DiagnosisClinical DiagnosisCarnitine palmitoyltransferase I (CPT I) is a mitochondrial membrane protein that converts long-chain fatty acyl-CoA molecules to their corresponding acylcarnitine molecules. The resulting acylcarnitines are then available for transport into the mitochondrial matrix where they can undergo fatty acid oxidation. Mitochondrial fatty acid oxidation by the liver provides an alternative source of fuel when glycogen reserves are significantly reduced, most often due to fasting or other intercurrent illness. The pathway fuels ketogenesis for metabolism in peripheral tissues that cannot oxidize fatty acids.Clinical symptoms usually occur in an individual with a concurrent febrile or gastrointestinal illness when energy demands are increased. The precipitating illness may be a relatively common infectious disease, but the onset of symptoms is usually rapid and should alert the clinician to the possibility of a fatty acid oxidation defect.Three phenotypes of CPT1A deficiency are recognized and suspected based on the following findings:Hepatic encephalopathy. Individuals (typically children) present with the laboratory findings of hypoketotic hypoglycemia and sudden onset of liver failure and hepatic encephalopathy precipitated by fasting or fever. The presentation is similar to that seen in Reye syndrome.Adult-onset myopathy. In a single individual of Inuit origin who was homozygous for the p.Pro479Leu mutation, the presenting feature was a history of exercise-induced sudden-onset muscle cramping with no indication of hypoglycemia or hepatic failure. There is some doubt as to whether this myopathic presentation is related to the genetic alteration.Acute fatty liver of pregnancy. Fetal homozygosity for CPT1A deficiency has been associated with acute fatty liver of pregnancy.TestingHypoglycemia, absent or low levels of ketones, elevated liver transaminases, elevated serum ammonia concentration, and elevated total serum carnitine are typical laboratory findings.Hypoketotic hypoglycemia. In most cases, hypoketotic hypoglycemia is defined as low blood glucose concentration (<40 mg/dL) in the absence of ketone bodies in the urine.Hepatic encephalopathy includes liver enzymes AST and ALT that are two- to tenfold the upper limit of normal and hyperammonemia (i.e., plasma ammonia concentrations usually 100-500 µmol/L [normal: <70 µmol/L]).Elevated total serum carnitine. The total serum carnitine concentration may be elevated, in the range of 70-170 µmol/L (normal total serum carnitine: 25-69 µmol/L). The elevation of total carnitine hypoketotic hypoglycemia should increase suspicion specifically for CPT1A deficiency.Elevated ratio of C0/C16+C18 acylcarnitines. In CPT1A deficiency, there is marked reduction in the synthesis of all acylcarnitine species and increased levels of free carnitine (C0). Measurement of total C0 or the ratio of free carnitine to long-chain species (C16 and C18) has been used successfully both in newborn screening and in clinical diagnosis of CPT1A deficiency (see ).OtherMeasurement of urine organic acids is useful in the diagnosis of CPT1A deficiency during acute periods of metabolic decompensation, and can aid in the differential diagnosis of other fatty acid oxidation and organic acid defects, many of which have unique profiles.
