Carnitine palmitoyltransferase 1A (CPT1A) deficiency is an autosomal recessive inborn error of long-chain fatty acid oxidation caused by biallelic pathogenic variants in CPT1A. CPT1A is the liver isoform of carnitine palmitoyltransferase 1, located on the outer mitochondrial membrane, where it catalyzes the first and rate-limiting step of the carnitine shuttle: conjugation of long-chain acyl-CoA to carnitine to form long-chain acylcarnitine for import into the mitochondrial matrix and subsequent beta-oxidation. Loss of CPT1A activity impairs hepatic long-chain fatty acid oxidation, so that during fasting or intercurrent febrile or gastrointestinal illness affected individuals develop hypoketotic hypoglycemia, hepatic encephalopathy, hepatomegaly, and elevated liver transaminases, ammonia, and creatine kinase. The biochemical signature is distinctive and essentially the mirror image of most fatty acid oxidation disorders: low total and long-chain acylcarnitines with high free carnitine and an elevated free-carnitine to long-chain-acylcarnitine ratio [C0/(C16 + C18)]. Because skeletal muscle and heart rely on the separate CPT1B isoform, CPT1A deficiency characteristically spares cardiac and skeletal muscle, distinguishing it from CPT2, CACT, and VLCAD deficiencies. The p.P479L ("Arctic") variant is a common founder allele in Inuit, Alaska Native, and other northern populations and is associated with hypoketotic hypoglycemia, infectious illness, and elevated infant mortality/sudden unexpected infant death.
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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
description: >
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is an autosomal recessive
inborn error of long-chain fatty acid oxidation caused by biallelic pathogenic
variants in CPT1A. CPT1A is the liver isoform of carnitine palmitoyltransferase 1,
located on the outer mitochondrial membrane, where it catalyzes the first and
rate-limiting step of the carnitine shuttle: conjugation of long-chain acyl-CoA
to carnitine to form long-chain acylcarnitine for import into the mitochondrial
matrix and subsequent beta-oxidation. Loss of CPT1A activity impairs hepatic
long-chain fatty acid oxidation, so that during fasting or intercurrent febrile
or gastrointestinal illness affected individuals develop hypoketotic
hypoglycemia, hepatic encephalopathy, hepatomegaly, and elevated liver
transaminases, ammonia, and creatine kinase. The biochemical signature is
distinctive and essentially the mirror image of most fatty acid oxidation
disorders: low total and long-chain acylcarnitines with high free carnitine and
an elevated free-carnitine to long-chain-acylcarnitine ratio [C0/(C16 + C18)].
Because skeletal muscle and heart rely on the separate CPT1B isoform, CPT1A
deficiency characteristically spares cardiac and skeletal muscle, distinguishing
it from CPT2, CACT, and VLCAD deficiencies. The p.P479L ("Arctic") variant is a
common founder allele in Inuit, Alaska Native, and other northern populations and
is associated with hypoketotic hypoglycemia, infectious illness, and elevated
infant mortality/sudden unexpected infant death.
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:
- notes: >-
Classic CPT1A deficiency is ultra-rare. The p.P479L (c.1436C>T) founder allele,
however, reaches extremely high frequency in Arctic Indigenous populations of
Alaska, Canada, and Greenland; in a Nunavik Inuit exome study it was the
highest-frequency variant at an allele frequency of 0.955, and in a Nunavut
Inuit cohort the p.P479L allele frequency was 0.82.
evidence:
- reference: PMID:41017303
reference_title: "Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ultra-rare autosomal recessive disorder of the carnitine cycle caused by"
explanation: Human case series describes CPT1A deficiency as an ultra-rare autosomal recessive disorder of the carnitine cycle.
- 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
snippet: "The latter has the highest frequency (0.955)"
explanation: Nunavik Inuit exome study reports the CPT1A p.P479L Arctic founder variant at an allele frequency of 0.955.
