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Carnitine Palmitoyltransferase 1A Deficiency

Synonyms: CPT1A Deficiency, Hepatic Carnitine Palmitoyltransferase 1 Deficiency

, PhD, FRCPath, DABCC and , PhD, FACMG.

Author Information

Initial Posting: ; Last Update: March 17, 2016.

Summary

Clinical characteristics.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation. Clinical manifestations usually occur in an individual with a concurrent febrile or gastrointestinal illness when energy demands are increased; onset of symptoms is usually rapid. The recognized phenotypes are: acute fatty liver of pregnancy, in which the fetus has biallelic pathogenic variants in CPT1A that causes CPT1A deficiency; and hepatic encephalopathy, in which individuals (typically children) present with hypoketotic hypoglycemia and sudden onset of liver failure. Individuals with hepatic encephalopathy typically present with hypoglycemia, absent or low levels of ketones, and elevated serum concentrations of liver transaminases, ammonia, and total carnitine. Between episodes of hepatic encephalopathy, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage.

Diagnosis.

The diagnosis of CPT1A is established in a proband by the detection of biallelic pathogenic variants in CPT1A on molecular genetic testing or diminished carnitine palmitoyltransferase 1 (CPT 1) enzyme activity on cultured skin fibroblasts when molecular genetic testing is not definitive. Residual enzyme activity is 1%-5% in most individuals with CPT1A deficiency.

Management.

Treatment of manifestations: Prompt treatment of hypoglycemia with intravenous fluid containing 10% dextrose; the dextrose infusion should be maintained past the time that the blood glucose concentration has normalized in order to replete hepatic glycogen stores. Affected individuals, parents/guardians, and health care providers need to have readily available emergency treatment protocols for catastrophic metabolic crises.

Prevention of primary manifestations: To prevent hypoglycemia, infants should eat frequently during the day and have cornstarch continuously at night; fasting should not last more than 12 hours during illness, surgery, or medical procedures; adults need a high-carbohydrate, low-fat diet to provide a constant supply of carbohydrate energy and medium-chain triglycerides to provide approximately one third of total calories (C6-C10 fatty acids do not require the carnitine shuttle for entry into the mitochondrion).

Prevention of secondary complications: Prevention of hypoglycemia reduces the risk for related neurologic damage.

Surveillance: Individuals with CPT1A deficiency should have testing of liver enzymes (AST, ALT, alkaline phosphatase) and liver function (including PT and PTT) at clinic appointments, even when asymptomatic, and during periods of reduced caloric intake and febrile illness.

Agents/circumstances to avoid: Prolonged fasting; potentially hepatotoxic agents such as valproate and salicylate.

Evaluation of relatives at risk: Regardless of age, each sib of a proband should be evaluated for CPT1A deficiency by either molecular genetic testing (if both pathogenic variants have been identified in the proband) or by enzyme analysis in cultured skin fibroblasts.

Pregnancy management: Heterozygous pregnant women should be monitored for acute fatty liver of pregnancy.

Genetic counseling.

CPT1A deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic, although heterozygous pregnant women may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency. At conception, each sib of an affected individual has 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. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible by biochemical testing if the enzyme defect has been confirmed in an affected family member or by molecular genetic testing if both pathogenic variants have been identified in an affected family member.

Diagnosis

Suggestive Findings

Carnitine palmitoyltransferase IA (CPT IA) deficiency should be suspected in an individual with the following prenatal history, newborn screening results, postnatal clinical features, and supportive laboratory findings:

Prenatal history

  • Maternal acute fatty liver of pregnancy. CPT1A deficiency in a fetus can lead to the following maternal findings during pregnancy:
    • Hypoglycemia
    • Abnormal liver enzymes
    • Hyperammonemia
    • Abnormal hepatic synthetic function resulting in bleeding diathesis

Newborn screening results

Postnatal clinical findings

  • Hepatic encephalopathy (similar to that seen in Reye syndrome) precipitated by fasting or fever (see Supportive laboratory findings)
  • Rapid onset of symptoms in association with a relatively common infectious disease, such as a febrile or gastrointestinal illness

