Carnitine Palmitoyltransferase 1A Deficiency

Mendelian MONDO:0009705 Pathograph 36 Show in embeddings browser Fatty Acid Oxidation Disorder Inborn Error of Metabolism

Carnitine palmitoyltransferase 1A deficiency is an autosomal recessive disorder of the first reaction of the mitochondrial carnitine shuttle. Loss of CPT1A activity restricts long-chain acylcarnitine formation and hepatic fatty acid oxidation, impairing fasting ketogenesis and glucose homeostasis. Classic disease causes episodic hypoketotic hypoglycemia and hepatic decompensation, often during illness or reduced intake. Renal tubular acidosis and uncommon cardiac, muscle and neurodevelopmental manifestations broaden the phenotype. Some hypomorphic genotypes are largely asymptomatic. Elevated free carnitine and the C0/(C16+C18) ratio can suggest the diagnosis, but normal plasma results do not exclude it.

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Classifications

Harrison's Part

⚙

Pathophysiology

Variant-dependent CPT1A protein instability

Some pathogenic variants reduce CPT1A protein stability. This is variant dependent: p.Gly710Glu retains protein stability and mitochondrial targeting despite catalytic inactivity.

Experimental models

Variant-expressing COS cells CELL LINE Cell-based expression and biochemical assays reproduce the variant-specific protein defect.

Downstream

Reduced CPT1A catalytic activity Loss of stable enzyme reduces available CPT1A activity.

Show evidence (1 reference)

PMID:11441142 SUPPORT PRIMARY RESULT In Vitro

"Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability."

Mutant expression in COS cells supports instability for the variants tested, not for every pathogenic allele.

Reduced CPT1A catalytic activity

Biallelic pathogenic variants reduce CPT1A catalytic capacity. Residual activity and regulation differ substantially among alleles.

CPT1A hgnc:2328

carnitine O-palmitoyltransferase activity GO:0004095 ↓ DECREASED

mitochondrial outer membrane GO:0005741

Experimental models

Patient fibroblasts and heterologous yeast expressing p.Gly710Glu OTHER Cell-based expression and biochemical assays reproduce the variant-specific protein defect.

Downstream

Reduced long-chain acylcarnitine formation Reduced enzyme activity restricts conversion of long-chain acyl-CoA to acylcarnitine.

Reduced distal renal acid secretion Renal expression of CPT1A provides a basis for kidney involvement, but the specific route to defective distal acid secretion is unresolved.

Show evidence (2 references)

PMID:11350182 SUPPORT PRIMARY RESULT In Vitro

"By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A."

Patient fibroblast and heterologous yeast assays distinguish catalytic loss from protein instability.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Mechanism of disease causation. Loss of CPT1A function may occur from loss of mRNA expression or reduction of functional activity of CPT1A."

Summarizes molecular routes to functional deficiency.

Reduced long-chain acylcarnitine formation

Formation of long-chain acylcarnitines is reduced at the first step of the carnitine shuttle. Circulating long-chain acylcarnitines may therefore be low and the free-to-long-chain acylcarnitine ratio elevated.

carnitine shuttle GO:0006853 ↓ DECREASED

Downstream

Reduced hepatic long-chain fatty acid oxidation Insufficient acylcarnitine formation restricts mitochondrial delivery of long-chain fatty acyl groups for oxidation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Carnitine O-palmitoyltransferase 1, liver isoform (also called carnitine palmitoyltransferase 1A; CPT1A), encoded by CPT1A, and located on the outer mitochondrial membrane, converts long-chain acyl-CoAs to their acylcarnitine equivalents."

Defines the reaction impaired by CPT1A deficiency.

Reduced hepatic long-chain fatty acid oxidation

Hepatic mitochondrial oxidation of long-chain fatty acids is restricted. The defect becomes clinically important when carbohydrate reserves are limited.

hepatocyte CL:0000182

fatty acid beta-oxidation GO:0006635 ↓ DECREASED

liver UBERON:0002107

Downstream

Hepatic energy deficit during catabolic stress Restricted fatty acid oxidation limits hepatic energy availability during fasting.

Impaired hepatic ketogenesis Reduced oxidation limits ketone production despite circulating fatty acid availability.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The reduced activity of CPT1A caused by biallelic pathogenic variants of CPT1A prevents fatty acids from entering the mitochondria for energy production"

Links deficient activity to restricted long-chain fatty acid entry and energy production.

Hepatic energy deficit during catabolic stress

Hepatic fatty-acid-derived energy availability becomes insufficient during catabolic stress.

liver UBERON:0002107

Downstream

Impaired fasting glucose homeostasis Loss of fatty-acid-derived ATP limits energy available to support gluconeogenesis.

Hepatic dysfunction during metabolic crises Catabolic energy failure accompanies acute hepatic decompensation; detailed injury pathways are incompletely defined.

Show evidence (2 references)

PMID:21763168 SUPPORT BACKGROUND Human Clinical

"ATP derived from fatty acid oxidation also energizes de novo glucose synthesis from amino acids and other substrates in the liver."

Physiologic background explaining the energy requirement for hepatic gluconeogenesis.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The reduced activity of CPT1A caused by biallelic pathogenic variants of CPT1A prevents fatty acids from entering the mitochondria for energy production"

Links deficient activity to restricted long-chain fatty acid entry and energy production.

Impaired hepatic ketogenesis

Ketone production is inappropriately low during fasting, limiting an alternative fuel supply.

ketone body biosynthetic process GO:0046951 ↓ DECREASED

Downstream

Hypoketotic hypoglycemia Insufficient ketogenesis produces the hypoketotic component when glucose homeostasis also fails.

Show evidence (1 reference)

PMID:21763168 SUPPORT PRIMARY RESULT Human Clinical

"Plasma free fatty acids increased normally in these children but their long-chain acylcarnitine and ketone production was significantly blunted."

Five p.Pro479Leu homozygous children underwent supervised fasting; findings support impaired ketogenesis despite substrate availability.

Impaired fasting glucose homeostasis

Glucose homeostasis fails during fasting in susceptible individuals, particularly as glycogen reserves decline.

Downstream

Hypoketotic hypoglycemia Falling glucose with limited ketogenesis produces hypoketotic hypoglycemia.

Metabolic brain dysfunction and injury Hypoglycemia can impair brain function and cause injury during metabolic crises.

Show evidence (1 reference)

PMID:21763168 SUPPORT PRIMARY RESULT Human Clinical

"Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children."

The small physiological study establishes possible fasting intolerance, not population penetrance.

Hepatocyte lipid accumulation

Macrovesicular or mixed hepatic steatosis is documented in affected individuals, including rare chronic liver disease without recognized metabolic crises.

hepatocyte CL:0000182

liver UBERON:0002107

Show evidence (2 references)

PMID:32781271 SUPPORT PRIMARY RESULT Human Clinical

"Further investigations showed transaminitis, hepatosteatosis and cirrhosis."

A molecularly and enzymatically characterized case demonstrates chronic hepatic lipid storage and injury.

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"A liver biopsy revealed massive macrovesicular steatosis."

Documents hepatic fatty change in an enzyme-confirmed infant.

Hepatic dysfunction during metabolic crises

Acute liver dysfunction can develop during fasting or illness and may progress to liver failure.

liver UBERON:0002107

Downstream

Elevated hepatic transaminases Hepatic injury is accompanied by transaminase elevation.

Hyperammonemia Liver decompensation may include ammonia accumulation; a specific urea-cycle enzyme defect is not established here.

Hepatic encephalopathy Severe hepatic decompensation can impair cerebral function.

Hepatic failure Severe decompensation may progress to liver failure.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Many symptomatic individuals with CPT1A deficiency present with fasting-induced hepatic encephalopathy in early childhood or later in life, a potentially fatal presentation."

Links fasting decompensation with hepatic dysfunction.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia."

Identifies the associated hepatic and biochemical manifestations.

Metabolic brain dysfunction and injury

Metabolic crises can cause transient neurological dysfunction or lasting brain injury. This mechanism does not explain all developmental or speech findings in late-diagnosed patients.

Downstream

Lethargy Hypoglycemic brain dysfunction can reduce alertness.

Seizure Hypoglycemia can provoke seizures.

Coma Severe encephalopathic decompensation may progress to coma.

Global developmental delay Prior metabolic brain injury can cause lasting motor and developmental impairment.

Delayed speech and language development Neurological injury after crises can contribute to speech delay, but not all speech disorders require a recognized crisis.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Between episodes of metabolic decompensation, individuals with CPT1A deficiency typically appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage (leading to motor and/or speech delays)."

Supports acquired neurological injury after crises, without accounting for all developmental findings.

Reduced distal renal acid secretion

A rate-dependent failure of distal renal acid secretion has been demonstrated in an individual with CPT1A deficiency. The molecular explanation remains uncertain.

Downstream

Distal renal tubular acidosis Impaired distal proton secretion produces the demonstrated acidification phenotype.

Metabolic acidosis Insufficient renal acid excretion contributes to persistent metabolic acidosis in the reported infant.

Show evidence (2 references)

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"Evaluation of the renal acidification capacity showed a failure to acidify the urine during spontaneous acidosis but increased acid excretion and a normal decrease of urinary pH after acid loading."

Physiological testing in one infant demonstrated a rate-dependent distal acidification defect.

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"This acidification defect can best be explained as an abnormality in distal tubular H+ secretion: a rate-dependent distal tubular acidosis."

Authors localize the acidification abnormality; the upstream molecular mechanism remains uncertain.

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Histopathology

Hepatic macrovesicular steatosis

Massive macrovesicular hepatic steatosis was documented in an enzyme-confirmed infant; other reports describe hepatic steatosis without a uniform histological subtype. Fatty change is not specific for CPT1A deficiency.

Show evidence (2 references)

PMID:32781271 SUPPORT PRIMARY RESULT Human Clinical

"Further investigations showed transaminitis, hepatosteatosis and cirrhosis."

A molecularly and enzymatically characterized case demonstrates chronic hepatic lipid storage and injury.

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"A liver biopsy revealed massive macrovesicular steatosis."

Documents hepatic fatty change in an enzyme-confirmed infant.

⬡

Pathograph

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

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Phenotypes

Cardiovascular 1

Cardiomyopathy HP:0001638

The clinical series included molecularly and biochemically diagnosed patients; alternative contributors and the mechanism of cardiac involvement are incompletely resolved.

Show evidence (1 reference)

PMID:38090675 SUPPORT PRIMARY RESULT Human Clinical

"Cardiomyopathy was detected in two patients on echocardiography. Cardiomyopathy resolved in one patient after the first year of dietary treatment."

Observational findings do not establish controlled treatment efficacy.

Digestive 4

Hepatomegaly HP:0002240

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia."

Identifies the associated hepatic and biochemical manifestations.

Hepatic failure HP:0001399

Show evidence (1 reference)

PMID:20301700 SUPPORT REVIEW SYNTHESIS Human Clinical

"hepatic encephalopathy, hypoketotic hypoglycemia, and sudden onset of liver failure"

Describes severe infantile disease.

Cirrhosis HP:0001394

Show evidence (1 reference)

PMID:32781271 SUPPORT PRIMARY RESULT Human Clinical

"We describe an atypical case of an 8-year-old male with CPT1A deficiency presenting with chronic liver steatosis and cirrhosis."

Case-level finding, not a common outcome.

Vomiting HP:0002013

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Manifestations can include vomiting and altered mental status ranging from fatigue and lethargy to coma and/or death."

Clinical presentation of hepatic encephalopathy.

Genitourinary 2

Distal renal tubular acidosis HP:0008341

Other reports describe renal tubular acidosis without a uniformly established subtype. GeneReviews states that its prevalence is unknown; do not generalize the distal subtype to every affected individual.

Show evidence (2 references)

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"Evaluation of the renal acidification capacity showed a failure to acidify the urine during spontaneous acidosis but increased acid excretion and a normal decrease of urinary pH after acid loading."

Physiological testing in one infant demonstrated a rate-dependent distal acidification defect.

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"This acidification defect can best be explained as an abnormality in distal tubular H+ secretion: a rate-dependent distal tubular acidosis."

Authors localize the acidification abnormality; the upstream molecular mechanism remains uncertain.

Dicarboxylic aciduria HP:0003215

Show evidence (1 reference)

PMID:16146704 SUPPORT PRIMARY RESULT Human Clinical

"Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid."

Observed in three affected infants; urine profiles are not invariably abnormal.

Metabolism 6

Hypoketotic hypoglycemia HP:0001985

Show evidence (2 references)

PMID:21763168 SUPPORT PRIMARY RESULT Human Clinical

"Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children."

The small physiological study establishes possible fasting intolerance, not population penetrance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hypoketotic hypoglycemia can present in the neonatal period or later in life."

Supports neonatal through later onset.

Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia."

Identifies the associated hepatic and biochemical manifestations.

Hyperammonemia HP:0001987

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia."

Identifies the associated hepatic and biochemical manifestations.

Elevated creatine kinase Elevated circulating creatine kinase activity HP:0003236

Only six of the 14 cohort patients had molecular confirmation, with parental variants supporting one additional deceased case. Remaining diagnoses relied on biochemical profiles; ascertainment and diagnostic limitations restrict generalization.