- 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
snippet: "The p.P479L allele frequency was 0.82."
explanation: Nunavut Inuit cohort reports the p.P479L founder allele frequency at 0.82.
progression:
- notes: >-
Individuals are typically asymptomatic between episodes and appear
developmentally and cognitively normal unless prior metabolic decompensation
has caused neurologic damage. Acute crises are precipitated by fasting or by
concurrent febrile or gastrointestinal illness when energy demands rise, and
onset of manifestations is usually rapid. With newborn screening and prevention
of hypoglycemia, the risk of related neurologic injury is reduced.
pathophysiology:
- name: CPT1A enzyme deficiency
description: >
Biallelic pathogenic variants in CPT1A reduce the activity of the liver
isoform of carnitine palmitoyltransferase 1 on the outer mitochondrial
membrane. CPT1A catalyzes conjugation of long-chain acyl-CoA to carnitine to
form long-chain acylcarnitine, the first and rate-limiting step of the
carnitine shuttle. Residual enzyme activity is typically 1%-5% in affected
individuals.
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
biological_processes:
- preferred_term: carnitine shuttle
term:
id: GO:0006853
label: carnitine shuttle
modifier: DECREASED
locations:
- preferred_term: mitochondrial outer membrane
term:
id: GO:0005741
label: mitochondrial outer membrane
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
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
snippet: "Carnitine palmitoyltransferase 1A (CPT1A) catalyzes the synthesis of long chain acylcarnitines and is required for mitochondrial fatty acid oxidation in the liver."
explanation: Defines the CPT1A-catalyzed reaction (synthesis of long-chain acylcarnitines) as required for hepatic mitochondrial fatty acid oxidation.
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Residual enzyme activity is 1%-5% in"
explanation: GeneReviews documents residual CPT1 enzyme activity of 1%-5% in most individuals with CPT1A deficiency.
- reference: PMID:22301540
reference_title: "Carnitine palmitoyltransferase-1A deficiency: a look at classic and arctic variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "palmitoyltransferase-1A is the rate-limiting enzyme that allows the body to"
explanation: Review identifies CPT1A as the rate-limiting enzyme for using fat for energy during fasting and illness.
downstream:
- target: Impaired hepatic long-chain fatty acid oxidation
description: Loss of the rate-limiting CPT1A step blocks entry of long-chain fatty acids into hepatic mitochondrial beta-oxidation.
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
snippet: "CPT1A deficiency is an inherited disorder of hepatic fatty acid oxidation that affects the tolerance to fasting and presents clinically with hypoketotic hypoglycemia."
explanation: Directly links CPT1A deficiency to impaired hepatic fatty acid oxidation, fasting intolerance, and hypoketotic hypoglycemia.
- name: Carnitine shuttle first step
description: >
The carnitine shuttle imports long-chain fatty acids into the mitochondrial
matrix in three steps: CPT1 on the outer mitochondrial membrane converts
long-chain acyl-CoA to acylcarnitine, CACT translocates acylcarnitine across
the inner membrane, and CPT2 regenerates acyl-CoA in the matrix. CPT1A is the
liver isoform of the outer-membrane CPT1 step, so its loss blocks the shuttle
at its committed, rate-limiting entry point.
biological_processes:
- preferred_term: carnitine shuttle
term:
id: GO:0006853
label: carnitine shuttle
locations:
- preferred_term: mitochondrial outer membrane
term:
id: GO:0005741
label: mitochondrial outer membrane
evidence:
- reference: PMID:15363638
reference_title: "Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects."
supports: SUPPORT
evidence_source: OTHER
snippet: "proteins located in the outer (CPT1) and inner (CPT2) mitochondrial membranes."
explanation: Establishes that the CPT system comprises outer-membrane CPT1 and inner-membrane CPT2 proteins.
downstream:
- target: Impaired hepatic long-chain fatty acid oxidation
description: Blocking the outer-membrane CPT1A step prevents formation of long-chain acylcarnitine and downstream mitochondrial beta-oxidation.
causal_link_type: DIRECT
evidence:
- reference: PMID:15363638
reference_title: "Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects."
supports: SUPPORT
evidence_source: OTHER
snippet: "CPT1-A deficiency presents as recurrent"
explanation: Review states that CPT1-A deficiency presents as recurrent attacks of fasting hypoketotic hypoglycemia, the clinical readout of the blocked shuttle.