Supportive laboratory findings

  • Hypoketotic hypoglycemia, defined as low blood glucose concentration (<40 mg/dL) in the absence of ketone bodies in the urine
  • Elevated liver enzymes. AST and ALT that are two- to tenfold the upper limit of normal
  • Hyperammonemia. Plasma ammonia concentrations usually 100-500 µmol/L (normal: <70 µmol/L)
  • Elevated total serum carnitine in the range of 70-170 µmol/L (normal total serum carnitine: 25-69 µmol/L). The elevation of total carnitine and hypoketotic hypoglycemia should increase suspicion specifically for CPT1A deficiency.
  • Elevated ratio of C0/C16+C18 acylcarnitines. CPT1A deficiency is charaterized by marked reduction in the synthesis of all acylcarnitine species and increased levels of free carnitine (C0) (see ACMG ACT Sheet).
  • Urine organic acids that demonstrate elevated dodecanedioic acid during acute crisis and for several days following [Korman et al 2005]. The authors have also observed C12 dicarboxylic acid elevation during acute crisis in individuals subsequently diagnosed with CPT1A deficiency [Bennett, personal unpublished observation].

Establishing the Diagnosis

The diagnosis of CPT1A is established in a proband by the detection of biallelic pathogenic variants in CPT1A on molecular genetic testing (see Table 1) or diminished carnitine palmitoyltransferase 1 (CPT 1) enzyme activity measured on cultured skin fibroblasts when molecular genetic testing is not definitive.

Molecular genetic testing approaches can include single-gene testing and use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of CPT1A is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Note: Targeted analysis may be considered first for the following pathogenic variants:
  • A multi-gene panel that includes CPT1A and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Commercially offered multi-gene panels may include genes not associated with the condition discussed in this GeneReview; clinicians need to determine which multi-gene panel provides the best opportunity to identify the associated gene(s) at the most reasonable cost.

Table 1.

Molecular Genetic Testing Used in Carnitine Palmitoyltransferase 1A Deficiency

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
CPT1ASequence analysis 3>90% 4, 5
Gene-targeted deletion/duplication analysis 6Rare 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Sequence analysis also detects the common p.Gly710Glu pathogenic variant in the Hutterite population [Prasad et al 2001] and the p.Pro479Leu pathogenic variant in the Inuit population [Brown et al 2001].

5.

In individuals with enzymatic confirmation of CPT1A deficiency

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Exon and multiexon deletions have been rarely reported [Gobin et al 2002].

Carnitine palmitoyltransferase 1 (CPT 1) enzyme activity on cultured skin fibroblasts. Residual enzyme activity is 1%-5% in most individuals with CPT1A deficiency.

Clinical Characteristics

Clinical Description

Carnitine 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.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation.

Fetal CPT1A deficiency has been associated with acute fatty liver of pregnancy [Innes et al 2000]. A heterozygous female carrying an affected 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, prompting further investigation of the newborn for a fatty acid oxidation defect in this situation.

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. For example, 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, Stanley et al 2014].

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 with other long-chain fatty acid oxidation defects, cardiac or skeletal muscle involvement is not common [Bonnefont et al 2004, Stanley et al 2014].

Genotype-Phenotype Correlations

The p.Pro479Leu pathogenic variant observed in the Inuit, which has high residual enzymatic activity (15%-20%), does not appear to cause acute hepatic failure as do the other pathogenic variants associated with the more severe phenotype [Brown et al 2001]. However, 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]. In a study using whole-genome high-coverage sequence data of Arctic populations, this CPT1A variant was identified as deleterious and associated with increased infant mortality in circum-Arctic populations [Clemente et al 2014].

Nomenclature

The disorder has been previously described as non-ketotic hypoglycemia, hepatic CPT deficiency, hepatic CPT1, and L-CPT1 deficiency.

Prevalence

CPT1A deficiency caused by variants other than p.Pro479Leu appears to be very rare in the general population, with fewer than 60 affected individuals reported.

Improved detection of CPT1A deficiency in the newborn period may increase the detection rate for the disorder [Sim et al 2001]. The number of non-Inuit diagnoses in the Region 4 Stork (R4S) newborn screening collaborative for 2015 was five cases, giving an estimated prevalence of 1:500,000 to 1:1,000,000 newborns [Piero Rinaldo, personal communication].

The frequency of homozygosity for the p.Pro479Leu pathogenic variant is very high in the native Alaskan population (1.3:1,000 live births) when ascertained by expanded newborn screening (available through Alaska Division of Public Health [pdf]). Given the high residual enzyme activity associated with this allele, p.Pro479Leu homozygosity is generally regarded as non-pathogenic but may still be associated with increased infant mortality [Clemente et al 2014] (see Genotype-Phenotype Correlations).

The carrier rate for the p.Gly710Glu pathogenic variant in the Hutterite population may be as high as 1:16 [Prasad et al 2001].

