⚙

Pathophysiology

13

SLC25A20 transporter molecular function deficiency

Mechanism confidence: Established

Loss of CACT transport activity limits acylcarnitine/carnitine exchange across the mitochondrial inner membrane.

SLC25A20 hgnc:1421

carnitine-acylcarnitine translocase activity GO:0015227 ↓ DECREASED

mitochondrial inner membrane GO:0005743

Computational models

Human SLC25A20 conformational models and molecular dynamics MOLECULAR DOCKING AlphaFold 2.2.0; ColabFold AlphaFold2_advanced; AMBER22; CPPTRAJ Molecular structural proxies inform the normal transport architecture and interpretations of pathogenic substitutions.

Downstream

Impaired mitochondrial long-chain fatty acid oxidation Restricted matrix delivery limits oxidation of long-chain acyl groups.

Long-chain acylcarnitine accumulation Substrates accumulate upstream of the deficient inner-membrane carrier.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Carnitine acylcarnitine translocase (CACT) transfers acylcarnitines formed by the action of carnitine palmitoyl-transferase I (CPT1) in the outer mitochondrial membrane into the mitochondrial matrix in exchange for free carnitine."

Defines the transporter activity lost in SLC25A20 deficiency.

Impaired mitochondrial long-chain fatty acid oxidation

Long-chain fatty acid oxidation is restricted by inadequate mitochondrial substrate delivery.

fatty acid beta-oxidation GO:0006635 ↓ DECREASED

Downstream

Energy deficit during catabolic stress Insufficient fatty acid-derived energy becomes critical when demand rises or glucose availability falls.

Impaired hepatic ketogenesis Reduced fatty acid-derived acetyl-CoA limits hepatic ketone production.

Intracellular lipid accumulation Defective fatty acid utilization is associated with cellular lipid storage; tissue-level intermediates are incompletely resolved.

Proposed impairment of N-acetylglutamate-dependent ureagenesis Reduced acetyl-CoA supply is proposed to limit NAG production and urea-cycle activation.

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS Human Clinical

"CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity."

Supports the central metabolic defect.

Energy deficit during catabolic stress

Inadequate energy availability during fasting, birth transition, illness or poor intake increases reliance on glucose and protein substrates.

Downstream

Hypoketotic hypoglycemia Increased glucose consumption during the fatty acid oxidation block contributes to hypoglycemia.

Cardiac energy deficit Cardiac tissue loses a major fuel source during metabolic stress.

Rhabdomyolysis When alternate substrates are depleted, muscle protein catabolism contributes to muscle breakdown.

Metabolic and hypoxic brain injury Hypoglycemia during metabolic crises contributes to brain injury.

Hyperammonemia during metabolic crises Loss of fatty-acid-derived energy and depletion of alternative fuels are associated with ammonia accumulation. This route does not require the specific proposed NAG/CPS1 mechanism to be established.

Muscle weakness Restricted energy availability in skeletal muscle contributes to weakness during severe metabolic disease.

Encephalopathy Acute failure of energy supply contributes to encephalopathy during severe metabolic decompensation; permanent structural injury is not required.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited."

Connects the oxidation defect to inadequate energy availability.

PMID:33024728 SUPPORT REVIEW SYNTHESIS Human Clinical

"A characteristic feature of all mFAO disorders is hypoglycemia, which is the direct result of the inability to oxidize FAs and concurrent increased consumption of glucose by tissues to match energy demands."

Review-level explanation of glucose dependence in mitochondrial fatty acid oxidation defects.

Impaired hepatic ketogenesis

Insufficient hepatic ketone production limits alternative fuel availability during fasting.

hepatocyte CL:0000182

ketone body biosynthetic process GO:0046951 ↓ DECREASED

Downstream

Hypoketotic hypoglycemia Ketone availability is inappropriately low during hypoglycemia in fatty acid oxidation defects.

Show evidence (1 reference)

PMID:33024728 SUPPORT REVIEW SYNTHESIS Human Clinical

"the liver can convert the end product of mFAO (i.e., acetyl-CoA) into the ketone bodies acetoacetate and 3-hydroxybutyrate, which can then be used in virtually all other organs (except erythrocytes) as a source of energy."

Explains why restricted hepatic fatty acid oxidation limits ketone fuel production.

Long-chain acylcarnitine accumulation

Long-chain acylcarnitines accumulate upstream of the CACT transport block; blood concentrations vary with metabolic state.

Downstream

Secondary free carnitine depletion Reduced availability of unesterified carnitine accompanies abnormal acylcarnitine handling; its magnitude depends on metabolic state.

Proposed acylcarnitine-mediated cardiac toxicity Cytosolic long-chain acylcarnitines are proposed contributors to cardiac toxicity.

Elevated circulating acylcarnitine concentration Accumulated long-chain acylcarnitines are measured as the characteristic circulating elevation.

Show evidence (1 reference)

PMID:33024728 SUPPORT REVIEW SYNTHESIS Human Clinical

"CACT deficiency leads to the accumulation of acylcarnitines in the cytosol, but not inside mitochondria"

Review describes the predicted localization of substrate accumulation upstream of the transport block.

Secondary free carnitine depletion

Circulating free carnitine may become depleted, particularly during symptomatic disease. It may remain normal before symptoms.

Downstream

Decreased circulating carnitine concentration Secondary depletion is measured as reduced circulating free carnitine.

Show evidence (2 references)

PMID:29502916 SUPPORT REVIEW SYNTHESIS Human Clinical

"Free carnitine is low in blood, with marked elevations of C16, C18, and C18:1 carnitine species."

CACT-specific review section describes secondary free-carnitine depletion.

PMID:37305732 SUPPORT PRIMARY RESULT 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."

Shows that low free carnitine can occur even without an elevated long-chain profile.

Intracellular lipid accumulation

Microvesicular lipid accumulation can involve liver, heart, proximal renal tubules and skeletal muscle. Histology is not specific to CACT deficiency.

hepatocyte CL:0000182 cardiac muscle cell CL:0000746 epithelial cell of proximal tubule CL:0002306 skeletal muscle fiber CL:0008002

Downstream

Hepatomegaly Hepatocyte fatty change contributes to liver enlargement.

Elevated circulating hepatic transaminase concentration Hepatocyte lipid accumulation can contribute to hepatic dysfunction and injury; the detailed causal intermediates are incompletely resolved.

Show evidence (1 reference)

PMID:38628283 SUPPORT PRIMARY RESULT 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."

Documents cellular lipid storage in one autopsy; it does not identify the stored lipid chemically or demonstrate acylcarnitine toxicity.

Cardiac energy deficit

Impaired use of long-chain fatty acids restricts cardiomyocyte energy availability.

cardiac muscle cell CL:0000746

Downstream

Hypertrophic cardiomyopathy Cardiac energetic stress is a mechanistic contributor to hypertrophic remodeling; the complete causal sequence is unresolved.

Reduced left ventricular ejection fraction Energetic impairment contributes to reduced systolic performance alongside other incompletely resolved mechanisms.

Cardiac electrical instability Energetic failure is one candidate contributor to electrophysiological instability; lipid effects may coexist.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Fatty acid β-oxidation is an important pathway for energy production during times of stress or fasting, particularly in energy-demanding tissue such as cardiac muscle, skeletal muscle, and liver."

Establishes cardiac reliance on the affected fuel pathway.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited."

Connects the oxidation defect to inadequate energy availability.

Proposed acylcarnitine-mediated cardiac toxicity

Mechanism confidence: Provisional

Cytosolic long-chain acylcarnitines may contribute to cardiomyocyte rhythm disturbances. Evidence cited by the mechanistic review derives mainly from VLCAD-deficient iPSC cardiomyocytes and exposed rodent cells, not direct CACT patient-cell testing.

Downstream

Cardiac electrical instability The proposed lipid effect could contribute to arrhythmias; disease-specific confirmation remains limited.

Show evidence (1 reference)

PMID:33024728 SUPPORT REVIEW SYNTHESIS Other

"This conclusion would be in line with the notion that patients affected by CACT deficiency also show severe cardiac abnormalities which include arrhythmias and cardiomyopathy."

The review extrapolates from VLCAD-deficient iPSC cardiomyocytes to CACT; this is indirect support for a hypothesis, not an experiment in CACT cardiomyocytes.

Proposed impairment of N-acetylglutamate-dependent ureagenesis

Mechanism confidence: Hypothetical

Reduced acetyl-CoA may limit N-acetylglutamate availability and thereby CPS1 activation. This is a proposed explanation for impaired nitrogen disposal, not an established patient-specific biochemical sequence.

Downstream

Hyperammonemia during metabolic crises Reduced urea-cycle activation could contribute to ammonia accumulation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"CACT deficiency has been proposed to ↓ acetyl-CoA & therefore NAG (essential in the urea cycle)."

Explicitly a proposed explanation for hyperammonemia, not a demonstrated defect of NAG synthesis or CPS1 in these patients.

Hyperammonemia during metabolic crises

Ammonia accumulates during acute crises and can remain chronically or recurrently elevated in severe disease.

Downstream

Hyperammonemia The systemic ammonia elevation is measured clinically as hyperammonemia.

Metabolic and hypoxic brain injury Recurrent severe hyperammonemia contributes to neurodevelopmental injury.

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS Human Clinical

"Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome."

Describes the clinical hyperammonemic state and its relevance to brain injury.

Metabolic and hypoxic brain injury

Brain injury may follow hypoglycemia, hypoxia during cardiac arrest and recurrent hyperammonemic crises. Neurodevelopmental outcomes range from normal to impaired.

Downstream

Global developmental delay Acquired metabolic/hypoxic injury contributes to developmental impairment.

Intellectual disability Metabolic/hypoxic injury contributes to cognitive impairment in some survivors.

Seizures Seizures may follow hypoglycemic or hypoxic brain injury.

Lethargy Neurological injury and dysfunction during metabolic crises can manifest as reduced alertness.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Contributing factors for neurodevelopmental delay are brain injury at presentation (often due to cardiac arrest) and the subsequent frequency and severity of metabolic decompensations featuring hyperammonemia."

Supports multiple contributors to neurological injury rather than a single direct lipid-toxicity pathway.

Cardiac electrical instability

Tachyarrhythmias and bradyarrhythmias can accompany severe CACT deficiency, including ventricular tachycardia that can culminate in arrest.

Downstream

Cardiac arrhythmia The clinical rhythm phenotype reflects electrical instability.

Ventricular tachycardia Ventricular tachycardia is a prominent expression of the rhythm disturbance.

Cardiac arrest Severe ventricular rhythm disturbances can culminate in arrest.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The most prominent cardiac feature in the neonatal period is arrhythmia, particularly ventricular tachycardia, followed by various tachyarrhythmias and bradyarrhythmias"

Defines cardiac electrical instability.

✶

Histopathology

2

Hepatic microvesicular steatosis

Hepatic microvesicular steatosis was present together with macrovesicular steatosis in a reported autopsy. The index liver lacked inflammation or fibrosis. The morphology is not disease-specific.

Show evidence (2 references)

PMID:38628283 SUPPORT PRIMARY RESULT Human Clinical

"The steatosis was both macrovesicular (~100% hepatocytes) and microvesicular, with the microvesicular fat being obscured by the macrovesicular fat."

Documents both hepatic patterns in the index autopsy.

PMID:38628283 SUPPORT PRIMARY RESULT Human Clinical

"No inflammation, portal or perisinusoidal fibrosis, or cholangiopathy was seen."

Distinguishes the index liver from fibrosis reported in a sibling without genetic confirmation.

Extrahepatic microvesicular lipid accumulation

Oil-red-O-positive microvesicular fat was reported in cardiac myocytes, proximal renal tubules, occasional skeletal myocytes and pancreatic exocrine acini.

Show evidence (1 reference)

PMID:38628283 SUPPORT PRIMARY RESULT Human Clinical

"Similar microvesicular steatosis was also noted in the cardiac myocytes (Figures 2A and 2B), proximal convoluted tubules of the kidneys (Figures 2C and 2D), occasional skeletal muscle cells (Figure 2E), and pancreatic exocrine acini (Figure 2F), confirmed by oil red O stain performed on the..."

Directly describes the extrahepatic distribution.

⬡

Pathograph

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Phenotypes

30

Cardiovascular 5

Cardiac arrhythmia HP:0011675

In the 2021 retrospective cohort, 15 of 16 classical patients had cardiac involvement: 9/15 arrhythmia, 7/15 arrest and 9/15 hypertrophy. These overlapping outcomes describe the cardiac subgroup.

Show evidence (3 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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.

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15)."

Retrospective severe-subgroup counts; not a global CACT prevalence estimate.

Cardiac arrest HP:0001695

In the 2021 retrospective cohort, 15 of 16 classical patients had cardiac involvement: 9/15 arrhythmia, 7/15 arrest and 9/15 hypertrophy. These overlapping outcomes describe the cardiac subgroup.

Show evidence (2 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS Human Clinical

"Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest."

GeneReviews directly reports high rates of cardiac arrest in early-onset CACT deficiency.

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15)."

Retrospective severe-subgroup counts; not a global CACT prevalence estimate.

Hypertrophic cardiomyopathy HP:0001639

In the 2021 retrospective cohort, 15 of 16 classical patients had cardiac involvement: 9/15 arrhythmia, 7/15 arrest and 9/15 hypertrophy. These overlapping outcomes describe the cardiac subgroup.

Show evidence (3 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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.

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15)."

Retrospective severe-subgroup counts; not a global CACT prevalence estimate.

Ventricular tachycardia HP:0004756

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The most prominent cardiac feature in the neonatal period is arrhythmia, particularly ventricular tachycardia, followed by various tachyarrhythmias and bradyarrhythmias"

Supports this specific ventricular rhythm phenotype.