Show evidence (2 references)

PMID:38090675 SUPPORT PRIMARY RESULT Human Clinical

"Additionally, elevated creatine kinase (CK) levels ranging between 250 and 800 U/L (normal range: 20–180 U/L) were detected in seven patients both at the time of initial diagnosis and during the follow-up period."

Selected cohort proportion; not a population frequency.

PMID:11286380 SUPPORT PRIMARY RESULT Human Clinical

"We discuss four new cases in three families showing, variously, renal tubular acidosis, transient hyperlipidaemia and, paradoxically, myopathy with elevated creatinine kinase or cardiac involvement in the neonatal period as additional features that deserve wider recognition."

The four-case report broadens the classic hepatic presentation; no population frequency is inferred.

Metabolic acidosis HP:0001942

Show evidence (1 reference)

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"Mild, persistent metabolic acidosis was a constant feature, even during periods between metabolic decompensation."

Documents persistent acidosis in the renal case.

Hyperlipidemia HP:0003077

Show evidence (1 reference)

PMID:11286380 SUPPORT PRIMARY RESULT Human Clinical

The four-case report broadens the classic hepatic presentation; no population frequency is inferred.

Musculoskeletal 1

Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:38090675 SUPPORT PRIMARY RESULT Human Clinical

"Similarly, in our study, three patients presented with muscle weakness, fatigue, and muscle pain"

Describes the muscle presentation in a selected cohort.

Nervous System 6

Hepatic encephalopathy HP:0002480

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Many symptomatic individuals with CPT1A deficiency present with fasting-induced hepatic encephalopathy in early childhood or later in life, a potentially fatal presentation."

Links fasting decompensation with hepatic dysfunction.

Lethargy HP:0001254

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Lethargy, altered mental status, and/or seizures (related to hypoglycemia)"

Describes acute neurological symptoms.

Seizure HP:0001250

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Symptomatic individuals may manifest seizures (related to hypoglycemia) often associated with a precipitating illness or poor oral intake."

Defines the clinical context.

Coma HP:0001259

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Manifestations can include vomiting and altered mental status ranging from fatigue and lethargy to coma and/or death."

Places coma within the encephalopathic spectrum.

Global developmental delay HP:0001263

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

Supports acquired neurological injury after crises, without accounting for all developmental findings.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"global developmental delay or isolated speech delay may be possible without preceding metabolic decompensation"

Supports the broader phenotype and uncertainty about cause.

Delayed speech and language development HP:0000750

The retrospective cohort had limited molecular confirmation and no genome-wide exclusion of other causes. Developmental surveillance is warranted, but a specific direct neurodevelopmental mechanism is unproven.

Show evidence (1 reference)

PMID:38090675 SUPPORT PRIMARY RESULT Human Clinical

"Speech disorders including delayed expressive language development, speech articulation disorder, speech retardation, and stuttering were present in nine patients."

Nine patients had heterogeneous speech disorders, not nine with a uniform delay phenotype.

Constitutional 2

Myalgia HP:0003326

Show evidence (1 reference)

PMID:38090675 SUPPORT PRIMARY RESULT Human Clinical

"Similarly, in our study, three patients presented with muscle weakness, fatigue, and muscle pain"

Documents myalgia without assigning a population frequency.

Sudden death HP:0001699

Show evidence (1 reference)

PMID:11350182 SUPPORT BACKGROUND Human Clinical

"Symptomatology comprises attacks of hypoketotic hypoglycemia with risk of sudden death or neurological sequelae."

Clinical background describing severe disease risk.

🧬

Genetic Associations

CPT1A (Biallelic loss of function)

Gene: CPT1A hgnc:2328 gene page relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Sequence analysis of CPT1A can be performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions."

Summarizes variant classes.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Exon and multiexon deletions have been rarely reported"

Adds structural alleles.

Variants (5)

p.Pro479Leu (c.1436C>T)

Common hypomorphic allele in several northern Indigenous populations. A patient fibroblast study found approximately 20% residual activity and partial resistance to malonyl-CoA inhibition. Most homozygotes are asymptomatic, but supervised fasting in five children demonstrated reduced ketogenesis and symptomatic hypoglycemia in two. Population associations with infectious illness and infant mortality do not establish a direct immune defect or an inevitable clinical outcome. In the Nunavik population-genetic study, the allele frequency was 95.5% among 100 analyzed adults after exclusions from 113 recruits; this is not disease prevalence or penetrance.

Show evidence (6 references)

PMID:11441142 SUPPORT PRIMARY RESULT In Vitro

"The patient with atypical symptoms had approximately 20% of normal L-CPT I activity and was homozygous for a mutation (c.1436C-->T) that substituted leucine for proline at codon 479."

Single-patient biochemical characterization.

PMID:11441142 SUPPORT PRIMARY RESULT In Vitro

"Assays performed with his cultured skin fibroblasts indicated that this mutation confers partial resistance to the inhibitory effects of malonyl-CoA."

Functional regulation differs from complete enzyme loss.

PMID:21763168 SUPPORT PRIMARY RESULT Human Clinical

"Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children."

The small physiological study establishes possible fasting intolerance, not population penetrance.

+ 3 more references

p.Gly710Glu (c.2129G>A)

Hutterite founder allele causing catalytic inactivity despite preserved protein stability and mitochondrial targeting.

Show evidence (2 references)

PMID:11350182 SUPPORT PRIMARY RESULT In Vitro

"Studies in fibroblasts from one patient as well as heterologous expression of the mutagenized CPT1A in yeast show that the G710E mutation alters neither mitochondrial targeting nor stability of the CPT1A protein."

Distinguishes a catalytic defect from instability.

PMID:11350182 SUPPORT PRIMARY RESULT In Vitro

"By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A."

Patient fibroblast and heterologous yeast assays distinguish catalytic loss from protein instability.

p.Ser34Pro (c.100T>C)

Micronesian founder allele associated with a mild biochemical phenotype. Twenty-two homozygotes had no significant metabolic decompensation in the reported follow-up, including ten without dietary management. Residual activity of 26% was measured in one asymptomatic adult, not across all 22 patients.

Show evidence (2 references)

PMID:35822099 SUPPORT PRIMARY RESULT Human Clinical

"There have been no episodes of significant metabolic decompensation in any of the 22 cases, including 10 patients who were not treated with dietary management, and one who was admitted to the intensive care unit with sepsis."

Documents the p.Ser34Pro cohort and treatment context.

PMID:35822099 SUPPORT PRIMARY RESULT In Vitro

"Enzymology in cultured skin fibroblasts in an asymptomatic adult, showed residual CPT1 activity at 26% of normal controls, despite abnormal acylcarnitine metabolites consistent with CPT1A deficiency"

Single-adult functional result; the series does not establish lifetime penetrance.

p.Ser708Arg (c.2122A>C)

Niuean founder allele associated with classic disease. Among three reported homozygotes, two presented clinically and the third was identified through sibling testing before later mild illness-associated decompensations.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"CPT1A pathogenic variant p.Ser708Arg has been reported in the Niuean population"

Identifies the founder allele; the primary series provides the individual ascertainment details.

PMID:35822099 SUPPORT PRIMARY RESULT Human Clinical

"Two presented clinically with classical CPT1A deficiency symptoms, the third was an asymptomatic younger sibling, diagnosed prospectively."

Primary full text distinguishes presentation from prospective ascertainment.

p.Lys455Thr (c.1364A>C)

Finnish recurrent allele: five of six reported patients were homozygous and one was compound heterozygous with p.Tyr498Ser. Crises generally occurred with illness or fasting and were uncommon during dietary treatment.

Show evidence (2 references)

PMID:21962599 SUPPORT PRIMARY RESULT Human Clinical

"Five cases carried a homozygous c.1364A>C (p.K455T) mutation, whereas 1 case had a compound c.1364A>C/c.1493A>C (p.Y498S) mutation."

Defines the genotypes in this six-person series.

PMID:21962599 SUPPORT PRIMARY RESULT Human Clinical

"During dietary therapy, the patients had few transient decompensations."

Uncontrolled follow-up, not a comparative treatment estimate.

💊

Medical Actions

Age-appropriate fasting avoidance

Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Frequent feeding prevents catabolic crises. GeneReviews recommends feeding neonates and infants every two to three hours. Suggested maximum fasting intervals when well are eight hours at 6–12 months, ten hours during the second year and twelve hours after age two. Illness, surgery and reduced intake require a more cautious individualized emergency plan, not a blanket twelve-hour allowance. Cornstarch or overnight feeding may be appropriate after infancy.

Mechanism Target:

INHIBITS Hepatic energy deficit during catabolic stress — Carbohydrate availability reduces reliance on impaired hepatic fatty acid oxidation.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Neonates and infants require frequent feedings every two to three hours."

Age-specific preventive guidance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Up to eight hours in infants between ages six and 12 months ⚬ Up to ten hours during the second year of life ⚬ Up to 12 hours after age two years"

Suggested maxima only in the absence of infection, fever or other stress.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Neonates and infants require frequent feedings every two to three hours."

Age-specific preventive guidance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Up to eight hours in infants between ages six and 12 months ⚬ Up to ten hours during the second year of life ⚬ Up to 12 hours after age two years"

Suggested maxima only in the absence of infection, fever or other stress.

Individualized high-carbohydrate, low-long-chain-fat diet

Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

A metabolic dietitian guides carbohydrate supply, long-chain fat restriction and essential fatty acid replacement. The degree of fat restriction is controversial in mild or asymptomatic p.Pro479Leu homozygotes. Avoid overfeeding when well and monitor growth and nutrient status.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"High-carbohydrate diet (70% of calories) that is low in long-chain fat (<20% of calories)"

GeneReviews long-term diet table; specialist individualization is required.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"If the physician chooses to recommend a low-fat diet when the affected individual is well, supplementation with essential fatty acids is necessary."

Preserves nutritional requirements during restriction.

Medium-chain triglyceride supplementation

Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Medium-chain fat provides an alternative oxidizable substrate that bypasses the CPT1A-dependent long-chain shuttle. It does not restore CPT1A activity. Dose and caloric contribution vary with age, tolerance and acute versus maintenance needs.

Mechanism Target:

BYPASSES Reduced CPT1A catalytic activity — Medium-chain substrate can support ketogenesis despite deficient long-chain acylcarnitine formation.

Show evidence (1 reference)

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"Ketogenesis was absent after a long-chain triglyceride loading test; in contrast, the medium-chain triglyceride loading test resulted in a brisk rise in plasma ketone concentration."

Physiological response in one affected infant supports bypass of long-chain transport.

Show evidence (1 reference)

PMID:7877875 SUPPORT PRIMARY RESULT Human Clinical

"Ketogenesis was absent after a long-chain triglyceride loading test; in contrast, the medium-chain triglyceride loading test resulted in a brisk rise in plasma ketone concentration."

Physiological response in one affected infant supports bypass of long-chain transport.

Triheptanoin

Action: Pharmacotherapy NCIT:C15986

Agent: triheptanoin CHEBI:757060

Platform: Small molecule

This odd-chain triglyceride supplies medium-chain substrate and anaplerotic propionyl-CoA. GeneReviews lists it as targeted therapy. CPT1A-specific clinical evidence remains sparse: only one CPT I participant was included in the CL202 extension cohort, so pooled LC-FAOD event reductions should not be presented as a CPT1A effect estimate. Gastrointestinal intolerance can limit dosing.

Mechanism Target:

BYPASSES Reduced CPT1A catalytic activity — Odd-chain medium-chain substrate bypasses the long-chain transport defect.

Show evidence (2 references)

PMID:20301700 SUPPORT REVIEW SYNTHESIS Human Clinical

"Targeted therapies: Triheptanoin (an odd-carbon triglyceride) or MCT oil."

GeneReviews lists the metabolic therapies.

PMID:32885845 SUPPORT BACKGROUND Human Clinical

"Propionyl‐CoA is further metabolized to succinyl‐CoA, which resupplies TCA cycle intermediates (anaplerosis) that may be secondarily deficient in patients with LC‐FAOD"

Mechanistic rationale in the trial introduction, not proof of CPT1A-specific efficacy.

Show evidence (2 references)

PMID:20301700 SUPPORT REVIEW SYNTHESIS Human Clinical

"Targeted therapies: Triheptanoin (an odd-carbon triglyceride) or MCT oil."

GeneReviews lists the metabolic therapies.

PMID:32885845 SUPPORT BACKGROUND Human Clinical

"Propionyl‐CoA is further metabolized to succinyl‐CoA, which resupplies TCA cycle intermediates (anaplerosis) that may be secondarily deficient in patients with LC‐FAOD"

Mechanistic rationale in the trial introduction, not proof of CPT1A-specific efficacy.

Emergency intravenous glucose

Action: Pharmacotherapy NCIT:C15986

Agent: dextrose CHEBI:17234

Platform: Small molecule

Prompt intravenous dextrose corrects hypoglycemia and supports anabolism during acute decompensation. GeneReviews describes at least 10% dextrose, approximately 8–10 mg/kg/min, with fluids and electrolytes adjusted clinically. Continue glucose beyond normalization to replenish hepatic glycogen, and taper as oral intake recovers.