- name: Impaired hepatic long-chain fatty acid oxidation
description: >
Loss of CPT1A blocks hepatic oxidation of long-chain fatty acids. During
fasting or illness, when hepatic glycogen is depleted and the liver normally
switches to fatty acid oxidation to fuel ketogenesis and gluconeogenesis, this
block leaves the liver unable to generate ketones or sustain energy production,
and long-chain acyl groups cannot be esterified to carnitine for import.
biological_processes:
- preferred_term: fatty acid beta-oxidation
term:
id: GO:0006635
label: fatty acid beta-oxidation
modifier: DECREASED
- preferred_term: long-chain fatty acid metabolic process
term:
id: GO:0001676
label: long-chain fatty acid metabolic process
modifier: DECREASED
chemical_entities:
- preferred_term: ketone body
term:
id: CHEBI:73693
label: ketone body
modifier: DECREASED
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "is a disorder of long-chain fatty acid oxidation."
explanation: GeneReviews characterizes CPT1A deficiency as a disorder of long-chain fatty acid oxidation.
downstream:
- target: Hypoketotic hypoglycemia
description: Impaired hepatic fatty acid oxidation prevents compensatory ketogenesis during fasting, producing hypoglycemia with inappropriately low ketones.
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
snippet: "at the termination of the fast the mean level of serum ketones was decreased"
explanation: Supervised-fast study documents blunted ketone production in CPT1A-variant children, the biochemical basis of hypoketotic hypoglycemia.
- target: Distinctive carnitine and acylcarnitine signature
description: Inability to generate long-chain acylcarnitine lowers long-chain acylcarnitine species and raises free carnitine, giving an elevated C0/(C16 + C18) ratio.
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
snippet: "the ratio of free carnitine (C0) to the sum of the C16 and C18 acylcarnitines (C0/C16+C18) was significantly elevated (mean 199 ± 68, normal < 130 in infants), which is characteristic of CPT1A deficiency, reflecting the decreased ability to generate long chain acylcarnitines"
explanation: Directly links the CPT1A block to the elevated C0/(C16+C18) ratio through decreased generation of long-chain acylcarnitines.
- target: Hepatic crisis
description: Acute hepatic energy failure during fasting or illness produces hepatomegaly, elevated transaminases, hyperammonemia, and hepatic encephalopathy.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Acute hepatic energy failure and impaired ureagenesis during metabolic decompensation.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "serum concentrations of liver transaminases, ammonia, and creatine kinase."
explanation: GeneReviews lists elevated liver transaminases, ammonia, and creatine kinase among later-onset manifestations of hepatic decompensation.
- name: Distinctive carnitine and acylcarnitine signature
description: >
Unlike most fatty acid oxidation disorders, which accumulate acylcarnitines,
CPT1A deficiency cannot form long-chain acylcarnitines. The result is low total
and long-chain acylcarnitines with high free carnitine and an elevated
free-carnitine to long-chain-acylcarnitine ratio [C0/(C16 + C18)], the
diagnostic biochemical hallmark used on newborn screening.
chemical_entities:
- preferred_term: carnitine
term:
id: CHEBI:17126
label: carnitine
modifier: INCREASED
evidence:
- reference: PMID:41017303
reference_title: "Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "comprise elevated concentrations of free"
explanation: Human case series identifies elevated free carnitine and an elevated metabolite ratio as the diagnostic abnormalities of CPT1A deficiency.
- 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
snippet: "an elevated free-to-total carnitine ratio,"
explanation: Human case report documents a low proportion of acylcarnitine species and an elevated free-to-total carnitine ratio in CPT1A deficiency.
- name: Sparing of muscle and heart
description: >
Carnitine palmitoyltransferase 1 exists as tissue-specific isoforms: the liver
isoform CPT1A, the muscle isoform CPT1B, and the brain isoform CPT1C. Because
skeletal muscle and heart depend on CPT1B rather than CPT1A, CPT1A deficiency
is largely restricted to a hepatic phenotype and characteristically spares
cardiac and skeletal muscle, contrasting with CPT2, CACT, and VLCAD
deficiencies, which cause cardiomyopathy and rhabdomyolysis.
molecular_functions:
- preferred_term: carnitine O-palmitoyltransferase activity
term:
id: GO:0004095
label: carnitine O-palmitoyltransferase activity
evidence:
- reference: PMID:15363638
reference_title: "Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects."
supports: SUPPORT
evidence_source: OTHER
snippet: "While CPT2 is an ubiquitous protein, three tissue-specific CPT1 isoforms--the"
explanation: Establishes the tissue-specific CPT1 isoforms (liver CPT1A, muscle CPT1B, brain CPT1C) that explain the muscle-sparing hepatic phenotype of CPT1A deficiency.