Reduced left ventricular ejection fraction HP:0012664

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac dysfunction due to reduced left ventricular ejection fraction (<55%) is common."

Supports echocardiographic systolic dysfunction.

Digestive 2

Hepatomegaly HP:0002240

Show evidence (2 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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 Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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.

Genitourinary 5

Dicarboxylic aciduria HP:0003215

Show evidence (1 reference)

PMID:29502916 SUPPORT REVIEW SYNTHESIS Human Clinical

"Urine organic acids may show dicarboxylic aciduria."

Review evidence supports dicarboxylic aciduria as a biochemical finding in CACT deficiency.

Renal Fanconi syndrome HP:0001994

GeneReviews states that the pathophysiology and natural history of these renal findings are unclear. Proximal-tubule fat in a separate autopsy does not establish the cause of this particular renal manifestation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Renal abnormalities may include nephromegaly, renal Fanconi syndrome, proximal renal tubular acidosis, and acute renal injury"

Documents reported renal manifestations; their mechanism and natural history are uncertain.

Proximal renal tubular acidosis HP:0002049

GeneReviews states that the pathophysiology and natural history of these renal findings are unclear. Proximal-tubule fat in a separate autopsy does not establish the cause of this particular renal manifestation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Renal abnormalities may include nephromegaly, renal Fanconi syndrome, proximal renal tubular acidosis, and acute renal injury"

Documents reported renal manifestations; their mechanism and natural history are uncertain.

Acute kidney injury HP:0001919

GeneReviews states that the pathophysiology and natural history of these renal findings are unclear. Proximal-tubule fat in a separate autopsy does not establish the cause of this particular renal manifestation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Renal abnormalities may include nephromegaly, renal Fanconi syndrome, proximal renal tubular acidosis, and acute renal injury"

Documents reported renal manifestations; their mechanism and natural history are uncertain.

Nephromegaly Enlarged kidney HP:0000105

GeneReviews states that the pathophysiology and natural history of these renal findings are unclear. Proximal-tubule fat in a separate autopsy does not establish the cause of this particular renal manifestation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Renal abnormalities may include nephromegaly, renal Fanconi syndrome, proximal renal tubular acidosis, and acute renal injury"

Documents reported renal manifestations; their mechanism and natural history are uncertain.

Metabolism 7

Hypoketotic hypoglycemia HP:0001985

Show evidence (3 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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 HP:0001987

Show evidence (2 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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 acylcarnitine concentration HP:0045045

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 directly supports elevated circulating long-chain acylcarnitines.

Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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.

Metabolic acidosis HP:0001942

Reported during metabolic decompensation. The cited clinical list does not isolate a specific causal route from energetic failure, hepatic dysfunction or renal abnormalities.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Metabolic derangements can include hypoketotic hypoglycemia, hyperammonemia, transaminitis, liver dysfunction, lactic acidosis, metabolic acidosis, and rhabdomyolysis"

Documents metabolic/lactic acidosis among reported derangements.

Lactic acidosis HP:0003128

Reported during metabolic decompensation. The cited clinical list does not isolate a specific causal route from energetic failure, hepatic dysfunction or renal abnormalities.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Metabolic derangements can include hypoketotic hypoglycemia, hyperammonemia, transaminitis, liver dysfunction, lactic acidosis, metabolic acidosis, and rhabdomyolysis"

Documents metabolic/lactic acidosis among reported derangements.

Elevated circulating creatine kinase concentration Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Long-term survivors may continue to experience chronic hyperammonemia and mild-to-moderate hyperCKemia"

Supports persistent hyperCKemia beyond acute crises.

Musculoskeletal 3

Muscular hypotonia HP:0001252

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 HP:0003201

Show evidence (2 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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.

Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:29502916 SUPPORT REVIEW SYNTHESIS 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 skeletal muscle weakness among severe neonatal manifestations.

Nervous System 5

Lethargy HP:0001254

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 HP:0001263

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 HP:0001250

Show evidence (1 reference)

PMID:34449152 SUPPORT BACKGROUND 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 HP:0001298

Show evidence (1 reference)

PMID:29502916 SUPPORT REVIEW SYNTHESIS 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.

Intellectual disability HP:0001249

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Most affected individuals have mild-to-moderate developmental delay and/or intellectual disability."

Describes the neurodevelopmental spectrum in the clinical synthesis.

Respiratory 2

Respiratory distress HP:0002098

Show evidence (1 reference)

PMID:25614308 SUPPORT REVIEW SYNTHESIS 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 HP:0002104

Show evidence (1 reference)

PMID:29502916 SUPPORT REVIEW SYNTHESIS 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.

Cellular 1

Decreased circulating carnitine concentration HP:0003234

Show evidence (1 reference)

PMID:29502916 SUPPORT REVIEW SYNTHESIS Human Clinical

"Free carnitine is low in blood, with marked elevations of C16, C18, and C18:1 carnitine species."

The review directly reports low circulating free carnitine in CACT deficiency.

🧬

Genetic Associations

1

SLC25A20

Gene: SLC25A20 hgnc:1421 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Sequence analysis of SLC25A20 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants."

Documents the small-variant spectrum.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications."

Supports inclusion of structural deletions/duplications in diagnostic evaluation.

Variants (6)

c.199-10T>G splice variant in SLC25A20

Gene: SLC25A20 hgnc:1421

Recurrent c.199-10T>G splice variant associated with severe neonatal disease, especially in individuals of East or Southeast Asian descent.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Homozygosity for this pathogenic splice site variant is associated with the severe neonatal-onset form"

The sentence concerns c.199-10T>G in the genotype-phenotype section.

p.Gly20Asp (c.59G>A) variant

Gene: SLC25A20 hgnc:1421

Novel variant identified in a Spanish patient with severe neonatal-onset disease and fatal outcome during intercurrent infection in the first year.

Show evidence (1 reference)

PMID:25614308 SUPPORT PRIMARY RESULT Human Clinical

"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"

Spanish case series reporting novel pathogenic variants with clinical outcomes.

Asp231His and Ala281Val pathogenic mutations

Gene: SLC25A20 hgnc:1421

Molecular dynamics models suggest that Asp231His perturbs matrix salt-bridge interactions and that Ala281Val may disturb helix packing. These are structural predictions, not direct measurements of mutant transport in patients.

Show evidence (1 reference)

PMID:36835358 SUPPORT PRIMARY RESULT Computational

"the data suggest that the pathogenic mutation Asp231His perturbs the matrix salt bridge Asp231-Lys35 and/or the Asp231-Arg178 interactions, which are involved in the stability of the c- and m-state."

Reports an explicitly computational interpretation of Asp231His.

c.82G>T (p.Gly28Cys)

Gene: SLC25A20 hgnc:1421

Associated with milder neonatal or later-onset presentations in reported families, often of Pakistani or Indian descent; it is not an absolute predictor of outcome.

Show evidence (1 reference)

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Seven attenuated patients of Pakistani heritage, six of these homozygous c.82G>T, had later onset manifestations and long-term survival without chronic hyperammonemia."

Defines the attenuated subgroup of the retrospective cohort.

c.270delC (p.Phe91fs)

Gene: SLC25A20 hgnc:1421

Reported in association with severe neonatal disease; the association is not an individual prognostic rule.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Homozygosity for this pathogenic deletion of Turkish origin has been correlated with the severe neonatal-onset form of CACT deficiency"

Genotype-phenotype synthesis for the named recurrent allele.

c.713A>G (p.Gln238Arg)

Gene: SLC25A20 hgnc:1421

Reported in association with severe neonatal disease; the association is not an individual prognostic rule.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Homozygosity for this pathogenic variant of Middle Eastern origin has also been correlated with the severe neonatal-onset form of CACT deficiency"

Genotype-phenotype synthesis for the named recurrent allele.

💊

Medical Actions

11

High-carbohydrate, long-chain fat-restricted diet

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

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 REVIEW SYNTHESIS 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 Energy deficit during catabolic stress — Preventing fasting and maintaining uninterrupted calories reduces catabolic decompensation risk.

Show evidence (1 reference)

PMID:39203843 SUPPORT REVIEW SYNTHESIS 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 HP:0001985 Hyperammonemia HP:0001987

Show evidence (3 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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 PRIMARY RESULT 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 Support NCIT:C15433

Agent: triheptanoin CHEBI:757060

Platform: Small molecule

Triheptanoin supplies heptanoate-derived acetyl-CoA and propionyl-CoA for energy and anaplerosis. GeneReviews recommends it as part of specialist dietary management. CACT-specific evidence consists mainly of uncontrolled cases with concurrent intensive care; improvement in cardiac function does not establish a comparative treatment effect or cure.

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 REVIEW SYNTHESIS 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.

Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639 Cardiac arrhythmia HP:0011675 Hyperammonemia HP:0001987 Rhabdomyolysis HP:0003201

Show evidence (3 references)

PMID:27590926 SUPPORT PRIMARY RESULT Human Clinical

"Pre-treatment EF was 21% and within 3 days improved to 67%."

CACT patient 5 improved after triheptanoin during concurrent pressors, dextrose and intensive care; an uncontrolled observation.

PMID:27590926 SUPPORT PRIMARY RESULT Human Clinical

"He has continued on triheptanoin, and his most recent 2D ECHO at age 5 ½ years, showed normal ventricular morphology and function."

CACT patient 10 had sustained cardiac improvement; the mixed ten-patient series contains two CACT cases.

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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)."

Disease-specific management recommendation, based on limited CACT evidence.

Medium-chain triglyceride supplementation

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

MCT can provide alternate fuel when triheptanoin is unavailable. GeneReviews suggests 10%-30% of calories. C8 can bypass the shuttle; C10 and longer fatty acyl moieties in commercial formulations remain shuttle-dependent, so some centers prefer C8 oil. Formulation and dose require metabolic-dietitian supervision.

Mechanism Target:

BYPASSES Impaired mitochondrial long-chain fatty acid oxidation — Shorter medium-chain substrates provide an alternative to long-chain transport; bypass is incomplete for C10 and longer components.

Show evidence (1 reference)

PMID:29502916 SUPPORT REVIEW SYNTHESIS 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 HP:0001985 Hyperammonemia HP:0001987

Show evidence (2 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Fatty acyl moieties of C10 length or longer (which are dependent on the carnitine shuttle) account for 20%-50% of total fatty acids in most commercially available MCT formulas."

Explains the chain-length limitation and why MCT formulations are not interchangeable.

Carnitine supplementation

Action: Nutritional Support NCIT:C15433

Agent: L-carnitine CHEBI:16347

Platform: Small molecule

Specialist-directed L-carnitine can replenish low free carnitine. GeneReviews recommends supplementation, but benefit and potential long-chain acylcarnitine-related cardiac risk remain debated in FAOD reviews. Monitor biochemical and cardiac status; this is neither an established universal contraindication nor a proven risk-free therapy.

Mechanism Target:

MODULATES Secondary free 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 REVIEW SYNTHESIS 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 (2 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Other

"Carnitine supplementation in LC-FAO has been controversial due to previous mouse models showing signs of cardiotoxicity following L-carnitine administration."

Explains the origin of the safety concern; it is not direct proof of cardiotoxicity in CACT patients.

Emergency metabolic crisis management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Reverse catabolism urgently with high-dextrose oral/enteral carbohydrate or hospital intravenous glucose. GeneReviews specifies 12-15 g/kg/day in infants and 10-12 g/kg/day at ages 1-6 years, with close glucose, fluid, ammonia and cardiac monitoring. Ammonia scavengers may be insufficient; refractory hyperammonemia can require extracorporeal clearance. Treat arrhythmia, cardiomyopathy, rhabdomyolysis and renal injury in specialist intensive care as indicated.

Mechanism Target:

INHIBITS Energy deficit during catabolic stress — High-dextrose fluids reverse catabolism and reduce endogenous lipolysis during acute crises.

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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 HP:0001987 Hypoketotic hypoglycemia HP:0001985 Cardiac arrhythmia HP:0011675 Hypertrophic cardiomyopathy HP:0001639 Rhabdomyolysis HP:0003201

Show evidence (2 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Extracorporeal ammonia clearance could be considered if medical therapy fails."

Listed among acute management options when medical measures are insufficient.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

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 REVIEW SYNTHESIS 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 Ontology label: Supportive Care NCIT:C15747

Avoid prolonged fasting, maintain a written illness regimen and plan perioperative calories and intravenous dextrose with the metabolic team. Prolonged propofol administration is a concern because of long-chain lipid content; GeneReviews notes that short procedures may be tolerated. Anesthetic choice and monitoring remain individualized.

Mechanism Target:

INHIBITS Energy deficit during catabolic stress — Avoiding fasting and maintaining emergency plans reduce catabolic stress exposures that precipitate crises.

Show evidence (1 reference)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 HP:0001985 Hyperammonemia HP:0001987 Encephalopathy HP:0001298

Show evidence (3 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Anesthetics that contain high doses of long-chain fatty acids, such as propofol, although use for short procedures is likely to be tolerated"

Preserves the distinction between prolonged exposure and short procedures.

Carglumic acid for hyperammonemia

Action: Pharmacotherapy NCIT:C15986

Agent: carglumic acid CHEBI:71028

Platform: Small molecule

Off-label adjunct targeting CPS1 activation through an NAG analogue. Reported responses are inconsistent; caloric correction remains central and this is not reliably effective CACT-specific therapy.

Mechanism Target:

BYPASSES Proposed impairment of N-acetylglutamate-dependent ureagenesis — NAG analogue therapy attempts to bypass a proposed activation defect; clinical response is inconsistent.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"has been used off-label in 2 affected persons, 1 of whom had a successful & stable outcome."

GeneReviews reports limited case experience with carglumic acid.

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises."