Mechanism Target:

INHIBITS Impaired fasting glucose homeostasis — Exogenous glucose corrects inadequate endogenous glucose availability.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia"

Recommends prompt carbohydrate replacement.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"continue glucose infusion beyond normalization of blood glucose to provide sufficient substrate for glycogen synthesis."

Explains why normalization of blood glucose alone does not end acute support.

BYPASSES Hepatic energy deficit during catabolic stress — Carbohydrate supplies energy during catabolic decompensation.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia"

Recommends prompt carbohydrate replacement.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"continue glucose infusion beyond normalization of blood glucose to provide sufficient substrate for glycogen synthesis."

Explains why normalization of blood glucose alone does not end acute support.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia"

Recommends prompt carbohydrate replacement.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"continue glucose infusion beyond normalization of blood glucose to provide sufficient substrate for glycogen synthesis."

Explains why normalization of blood glucose alone does not end acute support.

Emergency planning and perioperative metabolic care

Action: Supportive Care NCIT:C15747

Platform: Other

Families need a written emergency plan, recognition of early decompensation and coordinated care during illness, surgery or sedation. Provide carbohydrate-containing fluids when adequate intake cannot be maintained.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Carry written info re child's disorder & appropriate treatment in emergency setting."

Supports a written emergency plan.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Avoid fasting, including during periods of preparation and recovery from planned surgery or sedation"

Extends fasting precautions to procedures.

Metabolic, nutritional, renal and developmental surveillance

Action: Supportive Care NCIT:C15747

Platform: Other

Assess growth, feeding and dietary adherence at visits. Monitor carnitine/acylcarnitines, essential fatty acids, fat-soluble vitamins, blood count, metabolic profile and CK according to age and diet. Check hepatic function and renal indices when indicated; assess development throughout childhood and refer for physical, occupational or speech-language therapy as needed.

Show evidence (3 references)

PMID:20301700 SUPPORT REVIEW SYNTHESIS Human Clinical

"Assess growth, feeding, and adherence to diet at each visit"

Summarizes routine surveillance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Nephrology BUN, serum creatinine concentration, & urinalysis for urine protein As clinically indicated to assess for renal tubular acidosis"

Adds renal surveillance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Assess developmental & educational progress w/ referrals for social services, physical therapy, occupational therapy, & speech & language services as needed"

Supports developmental follow-up and rehabilitation.

Caution with potentially hepatotoxic medicines

Action: Supportive Care NCIT:C15747

Platform: Other

Use valproate or salicylate cautiously if hepatic dysfunction is present. GeneReviews notes that CPT1A-specific adverse pharmacologic effects have not been reported; this is a conditional precaution.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Potentially hepatotoxic agents such as valproate and salicylate should be used with caution if there is evidence of hepatic dysfunction"

States the condition for caution.

Liver transplantation consideration

Action: Liver Transplantation NCIT:C15271

Platform: Surgery

GeneReviews advises considering liver transplantation in liver failure. Disease-specific outcome evidence is limited; it is not routine therapy for otherwise stable CPT1A deficiency.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Liver disease Consider orthotic liver transplantation. In those w/liver failure"

The source recommendation concerns liver failure; no outcome rate is asserted.

Pregnancy metabolic and hepatic monitoring

Action: Supportive Care NCIT:C15747

Platform: Other

Affected pregnant individuals require avoidance of fasting, hypoglycemia, dehydration and catabolism, with metabolic and maternal-fetal medicine care. Monitor liver function at prenatal visits during the first two trimesters and more often in the third in pregnancies at risk. Counsel carriers carrying an affected fetus about the limited evidence for maternal acute fatty liver. Triheptanoin has not been studied in pregnancy.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Management of women with CPT1A deficiency during pregnancy should include avoidance of fasting, hypoglycemia, dehydration, and catabolic stress."

Specifies maternal metabolic precautions.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Use of triheptanoin has not been studied in pregnancy."

Limits treatment extrapolation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"it is recommended that liver function testing be performed at each prenatal visit during the first two trimesters and more frequently during the third trimester, when the risk for AFLP is greatest."

Supports liver monitoring in subsequent pregnancies after an affected child.

Genetic counseling and family testing

Action: Genetic Counseling NCIT:C15240

Platform: Other

Explain genotype-dependent clinical uncertainty as well as autosomal recessive recurrence risk. Familial variant testing permits carrier, prenatal and preimplantation testing. Evaluate siblings regardless of age; at-risk newborns can undergo molecular testing in parallel with newborn screening.

Show evidence (3 references)

PMID:20301700 SUPPORT REVIEW SYNTHESIS Human Clinical

"When both parents are carriers of a CPT1A 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 being unaffected and not a carrier."

Specifies recurrence risks for two carrier parents.

PMID:20301700 SUPPORT REVIEW SYNTHESIS Human Clinical

"Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the CPT1A pathogenic variants in the family are known."

Supports familial variant testing.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"molecular genetic testing for the familial CPT1A pathogenic variants can be done in parallel with newborn screening."

Avoids reliance on biochemical newborn screening alone.

🌍

Environmental Factors

Febrile or gastrointestinal illness

Concurrent febrile or gastrointestinal illness increases energy demand and precipitates acute metabolic decompensation in CPT1A deficiency.

Show evidence (1 reference)

PMID:28748224 SUPPORT PRIMARY RESULT Human Clinical

"elevated liver transaminases in the setting of acute gastroenteritis."

The case illustrates hepatic illness-associated decompensation.

Mechanism Target:

EXACERBATES Hepatic energy deficit during catabolic stress — Reduced carbohydrate availability and increased reliance on fatty acid oxidation expose the pre-existing metabolic limitation; they do not create the inherited enzyme defect.

Show evidence (1 reference)

PMID:28748224 SUPPORT PRIMARY RESULT Human Clinical

"elevated liver transaminases in the setting of acute gastroenteritis."

The case illustrates hepatic illness-associated decompensation.

Fasting

Prolonged fasting depletes glycogen and forces reliance on fatty acid oxidation, unmasking the CPT1A block and triggering hypoketotic hypoglycemia.

Show evidence (1 reference)

PMID:21763168 SUPPORT PRIMARY RESULT Human Clinical

"Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children."

The small physiological study establishes possible fasting intolerance, not population penetrance.

Mechanism Target:

Show evidence (1 reference)

PMID:21763168 SUPPORT PRIMARY RESULT Human Clinical

"Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children."

The small physiological study establishes possible fasting intolerance, not population penetrance.

🔬

Biochemical Markers

Free carnitine and C0/(C16+C18) ratio (INCREASED)

Show evidence (2 references)

PMID:41017303 SUPPORT PRIMARY RESULT Human Clinical

"Our cases demonstrate that acylcarnitine profiles and especially concentrations of free carnitine can be normal in plasma in infants with CPT1AD at confirmation diagnosis after screening and during follow-up."

Qualifies the expected biochemical profile.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"CPT1A deficiency is characterized by marked reduction in the synthesis of all acylcarnitine species and increased levels of free carnitine (C0)."

Explains the usual profile.

Long-chain acylcarnitines (DECREASED)

Show evidence (1 reference)

PMID:21763168 SUPPORT PRIMARY RESULT Human Clinical

"Plasma free fatty acids increased normally in these children but their long-chain acylcarnitine and ketone production was significantly blunted."

Fasting physiological evidence in p.Pro479Leu homozygotes.

Urinary dodecanedioic and 3-hydroxyglutaric acids (INCREASED)

Show evidence (2 references)

PMID:16146704 SUPPORT PRIMARY RESULT Human Clinical

"Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid."

Supports dodecanedioic aciduria.

PMID:16146704 SUPPORT PRIMARY RESULT Human Clinical

"In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients"

Supports the additional urine finding.

🔬

Diagnosis

Molecular confirmation with complementary enzyme testing

Confirm biallelic pathogenic or likely pathogenic CPT1A variants. One pathogenic allele plus a VUS, or two VUSs, is not diagnostic. Sequence analysis may require complementary deletion/duplication analysis. Fibroblast CPT1 enzyme testing can clarify unresolved results where available; residual activity is often 1–5% in classic disease but higher in hypomorphic genotypes.

Genetic Testing NCIT:C15709

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The diagnosis of CPT1A deficiency is established in a proband with biallelic pathogenic (or likely pathogenic) variants in CPT1A identified by molecular genetic testing."

Defines the primary diagnostic criterion.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.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."

Specifies additional testing for unresolved sequence results.

PMID:20301700 SUPPORT REVIEW SYNTHESIS Human Clinical

"Diminished carnitine palmitoyltransferase 1 (CPT1) enzyme activity on cultured skin fibroblasts when molecular genetic testing is not definitive may be an available option in some countries."

Enzyme testing is not universally available.

Newborn screening and biochemical follow-up

Elevated free carnitine and C0/(C16+C18) can identify risk, but a normal plasma profile at confirmation or follow-up does not exclude CPT1A deficiency. Dried blood spots are preferable for biochemical detection. Follow an abnormal newborn screen with molecular confirmation rather than dismissing it after a normal plasma result.

Show evidence (2 references)

PMID:41017303 SUPPORT PRIMARY RESULT Human Clinical

Documents false reassurance from plasma testing.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"individuals with this variant may be missed by NBS with acylcarnitine profile alone"

The p.Pro479Leu genotype can be missed by acylcarnitine screening alone.

📈

Progression

Episodic metabolic decompensation

Onset ranges from the newborn period to adulthood. Fasting or intercurrent illness can cause rapid deterioration. Between episodes development may be normal, but prior crises can cause permanent injury and late-diagnosed patients can have developmental or speech abnormalities without recognized decompensation.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Age of onset of manifestations can vary from the newborn period to adulthood, and some individuals are asymptomatic."

Defines the onset spectrum.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"global developmental delay or isolated speech delay may be possible without preceding metabolic decompensation"

Limits the assumption that every developmental abnormality follows a recognized crisis.

Hypomorphic genotype presentations

Most p.Pro479Leu homozygotes remain asymptomatic, although fasting ketogenesis may be impaired. Twenty-two reported p.Ser34Pro homozygotes had no significant metabolic decompensation during follow-up; this small cohort does not establish zero lifetime risk. These genotypes share the same CPT1A reaction defect and are not separate mechanistic diseases.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"In fact, most children homozygous for this variant never develop any manifestations of CPT1A deficiency."

The preceding sentence identifies p.Pro479Leu.

PMID:35822099 SUPPORT PRIMARY RESULT Human Clinical

Documents the p.Ser34Pro cohort and treatment context.

📊

Prevalence

Newborns screened in Australia, Germany and the United States

Birth Prevalence 0.05–0.1333333333 per 100,000 live births 1–9 per 1,000,000 (births)

Historical combined screening incidence of approximately 1 in 750,000 to 2,000,000, summarized in the 2025 GeneReviews chapter. Screening sensitivity and genotype composition affect ascertainment; this is not an estimate of symptomatic disease among all CPT1A variant carriers. The normalized range is 0.05–0.1333 cases per 100,000 live births. It spans the below-one-per-million and one-to-nine-per-million bands; the coarse class represents the upper bound, while the numeric interval preserves the full source range.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Combined results of NBS programs in Australia, Germany, and the United States show an incidence of CPT1A deficiency of 1:750,000-2,000,000"

Provides the geographic scope and screening-based range.

🔬

Clinical Trials

NCT00653666 NOT_APPLICABLE COMPLETED

Completed physiological fasting and liver-fat study in Alaska Native children with CPT1A deficiency. The registry estimated enrollment of twelve; the published fasting report studied five p.Pro479Leu homozygotes with historical comparison data.

Show evidence (1 reference)

clinicaltrials:NCT00653666 SUPPORT PRIMARY RESULT Other

"The purpose of this study is to learn more about how long children with CPT-1 deficiency can wait between meals without developing low blood sugar or symptoms of low blood sugar."

Describes the physiological study objective.

NCT02214160 PHASE_II COMPLETED

CL202 was a phase II open-label triheptanoin extension study across long-chain fatty acid oxidation disorders, with 94 participants in the final report. Only one had CPT I deficiency; pooled reductions in major clinical events do not establish a disease-specific effect.

Show evidence (1 reference)

clinicaltrials:NCT02214160 SUPPORT PRIMARY RESULT Other

"The primary objective of this study is to evaluate the long-term safety and efficacy of UX007 in participants with LC-FAOD."

Registry objective, not an efficacy result.

NCT03773770 NOT_APPLICABLE UNKNOWN

Expanded access to triheptanoin for eligible patients with long-chain fatty acid oxidation disorders, including CPT I deficiency, who have limited treatment options and cannot enter a clinical 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."

Access program scope, not evidence of efficacy.

🧫

Experimental Models

Variant-expressing COS cells CELL_LINE

Comparable transcript abundance but reduced mutant protein supports variant-dependent protein instability.

Cell source

COS cells transfected with patient-derived mutant or wild-type CPT1A cDNA

Pathograph links

Variant-dependent CPT1A protein instability recapitulates observes: molecular Cell-based expression and biochemical assays reproduce the variant-specific protein defect.