Note: (1) No distinctive organic acids are produced by CPT1A deficiency when the individual is well, but many of the other defects considered in the differential diagnosis have characteristic patterns. (2) In a recent study, dodecanedioic acid was elevated in individuals during acute crisis and for several days following [Korman et al 2005]. The authors have also seen C12 dicarboxylic acid elevation during acute crisis in individuals subsequently diagnosed with CPT1A deficiency [Bennett, personal unpublished observation].Metabolic flux studies of fatty acid oxidation using tritiated fatty acids and measuring incorporation of tritium into cellular water yield abnormal results [Olpin et al 2001]. Such testing requires a skin biopsy and subsequent generation of cultured skin fibroblasts. The fatty acid pathway study using tandem mass spectrometry and measurement of accumulating acylcarnitine species may demonstrate an elevated C0/C16+C18 ratio but may be normal as the sensitivity and specificity of the testing have not been established.Acute fatty liver of pregnancy. Maternal laboratory findings include hypoglycemia, abnormal liver enzymes, and hyperammonemia similar to that seen in individuals with acute CPT1A deficiency. As the liver failure progresses, abnormal hepatic synthetic function results in bleeding diathesis.Assay of carnitine palmitoyltransferase 1 enzyme activity on cultured skin fibroblasts [McGarry & Brown 1997]:In normal fibroblasts, CPT1A enzyme activity is 0.58±0.11 nmol/min/mg fibroblast protein [Bennett et al 2004].In most individuals described with CPT1A deficiency, residual enzyme activity is 1%-5%.In the Inuit, the residual enzyme activity in those with the myopathic phenotype is 15%-25%.Newborn screening. The ratio of free to total carnitine in serum or plasma or on a newborn screen blood spot is elevated [Sim et al 2001]. CPT1A deficiency screening is available in some state newborn screening programs using the ratio of C16:0 (palmitoylcarnitine) to free carnitine. The sensitivity of this metabolite approach appears to be high; in three confirmed cases, the C0/(C16+C18) ratios were five to 60 times higher than the 99.9th centile of 177,000 cases [Fingerhut et al 2001]. See National Newborn Screening Status Report (pdf).Molecular Genetic TestingGene. CPT1A is the only gene in which mutations are known to cause CPT1A deficiency.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Carnitine Palmitoyltransferase 1A DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityCPT1ASequence analysis / mutation scanning 2Sequence variants 3 >90% 4, 5ClinicalTargeted mutation analysis p.Pro479Leu
p.Gly710Glu 2, 6~100% in high-risk infants 7Deletion / duplication analysis 8Partial- or whole-gene deletionsUnknown 9, rare1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies, although mutation scanning detection rates may vary considerable between laboratories as that method is highly dependent on details of methodology employed.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Note: Sequence analysis also detects the common mutations p.Gly710Glu in the Hutterite population [Prasad et al 2001] and p.Pro479Leu in the Inuit population [Brown et al 2001]. 5. In individuals with enzymatic confirmation of CPT1A deficiency 6. Mutations tested may vary among laboratories.7. Infants in the state of Alaska who test positive for CPT1A deficiency by expanded newborn screening. Targeted mutation analysis for the p.Pro479Leu mutation is useful in populations with a very high frequency of this allele, including infants who test positive for CPT1A deficiency in the state of Alaska newborn screening program and in the Canadian First Nations population in Nunavut [Collins et al 2010]. Most affected individuals in these populations are homozygous for p.Pro479Leu [Park et al 2006]. The p.Gly710Glu mutation is common in the Hutterite population.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.9. Exonic and multiexonic deletions would be detected with deletion/duplication analysis [Gobin et al 2002, Bonnefont et al 2004, Stoler et al 2004, Korman et al 2005]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandIn an acutely ill proband:Measure plasma or serum concentrations of glucose, ammonia, liver enzymes, and creatine kinase.Measure total and free plasma carnitine concentration; obtain acylcarnitine profile; measure blood free fatty acids and 3-hydroxybutyrate.Analyze urine for ketones and organic acids [Korman et al 2005].Perform molecular genetic testing to confirm the enzymatic diagnosis. Test patients from Canadian First Nation and Inuit populations for the p.Pro479Leu mutation [Park et al 2006]. Deletion/duplication analysis can be considered if sequence analysis identifies only one mutant allele.Confirm the enzyme