The 23-case study reports poor response, limiting generalization from isolated successes.

Target Phenotypes: Hyperammonemia HP:0001987

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"has been used off-label in 2 affected persons, 1 of whom had a successful & stable outcome."

GeneReviews reports limited case experience with carglumic acid.

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises."

The 23-case study reports poor response, limiting generalization from isolated successes.

Investigational d,l-3-hydroxybutyrate supplementation

Action: Nutritional Support NCIT:C15433

Experimental ketone-based adjunct reported in individual CACT cases. Evidence is insufficient to establish comparative efficacy or routine use.

Mechanism Target:

BYPASSES Energy deficit during catabolic stress — Provides an alternative fuel strategy in selected cases; benefit is uncertain.

Show evidence (1 reference)

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases."

Individual-case observations of several adjuncts, not a controlled estimate for each intervention.

Show evidence (1 reference)

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases."

Supports investigational status and limits efficacy interpretation.

Feeding support and developmental rehabilitation

Action: Supportive Care NCIT:C15747

Enteral tube feeding or gastrostomy may maintain calories when oral intake is inadequate. Physical, occupational and feeding therapies address functional needs; they do not reverse established brain injury.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"In individuals who survive long term, feeding issues may persist and use of a feeding tube, including gastrostomy, is often necessary:"

Supports long-term feeding assistance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Physical therapy • Occupational/feeding therapy • Aggressive rehab therapy"

Lists rehabilitation options in the treatment table.

Metabolic, cardiac and nutritional surveillance

Action: Supportive Care NCIT:C15747

Monitor growth and development at each visit; individualize glucose, ammonia, CK and liver testing to metabolic stability and age. GeneReviews recommends annual or clinically indicated echocardiography, ECG/Holter as indicated, renal assessment when indicated, and annual nutritional and vitamin assessment after age one year.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Arrhythmias EKG or 24-hr Holter test Periodically as clinically indicated Cardiomyopathy or cardiac dysfunction Echocardiogram Annually or as clinically indicated"

Provides cardiac surveillance modalities and frequency.

PMID:35862567 SUPPORT REVIEW SYNTHESIS Human Clinical

"Surveillance: Regular evaluations by a metabolic specialist and metabolic dietitian."

Supports multidisciplinary longitudinal follow-up.

🔬

Biochemical Markers

4

Long-chain acylcarnitines (C16, C18, C18:1) (INCREASED)

Context: C16, C18 and C18:1 elevations are characteristic but overlap CPT II deficiency. Normal long-chain concentrations occurred in two of 15 patients in a selected Chinese series, so a normal single profile does not exclude CACT deficiency.

Pathograph Readouts

Readout Of Long-chain acylcarnitine accumulation Positive Diagnostic

Observational biochemical readout of the named metabolic state; not an independent test of the proposed tissue-toxicity mechanism.

Show evidence (1 reference)

PMID:37305732 SUPPORT PRIMARY RESULT 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 (3 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS 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 PRIMARY RESULT 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.

PMID:37305732 SUPPORT PRIMARY RESULT 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."

Documents an important limitation of single-marker screening.

Free carnitine (C0) (DECREASED)

Context: Free carnitine is often low in symptomatic disease, but can be normal before symptoms. A low C0 concentration alone is not specific for CACT deficiency.

Pathograph Readouts

Readout Of Secondary free carnitine depletion Negative Diagnostic

Observational biochemical readout of the named metabolic state; not an independent test of the proposed tissue-toxicity mechanism.

Show evidence (1 reference)

PMID:29502916 SUPPORT REVIEW SYNTHESIS 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 PRIMARY RESULT 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: Ratios including (C16+C18:1)/C2 and C16/C2 improved discrimination in a selected study of 15 affected patients and newborn-screening comparators. This does not establish population-wide sensitivity or distinguish CACT from CPT II deficiency.

Pathograph Readouts

Readout Of Long-chain acylcarnitine accumulation Positive Diagnostic

Observational biochemical readout of the named metabolic state; not an independent test of the proposed tissue-toxicity mechanism.

Show evidence (1 reference)

PMID:37305732 SUPPORT PRIMARY RESULT 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 PRIMARY RESULT 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

Observational biochemical readout of the named metabolic state; not an independent test of the proposed tissue-toxicity mechanism.

Show evidence (1 reference)

PMID:29502916 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS Human Clinical

"Urine organic acids may show dicarboxylic aciduria."

Review evidence supports dicarboxylic aciduria as a urinary biochemical finding in CACT deficiency.

🔬

Diagnosis

4

Newborn screening and urgent metabolic evaluation

Tandem mass spectrometry detects characteristic acylcarnitine abnormalities; ratio indices can aid discrimination. CACT can present before screening results or with normal long-chain analytes, so symptomatic infants need urgent glucose, ammonia, CK, liver and cardiac assessment without waiting for screening.

disease screening NCIT:C15419

Show evidence (3 references)

PMID:37305732 SUPPORT BACKGROUND 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 PRIMARY RESULT 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.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The clinical features of severe CACT deficiency generally present around age two days, prior to receipt of the newborn screening result."

Defines typical timing and the limitation of newborn screening.

SLC25A20 molecular confirmation and functional testing

Biallelic pathogenic or likely pathogenic SLC25A20 variants establish the diagnosis. If one or no allele is found, add deletion/duplication analysis. Cultured fibroblast CACT activity can resolve selected cases. Two VUS, or one pathogenic allele plus a VUS, do not establish or exclude the diagnosis.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The diagnosis of CACT deficiency is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in SLC25A20 by molecular genetic testing"

Defines molecular confirmation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications."

Supports inclusion of structural deletions/duplications in diagnostic evaluation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"identification of biallelic SLC25A20 variants of uncertain significance (or identification of one known SLC25A20 pathogenic variant and one SLC25A20 variant of uncertain significance) does not establish or rule out the diagnosis; in this case enzymatic testing may be required."

Specifies which uncertain genotypes require further interpretation or functional assessment.

Distinguishing CACT from CPT II deficiency

The characteristic long-chain acylcarnitine pattern is indistinguishable from CPT II deficiency. Resolve the differential with gene testing or appropriate functional assays; a biochemical pattern alone does not establish SLC25A20 deficiency.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"This profile is indistinguishable from CPT II deficiency, and thus follow-up testing is required to establish the diagnosis"

Requires confirmatory testing after an overlapping acylcarnitine profile.

Testing relatives at risk

Test at-risk siblings of any age. Newborn siblings need familial variant testing or an acylcarnitine profile in parallel with routine screening; confirm parental segregation for recurrence counseling.

Show evidence (2 references)

PMID:35862567 SUPPORT REVIEW SYNTHESIS Human Clinical

"Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of CACT deficiency."

Recommends proactive evaluation of siblings.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"In parallel with newborn screening either test for the familial SLC25A20 pathogenic variants or measure acylcarnitine profile."

Avoids reliance on routine newborn screening alone in an at-risk family.

📈

Progression

2

Severe neonatal presentation

Symptoms commonly emerge around age two days, before screening results. Cardiac arrest and recurrent hyperammonemia contribute to mortality and neurodevelopmental injury, but long-term survival is possible. In a retrospective 23-case cohort, nine of 16 classical patients survived longer term; this is an ascertained cohort, not a prospective survival estimate.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The clinical features of severe CACT deficiency generally present around age two days, prior to receipt of the newborn screening result."

Defines typical timing and the limitation of newborn screening.

PMID:33634872 SUPPORT PRIMARY RESULT Human Clinical

"Nine classical patients survived longer-term-most with feeding difficulties and cognitive delay."

Describes survival and morbidity in the classical subgroup of a retrospective cohort.

Milder neonatal or later-onset presentation

Later onset may occur after one month or after one year. These clinical presentations share the same transport defect and do not define distinct mechanistic diseases. Residual enzyme activity can inform assessment but cannot determine prognosis alone; severe presentations occur despite measurable residual activity.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"A small group of affected individuals experience symptoms after age one month; a fraction of these manifest symptoms after age one year"

Describes the later-onset spectrum.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"However, enzyme activity should not entirely guide the prognosis, as there are individuals with enzyme activity in the 1%-10% range who had clinical features consistent with the severe neonatal form"

Limits prognostic interpretation of residual enzyme activity.

📊

Prevalence

1

Newborns in the Hong Kong expanded metabolic screening pilot

Birth Prevalence 3.28 per 100,000 1–9 per 100,000 (births)

One CACT case among 30,448 screened newborns (approximately 3.28 per 100,000). This single-case pilot estimate is imprecise and is not a population-wide prevalence or evidence of ancestry-specific enrichment.

Show evidence (2 references)

PMID:28862145 SUPPORT PRIMARY RESULT Human Clinical

"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."

Documents the single CACT diagnosis; the separate denominator quote supports the derived screening estimate.

PMID:28862145 SUPPORT PRIMARY RESULT Human Clinical

"During the study period, 30 448 newborns referred from 13 private and public units were screened."

Provides the screened denominator for the single CACT diagnosis.

🔬

Clinical Trials

1

NCT03773770 NOT_APPLICABLE UNKNOWN

Expanded access to triheptanoin for eligible patients with limited treatment options who cannot enter a UX007 trial. CACT is included among the listed conditions/keywords. This is an individual expanded-access program, not a controlled efficacy trial.

Show evidence (1 reference)

clinicaltrials:NCT03773770 SUPPORT PRIMARY RESULT Other

"Expanded access may be provided for qualified patients who have limited treatment options and are not eligible for a clinical trial."

The registry summary supports expanded access rather than an efficacy trial. The complete API record in references supplies status, scope and date.

🧮

Computational Models

1

Human SLC25A20 conformational models and molecular dynamics AlphaFold 2.2.0; ColabFold AlphaFold2_advanced; AMBER22; CPPTRAJ MOLECULAR_DOCKING

AlphaFold2/ColabFold models of cytoplasmic-open and matrix-open human SLC25A20, molecular dynamics and substrate docking explore conformational asymmetry and binding determinants. Structural analysis suggests explanations for Asp231His and Ala281Val. The reported simulations do not directly quantify patient-mutant transport or clinical phenotype.

PMID:36835358

Pathograph links

SLC25A20 transporter molecular function deficiency measures fidelity: low observes: molecular Molecular structural proxies inform the normal transport architecture and interpretations of pathogenic substitutions.

Limitations: Simulations and docking of modeled conformations do not directly measure deficient substrate transport. Clinical effects of mutations are inferred from their positions and interactions.

Divergences from the human mechanism

proxy quantity

Salt-bridge persistence, helix packing and docked substrate contacts are structural proxies for transport activity.

cause unrepresented

The disease variants are interpreted from carrier structures; the reported simulations are not direct functional tests of variant-specific transport deficiency.

boundary omission

Cellular energy metabolism, tissue injury and clinical outcomes lie outside the isolated transporter model.

Show evidence (2 references)

PMID:36835358 SUPPORT PRIMARY RESULT Computational

"The generation of the structural models of the two SLC25A20 conformational states, coupled to extended MD simulations, allowed for insight into the molecular determinants of the protein dynamics of this transporter."

Defines the structural modeling and dynamics scope.

+ 1 more reference

Findings

Predicted Asp231His effects involve matrix salt-bridge interactions; Ala281Val may perturb H5/H6 packing. Experimental mutant-transport confirmation is not supplied by this modeling study.

Show evidence (2 references)

PMID:36835358 SUPPORT PRIMARY RESULT Computational

"The generation of the structural models of the two SLC25A20 conformational states, coupled to extended MD simulations, allowed for insight into the molecular determinants of the protein dynamics of this transporter."

Defines the structural modeling and dynamics scope.

PMID:36835358 SUPPORT PRIMARY RESULT Computational

"the data suggest that the pathogenic mutation Asp231His perturbs the matrix salt bridge Asp231-Lys35 and/or the Asp231-Arg178 interactions, which are involved in the stability of the c- and m-state."

A computational interpretation of a disease allele, not a mutant functional experiment.