Limitations: These assays do not recapitulate whole-organ or organism-level clinical outcomes.

Show evidence (1 reference)

PMID:11441142 SUPPORT PRIMARY RESULT In Vitro

"Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability."

Mutant expression in COS cells supports instability for the variants tested, not for every pathogenic allele.

Show evidence (1 reference)

PMID:11441142 SUPPORT PRIMARY RESULT In Vitro

"Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability."

Mutant expression in COS cells supports instability for the variants tested, not for every pathogenic allele.

Patient fibroblasts and heterologous yeast expressing p.Gly710Glu OTHER

Cell-based assays distinguish preserved mitochondrial targeting and stability from loss of catalytic activity. The yeast expression system is not a whole-animal disease model.

Cell source

Patient skin fibroblasts and engineered yeast

Pathograph links

Reduced CPT1A catalytic activity recapitulates observes: molecular Cell-based expression and biochemical assays reproduce the variant-specific protein defect.

Limitations: These assays do not recapitulate whole-organ or organism-level clinical outcomes.

Show evidence (2 references)

PMID:11350182 SUPPORT PRIMARY RESULT In Vitro

"By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A."

Patient fibroblast and heterologous yeast assays distinguish catalytic loss from protein instability.

+ 1 more reference

Show evidence (2 references)

PMID:11350182 SUPPORT PRIMARY RESULT In Vitro

"By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A."

Patient fibroblast and heterologous yeast assays distinguish catalytic loss from protein instability.

PMID:11350182 SUPPORT PRIMARY RESULT In Vitro

Distinguishes a catalytic defect from instability.