defect in cultured skin fibroblasts or white blood cells.In a clinically stable proband, such as those identified through expanded newborn screening programs or newborn sibs of known affected individuals:Obtain plasma total and free carnitine and acylcarnitine profiles, which should be informative even if the markers of metabolic decompensation are normal.Perform the following molecular genetic testing to confirm the enzymatic diagnosis:Targeted mutation analysis of p.Pro479Leu in those of Inuit or Canadian First Nations ancestrySequence analysis on all others with an enzymatically confirmed diagnosisConfirmation of the enzyme defect in cultured skin fibroblasts or white blood cellsCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with mutations in CPT1A.}

Natural HistoryCarnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation.Hepatic encephalopathy. Although some neonates present with "physiologic" hypoglycemia of the newborn, most individuals with CPT1A deficiency present with fasting-induced hepatic encephalopathy in early childhood. This is a potentially fatal presentation; children who recover are at risk for recurrent episodes of life-threatening illness.Survival through infancy without symptoms has been reported; initial presentation may occur later in life with similar life-threatening acute hepatic illness.Death as a result of rapid-onset hepatic failure in CPT1A deficiency occurred in an individual age 17 years despite the early recognition of a fatty acid oxidation defect [Brown et al 2001].Between episodes of metabolic decompensation, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage.Recognition of CPT1A deficiency and initiating management to prevent lipolysis reduces the episodes of decompensation [Stoler et al 2004].Long-term liver damage as a result of recurring hepatosteatosis has not been reported.Some individuals with the hepatic encephalopathy phenotype have also had renal tubular acidosis.Unlike other long-chain fatty acid oxidation defects, cardiac or skeletal muscle involvement is not common [Bonnefont et al 2004].Adult-onset myopathic presentation. To date, a single individual homozygous for the p.Pro479Leu Inuit mutation has been described [Brown et al 2001]. The clinical findings were recurrent episodes of activity-associated muscle pain with elevated serum CK concentration. There is some doubt whether the myopathy in this individual was related to CPT1A sequence variation as multiple other individuals who are homozygous for the variant have been identified and are not reported to have myopathy [Greenberg et al 2009, Rajakumar et al 2009, Collins et al 2010].Fetal CPT1A deficiency has been associated with acute fatty liver of pregnancy [Innes et al 2000]. A heterozygous female carrying a homozygous fetus is at risk of developing this obstetric complication. A number of other fetal fatty acid oxidation defects also carry a similar risk to the heterozygous mother of developing acute fatty liver of pregnancy, typically in the third trimester. Investigation of a newborn following maternal acute fatty liver of pregnancy should include rapid plasma acylcarnitine and urine organic acid analysis. In CPt1A deficiency, the ratio of C0/C16+C18 acylcarnitines should be elevated and the urine organic acids may be normal or show a nonspecific medium-chain dicarboxylic aciduria.

Genotype-Phenotype CorrelationsThe p.Pro479Leu Inuit sequence variant, which has high residual enzymatic activity, does not appear to present with acute hepatic failure as do the other sequence variants associated with the more severe phenotype. However, recent evidence suggests that infants who are homozygous for the variant have impaired fasting tolerance [Gillingham et al 2011], and increased risk of infant mortality [Gessner et al 2010]. However a separate study identified the p.Pro479Leu variant to be cardioprotective through increased HDL-cholesterol and associated with reduced adiposity [Lemas et al 2012].In all other individuals, the residual enzyme activity is between 0% and 5% and mutations have been identified throughout the gene.