Differential Diagnosis

The 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:

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:

Management

Evaluations Following Initial Diagnosis

To 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 damage
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Guidelines 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 Manifestations

A 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 affected individuals are well. If the physician chooses to recommend a low-fat diet when the affected individual 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 Complications

Prevention of hypoglycemia reduces the risk of related neurologic damage.

Surveillance

At 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, alkaline phosphatase (ALP), and functional liver tests (including the blood-clotting tests PT and PTT).

Agents/Circumstances to Avoid

Prolonged 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 Risk

Because presentation in later childhood is possible, it is appropriate to evaluate each sib of a proband, regardless of age, in order to identify as early as possible those who would benefit from initiation of preventive measures.

Evaluations can include:

  • Molecular genetic testing if the CPT1A pathogenic variants in the family are known.
  • Enzyme analysis in cultured skin fibroblasts if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although data are limited, it is prudent to counsel unaffected 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 females who are heterozygous for a CPT1A pathogenic variant should be monitored for acute fatty liver of pregnancy. In any pregnancies that follow identification of a child with CPT1A deficiency, 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 Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one CPT1A pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic. Pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.

Sibs of a proband

  • At conception, each sib of an affected individual has 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.
  • Heterozygotes (carriers) are asymptomatic. Pregnant females who are heterozygous for a CPT1A pathogenic variant may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.

Offspring of a proband

  • The offspring of an individual with CPT1A deficiency are obligate heterozygotes (carriers) for a pathogenic variant in CPT1A.
  • In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be affected or a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic and/or biochemical testing of the proband's reproductive partner.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CPT1A pathogenic variant.

Heterozygote (Carrier) Detection

Carrier testing for at-risk relatives requires prior identification of the CPT1A pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the CPT1A pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for CPT1A deficiency are possible options.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Save Babies Through Screening Foundation, Inc.
    P. O. Box 42197
    Cincinnati OH 45242
    Phone: 888-454-3383
    Email: email@savebabies.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    United Kingdom
    Phone: 0800-652-3181
    Email: info.svcs@climb.org.uk
  • FOD Family Support Group (Fatty Oxidation Disorder)
    PO Box 54
    Okemos MI 48805-0054
    Phone: 517-381-1940
    Fax: 866-290-5206 (toll-free)
    Email: deb@fodsupport.org; fodgroup@gmail.com

Molecular Genetics

Information 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 Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)

255120CARNITINE PALMITOYLTRANSFERASE I DEFICIENCY
600528CARNITINE PALMITOYLTRANSFERASE I, LIVER; CPT1A

Molecular Genetic Pathogenesis

The 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 biallelic pathogenic variants of CPT1A, fatty acids cannot enter the mitochondria for energy production (see Figure 1); the result is a clinical and biochemical phenotype of fasting intolerance.

Figure 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 by carnitine palmitoyltransferase 2.

Figure 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 by (more...)

Of the three CPT I family members, CPT1A is expressed in liver, kidney, leukocytes, and skin fibroblasts; CPT1B is expressed in muscle; and CPT1C is brain specific. Pathogenic variants in CPT1A and CPT1C have been associated with genetic disease. A dominantly inherited pathogenic variant in CPT1C has recently been associated with and is likely to be causative of spastic paraplegia 73 (OMIM), a condition with no similarity to CPT1A deficiency [Rinaldi et al 2015].

Gene structure. CPT1A spans more than 60 kb of genomic DNA, of which 18 exons (2-19) are transcribed. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Outside the Hutterite and Inuit populations, all pathogenic variants characterized to date have been within single families (see Table 2 [pdf]) and many span the catalytic region. These include 15 pathogenic missense variants (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 unique pathogenic variant.

Table 3.

Selected CPT1A Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.96T>Gp.Tyr32TerNM_001876​.3
NP_001867​.2
c.298C>Tp.Gln100Ter
c.367C>Tp.Arg123Cys
c.478C>Tp.Arg160Ter
c.912C>Gp.Cys304Trp
c.941C>Tp.Thr314Ile
c.946C>Gp.Arg316Gly
c.1027T>Gp.Phe343Val
c.1069C>Tp.Arg357Trp
c.1079A>Gp.Glu360Gly
c.1241C>Tp.Ala414Val
c.1361A>Gp.Asp454Gly
c.1395G>Tp.Gly465Trp
c.1425G>Ap.Trp475Ter
c.1436C>Tp.Pro479Leu
c.1451T>Cp.Leu484Pro
c.1493A>Gp.Tyr498Cys
c.1494T>Ap.Tyr498Ter
c.1600delCp.Leu534Ter
(Leu534fsTer)
c.1737C>Ap.Tyr579Ter
c.2126G>Ap.Gly709Glu
c.2129G>Ap.Gly710Glu

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal 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 pathogenic variants result in very low to undetectable enzymatic activity and no detectable protein product [Brown et al 2001, Gobin et al 2002].