{ }

Source YAML

click to show

name: Carnitine Palmitoyltransferase 1A Deficiency
category: Mendelian
creation_date: '2026-07-02T00:00:00Z'
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
synonyms:
- CPT1A deficiency
- CPT-1A deficiency
- CPT IA deficiency
- Carnitine palmitoyltransferase 1A deficiency
- Hepatic carnitine palmitoyltransferase deficiency
- L-CPT1 deficiency
- Carnitine palmitoyltransferase I deficiency
description: Carnitine palmitoyltransferase 1A deficiency is an autosomal recessive disorder of the first reaction of the mitochondrial carnitine shuttle. Loss of CPT1A activity restricts long-chain acylcarnitine formation and hepatic fatty acid oxidation, impairing fasting ketogenesis and glucose homeostasis. Classic disease causes episodic hypoketotic hypoglycemia and hepatic decompensation, often during illness or reduced intake. Renal tubular acidosis and uncommon cardiac, muscle and neurodevelopmental manifestations broaden the phenotype. Some hypomorphic genotypes are largely asymptomatic. Elevated free carnitine and the C0/(C16+C18) ratio can suggest the diagnosis, but normal plasma results do not exclude it.
disease_term:
  preferred_term: carnitine palmitoyltransferase 1A deficiency
  term:
    id: MONDO:0009705
    label: carnitine palmitoyl transferase 1A deficiency
parents:
- Fatty Acid Oxidation Disorder
- Inborn Error of Metabolism
prevalence:
- population: Newborns screened in Australia, Germany and the United States
  notes: Historical combined screening incidence of approximately 1 in 750,000 to 2,000,000, summarized in the 2025 GeneReviews chapter. Screening sensitivity and genotype composition affect ascertainment; this is not an estimate of symptomatic disease among all CPT1A variant carriers. The normalized range is 0.05–0.1333 cases per 100,000 live births. It spans the below-one-per-million and one-to-nine-per-million bands; the coarse class represents the upper bound, while the numeric interval preserves the full source range.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Combined results of NBS programs in Australia, Germany, and the United States show an incidence of CPT1A deficiency of 1:750,000-2,000,000
    explanation: Provides the geographic scope and screening-based range.
  measure_type: BIRTH_PREVALENCE
  rate_denominator: LIVE_BIRTHS
  rate_low: 0.05
  rate_high: 0.1333333333
  prevalence_class: BAND_1_9_PER_1000000
progression:
- phase: Episodic metabolic decompensation
  notes: Onset ranges from the newborn period to adulthood. Fasting or intercurrent illness can cause rapid deterioration. Between episodes development may be normal, but prior crises can cause permanent injury and late-diagnosed patients can have developmental or speech abnormalities without recognized decompensation.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Age of onset of manifestations can vary from the newborn period to adulthood, and some individuals are asymptomatic.
    explanation: Defines the onset spectrum.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: global developmental delay or isolated speech delay may be possible without preceding metabolic decompensation
    explanation: Limits the assumption that every developmental abnormality follows a recognized crisis.
- phase: Hypomorphic genotype presentations
  notes: Most p.Pro479Leu homozygotes remain asymptomatic, although fasting ketogenesis may be impaired. Twenty-two reported p.Ser34Pro homozygotes had no significant metabolic decompensation during follow-up; this small cohort does not establish zero lifetime risk. These genotypes share the same CPT1A reaction defect and are not separate mechanistic diseases.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: In fact, most children homozygous for this variant never develop any manifestations of CPT1A deficiency.
    explanation: The preceding sentence identifies p.Pro479Leu.
  - reference: PMID:35822099
    reference_title: Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: There have been no episodes of significant metabolic decompensation in any of the 22 cases, including 10 patients who were not treated with dietary management, and one who was admitted to the intensive care unit with sepsis.
    explanation: Documents the p.Ser34Pro cohort and treatment context.
pathophysiology:
- name: Variant-dependent CPT1A protein instability
  description: 'Some pathogenic variants reduce CPT1A protein stability. This is variant dependent: p.Gly710Glu retains protein stability and mitochondrial targeting despite catalytic inactivity.'
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:11441142
    reference_title: 'Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability.
    explanation: Mutant expression in COS cells supports instability for the variants tested, not for every pathogenic allele.
  downstream:
  - target: Reduced CPT1A catalytic activity
    description: Loss of stable enzyme reduces available CPT1A activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11441142
      reference_title: 'Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability.
      explanation: Mutant expression in COS cells supports instability for the variants tested, not for every pathogenic allele.
- name: Reduced CPT1A catalytic activity
  description: Biallelic pathogenic variants reduce CPT1A catalytic capacity. Residual activity and regulation differ substantially among alleles.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:11350182
    reference_title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A.
    explanation: Patient fibroblast and heterologous yeast assays distinguish catalytic loss from protein instability.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Mechanism of disease causation. Loss of CPT1A function may occur from loss of mRNA expression or reduction of functional activity of CPT1A.
    explanation: Summarizes molecular routes to functional deficiency.
  genes:
  - preferred_term: CPT1A
    term:
      id: hgnc:2328
      label: CPT1A
  molecular_functions:
  - preferred_term: carnitine O-palmitoyltransferase activity
    term:
      id: GO:0004095
      label: carnitine O-palmitoyltransferase activity
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrial outer membrane
    term:
      id: GO:0005741
      label: mitochondrial outer membrane
  downstream:
  - target: Reduced long-chain acylcarnitine formation
    description: Reduced enzyme activity restricts conversion of long-chain acyl-CoA to acylcarnitine.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Carnitine O-palmitoyltransferase 1, liver isoform (also called carnitine palmitoyltransferase 1A; CPT1A), encoded by CPT1A, and located on the outer mitochondrial membrane, converts long-chain acyl-CoAs to their acylcarnitine equivalents.
      explanation: Defines the reaction impaired by CPT1A deficiency.
  - target: Reduced distal renal acid secretion
    description: Renal expression of CPT1A provides a basis for kidney involvement, but the specific route to defective distal acid secretion is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Since the isoform is also expressed in the kidney, renal tubular acidosis can also occur.
      explanation: Review-level attribution of renal disease to CPT1A deficiency.
- name: Reduced long-chain acylcarnitine formation
  description: Formation of long-chain acylcarnitines is reduced at the first step of the carnitine shuttle. Circulating long-chain acylcarnitines may therefore be low and the free-to-long-chain acylcarnitine ratio elevated.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Carnitine O-palmitoyltransferase 1, liver isoform (also called carnitine palmitoyltransferase 1A; CPT1A), encoded by CPT1A, and located on the outer mitochondrial membrane, converts long-chain acyl-CoAs to their acylcarnitine equivalents.
    explanation: Defines the reaction impaired by CPT1A deficiency.
  biological_processes:
  - preferred_term: carnitine shuttle
    term:
      id: GO:0006853
      label: carnitine shuttle
    modifier: DECREASED
  downstream:
  - target: Reduced hepatic long-chain fatty acid oxidation
    description: Insufficient acylcarnitine formation restricts mitochondrial delivery of long-chain fatty acyl groups for oxidation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The reduced activity of CPT1A caused by biallelic pathogenic variants of CPT1A prevents fatty acids from entering the mitochondria for energy production
      explanation: Links deficient activity to restricted long-chain fatty acid entry and energy production.
    intermediate_mechanisms:
    - Reduced carnitine-shuttle delivery of long-chain fatty acyl groups
- name: Reduced hepatic long-chain fatty acid oxidation
  description: Hepatic mitochondrial oxidation of long-chain fatty acids is restricted. The defect becomes clinically important when carbohydrate reserves are limited.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The reduced activity of CPT1A caused by biallelic pathogenic variants of CPT1A prevents fatty acids from entering the mitochondria for energy production
    explanation: Links deficient activity to restricted long-chain fatty acid entry and energy production.
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  downstream:
  - target: Hepatic energy deficit during catabolic stress
    description: Restricted fatty acid oxidation limits hepatic energy availability during fasting.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The reduced activity of CPT1A caused by biallelic pathogenic variants of CPT1A prevents fatty acids from entering the mitochondria for energy production
      explanation: Links deficient activity to restricted long-chain fatty acid entry and energy production.
  - target: Impaired hepatic ketogenesis
    description: Reduced oxidation limits ketone production despite circulating fatty acid availability.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21763168
      reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Plasma free fatty acids increased normally in these children but their long-chain acylcarnitine and ketone production was significantly blunted.
      explanation: Five p.Pro479Leu homozygous children underwent supervised fasting; findings support impaired ketogenesis despite substrate availability.
- name: Hepatic energy deficit during catabolic stress
  description: Hepatic fatty-acid-derived energy availability becomes insufficient during catabolic stress.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:21763168
    reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: ATP derived from fatty acid oxidation also energizes de novo glucose synthesis from amino acids and other substrates in the liver.
    explanation: Physiologic background explaining the energy requirement for hepatic gluconeogenesis.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The reduced activity of CPT1A caused by biallelic pathogenic variants of CPT1A prevents fatty acids from entering the mitochondria for energy production
    explanation: Links deficient activity to restricted long-chain fatty acid entry and energy production.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Impaired fasting glucose homeostasis
    description: Loss of fatty-acid-derived ATP limits energy available to support gluconeogenesis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21763168
      reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: ATP derived from fatty acid oxidation also energizes de novo glucose synthesis from amino acids and other substrates in the liver.
      explanation: Physiologic background explaining the energy requirement for hepatic gluconeogenesis.
    intermediate_mechanisms:
    - Reduced ATP support for hepatic gluconeogenesis
  - target: Hepatic dysfunction during metabolic crises
    description: Catabolic energy failure accompanies acute hepatic decompensation; detailed injury pathways are incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Many symptomatic individuals with CPT1A deficiency present with fasting-induced hepatic encephalopathy in early childhood or later in life, a potentially fatal presentation.
      explanation: Links fasting decompensation with hepatic dysfunction.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
      explanation: Identifies the associated hepatic and biochemical manifestations.
- name: Impaired hepatic ketogenesis
  description: Ketone production is inappropriately low during fasting, limiting an alternative fuel supply.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:21763168
    reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Plasma free fatty acids increased normally in these children but their long-chain acylcarnitine and ketone production was significantly blunted.
    explanation: Five p.Pro479Leu homozygous children underwent supervised fasting; findings support impaired ketogenesis despite substrate availability.
  biological_processes:
  - preferred_term: ketone body biosynthetic process
    term:
      id: GO:0046951
      label: ketone body biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: ketone body
    term:
      id: CHEBI:73693
      label: ketone body
    modifier: DECREASED
  downstream:
  - target: Hypoketotic hypoglycemia
    description: Insufficient ketogenesis produces the hypoketotic component when glucose homeostasis also fails.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21763168
      reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children.
      explanation: The small physiological study establishes possible fasting intolerance, not population penetrance.
    intermediate_mechanisms:
    - Concurrent fasting hypoglycemia
- name: Impaired fasting glucose homeostasis
  description: Glucose homeostasis fails during fasting in susceptible individuals, particularly as glycogen reserves decline.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:21763168
    reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children.
    explanation: The small physiological study establishes possible fasting intolerance, not population penetrance.
  downstream:
  - target: Hypoketotic hypoglycemia
    description: Falling glucose with limited ketogenesis produces hypoketotic hypoglycemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21763168
      reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children.
      explanation: The small physiological study establishes possible fasting intolerance, not population penetrance.
  - target: Metabolic brain dysfunction and injury
    description: Hypoglycemia can impair brain function and cause injury during metabolic crises.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
      explanation: Explicitly links neurological manifestations to hypoglycemia.
- name: Hepatocyte lipid accumulation
  description: Macrovesicular or mixed hepatic steatosis is documented in affected individuals, including rare chronic liver disease without recognized metabolic crises.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:32781271
    reference_title: A patient with atypical presentation of chronic hepatosteatosis harboring a novel variant in the CPT1A gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Further investigations showed transaminitis, hepatosteatosis and cirrhosis.
    explanation: A molecularly and enzymatically characterized case demonstrates chronic hepatic lipid storage and injury.
  - reference: PMID:7877875
    reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: A liver biopsy revealed massive macrovesicular steatosis.
    explanation: Documents hepatic fatty change in an enzyme-confirmed infant.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
- name: Hepatic dysfunction during metabolic crises
  description: Acute liver dysfunction can develop during fasting or illness and may progress to liver failure.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Many symptomatic individuals with CPT1A deficiency present with fasting-induced hepatic encephalopathy in early childhood or later in life, a potentially fatal presentation.
    explanation: Links fasting decompensation with hepatic dysfunction.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
    explanation: Identifies the associated hepatic and biochemical manifestations.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Elevated hepatic transaminases
    description: Hepatic injury is accompanied by transaminase elevation.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
      explanation: Identifies the associated hepatic and biochemical manifestations.
  - target: Hyperammonemia
    description: Liver decompensation may include ammonia accumulation; a specific urea-cycle enzyme defect is not established here.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
      explanation: Identifies the associated hepatic and biochemical manifestations.
  - target: Hepatic encephalopathy
    description: Severe hepatic decompensation can impair cerebral function.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Many symptomatic individuals with CPT1A deficiency present with fasting-induced hepatic encephalopathy in early childhood or later in life, a potentially fatal presentation.
      explanation: Links fasting decompensation with hepatic dysfunction.
  - target: Hepatic failure
    description: Severe decompensation may progress to liver failure.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301700
      reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: hepatic encephalopathy, hypoketotic hypoglycemia, and sudden onset of liver failure
      explanation: GeneReviews describes severe infantile manifestations.
- name: Metabolic brain dysfunction and injury
  description: Metabolic crises can cause transient neurological dysfunction or lasting brain injury. This mechanism does not explain all developmental or speech findings in late-diagnosed patients.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Between episodes of metabolic decompensation, individuals with CPT1A deficiency typically appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage (leading to motor and/or speech delays).
    explanation: Supports acquired neurological injury after crises, without accounting for all developmental findings.
  downstream:
  - target: Lethargy
    description: Hypoglycemic brain dysfunction can reduce alertness.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
      explanation: Clinical manifestations explicitly attributed to hypoglycemia.
  - target: Seizure
    description: Hypoglycemia can provoke seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Symptomatic individuals may manifest seizures (related to hypoglycemia) often associated with a precipitating illness or poor oral intake.
      explanation: Specifies a hypoglycemic route to seizures.
  - target: Coma
    description: Severe encephalopathic decompensation may progress to coma.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Manifestations can include vomiting and altered mental status ranging from fatigue and lethargy to coma and/or death.
      explanation: Describes the hepatic encephalopathy spectrum.
  - target: Global developmental delay
    description: Prior metabolic brain injury can cause lasting motor and developmental impairment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Between episodes of metabolic decompensation, individuals with CPT1A deficiency typically appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage (leading to motor and/or speech delays).
      explanation: Supports acquired neurological injury after crises, without accounting for all developmental findings.
  - target: Delayed speech and language development
    description: Neurological injury after crises can contribute to speech delay, but not all speech disorders require a recognized crisis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Between episodes of metabolic decompensation, individuals with CPT1A deficiency typically appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage (leading to motor and/or speech delays).
      explanation: Supports acquired neurological injury after crises, without accounting for all developmental findings.
- name: Reduced distal renal acid secretion
  description: A rate-dependent failure of distal renal acid secretion has been demonstrated in an individual with CPT1A deficiency. The molecular explanation remains uncertain.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:7877875
    reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Evaluation of the renal acidification capacity showed a failure to acidify the urine during spontaneous acidosis but increased acid excretion and a normal decrease of urinary pH after acid loading.
    explanation: Physiological testing in one infant demonstrated a rate-dependent distal acidification defect.
  - reference: PMID:7877875
    reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'This acidification defect can best be explained as an abnormality in distal tubular H+ secretion: a rate-dependent distal tubular acidosis.'
    explanation: Authors localize the acidification abnormality; the upstream molecular mechanism remains uncertain.
  downstream:
  - target: Distal renal tubular acidosis
    description: Impaired distal proton secretion produces the demonstrated acidification phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7877875
      reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Evaluation of the renal acidification capacity showed a failure to acidify the urine during spontaneous acidosis but increased acid excretion and a normal decrease of urinary pH after acid loading.
      explanation: Physiological testing in one infant demonstrated a rate-dependent distal acidification defect.
    - reference: PMID:7877875
      reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 'This acidification defect can best be explained as an abnormality in distal tubular H+ secretion: a rate-dependent distal tubular acidosis.'
      explanation: Authors localize the acidification abnormality; the upstream molecular mechanism remains uncertain.
  - target: Metabolic acidosis
    description: Insufficient renal acid excretion contributes to persistent metabolic acidosis in the reported infant.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7877875
      reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Mild, persistent metabolic acidosis was a constant feature, even during periods between metabolic decompensation.
      explanation: Links the persistent acidosis to the subsequently characterized renal defect.
phenotypes:
- name: Hypoketotic hypoglycemia
  phenotype_term:
    preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  description: Fasting or illness-associated hypoglycemia with inappropriately low ketones; penetrance varies by genotype.
  evidence:
  - reference: PMID:21763168
    reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children.
    explanation: The small physiological study establishes possible fasting intolerance, not population penetrance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Hypoketotic hypoglycemia can present in the neonatal period or later in life.
    explanation: Supports neonatal through later onset.
- name: Hepatomegaly
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  description: Liver enlargement during metabolic disease or, rarely, chronic steatotic liver disease.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
    explanation: Identifies the associated hepatic and biochemical manifestations.
- name: Elevated hepatic transaminases
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  description: Transaminase elevation accompanies hepatic involvement.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
    explanation: Identifies the associated hepatic and biochemical manifestations.
- name: Hyperammonemia
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  description: Ammonia elevation may accompany hepatic decompensation; it is not present in every episode.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
    explanation: Identifies the associated hepatic and biochemical manifestations.
- name: Elevated creatine kinase
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  description: Uncommon in the wider clinical spectrum, but found in seven of 14 patients in one selected retrospective series.
  evidence:
  - reference: PMID:38090675
    reference_title: A different perspective into clinical symptoms in CPT I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'Additionally, elevated creatine kinase (CK) levels ranging between 250 and 800 U/L (normal range: 20–180 U/L) were detected in seven patients both at the time of initial diagnosis and during the follow-up period.'
    explanation: Selected cohort proportion; not a population frequency.
  - reference: PMID:11286380
    reference_title: Features of carnitine palmitoyltransferase type I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We discuss four new cases in three families showing, variously, renal tubular acidosis, transient hyperlipidaemia and, paradoxically, myopathy with elevated creatinine kinase or cardiac involvement in the neonatal period as additional features that deserve wider recognition.
    explanation: The four-case report broadens the classic hepatic presentation; no population frequency is inferred.
  notes: Only six of the 14 cohort patients had molecular confirmation, with parental variants supporting one additional deceased case. Remaining diagnoses relied on biochemical profiles; ascertainment and diagnostic limitations restrict generalization.
- name: Hepatic encephalopathy
  phenotype_term:
    preferred_term: Hepatic encephalopathy
    term:
      id: HP:0002480
      label: Hepatic encephalopathy
  description: Potentially fatal fasting-induced encephalopathy associated with liver dysfunction.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Many symptomatic individuals with CPT1A deficiency present with fasting-induced hepatic encephalopathy in early childhood or later in life, a potentially fatal presentation.
    explanation: Links fasting decompensation with hepatic dysfunction.
- name: Hepatic failure
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  description: Severe presentations can progress rapidly to liver failure.
  evidence:
  - reference: PMID:20301700
    reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: hepatic encephalopathy, hypoketotic hypoglycemia, and sudden onset of liver failure
    explanation: Describes severe infantile disease.
- name: Lethargy
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  description: Reduced alertness can accompany hypoglycemic or hepatic decompensation.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
    explanation: Describes acute neurological symptoms.
- name: Seizure
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: Seizures may be precipitated by hypoglycemia, illness or poor intake.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Symptomatic individuals may manifest seizures (related to hypoglycemia) often associated with a precipitating illness or poor oral intake.
    explanation: Defines the clinical context.
- name: Coma
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  description: Severe hepatic or metabolic encephalopathy can progress to coma.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Manifestations can include vomiting and altered mental status ranging from fatigue and lethargy to coma and/or death.
    explanation: Places coma within the encephalopathic spectrum.
- name: Distal renal tubular acidosis
  phenotype_term:
    preferred_term: Distal renal tubular acidosis
    term:
      id: HP:0008341
      label: Distal renal tubular acidosis
  description: Rate-dependent distal acidification failure was demonstrated in one enzyme-confirmed infant.
  evidence:
  - reference: PMID:7877875
    reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Evaluation of the renal acidification capacity showed a failure to acidify the urine during spontaneous acidosis but increased acid excretion and a normal decrease of urinary pH after acid loading.
    explanation: Physiological testing in one infant demonstrated a rate-dependent distal acidification defect.
  - reference: PMID:7877875
    reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'This acidification defect can best be explained as an abnormality in distal tubular H+ secretion: a rate-dependent distal tubular acidosis.'
    explanation: Authors localize the acidification abnormality; the upstream molecular mechanism remains uncertain.
  notes: Other reports describe renal tubular acidosis without a uniformly established subtype. GeneReviews states that its prevalence is unknown; do not generalize the distal subtype to every affected individual.
- name: Metabolic acidosis
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  description: Persistent or crisis-associated metabolic acidosis is reported, including renal acidification failure.
  evidence:
  - reference: PMID:7877875
    reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Mild, persistent metabolic acidosis was a constant feature, even during periods between metabolic decompensation.
    explanation: Documents persistent acidosis in the renal case.
- name: Cardiomyopathy
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  description: Cardiac involvement is uncommon but is not categorically excluded. Two patients in a selected 14-person series had cardiomyopathy; one improved after dietary treatment.
  evidence:
  - reference: PMID:38090675
    reference_title: A different perspective into clinical symptoms in CPT I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Cardiomyopathy was detected in two patients on echocardiography. Cardiomyopathy resolved in one patient after the first year of dietary treatment.
    explanation: Observational findings do not establish controlled treatment efficacy.
  notes: The clinical series included molecularly and biochemically diagnosed patients; alternative contributors and the mechanism of cardiac involvement are incompletely resolved.
- name: Muscle weakness
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  description: Muscle weakness has been reported despite predominant CPT1B expression in skeletal muscle.
  evidence:
  - reference: PMID:38090675
    reference_title: A different perspective into clinical symptoms in CPT I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Similarly, in our study, three patients presented with muscle weakness, fatigue, and muscle pain