- reference: PMID:15363638
reference_title: "Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects."
supports: SUPPORT
evidence_source: OTHER
snippet: "attacks of fasting hypoketotic hypoglycemia."
explanation: The isolated fasting hypoketotic-hypoglycemia presentation of CPT1-A deficiency, without myopathy, reflects loss of the liver isoform only.
- name: Hypoketotic hypoglycemia
description: >
During fasting or intercurrent illness, hepatic glycogen is depleted and the
liver normally relies on fatty acid oxidation to fuel ketogenesis. CPT1A
deficiency blocks this response, producing hypoglycemia with inappropriately
low ketones and acute neurologic decompensation.
biological_processes:
- preferred_term: ketone body biosynthetic process
term:
id: GO:0046951
label: ketone body biosynthetic process
modifier: DECREASED
chemical_entities:
- preferred_term: glucose
term:
id: CHEBI:17234
label: glucose
modifier: DECREASED
- preferred_term: ketone body
term:
id: CHEBI:73693
label: ketone body
modifier: DECREASED
evidence:
- reference: PMID:22301540
reference_title: "Carnitine palmitoyltransferase-1A deficiency: a look at classic and arctic variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "various symptoms including hypoketotic hypoglycemia, lethargy, and seizures."
explanation: Review documents hypoketotic hypoglycemia, lethargy, and seizures as presenting features after illness.
downstream:
- target: Hepatic encephalopathy
description: Severe hypoketotic hypoglycemia and hepatic energy failure can produce hepatic encephalopathy.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Acute energy deprivation and hyperammonemia during hepatic decompensation.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "encephalopathy, hypoglycemia, absent or low levels of ketones, and elevated"
explanation: GeneReviews lists hepatic encephalopathy with hypoglycemia and absent/low ketones among later-onset manifestations.
- target: Lethargy
description: Acute energy failure manifests as lethargy during metabolic decompensation.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:22301540
reference_title: "Carnitine palmitoyltransferase-1A deficiency: a look at classic and arctic variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "various symptoms including hypoketotic hypoglycemia, lethargy, and seizures."
explanation: Review lists lethargy among symptoms after illness in CPT1A deficiency.
- target: Seizure
description: Severe hypoglycemia can progress to seizures.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:22301540
reference_title: "Carnitine palmitoyltransferase-1A deficiency: a look at classic and arctic variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "various symptoms including hypoketotic hypoglycemia, lethargy, and seizures."
explanation: Review lists seizures among presenting symptoms in CPT1A deficiency.
- target: Sudden death
description: In Arctic founder-variant populations, p.P479L homozygosity is associated with unexpected/sudden infant death.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23231747
reference_title: "Causes and risk factors for infant mortality in Nunavut, Canada 1999-2011."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Columbia First Nations populations, was associated with unexpected infant death (SIDS/SUDI, infection) throughout"
explanation: Epidemiologic study associates CPT1A P479L homozygosity with unexpected infant death (SIDS/SUDI, infection).
phenotypes:
- name: Hypoketotic hypoglycemia
frequency: FREQUENT
description: >
Fasting or illness-triggered hypoglycemia with inappropriately low or absent
ketones, the hallmark acute presentation of CPT1A deficiency.
phenotype_term:
preferred_term: Hypoketotic hypoglycemia
term:
id: HP:0001985
label: Hypoketotic hypoglycemia
evidence:
- reference: PMID:15363638
reference_title: "Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects."
supports: SUPPORT
evidence_source: OTHER
snippet: "attacks of fasting hypoketotic hypoglycemia."
explanation: Review identifies recurrent attacks of fasting hypoketotic hypoglycemia as the presentation of CPT1-A deficiency.
- 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
snippet: "CPT1A deficiency is an inherited disorder of hepatic fatty acid oxidation that affects the tolerance to fasting and presents clinically with hypoketotic hypoglycemia."
explanation: Supervised-fast study confirms hypoketotic hypoglycemia as the clinical presentation of CPT1A deficiency.