{ }

Source YAML

click to show

name: Carnitine-acylcarnitine Translocase Deficiency
category: Mendelian
creation_date: '2026-02-23T00:00:00Z'
synonyms:
- CACT deficiency
- CACTD
- SLC25A20 deficiency
- Carnitine-acylcarnitine carrier deficiency
description: Carnitine-acylcarnitine translocase (CACT) deficiency is an autosomal recessive SLC25A20 disorder of mitochondrial long-chain fatty acid transport. Impaired inner-membrane acylcarnitine exchange restricts fatty acid oxidation and energy supply during fasting or catabolic stress. Severe neonatal disease features hypoketotic hypoglycemia, hyperammonemia, arrhythmias, cardiomyopathy, hepatic dysfunction and muscle injury. Later-onset presentations can be milder, but severe decompensation remains possible. Energy deficiency is established; the contribution of long-chain acylcarnitine toxicity to individual organ manifestations remains incompletely defined.
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: Newborns in the Hong Kong expanded metabolic screening pilot
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.28
  notes: One CACT case among 30,448 screened newborns (approximately 3.28 per 100,000). This single-case pilot estimate is imprecise and is not a population-wide prevalence or evidence of ancestry-specific enrichment.
  evidence:
  - reference: PMID:28862145
    reference_title: 'Expanded newborn metabolic screening programme in Hong Kong: a three-year journey.'
    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: Documents the single CACT diagnosis; the separate denominator quote supports the derived screening estimate.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28862145
    reference_title: 'Expanded newborn metabolic screening programme in Hong Kong: a three-year journey.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: During the study period, 30 448 newborns referred from 13 private and public units were screened.
    explanation: Provides the screened denominator for the single CACT diagnosis.
progression:
- phase: Severe neonatal presentation
  notes: Symptoms commonly emerge around age two days, before screening results. Cardiac arrest and recurrent hyperammonemia contribute to mortality and neurodevelopmental injury, but long-term survival is possible. In a retrospective 23-case cohort, nine of 16 classical patients survived longer term; this is an ascertained cohort, not a prospective survival estimate.
  evidence:
  - &id004
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The clinical features of severe CACT deficiency generally present around age two days, prior to receipt of the newborn screening result.
    explanation: Defines typical timing and the limitation of newborn screening.
  - reference: PMID:33634872
    reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Nine classical patients survived longer-term-most with feeding difficulties and cognitive delay.
    explanation: Describes survival and morbidity in the classical subgroup of a retrospective cohort.
- phase: Milder neonatal or later-onset presentation
  notes: Later onset may occur after one month or after one year. These clinical presentations share the same transport defect and do not define distinct mechanistic diseases. Residual enzyme activity can inform assessment but cannot determine prognosis alone; severe presentations occur despite measurable residual activity.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: A small group of affected individuals experience symptoms after age one month; a fraction of these manifest symptoms after age one year
    explanation: Describes the later-onset spectrum.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: However, enzyme activity should not entirely guide the prognosis, as there are individuals with enzyme activity in the 1%-10% range who had clinical features consistent with the severe neonatal form
    explanation: Limits prognostic interpretation of residual enzyme activity.
pathophysiology:
- name: SLC25A20 transporter molecular function deficiency
  description: Loss of CACT transport activity limits acylcarnitine/carnitine exchange across the mitochondrial inner membrane.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Carnitine acylcarnitine translocase (CACT) transfers acylcarnitines formed by the action of carnitine palmitoyl-transferase I (CPT1) in the outer mitochondrial membrane into the mitochondrial matrix in exchange for free carnitine.
    explanation: Defines the transporter activity lost in SLC25A20 deficiency.
  genes:
  - &id002
    preferred_term: SLC25A20
    term:
      id: hgnc:1421
      label: SLC25A20
  molecular_functions:
  - preferred_term: carnitine-acylcarnitine translocase activity
    term:
      id: GO:0015227
      label: O-acyl-L-carnitine transmembrane transporter activity
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    description: Restricted matrix delivery limits oxidation of long-chain acyl groups.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Carnitine acylcarnitine translocase (CACT) transfers acylcarnitines formed by the action of carnitine palmitoyl-transferase I (CPT1) in the outer mitochondrial membrane into the mitochondrial matrix in exchange for free carnitine.
      explanation: Defines the transporter activity lost in SLC25A20 deficiency.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited.
      explanation: Connects the oxidation defect to inadequate energy availability.
  - target: Long-chain acylcarnitine accumulation
    description: Substrates accumulate upstream of the deficient inner-membrane carrier.
    causal_link_type: DIRECT
    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
      quote_role: REVIEW_SYNTHESIS
      snippet: CACT deficiency leads to the accumulation of acylcarnitines in the cytosol, but not inside mitochondria
      explanation: Review describes the predicted localization of substrate accumulation upstream of the transport block.
- name: Impaired mitochondrial long-chain fatty acid oxidation
  description: Long-chain fatty acid oxidation is restricted by inadequate mitochondrial substrate delivery.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:35862567
    reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity.
    explanation: Supports the central metabolic defect.
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  downstream:
  - target: Energy deficit during catabolic stress
    description: Insufficient fatty acid-derived energy becomes critical when demand rises or glucose availability falls.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited.
      explanation: Connects the oxidation defect to inadequate energy availability.
  - target: Impaired hepatic ketogenesis
    description: Reduced fatty acid-derived acetyl-CoA limits hepatic ketone production.
    causal_link_type: DIRECT
    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
      quote_role: REVIEW_SYNTHESIS
      snippet: the liver can convert the end product of mFAO (i.e., acetyl-CoA) into the ketone bodies acetoacetate and 3-hydroxybutyrate, which can then be used in virtually all other organs (except erythrocytes) as a source of energy.
      explanation: Explains why restricted hepatic fatty acid oxidation limits ketone fuel production.
  - target: Intracellular lipid accumulation
    description: Defective fatty acid utilization is associated with cellular lipid storage; tissue-level intermediates are incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38628283
      reference_title: 'Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      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: Documents cellular lipid storage in one autopsy; it does not identify the stored lipid chemically or demonstrate acylcarnitine toxicity.
  - target: Proposed impairment of N-acetylglutamate-dependent ureagenesis
    description: Reduced acetyl-CoA supply is proposed to limit NAG production and urea-cycle activation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: CACT deficiency has been proposed to ↓ acetyl-CoA & therefore NAG (essential in the urea cycle).
      explanation: Explicitly a proposed explanation for hyperammonemia, not a demonstrated defect of NAG synthesis or CPS1 in these patients.
- name: Energy deficit during catabolic stress
  description: Inadequate energy availability during fasting, birth transition, illness or poor intake increases reliance on glucose and protein substrates.
  biological_scale: ORGANISM
  evidence:
  - &id001
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited.
    explanation: Connects the oxidation defect to inadequate energy availability.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: A characteristic feature of all mFAO disorders is hypoglycemia, which is the direct result of the inability to oxidize FAs and concurrent increased consumption of glucose by tissues to match energy demands.
    explanation: Review-level explanation of glucose dependence in mitochondrial fatty acid oxidation defects.
  downstream:
  - target: Hypoketotic hypoglycemia
    description: Increased glucose consumption during the fatty acid oxidation block contributes to hypoglycemia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    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
      quote_role: REVIEW_SYNTHESIS
      snippet: A characteristic feature of all mFAO disorders is hypoglycemia, which is the direct result of the inability to oxidize FAs and concurrent increased consumption of glucose by tissues to match energy demands.
      explanation: Review-level explanation of glucose dependence in mitochondrial fatty acid oxidation defects.
    intermediate_mechanisms:
    - Increased glucose use and depletion of available glucose stores
  - target: Cardiac energy deficit
    description: Cardiac tissue loses a major fuel source during metabolic stress.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Fatty acid β-oxidation is an important pathway for energy production during times of stress or fasting, particularly in energy-demanding tissue such as cardiac muscle, skeletal muscle, and liver.
      explanation: Establishes cardiac reliance on the affected fuel pathway.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited.
      explanation: Connects the oxidation defect to inadequate energy availability.
  - target: Rhabdomyolysis
    description: When alternate substrates are depleted, muscle protein catabolism contributes to muscle breakdown.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: As these metabolites are depleted, hypoglycemia, hyperammonemia, and rhabdomyolysis (due to protein catabolism) supervene.
      explanation: GeneReviews links alternate fuel depletion and protein catabolism to rhabdomyolysis.
    intermediate_mechanisms:
    - Muscle protein catabolism
  - target: Metabolic and hypoxic brain injury
    description: Hypoglycemia during metabolic crises contributes to brain injury.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: This may be due to hypoglycemic/hypoxic brain injury and dietary interventions do not necessarily lead to improvement or resolution of the seizure disorder.
      explanation: Links neurological sequelae to hypoglycemic/hypoxic injury.
    intermediate_mechanisms:
    - Hypoglycemia and impaired cerebral fuel supply
  - target: Hyperammonemia during metabolic crises
    description: Loss of fatty-acid-derived energy and depletion of alternative fuels are associated with ammonia accumulation. This route does not require the specific proposed NAG/CPS1 mechanism to be established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The organs primarily affected subsequently utilize other energy sources, such as glycogen and protein. As these metabolites are depleted, hypoglycemia, hyperammonemia, and rhabdomyolysis (due to protein catabolism) supervene.
      explanation: The clinical synthesis explicitly connects the metabolic fuel deficit to hyperammonemia; its precise nitrogen-disposal intermediates remain unresolved.
  - target: Muscle weakness
    description: Restricted energy availability in skeletal muscle contributes to weakness during severe metabolic disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      quote_role: REVIEW_SYNTHESIS
      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 CACT-specific review links neonatal fatty acid energy dependence with severe muscle and neurological dysfunction.
  - target: Encephalopathy
    description: Acute failure of energy supply contributes to encephalopathy during severe metabolic decompensation; permanent structural injury is not required.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      quote_role: REVIEW_SYNTHESIS
      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 CACT-specific review links neonatal fatty acid energy dependence with severe muscle and neurological dysfunction.
- name: Impaired hepatic ketogenesis
  description: Insufficient hepatic ketone production limits alternative fuel availability during fasting.
  biological_scale: CELLULAR
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: the liver can convert the end product of mFAO (i.e., acetyl-CoA) into the ketone bodies acetoacetate and 3-hydroxybutyrate, which can then be used in virtually all other organs (except erythrocytes) as a source of energy.
    explanation: Explains why restricted hepatic fatty acid oxidation limits ketone fuel production.
  biological_processes:
  - preferred_term: ketone body biosynthetic process
    term:
      id: GO:0046951
      label: ketone body biosynthetic process
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  downstream:
  - target: Hypoketotic hypoglycemia
    description: Ketone availability is inappropriately low during hypoglycemia in fatty acid oxidation defects.
    causal_link_type: DIRECT
    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
      quote_role: REVIEW_SYNTHESIS
      snippet: A general feature of all mFAO disorders is hypoketotic hypoglycemia, simply because the block in mFAO eliminates FAs as an important substrate for energy provision and thereby causes an enhanced reliance on glucose oxidation instead.
      explanation: Review-level metabolic explanation for the composite phenotype.
- name: Long-chain acylcarnitine accumulation
  description: Long-chain acylcarnitines accumulate upstream of the CACT transport block; blood concentrations vary with metabolic state.
  biological_scale: MOLECULAR
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: CACT deficiency leads to the accumulation of acylcarnitines in the cytosol, but not inside mitochondria
    explanation: Review describes the predicted localization of substrate accumulation upstream of the transport block.
  downstream:
  - target: Secondary free carnitine depletion
    description: Reduced availability of unesterified carnitine accompanies abnormal acylcarnitine handling; its magnitude depends on metabolic state.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      quote_role: REVIEW_SYNTHESIS
      snippet: Free carnitine is low in blood, with marked elevations of C16, C18, and C18:1 carnitine species.
      explanation: CACT-specific review section describes secondary free-carnitine depletion.
  - target: Proposed acylcarnitine-mediated cardiac toxicity
    description: Cytosolic long-chain acylcarnitines are proposed contributors to cardiac toxicity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33024728
      reference_title: 'Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: This conclusion would be in line with the notion that patients affected by CACT deficiency also show severe cardiac abnormalities which include arrhythmias and cardiomyopathy.
      explanation: The review extrapolates from VLCAD-deficient iPSC cardiomyocytes to CACT; this is indirect support for a hypothesis, not an experiment in CACT cardiomyocytes.
  - target: Elevated circulating acylcarnitine concentration
    description: Accumulated long-chain acylcarnitines are measured as the characteristic circulating elevation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      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: Links the molecular accumulation state to its measured clinical phenotype, without implying toxicity.
- name: Secondary free carnitine depletion
  description: Circulating free carnitine may become depleted, particularly during symptomatic disease. It may remain normal before symptoms.
  biological_scale: MOLECULAR
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: Free carnitine is low in blood, with marked elevations of C16, C18, and C18:1 carnitine species.
    explanation: CACT-specific review section describes secondary free-carnitine depletion.
  - 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
    quote_role: PRIMARY_RESULT
    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: Shows that low free carnitine can occur even without an elevated long-chain profile.
  downstream:
  - target: Decreased circulating carnitine concentration
    description: Secondary depletion is measured as reduced 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
      quote_role: REVIEW_SYNTHESIS
      snippet: Free carnitine is low in blood, with marked elevations of C16, C18, and C18:1 carnitine species.
      explanation: CACT-specific review section describes the corresponding biochemical phenotype.
- name: Intracellular lipid accumulation
  description: Microvesicular lipid accumulation can involve liver, heart, proximal renal tubules and skeletal muscle. Histology is not specific to CACT deficiency.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:38628283
    reference_title: 'Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    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: Documents cellular lipid storage in one autopsy; it does not identify the stored lipid chemically or demonstrate acylcarnitine toxicity.
  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
  notes: The 2024 index autopsy had one likely pathogenic SLC25A20 variant and one variant of uncertain significance. The clinical/pathological diagnosis supports a reported association; it does not establish pathogenicity of the VUS or chemically identify the lipid droplets.
  downstream:
  - target: Hepatomegaly
    description: Hepatocyte fatty change contributes to liver enlargement.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38628283
      reference_title: 'Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The diffuse fatty change corroborates with the firm hepatomegaly and the increase in the weight of the liver.
      explanation: The autopsy authors explicitly relate diffuse fatty change to hepatomegaly; the index case genotype remains qualified.
  - target: Elevated circulating hepatic transaminase concentration
    description: Hepatocyte lipid accumulation can contribute to hepatic dysfunction and injury; the detailed causal intermediates are incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38628283
      reference_title: 'Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The fatty changes in the hepatocytes, proximal tubular epithelia, skeletal, and cardiac myocytes are responsible for the dysfunction of the respective organs, contributing to morbidity and mortality.
      explanation: The autopsy authors attribute organ dysfunction to cellular fatty change; the transaminase readout is a clinical extrapolation, not an experimentally isolated effect.
    - reference: PMID:35862567
      reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      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: Establishes transaminitis as a clinical manifestation of the hepatic disorder.
- name: Cardiac energy deficit
  description: Impaired use of long-chain fatty acids restricts cardiomyocyte energy availability.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Fatty acid β-oxidation is an important pathway for energy production during times of stress or fasting, particularly in energy-demanding tissue such as cardiac muscle, skeletal muscle, and liver.
    explanation: Establishes cardiac reliance on the affected fuel pathway.
  - *id001
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Hypertrophic cardiomyopathy
    description: Cardiac energetic stress is a mechanistic contributor to hypertrophic remodeling; the complete causal sequence is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Fatty acid β-oxidation is an important pathway for energy production during times of stress or fasting, particularly in energy-demanding tissue such as cardiac muscle, skeletal muscle, and liver.
      explanation: Establishes cardiac reliance on the affected fuel pathway.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited.
      explanation: Connects the oxidation defect to inadequate energy availability.
    - reference: PMID:33634872
      reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15).
      explanation: Defines cardiac outcomes in the severe cohort, without independently proving an energy-only mechanism.
  - target: Reduced left ventricular ejection fraction
    description: Energetic impairment contributes to reduced systolic performance alongside other incompletely resolved mechanisms.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Fatty acid β-oxidation is an important pathway for energy production during times of stress or fasting, particularly in energy-demanding tissue such as cardiac muscle, skeletal muscle, and liver.
      explanation: Establishes cardiac reliance on the affected fuel pathway.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited.
      explanation: Connects the oxidation defect to inadequate energy availability.
  - target: Cardiac electrical instability
    description: Energetic failure is one candidate contributor to electrophysiological instability; lipid effects may coexist.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Fatty acid β-oxidation is an important pathway for energy production during times of stress or fasting, particularly in energy-demanding tissue such as cardiac muscle, skeletal muscle, and liver.
      explanation: Establishes cardiac reliance on the affected fuel pathway.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited.
      explanation: Connects the oxidation defect to inadequate energy availability.
- name: Proposed acylcarnitine-mediated cardiac toxicity
  description: Cytosolic long-chain acylcarnitines may contribute to cardiomyocyte rhythm disturbances. Evidence cited by the mechanistic review derives mainly from VLCAD-deficient iPSC cardiomyocytes and exposed rodent cells, not direct CACT patient-cell testing.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:33024728
    reference_title: 'Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: This conclusion would be in line with the notion that patients affected by CACT deficiency also show severe cardiac abnormalities which include arrhythmias and cardiomyopathy.
    explanation: The review extrapolates from VLCAD-deficient iPSC cardiomyocytes to CACT; this is indirect support for a hypothesis, not an experiment in CACT cardiomyocytes.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Cardiac electrical instability
    description: The proposed lipid effect could contribute to arrhythmias; disease-specific confirmation remains limited.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33024728