    explanation: Describes the muscle presentation in a selected cohort.
- name: Myalgia
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  description: Muscle pain may occur in uncommon muscle presentations.
  evidence:
  - reference: PMID:38090675
    reference_title: A different perspective into clinical symptoms in CPT I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Similarly, in our study, three patients presented with muscle weakness, fatigue, and muscle pain
    explanation: Documents myalgia without assigning a population frequency.
- name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: Developmental impairment may follow metabolic brain injury; late-diagnosed patients can also have delays without recognized crises.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Between episodes of metabolic decompensation, individuals with CPT1A deficiency typically appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage (leading to motor and/or speech delays).
    explanation: Supports acquired neurological injury after crises, without accounting for all developmental findings.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: global developmental delay or isolated speech delay may be possible without preceding metabolic decompensation
    explanation: Supports the broader phenotype and uncertainty about cause.
- name: Delayed speech and language development
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  description: Speech or language delay is reported with or without broader developmental impairment; not every speech abnormality in the cohort was delay.
  evidence:
  - reference: PMID:38090675
    reference_title: A different perspective into clinical symptoms in CPT I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Speech disorders including delayed expressive language development, speech articulation disorder, speech retardation, and stuttering were present in nine patients.
    explanation: Nine patients had heterogeneous speech disorders, not nine with a uniform delay phenotype.
  notes: The retrospective cohort had limited molecular confirmation and no genome-wide exclusion of other causes. Developmental surveillance is warranted, but a specific direct neurodevelopmental mechanism is unproven.
- name: Cirrhosis
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  description: Rare chronic hepatic fibrosis/cirrhosis has been reported without recognized metabolic crises.
  evidence:
  - reference: PMID:32781271
    reference_title: A patient with atypical presentation of chronic hepatosteatosis harboring a novel variant in the CPT1A gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We describe an atypical case of an 8-year-old male with CPT1A deficiency presenting with chronic liver steatosis and cirrhosis.
    explanation: Case-level finding, not a common outcome.
- name: Dicarboxylic aciduria
  phenotype_term:
    preferred_term: Dicarboxylic aciduria
    term:
      id: HP:0003215
      label: Dicarboxylic aciduria
  description: Hypoketotic dicarboxylic aciduria, particularly dodecanedioic acid, can occur during or after crises.
  evidence:
  - reference: PMID:16146704
    reference_title: Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid.
    explanation: Observed in three affected infants; urine profiles are not invariably abnormal.
- name: Sudden death
  phenotype_term:
    preferred_term: Sudden death
    term:
      id: HP:0001699
      label: Sudden death
  description: Sudden death can complicate severe metabolic disease. This clinical risk is distinct from population-level p.Pro479Leu mortality associations.
  evidence:
  - reference: PMID:11350182
    reference_title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Symptomatology comprises attacks of hypoketotic hypoglycemia with risk of sudden death or neurological sequelae.
    explanation: Clinical background describing severe disease risk.
- name: Vomiting
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  description: Vomiting can accompany hepatic encephalopathy and worsen oral intake during a crisis.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Manifestations can include vomiting and altered mental status ranging from fatigue and lethargy to coma and/or death.
    explanation: Clinical presentation of hepatic encephalopathy.
- name: Hyperlipidemia
  phenotype_term:
    preferred_term: Hyperlipidemia
    term:
      id: HP:0003077
      label: Hyperlipidemia
  description: Transient hyperlipidemia has been reported during metabolic disease.
  evidence:
  - reference: PMID:11286380
    reference_title: Features of carnitine palmitoyltransferase type I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We discuss four new cases in three families showing, variously, renal tubular acidosis, transient hyperlipidaemia and, paradoxically, myopathy with elevated creatinine kinase or cardiac involvement in the neonatal period as additional features that deserve wider recognition.
    explanation: The four-case report broadens the classic hepatic presentation; no population frequency is inferred.
biochemical:
- name: Free carnitine and C0/(C16+C18) ratio
  presence: INCREASED
  notes: These are screening clues, not obligatory abnormalities. Normal plasma free carnitine and even a normal ratio can occur at diagnostic confirmation or follow-up; dried blood spots are more sensitive.
  evidence:
  - reference: PMID:41017303
    reference_title: Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Our cases demonstrate that acylcarnitine profiles and especially concentrations of free carnitine can be normal in plasma in infants with CPT1AD at confirmation diagnosis after screening and during follow-up.
    explanation: Qualifies the expected biochemical profile.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: CPT1A deficiency is characterized by marked reduction in the synthesis of all acylcarnitine species and increased levels of free carnitine (C0).
    explanation: Explains the usual profile.
- name: Long-chain acylcarnitines
  presence: DECREASED
  notes: Reduced formation underlies the high free-to-long-chain acylcarnitine ratio. Absolute values can normalize outside a crisis.
  evidence:
  - reference: PMID:21763168
    reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Plasma free fatty acids increased normally in these children but their long-chain acylcarnitine and ketone production was significantly blunted.
    explanation: Fasting physiological evidence in p.Pro479Leu homozygotes.
- name: Urinary dodecanedioic and 3-hydroxyglutaric acids
  presence: INCREASED
  notes: Reported in a three-patient series; useful supportive clues, not specific confirmatory markers.
  evidence:
  - reference: PMID:16146704
    reference_title: Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid.
    explanation: Supports dodecanedioic aciduria.
  - reference: PMID:16146704
    reference_title: Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients
    explanation: Supports the additional urine finding.
genetic:
- name: CPT1A
  gene_term:
    preferred_term: CPT1A
    term:
      id: hgnc:2328
      label: CPT1A
  relationship_type: CAUSATIVE
  association: Biallelic loss of function
  features: Pathogenic alleles include missense, nonsense, splice-site and small insertion/deletion variants, with rare exon or multiexon deletions. Residual enzyme activity and clinical penetrance vary by allele; hypomorphic population variants should not be equated with uniformly severe classic disease.
  inheritance:
  - name: Autosomal recessive
    description: For two carrier parents, recurrence risk is 25% affected, 50% carrier and 25% neither. For a carrier and an affected parent, risk is 50% affected and 50% carrier. Unaffected carriers generally have no metabolic phenotype; pregnancy with an affected fetus is a separate maternal risk context.
    evidence:
    - reference: PMID:20301700
      reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: When both parents are carriers of a CPT1A 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 being unaffected and not a carrier.
      explanation: Specifies recurrence risks for two carrier parents.
    - reference: PMID:20301700
      reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: When one parent is a carrier and the other parent has two CPT1A pathogenic variants, each sib of an affected individual has at conception a 50% chance of being affected and a 50% chance of being an asymptomatic carrier.
      explanation: Distinguishes the second parental configuration.
  variants:
  - name: p.Pro479Leu (c.1436C>T)
    description: Common hypomorphic allele in several northern Indigenous populations. A patient fibroblast study found approximately 20% residual activity and partial resistance to malonyl-CoA inhibition. Most homozygotes are asymptomatic, but supervised fasting in five children demonstrated reduced ketogenesis and symptomatic hypoglycemia in two. Population associations with infectious illness and infant mortality do not establish a direct immune defect or an inevitable clinical outcome. In the Nunavik population-genetic study, the allele frequency was 95.5% among 100 analyzed adults after exclusions from 113 recruits; this is not disease prevalence or penetrance.
    evidence:
    - reference: PMID:11441142
      reference_title: 'Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: The patient with atypical symptoms had approximately 20% of normal L-CPT I activity and was homozygous for a mutation (c.1436C-->T) that substituted leucine for proline at codon 479.
      explanation: Single-patient biochemical characterization.
    - reference: PMID:11441142
      reference_title: 'Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Assays performed with his cultured skin fibroblasts indicated that this mutation confers partial resistance to the inhibitory effects of malonyl-CoA.
      explanation: Functional regulation differs from complete enzyme loss.
    - reference: PMID:21763168
      reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children.
      explanation: The small physiological study establishes possible fasting intolerance, not population penetrance.
    - reference: PMID:34295859
      reference_title: Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: In multivariable analysis, p.P479L homozygosity was associated with LRTI admission (aOR:2.88 95%CI:1.46-5.64), otitis media (aOR:1.83, 95%CI:1.05-3.21), and gastroenteritis (aOR:1.74, 95%CI:1.09-2.77), compared to non-carriers.
      explanation: Adjusted associations in a retrospective Nunavut cohort; this does not demonstrate immunodeficiency.
    - reference: PMID:26010953
      reference_title: Increased missense mutation burden of Fatty Acid metabolism related genes in nunavik inuit population.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: In our study of the Nunavik Inuit, the p.P479L mutation has an allele frequency of 95.5%, the highest reported to date.
      explanation: Reports variant frequency in the studied population.
    - reference: PMID:26010953
      reference_title: Increased missense mutation burden of Fatty Acid metabolism related genes in nunavik inuit population.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Therefore a total of 100 Inuit samples were included in the genetic/statistical analysis
      explanation: Defines the analyzed denominator.
  - name: p.Gly710Glu (c.2129G>A)
    description: Hutterite founder allele causing catalytic inactivity despite preserved protein stability and mitochondrial targeting.
    evidence:
    - reference: PMID:11350182
      reference_title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Studies in fibroblasts from one patient as well as heterologous expression of the mutagenized CPT1A in yeast show that the G710E mutation alters neither mitochondrial targeting nor stability of the CPT1A protein.
      explanation: Distinguishes a catalytic defect from instability.
    - reference: PMID:11350182
      reference_title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A.
      explanation: Patient fibroblast and heterologous yeast assays distinguish catalytic loss from protein instability.
  - name: p.Ser34Pro (c.100T>C)
    description: Micronesian founder allele associated with a mild biochemical phenotype. Twenty-two homozygotes had no significant metabolic decompensation in the reported follow-up, including ten without dietary management. Residual activity of 26% was measured in one asymptomatic adult, not across all 22 patients.
    evidence:
    - reference: PMID:35822099
      reference_title: Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: There have been no episodes of significant metabolic decompensation in any of the 22 cases, including 10 patients who were not treated with dietary management, and one who was admitted to the intensive care unit with sepsis.
      explanation: Documents the p.Ser34Pro cohort and treatment context.
    - reference: PMID:35822099
      reference_title: Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Enzymology in cultured skin fibroblasts in an asymptomatic adult, showed residual CPT1 activity at 26% of normal controls, despite abnormal acylcarnitine metabolites consistent with CPT1A deficiency
      explanation: Single-adult functional result; the series does not establish lifetime penetrance.
  - name: p.Ser708Arg (c.2122A>C)
    description: Niuean founder allele associated with classic disease. Among three reported homozygotes, two presented clinically and the third was identified through sibling testing before later mild illness-associated decompensations.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: CPT1A pathogenic variant p.Ser708Arg has been reported in the Niuean population
      explanation: Identifies the founder allele; the primary series provides the individual ascertainment details.
    - reference: PMID:35822099
      reference_title: Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Two presented clinically with classical CPT1A deficiency symptoms, the third was an asymptomatic younger sibling, diagnosed prospectively.
      explanation: Primary full text distinguishes presentation from prospective ascertainment.
  - name: p.Lys455Thr (c.1364A>C)
    description: 'Finnish recurrent allele: five of six reported patients were homozygous and one was compound heterozygous with p.Tyr498Ser. Crises generally occurred with illness or fasting and were uncommon during dietary treatment.'
    evidence:
    - reference: PMID:21962599
      reference_title: Carrier frequency of a common mutation of carnitine palmitoyltransferase 1A deficiency and long-term follow-up in Finland.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Five cases carried a homozygous c.1364A>C (p.K455T) mutation, whereas 1 case had a compound c.1364A>C/c.1493A>C (p.Y498S) mutation.
      explanation: Defines the genotypes in this six-person series.
    - reference: PMID:21962599
      reference_title: Carrier frequency of a common mutation of carnitine palmitoyltransferase 1A deficiency and long-term follow-up in Finland.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: During dietary therapy, the patients had few transient decompensations.
      explanation: Uncontrolled follow-up, not a comparative treatment estimate.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Sequence analysis of CPT1A can be performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions.
    explanation: Summarizes variant classes.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Exon and multiexon deletions have been rarely reported
    explanation: Adds structural alleles.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_dcea255c-11e4-46fd-b0f7-2de68311a75c-2018-01-23T170000.000Z
    notes: 'ClinGen Fatty Acid Oxidation Disorders Expert Panel classified the autosomal recessive CPT1A–MONDO:0009705 relationship as Definitive on January 23, 2018. Assertion: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dcea255c-11e4-46fd-b0f7-2de68311a75c-2018-01-23T170000.000Z'
treatments:
- name: Age-appropriate fasting avoidance
  description: Frequent feeding prevents catabolic crises. GeneReviews recommends feeding neonates and infants every two to three hours. Suggested maximum fasting intervals when well are eight hours at 6–12 months, ten hours during the second year and twelve hours after age two. Illness, surgery and reduced intake require a more cautious individualized emergency plan, not a blanket twelve-hour allowance. Cornstarch or overnight feeding may be appropriate after infancy.
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Neonates and infants require frequent feedings every two to three hours.
    explanation: Age-specific preventive guidance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Up to eight hours in infants between ages six and 12 months ⚬ Up to ten hours during the second year of life ⚬ Up to 12 hours after age two years
    explanation: Suggested maxima only in the absence of infection, fever or other stress.
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Hepatic energy deficit during catabolic stress
    description: Carbohydrate availability reduces reliance on impaired hepatic fatty acid oxidation.
    treatment_effect: INHIBITS
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Neonates and infants require frequent feedings every two to three hours.
      explanation: Age-specific preventive guidance.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Up to eight hours in infants between ages six and 12 months ⚬ Up to ten hours during the second year of life ⚬ Up to 12 hours after age two years
      explanation: Suggested maxima only in the absence of infection, fever or other stress.
- name: Individualized high-carbohydrate, low-long-chain-fat diet
  description: A metabolic dietitian guides carbohydrate supply, long-chain fat restriction and essential fatty acid replacement. The degree of fat restriction is controversial in mild or asymptomatic p.Pro479Leu homozygotes. Avoid overfeeding when well and monitor growth and nutrient status.
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: High-carbohydrate diet (70% of calories) that is low in long-chain fat (<20% of calories)
    explanation: GeneReviews long-term diet table; specialist individualization is required.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: If the physician chooses to recommend a low-fat diet when the affected individual is well, supplementation with essential fatty acids is necessary.
    explanation: Preserves nutritional requirements during restriction.
  therapeutic_modality: BEHAVIORAL
- name: Medium-chain triglyceride supplementation
  description: Medium-chain fat provides an alternative oxidizable substrate that bypasses the CPT1A-dependent long-chain shuttle. It does not restore CPT1A activity. Dose and caloric contribution vary with age, tolerance and acute versus maintenance needs.
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:7877875
    reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Ketogenesis was absent after a long-chain triglyceride loading test; in contrast, the medium-chain triglyceride loading test resulted in a brisk rise in plasma ketone concentration.
    explanation: Physiological response in one affected infant supports bypass of long-chain transport.
  target_mechanisms:
  - target: Reduced CPT1A catalytic activity
    description: Medium-chain substrate can support ketogenesis despite deficient long-chain acylcarnitine formation.
    treatment_effect: BYPASSES
    evidence:
    - reference: PMID:7877875
      reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Ketogenesis was absent after a long-chain triglyceride loading test; in contrast, the medium-chain triglyceride loading test resulted in a brisk rise in plasma ketone concentration.
      explanation: Physiological response in one affected infant supports bypass of long-chain transport.
  therapeutic_modality: BEHAVIORAL
- name: Triheptanoin
  description: 'This odd-chain triglyceride supplies medium-chain substrate and anaplerotic propionyl-CoA. GeneReviews lists it as targeted therapy. CPT1A-specific clinical evidence remains sparse: only one CPT I participant was included in the CL202 extension cohort, so pooled LC-FAOD event reductions should not be presented as a CPT1A effect estimate. Gastrointestinal intolerance can limit dosing.'
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: triheptanoin
      term:
        id: CHEBI:757060
        label: triheptanoin
  evidence:
  - reference: PMID:20301700
    reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'Targeted therapies: Triheptanoin (an odd-carbon triglyceride) or MCT oil.'
    explanation: GeneReviews lists the metabolic therapies.
  - reference: PMID:32885845
    reference_title: 'Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Propionyl‐CoA is further metabolized to succinyl‐CoA, which resupplies TCA cycle intermediates (anaplerosis) that may be secondarily deficient in patients with LC‐FAOD
    explanation: Mechanistic rationale in the trial introduction, not proof of CPT1A-specific efficacy.
  notes: CL202 was open-label with historical pre-treatment comparisons. The 2020 interim report enrolled 75 participants and the 2023 final report 94; these are successive reports of the same study, not independent trials.
  target_mechanisms:
  - target: Reduced CPT1A catalytic activity
    description: Odd-chain medium-chain substrate bypasses the long-chain transport defect.
    treatment_effect: BYPASSES
    evidence:
    - reference: PMID:20301700
      reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: 'Targeted therapies: Triheptanoin (an odd-carbon triglyceride) or MCT oil.'
      explanation: GeneReviews lists the metabolic therapies.
    - reference: PMID:32885845
      reference_title: 'Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: Propionyl‐CoA is further metabolized to succinyl‐CoA, which resupplies TCA cycle intermediates (anaplerosis) that may be secondarily deficient in patients with LC‐FAOD
      explanation: Mechanistic rationale in the trial introduction, not proof of CPT1A-specific efficacy.
  therapeutic_modality: SMALL_MOLECULE
- name: Emergency intravenous glucose
  description: Prompt intravenous dextrose corrects hypoglycemia and supports anabolism during acute decompensation. GeneReviews describes at least 10% dextrose, approximately 8–10 mg/kg/min, with fluids and electrolytes adjusted clinically. Continue glucose beyond normalization to replenish hepatic glycogen, and taper as oral intake recovers.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dextrose
      term:
        id: CHEBI:17234
        label: glucose
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia
    explanation: Recommends prompt carbohydrate replacement.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: continue glucose infusion beyond normalization of blood glucose to provide sufficient substrate for glycogen synthesis.
    explanation: Explains why normalization of blood glucose alone does not end acute support.
  target_mechanisms:
  - target: Impaired fasting glucose homeostasis
    description: Exogenous glucose corrects inadequate endogenous glucose availability.
    treatment_effect: INHIBITS
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia
      explanation: Recommends prompt carbohydrate replacement.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: continue glucose infusion beyond normalization of blood glucose to provide sufficient substrate for glycogen synthesis.
      explanation: Explains why normalization of blood glucose alone does not end acute support.
  - target: Hepatic energy deficit during catabolic stress
    description: Carbohydrate supplies energy during catabolic decompensation.
    treatment_effect: BYPASSES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia
      explanation: Recommends prompt carbohydrate replacement.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: continue glucose infusion beyond normalization of blood glucose to provide sufficient substrate for glycogen synthesis.
      explanation: Explains why normalization of blood glucose alone does not end acute support.
  therapeutic_modality: SMALL_MOLECULE
- name: Emergency planning and perioperative metabolic care
  description: Families need a written emergency plan, recognition of early decompensation and coordinated care during illness, surgery or sedation. Provide carbohydrate-containing fluids when adequate intake cannot be maintained.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Carry written info re child's disorder & appropriate treatment in emergency setting.
    explanation: Supports a written emergency plan.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Avoid fasting, including during periods of preparation and recovery from planned surgery or sedation
    explanation: Extends fasting precautions to procedures.
  therapeutic_modality: OTHER
- name: Metabolic, nutritional, renal and developmental surveillance
  description: Assess growth, feeding and dietary adherence at visits. Monitor carnitine/acylcarnitines, essential fatty acids, fat-soluble vitamins, blood count, metabolic profile and CK according to age and diet. Check hepatic function and renal indices when indicated; assess development throughout childhood and refer for physical, occupational or speech-language therapy as needed.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301700
    reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Assess growth, feeding, and adherence to diet at each visit
    explanation: Summarizes routine surveillance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Nephrology BUN, serum creatinine concentration, & urinalysis for urine protein As clinically indicated to assess for renal tubular acidosis
    explanation: Adds renal surveillance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Assess developmental & educational progress w/ referrals for social services, physical therapy, occupational therapy, & speech & language services as needed
    explanation: Supports developmental follow-up and rehabilitation.
  therapeutic_modality: OTHER
- name: Caution with potentially hepatotoxic medicines
  description: Use valproate or salicylate cautiously if hepatic dysfunction is present. GeneReviews notes that CPT1A-specific adverse pharmacologic effects have not been reported; this is a conditional precaution.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Potentially hepatotoxic agents such as valproate and salicylate should be used with caution if there is evidence of hepatic dysfunction
    explanation: States the condition for caution.
  therapeutic_modality: OTHER
- name: Liver transplantation consideration
  description: GeneReviews advises considering liver transplantation in liver failure. Disease-specific outcome evidence is limited; it is not routine therapy for otherwise stable CPT1A deficiency.
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Liver disease Consider orthotic liver transplantation. In those w/liver failure
    explanation: The source recommendation concerns liver failure; no outcome rate is asserted.
  therapeutic_modality: SURGERY
- name: Pregnancy metabolic and hepatic monitoring
  description: Affected pregnant individuals require avoidance of fasting, hypoglycemia, dehydration and catabolism, with metabolic and maternal-fetal medicine care. Monitor liver function at prenatal visits during the first two trimesters and more often in the third in pregnancies at risk. Counsel carriers carrying an affected fetus about the limited evidence for maternal acute fatty liver. Triheptanoin has not been studied in pregnancy.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Management of women with CPT1A deficiency during pregnancy should include avoidance of fasting, hypoglycemia, dehydration, and catabolic stress.
    explanation: Specifies maternal metabolic precautions.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Use of triheptanoin has not been studied in pregnancy.
    explanation: Limits treatment extrapolation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: it is recommended that liver function testing be performed at each prenatal visit during the first two trimesters and more frequently during the third trimester, when the risk for AFLP is greatest.
    explanation: Supports liver monitoring in subsequent pregnancies after an affected child.
  therapeutic_modality: OTHER
- name: Genetic counseling and family testing
  description: Explain genotype-dependent clinical uncertainty as well as autosomal recessive recurrence risk. Familial variant testing permits carrier, prenatal and preimplantation testing. Evaluate siblings regardless of age; at-risk newborns can undergo molecular testing in parallel with newborn screening.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301700
    reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: When both parents are carriers of a CPT1A 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 being unaffected and not a carrier.
    explanation: Specifies recurrence risks for two carrier parents.
  - reference: PMID:20301700
    reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the CPT1A pathogenic variants in the family are known.
    explanation: Supports familial variant testing.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: molecular genetic testing for the familial CPT1A pathogenic variants can be done in parallel with newborn screening.
    explanation: Avoids reliance on biochemical newborn screening alone.
  therapeutic_modality: OTHER
environmental:
- name: Febrile or gastrointestinal illness
  influences_mechanisms:
  - target: Hepatic energy deficit during catabolic stress
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced carbohydrate availability and increased reliance on fatty acid oxidation expose the pre-existing metabolic limitation; they do not create the inherited enzyme defect.
    evidence:
    - reference: PMID:28748224
      reference_title: 'Utility of Genetic Testing for Confirmation of Abnormal Newborn Screening in Disorders of Long-Chain Fatty Acids: A Missed Case of Carnitine Palmitoyltransferase 1A (CPT1A) Deficiency.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: elevated liver transaminases in the setting of acute gastroenteritis.
      explanation: The case illustrates hepatic illness-associated decompensation.
  description: 'Concurrent febrile or gastrointestinal illness increases energy demand and precipitates acute metabolic decompensation in CPT1A deficiency.