- name: Hepatomegaly
frequency: FREQUENT
description: >
Enlarged, fat-laden liver during metabolic decompensation; may be a presenting
finding with intercurrent illness.
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
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
snippet: "marked hepatomegaly on physical exam that was later confirmed with an abdominal"
explanation: Case report documents marked hepatomegaly in a child with CPT1A deficiency presenting during acute illness.
- name: Elevated hepatic transaminases
description: >
Disproportionately elevated liver transaminases during acute decompensation,
reflecting hepatocellular stress.
phenotype_term:
preferred_term: Elevated hepatic transaminases
term:
id: HP:0002910
label: Elevated circulating hepatic transaminase concentration
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
snippet: "elevated liver transaminases in the setting of acute gastroenteritis."
explanation: Case report documents disproportionately elevated liver transaminases with acute gastroenteritis in CPT1A deficiency.
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "serum concentrations of liver transaminases, ammonia, and creatine kinase."
explanation: GeneReviews lists elevated serum liver transaminases among later-onset manifestations.
- name: Hyperammonemia
description: >
Elevated serum ammonia can occur during acute hepatic metabolic
decompensation.
phenotype_term:
preferred_term: Hyperammonemia
term:
id: HP:0001987
label: Hyperammonemia
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "serum concentrations of liver transaminases, ammonia, and creatine kinase."
explanation: GeneReviews lists elevated serum ammonia among later-onset manifestations of CPT1A deficiency.
- name: Elevated creatine kinase
description: >
Elevated serum creatine kinase can accompany acute metabolic decompensation in
CPT1A deficiency.
phenotype_term:
preferred_term: Elevated circulating creatine kinase concentration
term:
id: HP:0003236
label: Elevated circulating creatine kinase concentration
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "serum concentrations of liver transaminases, ammonia, and creatine kinase."
explanation: GeneReviews lists elevated serum creatine kinase among later-onset manifestations of CPT1A deficiency.
- name: Hepatic encephalopathy
description: >
Recurrent episodes of hepatic encephalopathy occur during metabolic
decompensation; individuals are typically normal between episodes.
phenotype_term:
preferred_term: Hepatic encephalopathy
term:
id: HP:0002480
label: Hepatic encephalopathy
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "encephalopathy, hypoglycemia, absent or low levels of ketones, and elevated"
explanation: GeneReviews identifies hepatic encephalopathy with hypoglycemia and low ketones as a recognized presentation.
- name: Hepatic failure
description: >
Sudden onset of liver failure can occur, particularly in individuals
identified by an out-of-range newborn screen who then decompensate.
phenotype_term:
preferred_term: Hepatic failure
term:
id: HP:0001399
label: Hepatic failure
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypoglycemia, and sudden onset of liver failure) and (2) later-onset"
explanation: GeneReviews lists sudden onset of liver failure among presentations of CPT1A deficiency.
- name: Lethargy
description: >
Progressive lethargy during metabolic decompensation following illness.
phenotype_term:
preferred_term: Lethargy
term:
id: HP:0001254
label: Lethargy
evidence:
- reference: PMID:22301540
reference_title: "Carnitine palmitoyltransferase-1A deficiency: a look at classic and arctic variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "various symptoms including hypoketotic hypoglycemia, lethargy, and seizures."
explanation: Review lists lethargy among symptoms after illness in CPT1A deficiency.
- name: Seizure
frequency: OCCASIONAL
description: >
Seizures may occur secondary to severe hypoglycemia during acute crises.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:22301540
reference_title: "Carnitine palmitoyltransferase-1A deficiency: a look at classic and arctic variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "various symptoms including hypoketotic hypoglycemia, lethargy, and seizures."
explanation: Review lists seizures among presenting symptoms in CPT1A deficiency.
- name: Sudden infant death
frequency: OCCASIONAL
description: >
In Arctic founder-variant populations, p.P479L homozygosity is associated with
unexpected/sudden infant death (SIDS/SUDI).
phenotype_term:
preferred_term: Sudden death
term:
id: HP:0001699
label: Sudden death
context: Arctic p.P479L founder populations
evidence:
- reference: PMID:23231747
reference_title: "Causes and risk factors for infant mortality in Nunavut, Canada 1999-2011."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Columbia First Nations populations, was associated with unexpected infant death (SIDS/SUDI, infection) throughout"
explanation: Epidemiologic study associates CPT1A P479L homozygosity with unexpected infant death.