      reference_title: 'Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: This conclusion would be in line with the notion that patients affected by CACT deficiency also show severe cardiac abnormalities which include arrhythmias and cardiomyopathy.
      explanation: The review extrapolates from VLCAD-deficient iPSC cardiomyocytes to CACT; this is indirect support for a hypothesis, not an experiment in CACT cardiomyocytes.
- name: Proposed impairment of N-acetylglutamate-dependent ureagenesis
  description: Reduced acetyl-CoA may limit N-acetylglutamate availability and thereby CPS1 activation. This is a proposed explanation for impaired nitrogen disposal, not an established patient-specific biochemical sequence.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: CACT deficiency has been proposed to ↓ acetyl-CoA & therefore NAG (essential in the urea cycle).
    explanation: Explicitly a proposed explanation for hyperammonemia, not a demonstrated defect of NAG synthesis or CPS1 in these patients.
  mechanism_confidence: HYPOTHETICAL
  downstream:
  - target: Hyperammonemia during metabolic crises
    description: Reduced urea-cycle activation could contribute to ammonia accumulation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: CACT deficiency has been proposed to ↓ acetyl-CoA & therefore NAG (essential in the urea cycle).
      explanation: Explicitly a proposed explanation for hyperammonemia, not a demonstrated defect of NAG synthesis or CPS1 in these patients.
- name: Hyperammonemia during metabolic crises
  description: Ammonia accumulates during acute crises and can remain chronically or recurrently elevated in severe disease.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:35862567
    reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome.
    explanation: Describes the clinical hyperammonemic state and its relevance to brain injury.
  downstream:
  - target: Hyperammonemia
    description: The systemic ammonia elevation is measured clinically as hyperammonemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome.
      explanation: Describes the clinical hyperammonemic state and its relevance to brain injury.
  - target: Metabolic and hypoxic brain injury
    description: Recurrent severe hyperammonemia contributes to neurodevelopmental injury.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Contributing factors for neurodevelopmental delay are brain injury at presentation (often due to cardiac arrest) and the subsequent frequency and severity of metabolic decompensations featuring hyperammonemia.
      explanation: Supports multiple contributors to neurological injury rather than a single direct lipid-toxicity pathway.
- name: Metabolic and hypoxic brain injury
  description: Brain injury may follow hypoglycemia, hypoxia during cardiac arrest and recurrent hyperammonemic crises. Neurodevelopmental outcomes range from normal to impaired.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Contributing factors for neurodevelopmental delay are brain injury at presentation (often due to cardiac arrest) and the subsequent frequency and severity of metabolic decompensations featuring hyperammonemia.
    explanation: Supports multiple contributors to neurological injury rather than a single direct lipid-toxicity pathway.
  downstream:
  - target: Global developmental delay
    description: Acquired metabolic/hypoxic injury contributes to developmental impairment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Contributing factors for neurodevelopmental delay are brain injury at presentation (often due to cardiac arrest) and the subsequent frequency and severity of metabolic decompensations featuring hyperammonemia.
      explanation: Supports multiple contributors to neurological injury rather than a single direct lipid-toxicity pathway.
  - target: Intellectual disability
    description: Metabolic/hypoxic injury contributes to cognitive impairment in some survivors.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Contributing factors for neurodevelopmental delay are brain injury at presentation (often due to cardiac arrest) and the subsequent frequency and severity of metabolic decompensations featuring hyperammonemia.
      explanation: Supports multiple contributors to neurological injury rather than a single direct lipid-toxicity pathway.
  - target: Seizures
    description: Seizures may follow hypoglycemic or hypoxic brain injury.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: This may be due to hypoglycemic/hypoxic brain injury and dietary interventions do not necessarily lead to improvement or resolution of the seizure disorder.
      explanation: The preceding sentence concerns tonic-clonic seizures in affected individuals.
  - target: Lethargy
    description: Neurological injury and dysfunction during metabolic crises can manifest as reduced alertness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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
      quote_role: REVIEW_SYNTHESIS
      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 CACT-specific review links neonatal fatty acid energy dependence with severe muscle and neurological dysfunction.
    - reference: PMID:35862567
      reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      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: Supports lethargy as part of the metabolic-neurological presentation; the specific injury-to-alertness intermediates are not established.
- name: Cardiac electrical instability
  description: Tachyarrhythmias and bradyarrhythmias can accompany severe CACT deficiency, including ventricular tachycardia that can culminate in arrest.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The most prominent cardiac feature in the neonatal period is arrhythmia, particularly ventricular tachycardia, followed by various tachyarrhythmias and bradyarrhythmias
    explanation: Defines cardiac electrical instability.
  downstream:
  - target: Cardiac arrhythmia
    description: The clinical rhythm phenotype reflects electrical instability.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35862567
      reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest.
      explanation: Describes the clinical rhythm phenotype.
  - target: Ventricular tachycardia
    description: Ventricular tachycardia is a prominent expression of the rhythm disturbance.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The most prominent cardiac feature in the neonatal period is arrhythmia, particularly ventricular tachycardia, followed by various tachyarrhythmias and bradyarrhythmias
      explanation: Supports this specific ventricular rhythm phenotype.
  - target: Cardiac arrest
    description: Severe ventricular rhythm disturbances can culminate in arrest.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The most common cause of death is cardiac arrest secondary to arrhythmias (ventricular tachycardia)
      explanation: Supports progression from the ventricular rhythm disturbance to cardiac arrest.
phenotypes:
- name: Hypoketotic hypoglycemia
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
- name: Hyperammonemia
  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: &id003
    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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
- name: Elevated circulating acylcarnitine concentration
  category: Biochemical
  diagnostic: true
  description: Characteristic long-chain acylcarnitine elevations, especially C16, C18 and C18:1, can support investigation; a normal single profile does not exclude CACT deficiency.
  phenotype_term:
    preferred_term: Elevated circulating acylcarnitine concentration
    term:
      id: HP:0045045
      label: Elevated circulating acylcarnitine concentration
  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 circulating long-chain acylcarnitines.
    quote_role: REVIEW_SYNTHESIS
- name: Decreased circulating carnitine concentration
  category: Biochemical
  description: Free carnitine may be depleted in symptomatic CACT deficiency but can remain normal before symptoms.
  phenotype_term:
    preferred_term: Decreased circulating carnitine concentration
    term:
      id: HP:0003234
      label: Decreased circulating carnitine concentration
  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 reports low circulating free carnitine in CACT deficiency.
    quote_role: REVIEW_SYNTHESIS
- name: Dicarboxylic aciduria
  category: Biochemical
  description: Urinary dicarboxylic acids can appear during the long-chain fatty-acid oxidation block.
  phenotype_term:
    preferred_term: Dicarboxylic aciduria
    term:
      id: HP:0003215
      label: Dicarboxylic aciduria
  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 biochemical finding in CACT deficiency.
    quote_role: REVIEW_SYNTHESIS
- name: Cardiac arrhythmia
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:33634872
    reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15).
    explanation: Retrospective severe-subgroup counts; not a global CACT prevalence estimate.
  notes: 'In the 2021 retrospective cohort, 15 of 16 classical patients had cardiac involvement: 9/15 arrhythmia, 7/15 arrest and 9/15 hypertrophy. These overlapping outcomes describe the cardiac subgroup.'
- name: Cardiac arrest
  category: Cardiovascular
  description: Cardiac arrest can occur in severe early-onset disease with prominent arrhythmia.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  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 directly reports high rates of cardiac arrest in early-onset CACT deficiency.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:33634872
    reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15).
    explanation: Retrospective severe-subgroup counts; not a global CACT prevalence estimate.
  notes: 'In the 2021 retrospective cohort, 15 of 16 classical patients had cardiac involvement: 9/15 arrhythmia, 7/15 arrest and 9/15 hypertrophy. These overlapping outcomes describe the cardiac subgroup.'
- name: Hypertrophic cardiomyopathy
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:33634872
    reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15).
    explanation: Retrospective severe-subgroup counts; not a global CACT prevalence estimate.
  notes: 'In the 2021 retrospective cohort, 15 of 16 classical patients had cardiac involvement: 9/15 arrhythmia, 7/15 arrest and 9/15 hypertrophy. These overlapping outcomes describe the cardiac subgroup.'
- name: Hepatomegaly
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
- name: Muscular hypotonia
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Rhabdomyolysis
  description: Muscle breakdown may occur during metabolic decompensation.
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
- name: Muscle weakness
  category: Neuromuscular
  description: Skeletal muscle weakness can be part of the severe neonatal CACT deficiency presentation.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  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 skeletal muscle weakness among severe neonatal manifestations.
    quote_role: REVIEW_SYNTHESIS
- name: Lethargy
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Poor feeding
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Global developmental delay
  description: Developmental delay can follow early brain injury and recurrent metabolic crises; some treated survivors have normal development.
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Respiratory distress
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Seizures
  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.
    quote_role: BACKGROUND
- 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.
    quote_role: REVIEW_SYNTHESIS
- 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.
    quote_role: REVIEW_SYNTHESIS
- name: Elevated circulating hepatic transaminase concentration
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Ventricular tachycardia
  description: A prominent neonatal arrhythmia; other tachyarrhythmias, bradyarrhythmias and conduction abnormalities are also reported.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The most prominent cardiac feature in the neonatal period is arrhythmia, particularly ventricular tachycardia, followed by various tachyarrhythmias and bradyarrhythmias
    explanation: Supports this specific ventricular rhythm phenotype.
- name: Reduced left ventricular ejection fraction
  description: Systolic dysfunction can accompany hypertrophic cardiomyopathy and may improve after metabolic stabilization.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Cardiac dysfunction due to reduced left ventricular ejection fraction (<55%) is common.
    explanation: Supports echocardiographic systolic dysfunction.
- name: Intellectual disability
  description: Cognitive impairment is reported among survivors, with variable severity.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Most affected individuals have mild-to-moderate developmental delay and/or intellectual disability.
    explanation: Describes the neurodevelopmental spectrum in the clinical synthesis.
- name: Metabolic acidosis
  description: May occur during metabolic decompensation.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Metabolic derangements can include hypoketotic hypoglycemia, hyperammonemia, transaminitis, liver dysfunction, lactic acidosis, metabolic acidosis, and rhabdomyolysis
    explanation: Documents metabolic/lactic acidosis among reported derangements.
  notes: Reported during metabolic decompensation. The cited clinical list does not isolate a specific causal route from energetic failure, hepatic dysfunction or renal abnormalities.
- name: Lactic acidosis
  description: Lactate elevation with acidosis may accompany metabolic crises.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Metabolic derangements can include hypoketotic hypoglycemia, hyperammonemia, transaminitis, liver dysfunction, lactic acidosis, metabolic acidosis, and rhabdomyolysis
    explanation: Documents metabolic/lactic acidosis among reported derangements.
  notes: Reported during metabolic decompensation. The cited clinical list does not isolate a specific causal route from energetic failure, hepatic dysfunction or renal abnormalities.
- name: Elevated circulating creatine kinase concentration
  description: HyperCKemia may persist in long-term survivors or accompany acute muscle injury.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Long-term survivors may continue to experience chronic hyperammonemia and mild-to-moderate hyperCKemia
    explanation: Supports persistent hyperCKemia beyond acute crises.
- name: Renal Fanconi syndrome
  description: Reported renal manifestation. The relationship to metabolic injury and dietary treatment is incompletely understood.
  phenotype_term:
    preferred_term: Renal Fanconi syndrome
    term:
      id: HP:0001994
      label: Renal Fanconi syndrome
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Renal abnormalities may include nephromegaly, renal Fanconi syndrome, proximal renal tubular acidosis, and acute renal injury
    explanation: Documents reported renal manifestations; their mechanism and natural history are uncertain.
  notes: GeneReviews states that the pathophysiology and natural history of these renal findings are unclear. Proximal-tubule fat in a separate autopsy does not establish the cause of this particular renal manifestation.
- name: Proximal renal tubular acidosis
  description: Reported renal manifestation. The relationship to metabolic injury and dietary treatment is incompletely understood.
  phenotype_term:
    preferred_term: Proximal renal tubular acidosis
    term:
      id: HP:0002049
      label: Proximal renal tubular acidosis
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Renal abnormalities may include nephromegaly, renal Fanconi syndrome, proximal renal tubular acidosis, and acute renal injury
    explanation: Documents reported renal manifestations; their mechanism and natural history are uncertain.
  notes: GeneReviews states that the pathophysiology and natural history of these renal findings are unclear. Proximal-tubule fat in a separate autopsy does not establish the cause of this particular renal manifestation.
- name: Acute kidney injury
  description: Reported renal manifestation. The relationship to metabolic injury and dietary treatment is incompletely understood.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Renal abnormalities may include nephromegaly, renal Fanconi syndrome, proximal renal tubular acidosis, and acute renal injury
    explanation: Documents reported renal manifestations; their mechanism and natural history are uncertain.
  notes: GeneReviews states that the pathophysiology and natural history of these renal findings are unclear. Proximal-tubule fat in a separate autopsy does not establish the cause of this particular renal manifestation.
- name: Nephromegaly
  description: Reported renal manifestation. The relationship to metabolic injury and dietary treatment is incompletely understood.
  phenotype_term:
    preferred_term: Enlarged kidney
    term:
      id: HP:0000105
      label: Enlarged kidney
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Renal abnormalities may include nephromegaly, renal Fanconi syndrome, proximal renal tubular acidosis, and acute renal injury
    explanation: Documents reported renal manifestations; their mechanism and natural history are uncertain.
  notes: GeneReviews states that the pathophysiology and natural history of these renal findings are unclear. Proximal-tubule fat in a separate autopsy does not establish the cause of this particular renal manifestation.
biochemical:
- name: Long-chain acylcarnitines (C16, C18, C18:1)
  presence: INCREASED
  context: C16, C18 and C18:1 elevations are characteristic but overlap CPT II deficiency. Normal long-chain concentrations occurred in two of 15 patients in a selected Chinese series, so a normal single profile does not exclude CACT deficiency.
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: PRIMARY_RESULT
  - 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
    quote_role: PRIMARY_RESULT
    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: Documents an important limitation of single-marker screening.
  readouts:
  - target: Long-chain acylcarnitine accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Observational biochemical readout of the named metabolic state; not an independent test of the proposed tissue-toxicity mechanism.
    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.
      quote_role: PRIMARY_RESULT
- name: Free carnitine (C0)
  presence: DECREASED
  context: Free carnitine is often low in symptomatic disease, but can be normal before symptoms. A low C0 concentration alone is not specific for CACT deficiency.
  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.
    quote_role: PRIMARY_RESULT
  readouts:
  - target: Secondary free carnitine depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Observational biochemical readout of the named metabolic state; not an independent test of the proposed tissue-toxicity 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.
      quote_role: REVIEW_SYNTHESIS
- name: Acylcarnitine ratio indices
  presence: INCREASED
  context: Ratios including (C16+C18:1)/C2 and C16/C2 improved discrimination in a selected study of 15 affected patients and newborn-screening comparators. This does not establish population-wide sensitivity or distinguish CACT from CPT II deficiency.
  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.
    quote_role: PRIMARY_RESULT
  readouts:
  - target: Long-chain acylcarnitine accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Observational biochemical readout of the named metabolic state; not an independent test of the proposed tissue-toxicity mechanism.
    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.
      quote_role: PRIMARY_RESULT
- 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.
    quote_role: REVIEW_SYNTHESIS
  readouts:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Observational biochemical readout of the named metabolic state; not an independent test of the proposed tissue-toxicity 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: 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.
      quote_role: REVIEW_SYNTHESIS
histopathology:
- name: Hepatic microvesicular steatosis
  finding_term:
    preferred_term: Microvesicular Steatosis
    term:
      id: NCIT:C82982
      label: Microvesicular Steatosis
  description: Hepatic microvesicular steatosis was present together with macrovesicular steatosis in a reported autopsy. The index liver lacked inflammation or fibrosis. The morphology is not disease-specific.
  evidence:
  - reference: PMID:38628283
    reference_title: 'Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The steatosis was both macrovesicular (~100% hepatocytes) and microvesicular, with the microvesicular fat being obscured by the macrovesicular fat.
    explanation: Documents both hepatic patterns in the index autopsy.
  - reference: PMID:38628283
    reference_title: 'Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: No inflammation, portal or perisinusoidal fibrosis, or cholangiopathy was seen.
    explanation: Distinguishes the index liver from fibrosis reported in a sibling without genetic confirmation.
  notes: The 2024 index autopsy had one likely pathogenic SLC25A20 variant and one variant of uncertain significance. The clinical/pathological diagnosis supports a reported association; it does not establish pathogenicity of the VUS or chemically identify the lipid droplets.
- name: Extrahepatic microvesicular lipid accumulation
  finding_term:
    preferred_term: Extrahepatic microvesicular steatosis
  description: Oil-red-O-positive microvesicular fat was reported in cardiac myocytes, proximal renal tubules, occasional skeletal myocytes and pancreatic exocrine acini.
  notes: NCIT:C82982 is defined as a hepatic finding and is therefore not assigned to the extrahepatic sites. The index case carried one likely pathogenic allele and one VUS; histology does not resolve the VUS.
  evidence:
  - reference: PMID:38628283
    reference_title: 'Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Similar microvesicular steatosis was also noted in the cardiac myocytes (Figures 2A and 2B), proximal convoluted tubules of the kidneys (Figures 2C and 2D), occasional skeletal muscle cells (Figure 2E), and pancreatic exocrine acini (Figure 2F), confirmed by oil red O stain performed on the cryosections of these tissues.
    explanation: Directly describes the extrahepatic distribution.
genetic:
- name: SLC25A20
  gene_term:
    preferred_term: SLC25A20
    term:
      id: hgnc:1421
      label: SLC25A20
  features: Biallelic loss-of-function alleles include missense, nonsense, splice-site variants, small insertions/deletions and exon or whole-gene deletions. Genotype influences clinical severity, but residual activity and individual variants do not perfectly predict outcome.
  inheritance:
  - name: Autosomal recessive
    description: Autosomal recessive. When both parents are heterozygous, each pregnancy has a 25% chance of an affected child, 50% of an unaffected carrier and 25% of a child inheriting neither familial allele. 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.