    '
  evidence:
  - reference: PMID:28748224
    reference_title: 'Utility of Genetic Testing for Confirmation of Abnormal Newborn Screening in Disorders of Long-Chain Fatty Acids: A Missed Case of Carnitine Palmitoyltransferase 1A (CPT1A) Deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: elevated liver transaminases in the setting of acute gastroenteritis.
    explanation: The case illustrates hepatic illness-associated decompensation.
- name: Fasting
  exposure_term:
    preferred_term: fasting
    term:
      id: XCO:0000102
      label: fasting
  influences_mechanisms:
  - target: Hepatic energy deficit during catabolic stress
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced carbohydrate availability and increased reliance on fatty acid oxidation expose the pre-existing metabolic limitation; they do not create the inherited enzyme defect.
    evidence:
    - reference: PMID:21763168
      reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children.
      explanation: The small physiological study establishes possible fasting intolerance, not population penetrance.
  description: 'Prolonged fasting depletes glycogen and forces reliance on fatty acid oxidation, unmasking the CPT1A block and triggering hypoketotic hypoglycemia.

    '
  evidence:
  - reference: PMID:21763168
    reference_title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children.
    explanation: The small physiological study establishes possible fasting intolerance, not population penetrance.
notes: CPT1A is expressed in liver, kidney and other tissues; predominant CPT1B expression in heart and muscle does not exclude uncommon cardiac or muscle manifestations. The mechanism of these findings and of developmental abnormalities without recognized hypoglycemia remains uncertain. Population associations of p.Pro479Leu with infectious illness and infant death should be distinguished from classic biallelic disease and from proof of causation. The Nunavut infant-death study genotyped only 35 unexpected deaths, compared them with a historical birth cohort, and found an association that weakened after regional stratification; sleep-environment and other risks also contributed. Maternal complications have been reported both in an affected mother with an unaffected fetus and in a mother whose two children had deficient CPT1 activity without molecular confirmation. These contexts should not be conflated with an established universal fetal-genotype mechanism.
diagnosis:
- name: Molecular confirmation with complementary enzyme testing
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: Confirm biallelic pathogenic or likely pathogenic CPT1A variants. One pathogenic allele plus a VUS, or two VUSs, is not diagnostic. Sequence analysis may require complementary deletion/duplication analysis. Fibroblast CPT1 enzyme testing can clarify unresolved results where available; residual activity is often 1–5% in classic disease but higher in hypomorphic genotypes.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The diagnosis of CPT1A deficiency is established in a proband with biallelic pathogenic (or likely pathogenic) variants in CPT1A identified by molecular genetic testing.
    explanation: Defines the primary diagnostic criterion.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.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: Specifies additional testing for unresolved sequence results.
  - reference: PMID:20301700
    reference_title: Carnitine Palmitoyltransferase 1A Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Diminished carnitine palmitoyltransferase 1 (CPT1) enzyme activity on cultured skin fibroblasts when molecular genetic testing is not definitive may be an available option in some countries.
    explanation: Enzyme testing is not universally available.
- name: Newborn screening and biochemical follow-up
  description: Elevated free carnitine and C0/(C16+C18) can identify risk, but a normal plasma profile at confirmation or follow-up does not exclude CPT1A deficiency. Dried blood spots are preferable for biochemical detection. Follow an abnormal newborn screen with molecular confirmation rather than dismissing it after a normal plasma result.
  evidence:
  - reference: PMID:41017303
    reference_title: Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Our cases demonstrate that acylcarnitine profiles and especially concentrations of free carnitine can be normal in plasma in infants with CPT1AD at confirmation diagnosis after screening and during follow-up.
    explanation: Documents false reassurance from plasma testing.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: individuals with this variant may be missed by NBS with acylcarnitine profile alone
    explanation: The p.Pro479Leu genotype can be missed by acylcarnitine screening alone.
references:
- reference: PMID:10625081
  title: Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy.
  findings:
  - statement: Maternal acute fatty liver in two pregnancies with enzyme-deficient children; no molecular confirmation.
- reference: PMID:11350182
  title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
- reference: PMID:11441142
  title: 'Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.'
- reference: PMID:15970898
  title: Serious pregnancy complications in a patient with previously undiagnosed carnitine palmitoyltransferase 1 deficiency.
  findings:
  - statement: Serious pregnancy complications in an affected mother with an unaffected fetus.
- reference: PMID:16146704
  title: Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency.
- reference: PMID:20301700
  title: Carnitine Palmitoyltransferase 1A Deficiency.
  tags:
  - GeneReviews
- reference: PMID:21763168
  title: Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.
- reference: PMID:21962599
  title: Carrier frequency of a common mutation of carnitine palmitoyltransferase 1A deficiency and long-term follow-up in Finland.
- reference: PMID:23231747
  title: Causes and risk factors for infant mortality in Nunavut, Canada 1999-2011.
  findings:
  - statement: Retrospective infant-death association; regional stratification attenuated the overall signal and the genotyped subset was small. Does not establish a direct mechanism of infant death.
- reference: PMID:26010953
  title: Increased missense mutation burden of Fatty Acid metabolism related genes in nunavik inuit population.
- reference: PMID:28748224
  title: 'Utility of Genetic Testing for Confirmation of Abnormal Newborn Screening in Disorders of Long-Chain Fatty Acids: A Missed Case of Carnitine Palmitoyltransferase 1A (CPT1A) Deficiency.'
- reference: PMID:32781271
  title: A patient with atypical presentation of chronic hepatosteatosis harboring a novel variant in the CPT1A gene.
- reference: PMID:32885845
  title: 'Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.'
- reference: PMID:34295859
  title: Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut.
- reference: PMID:35822099
  title: Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations.
- reference: PMID:37276053
  title: 'Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study.'
  findings:
  - statement: 'Final CL202 report: 94 heterogeneous LC-FAOD participants, including one with CPT I deficiency in the full-text baseline table. Pooled results are not a CPT1A-specific efficacy estimate.'
- reference: PMID:38090675
  title: A different perspective into clinical symptoms in CPT I deficiency.
- reference: PMID:41017303
  title: Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency.
- reference: PMID:7877875
  title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
- reference: clinicaltrials:NCT00653666
  title: Metabolic Consequences of CPT1A Deficiency in Alaska Native Children
- reference: clinicaltrials:NCT02214160
  title: An Open-label Long-Term Safety and Efficacy Extension Study in Subjects With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Previously Enrolled in UX007 or Triheptanoin Studies
- reference: clinicaltrials:NCT03773770
  title: Expanded Access to Triheptanoin
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT00653666
  title: https://clinicaltrials.gov/api/v2/studies/NCT00653666
  findings:
  - statement: Full registry record supplies trial status, enrollment and study-design metadata, distinct from the cached brief summary.
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT02214160
  title: https://clinicaltrials.gov/api/v2/studies/NCT02214160
  findings:
  - statement: Full registry record supplies trial status, enrollment and study-design metadata, distinct from the cached brief summary.
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT03773770
  title: https://clinicaltrials.gov/api/v2/studies/NCT03773770
  findings:
  - statement: Full registry record supplies trial status, enrollment and study-design metadata, distinct from the cached brief summary.
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dcea255c-11e4-46fd-b0f7-2de68311a75c-2018-01-23T170000.000Z
  title: curation results for Gene-Disease Validity
  findings:
  - statement: ClinGen Definitive autosomal recessive gene-disease validity assertion dated January 23, 2018.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
  title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf
  findings:
  - statement: 'Full GeneReviews chapter: Carnitine Palmitoyltransferase 1A Deficiency, updated February 20, 2025. Clinical spectrum, molecular diagnosis, genotype correlations, dietary and emergency management, surveillance, pregnancy and family counseling.'
- reference: PMID:11286380
  title: Features of carnitine palmitoyltransferase type I deficiency.
  findings:
  - statement: Four cases in three families with additional renal tubular acidosis, transient hyperlipidemia and muscle/cardiac findings; expression of the hepatic isoform extends beyond liver.
histopathology:
- name: Hepatic macrovesicular steatosis
  description: Massive macrovesicular hepatic steatosis was documented in an enzyme-confirmed infant; other reports describe hepatic steatosis without a uniform histological subtype. Fatty change is not specific for CPT1A deficiency.
  finding_term:
    preferred_term: Macrovesicular Steatosis
    term:
      id: NCIT:C82990
      label: Macrovesicular Steatosis
  evidence:
  - reference: PMID:32781271
    reference_title: A patient with atypical presentation of chronic hepatosteatosis harboring a novel variant in the CPT1A gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Further investigations showed transaminitis, hepatosteatosis and cirrhosis.
    explanation: A molecularly and enzymatically characterized case demonstrates chronic hepatic lipid storage and injury.
  - reference: PMID:7877875
    reference_title: Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: A liver biopsy revealed massive macrovesicular steatosis.
    explanation: Documents hepatic fatty change in an enzyme-confirmed infant.
clinical_trials:
- name: NCT00653666
  description: Completed physiological fasting and liver-fat study in Alaska Native children with CPT1A deficiency. The registry estimated enrollment of twelve; the published fasting report studied five p.Pro479Leu homozygotes with historical comparison data.
  phase: NOT_APPLICABLE
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT00653666
    reference_title: Metabolic Consequences of CPT1A Deficiency in Alaska Native Children
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: The purpose of this study is to learn more about how long children with CPT-1 deficiency can wait between meals without developing low blood sugar or symptoms of low blood sugar.
    explanation: Describes the physiological study objective.
  notes: Registry last updated February 25, 2010. This was not a therapeutic randomized trial.
- name: NCT02214160
  description: CL202 was a phase II open-label triheptanoin extension study across long-chain fatty acid oxidation disorders, with 94 participants in the final report. Only one had CPT I deficiency; pooled reductions in major clinical events do not establish a disease-specific effect.
  phase: PHASE_II
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT02214160
    reference_title: An Open-label Long-Term Safety and Efficacy Extension Study in Subjects With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Previously Enrolled in UX007 or Triheptanoin Studies
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: The primary objective of this study is to evaluate the long-term safety and efficacy of UX007 in participants with LC-FAOD.
    explanation: Registry objective, not an efficacy result.
  notes: Completed December 3, 2020; registry last updated August 1, 2023. Historical pre-treatment comparisons, heterogeneous disorders and treatment changes limit causal inference. The 2020 interim and 2023 final publications report the same trial.
- name: NCT03773770
  description: Expanded access to triheptanoin for eligible patients with long-chain fatty acid oxidation disorders, including CPT I deficiency, who have limited treatment options and cannot enter a clinical trial.
  phase: NOT_APPLICABLE
  status: UNKNOWN
  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: Access program scope, not evidence of efficacy.
  notes: The registry status was AVAILABLE at its July 31, 2026 update. The local status enum has no expanded-access AVAILABLE value, so UNKNOWN preserves that distinction; this is not an assertion that the registry status is missing.
experimental_models:
- name: Variant-expressing COS cells
  experimental_model_type: CELL_LINE
  cell_source: COS cells transfected with patient-derived mutant or wild-type CPT1A cDNA
  description: Comparable transcript abundance but reduced mutant protein supports variant-dependent protein instability.
  evidence:
  - reference: PMID:11441142
    reference_title: 'Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability.
    explanation: Mutant expression in COS cells supports instability for the variants tested, not for every pathogenic allele.
  modeled_mechanisms:
  - target: Variant-dependent CPT1A protein instability
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    description: Cell-based expression and biochemical assays reproduce the variant-specific protein defect.
    limitations: These assays do not recapitulate whole-organ or organism-level clinical outcomes.
    evidence:
    - reference: PMID:11441142
      reference_title: 'Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability.
      explanation: Mutant expression in COS cells supports instability for the variants tested, not for every pathogenic allele.
- name: Patient fibroblasts and heterologous yeast expressing p.Gly710Glu
  experimental_model_type: OTHER
  cell_source: Patient skin fibroblasts and engineered yeast
  description: Cell-based assays distinguish preserved mitochondrial targeting and stability from loss of catalytic activity. The yeast expression system is not a whole-animal disease model.
  evidence:
  - reference: PMID:11350182
    reference_title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A.
    explanation: Patient fibroblast and heterologous yeast assays distinguish catalytic loss from protein instability.
  - reference: PMID:11350182
    reference_title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Studies in fibroblasts from one patient as well as heterologous expression of the mutagenized CPT1A in yeast show that the G710E mutation alters neither mitochondrial targeting nor stability of the CPT1A protein.
    explanation: Distinguishes a catalytic defect from instability.
  modeled_mechanisms:
  - target: Reduced CPT1A catalytic activity
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    description: Cell-based expression and biochemical assays reproduce the variant-specific protein defect.
    limitations: These assays do not recapitulate whole-organ or organism-level clinical outcomes.
    evidence:
    - reference: PMID:11350182
      reference_title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A.
      explanation: Patient fibroblast and heterologous yeast assays distinguish catalytic loss from protein instability.
    - reference: PMID:11350182
      reference_title: Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Studies in fibroblasts from one patient as well as heterologous expression of the mutagenized CPT1A in yeast show that the G710E mutation alters neither mitochondrial targeting nor stability of the CPT1A protein.
      explanation: Distinguishes a catalytic defect from instability.