- name: Susceptibility to infectious illness
description: >
In Nunavut Inuit children, p.P479L homozygosity was associated with increased
childhood infectious illness, including hospitalization for lower respiratory
tract infection, otitis media, and gastroenteritis.
context: Arctic p.P479L founder populations
evidence:
- 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
snippet: "p.P479L homozygosity was associated with LRTI admission (aOR:2.88 95%CI:1.46-5.64)"
explanation: Cohort study links p.P479L homozygosity to increased lower respiratory tract infection admissions in Inuit children.
biochemical:
- name: Free carnitine (C0)
presence: INCREASED
context: >
Free carnitine is characteristically elevated in CPT1A deficiency because
long-chain acyl groups cannot be esterified to carnitine, the reverse of the
low-free-carnitine pattern seen in most fatty acid oxidation disorders.
biomarker_term:
preferred_term: free carnitine
term:
id: CHEBI:17126
label: carnitine
readouts:
- target: Distinctive carnitine and acylcarnitine signature
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Elevated free carnitine is a diagnostic readout of the CPT1A block on long-chain acylcarnitine formation.
evidence:
- reference: PMID:41017303
reference_title: "Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "comprise elevated concentrations of free"
explanation: Human case series identifies elevated free carnitine as a diagnostic abnormality of CPT1A deficiency.
evidence:
- reference: PMID:41017303
reference_title: "Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "comprise elevated concentrations of free"
explanation: Documents elevated free carnitine as a disease-specific biochemical marker of CPT1A deficiency.
- name: Long-chain acylcarnitines (C16, C18)
presence: DECREASED
context: >
Long-chain acylcarnitine species are low because CPT1A cannot form long-chain
acylcarnitine from long-chain acyl-CoA, giving a low proportion of
acylcarnitine species on the plasma profile.
readouts:
- target: Distinctive carnitine and acylcarnitine signature
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Decreased long-chain acylcarnitines report the failure of the CPT1A-catalyzed acylcarnitine-forming step.
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
snippet: "the ratio of free carnitine (C0) to the sum of the C16 and C18 acylcarnitines (C0/C16+C18) was significantly elevated (mean 199 ± 68, normal < 130 in infants), which is characteristic of CPT1A deficiency, reflecting the decreased ability to generate long chain acylcarnitines"
explanation: The elevated C0/(C16+C18) ratio reflects decreased generation of long-chain acylcarnitines.
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
snippet: "an elevated free-to-total carnitine ratio,"
explanation: Case report notes a low proportion of acylcarnitine species from plasma with an elevated free-to-total carnitine ratio.
- name: Free carnitine to long-chain acylcarnitine ratio [C0/(C16 + C18)]
presence: INCREASED
context: >
The C0/(C16 + C18) ratio is the diagnostic newborn-screening marker for CPT1A
deficiency and is markedly elevated because free carnitine is high while
long-chain acylcarnitines are low.
readouts:
- target: Distinctive carnitine and acylcarnitine signature
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: The elevated C0/(C16+C18) ratio is the composite diagnostic readout of the CPT1A block.
evidence:
- reference: PMID:41017303
reference_title: "Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Disease-specific and diagnostic abnormalities of CPT1A deficiency"
explanation: Identifies the elevated [C0/(C16 + C18)] blood ratio as a disease-specific diagnostic abnormality.
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
snippet: "the ratio of free carnitine (C0) to the sum of the C16 and C18 acylcarnitines (C0/C16+C18) was significantly elevated (mean 199 ± 68, normal < 130 in infants), which is characteristic of CPT1A deficiency, reflecting the decreased ability to generate long chain acylcarnitines"
explanation: Directly documents the elevated C0/(C16+C18) ratio characteristic of CPT1A deficiency.
genetic:
- name: CPT1A gene variants
gene_term:
preferred_term: CPT1A
term:
id: hgnc:2328
label: CPT1A
inheritance:
- name: Autosomal recessive
evidence:
- reference: PMID:41017303
reference_title: "Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ultra-rare autosomal recessive disorder of the carnitine cycle caused by"
explanation: States that CPT1A deficiency is an autosomal recessive disorder caused by biallelic CPT1A variants.