      quote_role: REVIEW_SYNTHESIS
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: If both parents are known to be heterozygous for an SLC25A20 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC25A20 pathogenic variants and therefore being unaffected.
      explanation: Provides the conditional recurrence probabilities and distinguishes carriers from those inheriting neither allele.
  variants:
  - name: c.199-10T>G splice variant in SLC25A20
    description: Recurrent c.199-10T>G splice variant associated with severe neonatal disease, especially in individuals of East or Southeast Asian descent.
    gene:
      preferred_term: SLC25A20
      term:
        id: hgnc:1421
        label: SLC25A20
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Homozygosity for this pathogenic splice site variant is associated with the severe neonatal-onset form
      explanation: The sentence concerns c.199-10T>G in the genotype-phenotype section.
  - 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.
      quote_role: PRIMARY_RESULT
  - name: Asp231His and Ala281Val pathogenic mutations
    description: Molecular dynamics models suggest that Asp231His perturbs matrix salt-bridge interactions and that Ala281Val may disturb helix packing. These are structural predictions, not direct measurements of mutant transport in patients.
    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
      quote_role: PRIMARY_RESULT
      snippet: the data suggest that the pathogenic mutation Asp231His perturbs the matrix salt bridge Asp231-Lys35 and/or the Asp231-Arg178 interactions, which are involved in the stability of the c- and m-state.
      explanation: Reports an explicitly computational interpretation of Asp231His.
  - name: c.82G>T (p.Gly28Cys)
    gene: *id002
    description: Associated with milder neonatal or later-onset presentations in reported families, often of Pakistani or Indian descent; it is not an absolute predictor of outcome.
    evidence:
    - reference: PMID:33634872
      reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Seven attenuated patients of Pakistani heritage, six of these homozygous c.82G>T, had later onset manifestations and long-term survival without chronic hyperammonemia.
      explanation: Defines the attenuated subgroup of the retrospective cohort.
  - name: c.270delC (p.Phe91fs)
    gene: *id002
    description: Reported in association with severe neonatal disease; the association is not an individual prognostic rule.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Homozygosity for this pathogenic deletion of Turkish origin has been correlated with the severe neonatal-onset form of CACT deficiency
      explanation: Genotype-phenotype synthesis for the named recurrent allele.
  - name: c.713A>G (p.Gln238Arg)
    gene: *id002
    description: Reported in association with severe neonatal disease; the association is not an individual prognostic rule.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Homozygosity for this pathogenic variant of Middle Eastern origin has also been correlated with the severe neonatal-onset form of CACT deficiency
      explanation: Genotype-phenotype synthesis for the named recurrent allele.
  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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Sequence analysis of SLC25A20 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants.
    explanation: Documents the small-variant spectrum.
  - &id005
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
    explanation: Supports inclusion of structural deletions/duplications in diagnostic evaluation.
  relationship_type: CAUSATIVE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_95c9aece-49b5-496f-9547-f6d03dd69b4f-2018-05-22T160000.000Z
    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.
      quote_role: PRIMARY_RESULT
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.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      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.
      quote_role: REVIEW_SYNTHESIS
  - target: Energy deficit during catabolic stress
    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.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: PRIMARY_RESULT
- name: Triheptanoin therapy
  description: Triheptanoin supplies heptanoate-derived acetyl-CoA and propionyl-CoA for energy and anaplerosis. GeneReviews recommends it as part of specialist dietary management. CACT-specific evidence consists mainly of uncontrolled cases with concurrent intensive care; improvement in cardiac function does not establish a comparative treatment effect or cure.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: triheptanoin
      term:
        id: CHEBI:757060
        label: triheptanoin
  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.
      quote_role: REVIEW_SYNTHESIS
  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:27590926
    reference_title: Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Pre-treatment EF was 21% and within 3 days improved to 67%.
    explanation: CACT patient 5 improved after triheptanoin during concurrent pressors, dextrose and intensive care; an uncontrolled observation.
  - reference: PMID:27590926
    reference_title: Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: He has continued on triheptanoin, and his most recent 2D ECHO at age 5 ½ years, showed normal ventricular morphology and function.
    explanation: CACT patient 10 had sustained cardiac improvement; the mixed ten-patient series contains two CACT cases.
  - reference: PMID:35862567
    reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    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: Disease-specific management recommendation, based on limited CACT evidence.
  therapeutic_modality: SMALL_MOLECULE
  notes: The 2024 Italian comparative series (PMID:39375714) included MTP, CPT II and VLCAD deficiencies, with no CACT patients; its pooled hospitalization reductions cannot be assigned to CACT. Published CACT reports may describe overlapping patients.
- name: Medium-chain triglyceride supplementation
  description: MCT can provide alternate fuel when triheptanoin is unavailable. GeneReviews suggests 10%-30% of calories. C8 can bypass the shuttle; C10 and longer fatty acyl moieties in commercial formulations remain shuttle-dependent, so some centers prefer C8 oil. Formulation and dose require metabolic-dietitian supervision.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Impaired mitochondrial long-chain fatty acid oxidation
    treatment_effect: BYPASSES
    description: Shorter medium-chain substrates provide an alternative to long-chain transport; bypass is incomplete for C10 and longer components.
    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.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Fatty acyl moieties of C10 length or longer (which are dependent on the carnitine shuttle) account for 20%-50% of total fatty acids in most commercially available MCT formulas.
    explanation: Explains the chain-length limitation and why MCT formulations are not interchangeable.
- name: Carnitine supplementation
  description: Specialist-directed L-carnitine can replenish low free carnitine. GeneReviews recommends supplementation, but benefit and potential long-chain acylcarnitine-related cardiac risk remain debated in FAOD reviews. Monitor biochemical and cardiac status; this is neither an established universal contraindication nor a proven risk-free therapy.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: L-carnitine
      term:
        id: CHEBI:16347
        label: (R)-carnitine
  target_mechanisms:
  - target: Secondary free 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.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Carnitine supplementation in LC-FAO has been controversial due to previous mouse models showing signs of cardiotoxicity following L-carnitine administration.
    explanation: Explains the origin of the safety concern; it is not direct proof of cardiotoxicity in CACT patients.
  therapeutic_modality: SMALL_MOLECULE
- name: Emergency metabolic crisis management
  description: Reverse catabolism urgently with high-dextrose oral/enteral carbohydrate or hospital intravenous glucose. GeneReviews specifies 12-15 g/kg/day in infants and 10-12 g/kg/day at ages 1-6 years, with close glucose, fluid, ammonia and cardiac monitoring. Ammonia scavengers may be insufficient; refractory hyperammonemia can require extracorporeal clearance. Treat arrhythmia, cardiomyopathy, rhabdomyolysis and renal injury in specialist intensive care as indicated.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Energy deficit during catabolic stress
    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.
      quote_role: REVIEW_SYNTHESIS
  - 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.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Extracorporeal ammonia clearance could be considered if medical therapy fails.
    explanation: Listed among acute management options when medical measures are insufficient.
- 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: NCIT:C15240
      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.
    quote_role: REVIEW_SYNTHESIS
- name: Fasting avoidance and emergency planning
  description: Avoid prolonged fasting, maintain a written illness regimen and plan perioperative calories and intravenous dextrose with the metabolic team. Prolonged propofol administration is a concern because of long-chain lipid content; GeneReviews notes that short procedures may be tolerated. Anesthetic choice and monitoring remain individualized.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Energy deficit during catabolic stress
    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.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Anesthetics that contain high doses of long-chain fatty acids, such as propofol, although use for short procedures is likely to be tolerated
    explanation: Preserves the distinction between prolonged exposure and short procedures.
- name: Carglumic acid for hyperammonemia
  description: Off-label adjunct targeting CPS1 activation through an NAG analogue. Reported responses are inconsistent; caloric correction remains central and this is not reliably effective CACT-specific therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carglumic acid
      term:
        id: CHEBI:71028
        label: carglumic acid
  target_mechanisms:
  - target: Proposed impairment of N-acetylglutamate-dependent ureagenesis
    treatment_effect: BYPASSES
    description: NAG analogue therapy attempts to bypass a proposed activation defect; clinical response is inconsistent.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: has been used off-label in 2 affected persons, 1 of whom had a successful & stable outcome.
      explanation: GeneReviews reports limited case experience with carglumic acid.
    - reference: PMID:33634872
      reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises.
      explanation: The 23-case study reports poor response, limiting generalization from isolated successes.
  target_phenotypes:
  - *id003
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: has been used off-label in 2 affected persons, 1 of whom had a successful & stable outcome.
    explanation: GeneReviews reports limited case experience with carglumic acid.
  - reference: PMID:33634872
    reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises.
    explanation: The 23-case study reports poor response, limiting generalization from isolated successes.
- name: Investigational d,l-3-hydroxybutyrate supplementation
  description: Experimental ketone-based adjunct reported in individual CACT cases. Evidence is insufficient to establish comparative efficacy or routine use.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Energy deficit during catabolic stress
    treatment_effect: BYPASSES
    description: Provides an alternative fuel strategy in selected cases; benefit is uncertain.
    evidence:
    - reference: PMID:33634872
      reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases.
      explanation: Individual-case observations of several adjuncts, not a controlled estimate for each intervention.
  evidence:
  - reference: PMID:33634872
    reference_title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases.
    explanation: Supports investigational status and limits efficacy interpretation.
- name: Feeding support and developmental rehabilitation
  description: Enteral tube feeding or gastrostomy may maintain calories when oral intake is inadequate. Physical, occupational and feeding therapies address functional needs; they do not reverse established brain injury.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'In individuals who survive long term, feeding issues may persist and use of a feeding tube, including gastrostomy, is often necessary:'
    explanation: Supports long-term feeding assistance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Physical therapy • Occupational/feeding therapy • Aggressive rehab therapy
    explanation: Lists rehabilitation options in the treatment table.
- name: Metabolic, cardiac and nutritional surveillance
  description: Monitor growth and development at each visit; individualize glucose, ammonia, CK and liver testing to metabolic stability and age. GeneReviews recommends annual or clinically indicated echocardiography, ECG/Holter as indicated, renal assessment when indicated, and annual nutritional and vitamin assessment after age one year.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Arrhythmias EKG or 24-hr Holter test Periodically as clinically indicated Cardiomyopathy or cardiac dysfunction Echocardiogram Annually or as clinically indicated
    explanation: Provides cardiac surveillance modalities and frequency.
  - reference: PMID:35862567
    reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'Surveillance: Regular evaluations by a metabolic specialist and metabolic dietitian.'
    explanation: Supports multidisciplinary longitudinal follow-up.
notes: Severe neonatal and later-onset presentations form a spectrum of the same SLC25A20 transport defect. Clinical severity is not determined by residual enzyme activity alone. An overlapping CPT II biochemical profile requires molecular or functional resolution. Outcome estimates from small historical series should not be treated as current population-wide prognosis.
diagnosis:
- name: Newborn screening and urgent metabolic evaluation
  description: Tandem mass spectrometry detects characteristic acylcarnitine abnormalities; ratio indices can aid discrimination. CACT can present before screening results or with normal long-chain analytes, so symptomatic infants need urgent glucose, ammonia, CK, liver and cardiac assessment without waiting for screening.
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  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.
    quote_role: BACKGROUND
  - 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.
    quote_role: PRIMARY_RESULT
  - *id004
- name: SLC25A20 molecular confirmation and functional testing
  description: Biallelic pathogenic or likely pathogenic SLC25A20 variants establish the diagnosis. If one or no allele is found, add deletion/duplication analysis. Cultured fibroblast CACT activity can resolve selected cases. Two VUS, or one pathogenic allele plus a VUS, do not establish or exclude the diagnosis.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The diagnosis of CACT deficiency is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in SLC25A20 by molecular genetic testing
    explanation: Defines molecular confirmation.
  - *id005
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: identification of biallelic SLC25A20 variants of uncertain significance (or identification of one known SLC25A20 pathogenic variant and one SLC25A20 variant of uncertain significance) does not establish or rule out the diagnosis; in this case enzymatic testing may be required.
    explanation: Specifies which uncertain genotypes require further interpretation or functional assessment.
- name: Distinguishing CACT from CPT II deficiency
  description: The characteristic long-chain acylcarnitine pattern is indistinguishable from CPT II deficiency. Resolve the differential with gene testing or appropriate functional assays; a biochemical pattern alone does not establish SLC25A20 deficiency.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: This profile is indistinguishable from CPT II deficiency, and thus follow-up testing is required to establish the diagnosis
    explanation: Requires confirmatory testing after an overlapping acylcarnitine profile.
- name: Testing relatives at risk
  description: Test at-risk siblings of any age. Newborn siblings need familial variant testing or an acylcarnitine profile in parallel with routine screening; confirm parental segregation for recurrence counseling.
  evidence:
  - reference: PMID:35862567
    reference_title: Carnitine-Acylcarnitine Translocase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of CACT deficiency.
    explanation: Recommends proactive evaluation of siblings.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: In parallel with newborn screening either test for the familial SLC25A20 pathogenic variants or measure acylcarnitine profile.
    explanation: Avoids reliance on routine newborn screening alone in an at-risk family.
clinical_trials:
- name: NCT03773770
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: Expanded access to triheptanoin for eligible patients with limited treatment options who cannot enter a UX007 trial. CACT is included among the listed conditions/keywords. This is an individual expanded-access program, not a controlled efficacy trial.
  notes: The registry lists AVAILABLE, verified July 2026 and updated July 31, 2026. AVAILABLE is not represented in the schema status enum, so UNKNOWN preserves the unmapped status. Access may be available outside the US before local regulatory approval. No results are posted.
  evidence:
  - reference: clinicaltrials:NCT03773770
    reference_title: Expanded Access to Triheptanoin
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: Expanded access may be provided for qualified patients who have limited treatment options and are not eligible for a clinical trial.
    explanation: The registry summary supports expanded access rather than an efficacy trial. The complete API record in references supplies status, scope and date.
computational_models:
- name: Human SLC25A20 conformational models and molecular dynamics
  model_type: MOLECULAR_DOCKING
  description: AlphaFold2/ColabFold models of cytoplasmic-open and matrix-open human SLC25A20, molecular dynamics and substrate docking explore conformational asymmetry and binding determinants. Structural analysis suggests explanations for Asp231His and Ala281Val. The reported simulations do not directly quantify patient-mutant transport or clinical phenotype.
  publication: PMID:36835358
  model_software: AlphaFold 2.2.0; ColabFold AlphaFold2_advanced; AMBER22; CPPTRAJ
  modeled_mechanisms:
  - target: SLC25A20 transporter molecular function deficiency
    relationship: MEASURES
    description: Molecular structural proxies inform the normal transport architecture and interpretations of pathogenic substitutions.
    model_scale: MOLECULAR
    fidelity: LOW
    limitations: Simulations and docking of modeled conformations do not directly measure deficient substrate transport. Clinical effects of mutations are inferred from their positions and interactions.
    divergences:
    - divergence_type: PROXY_QUANTITY
      description: Salt-bridge persistence, helix packing and docked substrate contacts are structural proxies for transport activity.
    - divergence_type: CAUSE_UNREPRESENTED
      description: The disease variants are interpreted from carrier structures; the reported simulations are not direct functional tests of variant-specific transport deficiency.
    - divergence_type: BOUNDARY_OMISSION
      description: Cellular energy metabolism, tissue injury and clinical outcomes lie outside the isolated transporter model.
    evidence: &id006
    - 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
      quote_role: PRIMARY_RESULT
      snippet: The generation of the structural models of the two SLC25A20 conformational states, coupled to extended MD simulations, allowed for insight into the molecular determinants of the protein dynamics of this transporter.
      explanation: Defines the structural modeling and dynamics scope.
    - 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
      quote_role: PRIMARY_RESULT
      snippet: the data suggest that the pathogenic mutation Asp231His perturbs the matrix salt bridge Asp231-Lys35 and/or the Asp231-Arg178 interactions, which are involved in the stability of the c- and m-state.
      explanation: A computational interpretation of a disease allele, not a mutant functional experiment.
  evidence: *id006
  findings:
  - statement: Predicted Asp231His effects involve matrix salt-bridge interactions; Ala281Val may perturb H5/H6 packing. Experimental mutant-transport confirmation is not supplied by this modeling study.
references:
- reference: CGGV:assertion_95c9aece-49b5-496f-9547-f6d03dd69b4f-2018-05-22T160000.000Z
  title: SLC25A20 / carnitine-acylcarnitine translocase deficiency (Definitive)
- reference: PMID:25614308
  title: 'Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature.'
- reference: PMID:27590926
  title: Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.
- reference: PMID:28862145
  title: 'Expanded newborn metabolic screening programme in Hong Kong: a three-year journey.'
- reference: PMID:29502916
  title: 'Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System.'
- reference: PMID:33024728
  title: 'Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment.'
- reference: PMID:33634872
  title: 'New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.'
- reference: PMID:34449152
  title: Clinical and molecular characteristics of carnitineacylcarnitine translocase deficiency with c.270delC and a novel c.408C>A variant.
- reference: PMID:35862567
  title: Carnitine-Acylcarnitine Translocase Deficiency.
  tags:
  - GeneReviews
- reference: PMID:36835358
  title: In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter.
- reference: PMID:37305732
  title: Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity.
- reference: PMID:38628283
  title: 'Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.'
- reference: PMID:39203843
  title: Nutritional Management of Patients with Fatty Acid Oxidation Disorders.
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT03773770
  title: https://clinicaltrials.gov/api/v2/studies/NCT03773770
  findings:
  - statement: ClinicalTrials.gov API record for NCT03773770, Expanded Access to Triheptanoin; registry update July 31, 2026.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
  title: https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf
  findings:
  - statement: Full-text PDF of the GeneReviews chapter Carnitine-Acylcarnitine Translocase Deficiency (July 21, 2022), including diagnosis, clinical course, molecular genetics and management tables.
- reference: clinicaltrials:NCT03773770
  title: Expanded Access to Triheptanoin