📚

References & Deep Research

References

PMID:10625081

Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy.

1 finding

Maternal acute fatty liver in two pregnancies with enzyme-deficient children; no molecular confirmation.

PMID:11350182

Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.

No top-level findings curated for this source.

PMID:11441142

Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.

No top-level findings curated for this source.

PMID:15970898

Serious pregnancy complications in a patient with previously undiagnosed carnitine palmitoyltransferase 1 deficiency.

1 finding

Serious pregnancy complications in an affected mother with an unaffected fetus.

PMID:16146704

Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency.

No top-level findings curated for this source.

PMID:20301700

Carnitine Palmitoyltransferase 1A Deficiency.

No top-level findings curated for this source.

PMID:21763168

Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.

No top-level findings curated for this source.

PMID:21962599

Carrier frequency of a common mutation of carnitine palmitoyltransferase 1A deficiency and long-term follow-up in Finland.

No top-level findings curated for this source.

PMID:23231747

Causes and risk factors for infant mortality in Nunavut, Canada 1999-2011.

1 finding

Retrospective infant-death association; regional stratification attenuated the overall signal and the genotyped subset was small. Does not establish a direct mechanism of infant death.

PMID:26010953

Increased missense mutation burden of Fatty Acid metabolism related genes in nunavik inuit population.

No top-level findings curated for this source.

PMID:28748224

Utility of Genetic Testing for Confirmation of Abnormal Newborn Screening in Disorders of Long-Chain Fatty Acids: A Missed Case of Carnitine Palmitoyltransferase 1A (CPT1A) Deficiency.

No top-level findings curated for this source.

PMID:32781271

A patient with atypical presentation of chronic hepatosteatosis harboring a novel variant in the CPT1A gene.

No top-level findings curated for this source.

PMID:32885845

Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.

No top-level findings curated for this source.

PMID:34295859

Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut.

No top-level findings curated for this source.

PMID:35822099

Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations.

No top-level findings curated for this source.

PMID:37276053

Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study.

1 finding

Final CL202 report: 94 heterogeneous LC-FAOD participants, including one with CPT I deficiency in the full-text baseline table. Pooled results are not a CPT1A-specific efficacy estimate.

PMID:38090675

A different perspective into clinical symptoms in CPT I deficiency.

No top-level findings curated for this source.

PMID:41017303

Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency.

No top-level findings curated for this source.

PMID:7877875

Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.

No top-level findings curated for this source.

clinicaltrials:NCT00653666

Metabolic Consequences of CPT1A Deficiency in Alaska Native Children

No top-level findings curated for this source.

clinicaltrials:NCT02214160

An Open-label Long-Term Safety and Efficacy Extension Study in Subjects With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Previously Enrolled in UX007 or Triheptanoin Studies

No top-level findings curated for this source.

clinicaltrials:NCT03773770

Expanded Access to Triheptanoin

No top-level findings curated for this source.

url:https://clinicaltrials.gov/api/v2/studies/NCT00653666

https://clinicaltrials.gov/api/v2/studies/NCT00653666

1 finding

Full registry record supplies trial status, enrollment and study-design metadata, distinct from the cached brief summary.

url:https://clinicaltrials.gov/api/v2/studies/NCT02214160

https://clinicaltrials.gov/api/v2/studies/NCT02214160

1 finding

Full registry record supplies trial status, enrollment and study-design metadata, distinct from the cached brief summary.

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

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

1 finding

Full registry record supplies trial status, enrollment and study-design metadata, distinct from the cached brief summary.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dcea255c-11e4-46fd-b0f7-2de68311a75c-2018-01-23T170000.000Z

curation results for Gene-Disease Validity

1 finding

ClinGen Definitive autosomal recessive gene-disease validity assertion dated January 23, 2018.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf

https://www.ncbi.nlm.nih.gov/sites/books/NBK1527/pdf/Bookshelf_NBK1527.pdf

1 finding

Full GeneReviews chapter: Carnitine Palmitoyltransferase 1A Deficiency, updated February 20, 2025. Clinical spectrum, molecular diagnosis, genotype correlations, dietary and emergency management, surveillance, pregnancy and family counseling.

PMID:11286380

Features of carnitine palmitoyltransferase type I deficiency.

1 finding

Four cases in three families with additional renal tubular acidosis, transient hyperlipidemia and muscle/cardiac findings; expression of the hepatic isoform extends beyond liver.

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References & Deep Research

References