-6, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2). - CL cell types (names): hepatocyte; cardiomyocyte; skeletal muscle fiber; renal proximal tubule epithelial cell; neurons/astrocytes (clinical CNS involvement) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2, kheirandish2024theroleof pages 7-8). - UBERON anatomy (names): liver; heart; skeletal muscle; kidney (renal cortex/proximal tubule); pancreas (exocrine) (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8, thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2). - CHEBI chemical entities (names): carnitine; palmitoylcarnitine (C16); oleoylcarnitine (C18:1); medium‑chain triglycerides; triheptanoin; glucose (acute treatment) (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, mahapatra2018triheptanoinarescue pages 2-4, porta2024triheptanoininpatients pages 2-4).

11.3 Visual evidence - SLC25A20/CACT function in the carnitine shuttle (schematic): Thunga et al. 2024 Figure 4 (thunga2024carnitineacylcarnitinetranslocasedeficiency media a9332e20). - Microvesicular steatosis in CACTD liver histology: Thunga et al. 2024 Figure 3 (thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6).

12) Key URLs and publication dates (most relevant sources) - Thunga et al. “Carnitine‑acylcarnitine translocase deficiency: a case report with autopsy.” Autopsy & Case Reports. 2024‑04. https://doi.org/10.4322/acr.2024.483 (thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8) - Shi et al. “Increased acylcarnitine ratio indices in newborn screening for CACT deficiency…” Translational Pediatrics. 2023‑05. https://doi.org/10.21037/tp-22-468 (shi2023increasedacylcarnitineratio pages 1-2) - Pasquadibisceglie et al. “In Silico Analysis… SLC25A20 Transporter.” Int J Mol Sci. 2023‑02. https://doi.org/10.3390/ijms24043946 (pasquadibisceglie2023insilicoanalysis pages 1-2) - Peña‑Quintana & Correcher‑Medina. “Nutritional Management of Patients with Fatty Acid Oxidation Disorders.” Nutrients. 2024‑08. https://doi.org/10.3390/nu16162707 (penaquintana2024nutritionalmanagementof pages 5-6) - Porta et al. “Triheptanoin in patients with LC‑FAOD: clinical experience in Italy.” Italian Journal of Pediatrics. 2024‑10. https://doi.org/10.1186/s13052-024-01782-y (porta2024triheptanoininpatients pages 2-4) - Mahapatra et al. “Triheptanoin: A Rescue Therapy for Cardiogenic Shock in CACT Deficiency.” JIMD Reports. 2018‑01. https://doi.org/10.1007/8904_2017_36 (mahapatra2018triheptanoinarescue pages 2-4) - ClinicalTrials.gov Expanded Access triheptanoin (Dojolvi/UX007) including CACTD: NCT03773770. https://clinicaltrials.gov/study/NCT03773770 (NCT03773770 chunk 1)

Limitations of this report - Several mechanistic statements in contemporary clinical reviews typically include PMID‑indexed primary citations; however, the retrieved evidence snippets available here did not consistently surface PMIDs in-text. Therefore, this report provides DOI/URL‑based citations and journal metadata for traceability, and uses extracted evidence only for all major claims (vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2, shi2023increasedacylcarnitineratio pages 1-2, pasquadibisceglie2023insilicoanalysis pages 1-2).

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