📚

References & Deep Research

References

16

CGGV:assertion_95c9aece-49b5-496f-9547-f6d03dd69b4f-2018-05-22T160000.000Z

SLC25A20 / carnitine-acylcarnitine translocase deficiency (Definitive)

No top-level findings curated for this source.

PMID:25614308

Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature.

No top-level findings curated for this source.

PMID:27590926

Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.

No top-level findings curated for this source.

PMID:28862145

Expanded newborn metabolic screening programme in Hong Kong: a three-year journey.

No top-level findings curated for this source.

PMID:29502916

Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System.

No top-level findings curated for this source.

PMID:33024728

Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment.

No top-level findings curated for this source.

PMID:33634872

New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.

No top-level findings curated for this source.

PMID:34449152

Clinical and molecular characteristics of carnitineacylcarnitine translocase deficiency with c.270delC and a novel c.408C>A variant.

No top-level findings curated for this source.

PMID:35862567

Carnitine-Acylcarnitine Translocase Deficiency.

No top-level findings curated for this source.

PMID:36835358

In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter.

No top-level findings curated for this source.

PMID:37305732

Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity.

No top-level findings curated for this source.

PMID:38628283

Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.

No top-level findings curated for this source.

PMID:39203843

Nutritional Management of Patients with Fatty Acid Oxidation Disorders.