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CPT1A deficiency is inherited in an autosomal recessive"
explanation: GeneReviews states CPT1A deficiency is inherited in an autosomal recessive manner.
variants:
- name: CPT1A - p.P479L (c.1436C>T, "Arctic" variant)
description: >
A proline-to-leucine substitution at residue 479, the common Arctic founder
allele in Inuit, Alaska Native, and Greenland populations. It produces a
hypomorphic enzyme with reduced activity and altered malonyl-CoA regulation
and is associated with impaired fasting ketogenesis, hypoketotic
hypoglycemia, infectious illness, and elevated infant mortality.
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
snippet: "This sequence variant results in a proline to leucine substitution at amino acid 479 (p.P479L) of the CPT1A protein."
explanation: Defines the c.1436C>T variant as the p.P479L substitution in CPT1A.
- 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
snippet: "CPT1C, CPT2 and CRAT, including three novel variants and one Inuit specific"
explanation: Population genetics study identifies CPT1A p.P479L as an Inuit-specific high-frequency variant.
features: >
CPT1A deficiency results from biallelic pathogenic variants in CPT1A encoding
the liver isoform of carnitine palmitoyltransferase 1. The p.P479L Arctic
founder allele is the predominant variant in northern Indigenous populations,
where it reaches very high allele frequency, whereas classic severe disease
outside these populations arises from private loss-of-function variants.
evidence:
- 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
snippet: "The latter has the highest frequency (0.955)"
explanation: Documents CPT1A p.P479L as the highest-frequency variant in the Nunavik Inuit population.
treatments:
- name: Avoidance of prolonged fasting and frequent feeding
description: >
Frequent feeding and avoidance of prolonged fasting are the cornerstone of
management; infants should eat frequently and fasting should not exceed about
12 hours during illness, surgery, or procedures. Cornstarch may be used to
extend overnight fasting tolerance.
treatment_term:
preferred_term: dietary intervention
term:
id: MAXO:0000088
label: dietary intervention
target_mechanisms:
- target: Hypoketotic hypoglycemia
treatment_effect: INHIBITS
description: Avoiding prolonged fasting removes the catabolic trigger for hypoketotic hypoglycemia.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "individuals fasting should not last more than 12 hours during illness, surgery,"
explanation: GeneReviews advises limiting fasting to prevent hypoglycemia in CPT1A deficiency.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "individuals fasting should not last more than 12 hours during illness, surgery,"
explanation: GeneReviews recommends limiting fasting duration to prevent hypoglycemia.
- name: High-carbohydrate, low-long-chain-fat diet with MCT
description: >
A high-carbohydrate diet low in long-chain fat provides a constant supply of
carbohydrate energy, supplemented with medium-chain triglycerides (MCT), which
bypass the CPT1A-dependent step and can supply roughly one third of total
calories.
treatment_term:
preferred_term: dietary intervention
term:
id: MAXO:0000088
label: dietary intervention
target_mechanisms:
- target: Impaired hepatic long-chain fatty acid oxidation
treatment_effect: RESTORES
description: MCT provides medium-chain fatty acids that enter mitochondria independent of the carnitine shuttle, bypassing the CPT1A block.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "high-carbohydrate diet low in long-chain fat and frequent feeding supplemented"
explanation: GeneReviews recommends a high-carbohydrate diet low in long-chain fat with MCT/triheptanoin supplementation.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "or medical procedures; adults need a high-carbohydrate, low-fat diet to provide"
explanation: GeneReviews recommends a high-carbohydrate, low-fat diet with MCT in CPT1A deficiency.
- name: Triheptanoin or MCT oil
description: >
Targeted therapy provides medium-chain or odd-carbon (triheptanoin) fat that
bypasses the CPT1A-dependent long-chain shuttle to supply mitochondrial
substrate.
treatment_term:
preferred_term: dietary intervention
term:
id: MAXO:0000088
label: dietary intervention
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "(an odd-carbon triglyceride) or MCT oil. Supportive care: Acute treatment"
explanation: GeneReviews lists triheptanoin (an odd-carbon triglyceride) or MCT oil as targeted therapies.