Differential DiagnosisThe absence (or paucity) of ketone bodies during a period of hypoglycemia should increase suspicion for one of the disorders of fatty acid oxidation or the carnitine cycle, including carnitine palmitoyltransferase 1A (CPT1A) deficiency.Because the CPT1A enzyme is primarily expressed in liver, CPT1A deficiency is clinically more closely related to fatty acid and ketogenesis disorders with hepatic phenotypes. These include the following:Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency3-hydroxy-3-methylglutaryl (HMG)-CoA synthase deficiencyHMG-CoA lyase deficiency (see Organic Acidemias Overview)In the absence of muscle or heart manifestations, the acute hepatic presentation of CPT1A deficiency cannot be clinically distinguished from other defects of long-chain fatty acid oxidation and conditions that present as a Reye-like illness. These include the following:Carnitine palmitoyltransferase II (CPT II) deficiencyCarnitine acylcarnitine translocase (CACT) deficiencyVery-long-chain acyl-CoA dehydrogenase deficiencyMitochondrial trifunctional protein deficiency including long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Urea cycle disordersOrganic acidurias such as methylmalonic and propionic acidemia (see Organic Acidemias Overview)Disorders of oxidative phosphorylation (see Mitochondrial Disorders Overview)Disorders of gluconeogenesis (including glycogen storage disease type I)Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed with carnitine palmitoyltransferase 1A (CPT1A) deficiency, the following evaluations are recommended:In affected individuals who have profound and/or prolonged exposure to hypoglycemia: a complete neurologic evaluation to detect secondary neurologic damageMedical genetics consultationTreatment of ManifestationsGuidelines for the treatment of CPT1A deficiency can be found at newbornscreening.info and ghr.nlm.nih.gov.When individuals present with acute hypoglycemia, sufficient amounts of intravenous fluid containing 10% dextrose should be provided as quickly as possible to correct hypoglycemia and to prevent lipolysis and subsequent mobilization of fatty acids into the mitochondria.Because individuals presenting with profound hypoglycemia have little to no residual hepatic glycogen, treating physicians should continue the glucose infusion beyond the time that blood glucose concentration has normalized in order to provide sufficient substrate for glycogen synthesis.A letter should be provided to affected individuals (or their parents/guardians) and involved health care providers alerting them to the potentially catastrophic metabolic crises for which these individuals are at risk and explaining the appropriate emergency treatment.Prevention of Primary ManifestationsA high-carbohydrate diet (70% of calories) that is low in fat (<20% of calories) is generally recommended to provide a constant supply of carbohydrate energy, particularly during illness. Restriction of dietary fat intake is somewhat controversial when patients are well. If the physician chooses to recommend a low-fat diet when the patient is well, supplementation with essential fatty acids is necessary.Provision of approximately one third of total calories as medium-chain triglycerides is recommended during periods of illness. C6-C10 fatty acids do not require the carnitine shuttle for entry into the mitochondrion.Frequent feeding is recommended, particularly for infants, given their limited glycogen reserves. Cornstarch feedings given overnight provide a constant source of slow-release carbohydrate to prevent hypoglycemia during sleep.Older children should not fast for more than 12 hours and for a shorter time if evidence of a febrile or gastrointestinal illness exists.Adults should be aware of the risks of fasting and they and their primary care physician should be aware of the risks during surgery when both metabolic stress and fasting occur.Brief hospital admission for administration of intravenous dextrose-containing fluid should be considered in individuals with known CPT1A deficiency who are required to fast more than 12 hours because of illness or surgical or medical procedures.Prevention of Secondary ComplicationsPrevention of hypoglycemia reduces the risk of related neurologic damage.SurveillanceAt clinic appointments and during periods of reduced caloric intake and febrile illness that could precipitate metabolic decompensation, individuals with CPT1A deficiency should undergo liver function testing whether they are symptomatic or not. Tests should include liver enzymes, AST, ALT, ALP, and functional liver tests (including the blood-clotting tests PT and PTT).Agents/Circumstances to AvoidProlonged fasting should be avoided, especially during a febrile or gastrointestinal illness.Potentially hepatotoxic agents such as valproate and salicylate should not be given, even though adverse effects of pharmacologic agents have not been reported in individuals with CPT1A deficiency.Evaluation of Relatives at RiskBecause presentation in later childhood is possible, each sib of a proband, regardless of age, should be evaluated for CPT1A deficiency by molecular genetic testing if both mutations have been identified in the proband. If the two known disease-causing mutations in the family are not identified, the healthy sib is unaffected. If one of the known mutations is identified in the sib, he or she is heterozygous for CPT1A deficiencySee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementAlthough data are limited, it is prudent to counsel female carriers regarding the risk for obstetric complications.Women who have had one child with CPT1A deficiency following an uneventful pregnancy remain at risk for acute fatty liver of pregnancy in subsequent pregnancies with an affected fetus.Pregnant female carriers should be monitored for acute fatty liver of pregnancy. During pregnancy following identification of an affected proband, liver function testing should be performed at each prenatal visit during the first two trimesters and more frequently during the third trimester when the risk for acute fatty liver of pregnancy is greatest. Management by a team comprising a maternal-fetal medicine specialist and a medical/biochemical geneticist is highly recommended.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Carnitine Palmitoyltransferase 1A Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCPT1A11q13​.3Carnitine O-palmitoyltransferase 1, liver isoformCPT1A homepage - Mendelian genesCPT1AData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Carnitine Palmitoyltransferase 1A Deficiency (View All in OMIM) View in own window 255120CARNITINE PALMITOYLTRANSFERASE I DEFICIENCY 600528CARNITINE PALMITOYLTRANSFERASE I, LIVER; CPT1AMolecular Genetic PathogenesisThe so-called carnitine shuttle mediates transport of long-chain fatty acyl species from the cytosol into the mitochondria for energy production by β-oxidation. Carnitine palmitoyltransferase I (CPT I) on the outer mitochondrial membrane converts long-chain acyl-CoAs to their acylcarnitine equivalents, which are transported into the inner mitochondrial compartment by carnitine acylcarnitine translocase and then reconverted to the acyl-CoA species by CPT II at the inner mitochondrial membrane [McGarry & Brown 1997]. CPT I is thus the rate-limiting factor for entry of long-chain fatty acids into the mitochondria for β-oxidation.In the reduced activity of CPT I caused by mutations of CPT1A, fatty acids cannot enter the mitochondria for energy production; the result is a clinical and biochemical phenotype of fasting intolerance.See Figure 1.FigureFigure 1. The carnitine shuttle
Acyl-CoAs are converted to acylcarnitines by carnitine palmitoyltransferase 1, translocated into the mitochondrial matrix by carnitine:acylcarnitine translocase, and reconverted to acyl-CoAs and free carnitine (more...)Of the three distinct genetic forms of CPT I, CPT1A is expressed in liver, kidney, leukocytes, and skin fibroblasts; CPT1B is expressed in muscle; and CPT1C is brain specific. Genetic defects of CPT1A alone have been described to date.Normal allelic variants. CPT1A spans more than 60 kb of genomic DNA, of which 18 exons (2-19) are transcribed. One putative normal allelic variant has been described: c.823G>A, which results in p.Ala275Thr in exon 8, has a heterozygote frequency of 0.138. The functional significance (if any) of this change, which is within the large catalytic region, has not been fully determined [Brown et al 2001, Gobin et al 2002].Pathologic allelic variants. Outside the Hutterite and Inuit populations, all mutations characterized to date have been private (see Table 2 [pdf]) and many span the catalytic region. These include 15 missense mutations (listed in Table 3) as well as insertions and deletions [Gobin et al 2002, Bonnefont et al 2004, Stoler et al 2004, Korman et al 2005]. Approximately 50% of individuals characterized to date are homozygous for a private mutation.Table 3. Selected CPT1A Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias ¹)Reference SequencesNormalc.823G>Ap.Ala275ThrNM_001876​.3
NP_001867​.2Pathologicc.96T>Gp.Tyr32*c.298C>Tp.Gln100*c.367C>Tp.Arg123Cysc.478C>Tp.Arg160*c.912C>Gp.Cys304Trpc.941C>Tp.Thr314Ilec.946C>Gp.Arg316Glyc.1027T>Gp.Phe343Valc.1069C>Tp.Arg357Trpc.1079A>Gp.Glu360Glyc.1241C>Tp.Ala414Valc.1361A>Gp.Asp454Glyc.1395G>Tp.Gly465Trpc.1425G>Ap.Trp475*c.1436C>Tp.Pro479Leuc.1451T>Cp.Leu484Proc.1493A>Gp.Tyr498Cysc.1494T>Ap.Tyr498*c.1600delCp.Leu534*
(Leu534fs*)c.1737C>Ap.Tyr579*c.2126G>Ap.Gly709Gluc.2129G>Ap.Gly710GluSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. CPT1A encodes a 773-amino acid polypeptide, which is expressed in liver, kidney, leukocytes, and skin fibroblasts. Two transmembrane domains exist and both the N and C termini are likely to be in the cytosolic compartment.Abnormal gene product. Immunoblot analysis suggests that most of the mutations result in very low to undetectable enzymatic activity and no detectable protein product [Brown et al 2001, Gobin et al 2002]. The p.Pro479Leu mutant allele has high residual activity and a detectable protein of normal size and amount on western blot analysis. It is believed that the product of the p.Pro479Leu allele affects malonyl-CoA interaction with CPT1A.