No top-level findings curated for this source.

url:https://clinicaltrials.gov/api/v2/studies/NCT03773770

https://clinicaltrials.gov/api/v2/studies/NCT03773770

1 finding

ClinicalTrials.gov API record for NCT03773770, Expanded Access to Triheptanoin; registry update July 31, 2026.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf

https://www.ncbi.nlm.nih.gov/sites/books/NBK582032/pdf/Bookshelf_NBK582032.pdf

1 finding

Full-text PDF of the GeneReviews chapter Carnitine-Acylcarnitine Translocase Deficiency (July 21, 2022), including diagnosis, clinical course, molecular genetics and management tables.

clinicaltrials:NCT03773770

Expanded Access to Triheptanoin

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Review CACT deficiency using full-text clinical and mechanistic evidence · 2026-10-04T14:52:33Z · View source

Comprehensive review against the Falcon report/citation sidecar, cached disease-specific literature, and the full GeneReviews PDF (clinical description, diagnosis, molecular genetics, counseling, treatment, surveillance and precautions). Replaced bundled mechanisms with 13 atomic nodes; distinguished established energetic deficiency from proposed lipid toxicity and NAG/CPS1 effects. Corrected unsupported frequency bands and historical/population denominator extrapolations. Added ventricular tachycardia, reduced ejection fraction, CK/acidosis, cognitive and renal manifestations. Separated hepatic NCIT microvesicular steatosis from extrahepatic findings and recorded the autopsy VUS limitation. Merged SLC25A20 entries with ClinGen-attributed Definitive validity, variant classes and conditional recurrence counseling. Added screening/confirmation/CPT2 differential and at-risk sibling testing. Replaced CACT treatment-effect claims from a zero-CACT mixed cohort with uncontrolled CACT-specific triheptanoin cases; included MCT chain-length limitations, carnitine controversy, mixed carglumic response, investigational ketones, feeding/rehabilitation and surveillance. Added the NCT03773770 expanded-access record, preserving AVAILABLE in notes because the enum lacks that status. Added the SLC25A20 structural/dynamics model with explicit proxy and disease-lesion limitations. Completeness: phenotype coverage adequate; clinical severity spectrum represented without separate mechanistic subtypes; proximal and downstream mechanisms covered with uncertainty preserved; treatments/access programs covered; gene/allele depth and external validity covered; biomarkers and diagnostic limitations covered; verified high-value references consumed; overall deep-research coverage adequate. No central dataset accession was identified in the reviewed sources. Full text obtained and read for PMID25614308,33024728,36835358,37305732,38628283,39203843,39375714,27590926 and GeneReviews. PMID33634872 and28689308 full-text retrieval remained unavailable; claims use cached abstracts where appropriate, without importing unverified details. PMID39375714 contains no CACT patients. A CAPTCHA response from PMC5953892 is excluded. ClinGen current export checked October4 retains the cited Definitive assertion. DR preflight CPT2 warning resolved as differential/shuttle/mixed-cohort context; unresolved DOI10.22037/ghfbb.v17i4.2960 not used. Independent PR review remains a separate gate.

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).

References

(vitoria2015carnitineacylcarnitinetranslocasedeficiency pages 1-2): Isidro Vitoria, Elena Martín-Hernández, Luis Peña-Quintana, María Bueno, Pilar Quijada-Fraile, Jaime Dalmau, Sofia Molina-Marrero, Belén Pérez, and Begoña Merinero. Carnitine-acylcarnitine translocase deficiency: experience with four cases in spain and review of the literature. JIMD reports, 20:11-20, Jan 2015. URL: https://doi.org/10.1007/8904_2014_382, doi:10.1007/8904_2014_382. This article has 52 citations and is from a peer-reviewed journal.
(thunga2024carnitineacylcarnitinetranslocasedeficiency pages 5-8): Chennakeshava Thunga, Suvradeep Mitra, Devi Dayal, and Sadhna Lal. Carnitine-acylcarnitine translocase deficiency: a case report with autopsy. Autopsy & Case Reports, 14:e2024483, Apr 2024. URL: https://doi.org/10.4322/acr.2024.483, doi:10.4322/acr.2024.483. This article has 2 citations.
(elgharbawy2018inbornerrorsof pages 4-6): Areeg El-Gharbawy and Jerry Vockley. Inborn errors of metabolism with myopathy. Apr 2018. URL: https://doi.org/10.1016/j.pcl.2017.11.006, doi:10.1016/j.pcl.2017.11.006. This article has 119 citations and is from a peer-reviewed journal.
(thunga2024carnitineacylcarnitinetranslocasedeficiency pages 2-5): Chennakeshava Thunga, Suvradeep Mitra, Devi Dayal, and Sadhna Lal. Carnitine-acylcarnitine translocase deficiency: a case report with autopsy. Autopsy & Case Reports, 14:e2024483, Apr 2024. URL: https://doi.org/10.4322/acr.2024.483, doi:10.4322/acr.2024.483. This article has 2 citations.
(thunga2024carnitineacylcarnitinetranslocasedeficiency media a9332e20): Chennakeshava Thunga, Suvradeep Mitra, Devi Dayal, and Sadhna Lal. Carnitine-acylcarnitine translocase deficiency: a case report with autopsy. Autopsy & Case Reports, 14:e2024483, Apr 2024. URL: https://doi.org/10.4322/acr.2024.483, doi:10.4322/acr.2024.483. This article has 2 citations.
(thunga2024carnitineacylcarnitinetranslocasedeficiency pages 1-2): Chennakeshava Thunga, Suvradeep Mitra, Devi Dayal, and Sadhna Lal. Carnitine-acylcarnitine translocase deficiency: a case report with autopsy. Autopsy & Case Reports, 14:e2024483, Apr 2024. URL: https://doi.org/10.4322/acr.2024.483, doi:10.4322/acr.2024.483. This article has 2 citations.
(kheirandish2024theroleof pages 8-8): Ali Kheirandish, Reza Shah Hosseini, Shirin Yaghoobpoor, Ashkan Bahrami, Alireza Aghajani, M. Fathi, Milad Alipour, Ameneh Zarebidoki, and Ashraf Mohamadkhani. The role of genetic defects in carnitine-associated hepatic encephalopathy: a review of literature. Gastroenterology and Hepatology From Bed to Bench, 17:357-378, 2024. URL: https://doi.org/10.22037/ghfbb.v17i4.2960, doi:10.22037/ghfbb.v17i4.2960. This article has 0 citations and is from a peer-reviewed journal.
(pasquadibisceglie2023insilicoanalysis pages 1-2): Andrea Pasquadibisceglie, Virginia Quadrotta, and Fabio Polticelli. In silico analysis of the structural dynamics and substrate recognition determinants of the human mitochondrial carnitine/acylcarnitine slc25a20 transporter. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043946, doi:10.3390/ijms24043946. This article has 12 citations.
(thunga2024carnitineacylcarnitinetranslocasedeficiency media 218ed3a6): Chennakeshava Thunga, Suvradeep Mitra, Devi Dayal, and Sadhna Lal. Carnitine-acylcarnitine translocase deficiency: a case report with autopsy. Autopsy & Case Reports, 14:e2024483, Apr 2024. URL: https://doi.org/10.4322/acr.2024.483, doi:10.4322/acr.2024.483. This article has 2 citations.
(pasquadibisceglie2023insilicoanalysis pages 4-7): Andrea Pasquadibisceglie, Virginia Quadrotta, and Fabio Polticelli. In silico analysis of the structural dynamics and substrate recognition determinants of the human mitochondrial carnitine/acylcarnitine slc25a20 transporter. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043946, doi:10.3390/ijms24043946. This article has 12 citations.
(pasquadibisceglie2023insilicoanalysis pages 18-19): Andrea Pasquadibisceglie, Virginia Quadrotta, and Fabio Polticelli. In silico analysis of the structural dynamics and substrate recognition determinants of the human mitochondrial carnitine/acylcarnitine slc25a20 transporter. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043946, doi:10.3390/ijms24043946. This article has 12 citations.
(pasquadibisceglie2023insilicoanalysis pages 2-4): Andrea Pasquadibisceglie, Virginia Quadrotta, and Fabio Polticelli. In silico analysis of the structural dynamics and substrate recognition determinants of the human mitochondrial carnitine/acylcarnitine slc25a20 transporter. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043946, doi:10.3390/ijms24043946. This article has 12 citations.
(penaquintana2024nutritionalmanagementof pages 5-6): Luis Peña-Quintana and Patricia Correcher-Medina. Nutritional management of patients with fatty acid oxidation disorders. Nutrients, 16:2707, Aug 2024. URL: https://doi.org/10.3390/nu16162707, doi:10.3390/nu16162707. This article has 7 citations.
(mahapatra2018triheptanoinarescue pages 1-2): Sidharth Mahapatra, Amitha Ananth, Nancy Baugh, Mihaela Damian, and Gregory M. Enns. Triheptanoin: a rescue therapy for cardiogenic shock in carnitine-acylcarnitine translocase deficiency. JIMD reports, 39:19-23, Jan 2018. URL: https://doi.org/10.1007/8904_2017_36, doi:10.1007/8904_2017_36. This article has 24 citations and is from a peer-reviewed journal.
(wanders2020mitochondrialfattyacid pages 12-13): Ronald J.A. Wanders, Gepke Visser, Sacha Ferdinandusse, Frédéric M. Vaz, and Riekelt H. Houtkooper. Mitochondrial fatty acid oxidation disorders: laboratory diagnosis, pathogenesis, and the complicated route to treatment. Journal of Lipid and Atherosclerosis, 9:313-333, Jul 2020. URL: https://doi.org/10.12997/jla.2020.9.3.313, doi:10.12997/jla.2020.9.3.313. This article has 81 citations.
(NCT03773770 chunk 1): Expanded Access to Triheptanoin. Ultragenyx Pharmaceutical Inc. ClinicalTrials.gov Identifier: NCT03773770
(kheirandish2024theroleof pages 7-8): Ali Kheirandish, Reza Shah Hosseini, Shirin Yaghoobpoor, Ashkan Bahrami, Alireza Aghajani, M. Fathi, Milad Alipour, Ameneh Zarebidoki, and Ashraf Mohamadkhani. The role of genetic defects in carnitine-associated hepatic encephalopathy: a review of literature. Gastroenterology and Hepatology From Bed to Bench, 17:357-378, 2024. URL: https://doi.org/10.22037/ghfbb.v17i4.2960, doi:10.22037/ghfbb.v17i4.2960. This article has 0 citations and is from a peer-reviewed journal.
(shi2023increasedacylcarnitineratio pages 1-2): Congcong Shi, Zhenzhen Ao, Bingqing Liu, Xin Xiao, Xia Gu, Qiuping Yang, Hu Hao, Yao Cai, and Sitao Li. Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity. Translational Pediatrics, 12:871-881, May 2023. URL: https://doi.org/10.21037/tp-22-468, doi:10.21037/tp-22-468. This article has 9 citations and is from a peer-reviewed journal.
(shi2023increasedacylcarnitineratio pages 8-10): Congcong Shi, Zhenzhen Ao, Bingqing Liu, Xin Xiao, Xia Gu, Qiuping Yang, Hu Hao, Yao Cai, and Sitao Li. Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity. Translational Pediatrics, 12:871-881, May 2023. URL: https://doi.org/10.21037/tp-22-468, doi:10.21037/tp-22-468. This article has 9 citations and is from a peer-reviewed journal.
(shi2023increasedacylcarnitineratio pages 2-3): Congcong Shi, Zhenzhen Ao, Bingqing Liu, Xin Xiao, Xia Gu, Qiuping Yang, Hu Hao, Yao Cai, and Sitao Li. Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity. Translational Pediatrics, 12:871-881, May 2023. URL: https://doi.org/10.21037/tp-22-468, doi:10.21037/tp-22-468. This article has 9 citations and is from a peer-reviewed journal.
(porta2024triheptanoininpatients pages 2-4): Francesco Porta, Arianna Maiorana, Vincenza Gragnaniello, Elena Procopio, Serena Gasperini, Roberta Taurisano, Marco Spada, Carlo Dionisi-Vici, and Alberto Burlina. Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in italy. Italian Journal of Pediatrics, Oct 2024. URL: https://doi.org/10.1186/s13052-024-01782-y, doi:10.1186/s13052-024-01782-y. This article has 10 citations and is from a peer-reviewed journal.
(porta2024triheptanoininpatients pages 1-2): Francesco Porta, Arianna Maiorana, Vincenza Gragnaniello, Elena Procopio, Serena Gasperini, Roberta Taurisano, Marco Spada, Carlo Dionisi-Vici, and Alberto Burlina. Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in italy. Italian Journal of Pediatrics, Oct 2024. URL: https://doi.org/10.1186/s13052-024-01782-y, doi:10.1186/s13052-024-01782-y. This article has 10 citations and is from a peer-reviewed journal.
(porta2024triheptanoininpatients pages 4-6): Francesco Porta, Arianna Maiorana, Vincenza Gragnaniello, Elena Procopio, Serena Gasperini, Roberta Taurisano, Marco Spada, Carlo Dionisi-Vici, and Alberto Burlina. Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in italy. Italian Journal of Pediatrics, Oct 2024. URL: https://doi.org/10.1186/s13052-024-01782-y, doi:10.1186/s13052-024-01782-y. This article has 10 citations and is from a peer-reviewed journal.
(mahapatra2018triheptanoinarescue pages 2-4): Sidharth Mahapatra, Amitha Ananth, Nancy Baugh, Mihaela Damian, and Gregory M. Enns. Triheptanoin: a rescue therapy for cardiogenic shock in carnitine-acylcarnitine translocase deficiency. JIMD reports, 39:19-23, Jan 2018. URL: https://doi.org/10.1007/8904_2017_36, doi:10.1007/8904_2017_36. This article has 24 citations and is from a peer-reviewed journal.
(porta2024triheptanoininpatients pages 6-9): Francesco Porta, Arianna Maiorana, Vincenza Gragnaniello, Elena Procopio, Serena Gasperini, Roberta Taurisano, Marco Spada, Carlo Dionisi-Vici, and Alberto Burlina. Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in italy. Italian Journal of Pediatrics, Oct 2024. URL: https://doi.org/10.1186/s13052-024-01782-y, doi:10.1186/s13052-024-01782-y. This article has 10 citations and is from a peer-reviewed journal.

Reference Validation

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Outcome	Count
References checked	10
Resolved	9
Unresolved (possible confabulation)	1
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Quoted claims checked	0
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Quoted claims not found in source	0
Quoted claims with nothing to check against	1
References weighed for topical relevance	9
On topic	1
Off topic	2

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DOI:10.22037/ghfbb.v17i4.2960 (4 mentions) - Identifier did not resolve to a record

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DOI:10.3390/ijms24043946 (10 mentions) - In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter
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DOI:10.3390/nu16162707 (4 mentions) - Nutritional Management of Patients with Fatty Acid Oxidation Disorders
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DOI:10.4322/acr.2024.483: "a crucial role in the oxidation of fatty acids"
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Carnitine-acylcarnitine Translocase Deficiency

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