- name: Emergency intravenous glucose
description: >
Acute treatment of hypoglycemia uses intravenous fluid containing 10% dextrose,
maintained until blood glucose normalizes and hepatic glycogen is repleted.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Hypoketotic hypoglycemia
treatment_effect: RESTORES
description: Intravenous dextrose restores carbohydrate energy supply during acute decompensation.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "includes prompt treatment of hypoglycemia with intravenous fluid containing 10%"
explanation: GeneReviews specifies prompt intravenous 10% dextrose for acute hypoglycemia.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "includes prompt treatment of hypoglycemia with intravenous fluid containing 10%"
explanation: GeneReviews specifies intravenous 10% dextrose as acute treatment for hypoglycemia.
- name: Avoidance of hepatotoxic agents
description: >
Potentially hepatotoxic agents such as valproate and salicylate should be
avoided, as should prolonged fasting.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "such as valproate and salicylate; viral or bacterial infections; avoid"
explanation: GeneReviews lists valproate and salicylate among agents to avoid in CPT1A deficiency.
- name: Genetic counseling
description: >
CPT1A deficiency is autosomal recessive; genetic counseling and carrier/prenatal
testing are offered to at-risk families.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CPT1A deficiency is inherited in an autosomal recessive"
explanation: GeneReviews describes autosomal recessive inheritance, the basis for genetic counseling.
environmental:
- name: Febrile or gastrointestinal illness
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
snippet: "elevated liver transaminases in the setting of acute gastroenteritis."
explanation: Case report shows acute gastroenteritis precipitating hepatic decompensation in CPT1A deficiency.
- name: Fasting
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
snippet: "CPT1A deficiency is an inherited disorder of hepatic fatty acid oxidation that affects the tolerance to fasting and presents clinically with hypoketotic hypoglycemia."
explanation: Supervised-fast study shows fasting intolerance and hypoketotic hypoglycemia in CPT1A deficiency.
notes: >
CPT1A deficiency is mechanistically distinctive among fatty acid oxidation
disorders. Because CPT1A is the outer-mitochondrial-membrane, rate-limiting,
liver-specific step of the carnitine shuttle, deficiency produces a
predominantly hepatic phenotype (fasting/illness-triggered hypoketotic
hypoglycemia, hepatic encephalopathy, hepatomegaly, elevated transaminases and
ammonia) while sparing skeletal and cardiac muscle, which use the separate CPT1B
isoform. Its biochemical signature is the inverse of most FAODs: low long-chain
acylcarnitines with high free carnitine and an elevated C0/(C16 + C18) ratio.
Maternal acute fatty liver of pregnancy/HELLP is classically linked to fetal
LCHAD/MTP deficiency; the GeneReviews entry notes a rare association of CPT1A
fetal genotype with acute fatty liver of pregnancy, but the strong maternal
association is with LCHAD/MTP and is not asserted here as a CPT1A mechanism.
Renal tubular acidosis has been reported in CPT1A deficiency but was not
documented in the sources cited here and is therefore omitted pending a
verifiable reference.
diagnosis:
- name: Molecular and enzymatic diagnosis of CPT1A deficiency
diagnosis_term:
preferred_term: genetic testing
term:
id: MAXO:0000127
label: genetic testing
description: >-
Diagnosis is established by biallelic pathogenic CPT1A variants on molecular
genetic testing; diminished CPT1 enzyme activity in cultured skin fibroblasts
is an available option in some countries when molecular testing is not
definitive.
results: Biallelic pathogenic CPT1A variants; residual CPT1 enzyme activity 1%-5%.
evidence:
- reference: PMID:20301700
reference_title: "Carnitine Palmitoyltransferase 1A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis of CPT1A deficiency is established in a proband with biallelic
pathogenic variants in CPT1A identified by molecular genetic testing.
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. Residual enzyme activity is
1%-5% in most individuals with CPT1A deficiency.
explanation: >-
GeneReviews diagnosis/testing criteria for CPT1A deficiency (molecular
testing, with fibroblast CPT1 enzyme activity as an adjunct).
references:
- reference: PMID:20301700
title: "Carnitine Palmitoyltransferase 1A Deficiency."
tags:
- GeneReviews
findings: []