The p.Pro479Leu variant results in high residual enzyme 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.

References

Literature Cited

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  2. Brown NF, Mullur RS, Subramanian I, Esser V, Bennett MJ, Saudubray JM, Feigenbaum AS, Kobari JA, Macleod PM, McGarry JD, Cohen JC. Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme. J Lipid Res. 2001;42:1134–42. [PubMed: 11441142]
  3. Clemente FJ, Cardona A, Inchley CE, Peter BM, Jacobs G, Pagani L, Lawson DJ, Antao T, Vicente M, Mitt M, DeGeorgio M, Faltyskova Z, Xue Y, Ayub Q, Szpak M, Magi R, Eriksson A, Manica A, Raghavan M, Rasmussen M, Rasmussen S, Willersley E, Vidal-Puig A, Tyler-Smith C, Villems R, Nielson R, Metspalu M, Malyarchuk B, Derenko M, Kivisild T. A selective sweep of a deleterious mutation in CPT1A in Arctic populations. Amer J Hum Genet. 2014;95:584–9. [PMC free article: PMC4225582] [PubMed: 25449608]
  4. Collins SA, Sinclair G, McIntosh S, Bamforth F, Thompson R, Sobol I, Osborne G, Corriveau A, Santos M, Hanley B, Greenberg CR, Vallance H, Arbour L. Carnitine palmitoyltransferase 1A(CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nanavut. Mol Genet Metab. 2010;101:200–4. [PubMed: 20696606]
  5. Fingerhut R, Roschinger W, Muntau AC, Dame T, Kreischer J, Arnecke R, Superti-Furga A, Troxler H, Liebl B, Olgemoller B, Roscher AA. Hepatic carnitine palmitoyltransferase I deficiency: acylcarnitine profiles in blood spots are highly specific. Clin Chem. 2001;47:1763–8. [PubMed: 11568084]
  6. Gessner BD, Gillingham MB., Birch S, Wood T, Koeller DM. Evidence for an association between infant mortality and a carnitine palmitoyltransferase 1A genetic variant. Pediatrics. 2010;126:945–51. [PubMed: 20937660]
  7. Gillingham MB, Hirschfeld M, Lowe S, Matern D, Shoemaker J, Lambert WE, Koeller DM. Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant. Mol Genet Metab. 2011;104:261–4. [PMC free article: PMC3197793] [PubMed: 21763168]
  8. Gobin S, Bonnefont JP, Prip-Buus C, Mugnier C, Ferrec M, Demaugre F, Saudubray JM, Rostane H, Djouadi F, Wilcox W, Cederbaum S, Haas R, Nyhan WL, Green A, Gray G, Girard J, Thuillier L. Organization of the human liver carnitine palmitoyltransferase 1 gene (CPT1A) and identification of novel mutations in hypoketotic hypoglycaemia. Hum Genet. 2002;111:179–89. [PubMed: 12189492]
  9. Innes AM, Seargeant LE, Balachandra K, Roe CR, Wanders RJ, Ruiter JP, Casiro O, Grewar DA, Greenberg CR. Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy. Pediatr Res. 2000;47:43–5. [PubMed: 10625081]
  10. Korman SH, Waterham HR, Gutman A, Jakobs C, Wanders RJ. Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency. Mol Genet Metab. 2005;86:337–43. [PubMed: 16146704]
  11. McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997;244:1–14. [PubMed: 9063439]
  12. Park JY, Narayan SB, Bennett MJ. Molecular assay for detection of the common carnitine palmitoyltransferase 1A 1436(C>T) mutation. Clin Chem Lab Med. 2006;44:1090–1. [PubMed: 16958601]
  13. Prasad C, Johnson JP, Bonnefont JP, Dilling LA, Innes AM, Haworth JC, Beischel L, Thuillier L, Prip-Buus C, Singal R, Thompson JR, Prasad AN, Buist N, Greenberg CR. Hepatic carnitine palmitoyl transferase 1 (CPT1 A) deficiency in North American Hutterites (Canadian and American): evidence for a founder effect and results of a pilot study on a DNA-based newborn screening program. Mol Genet Metab. 2001;73:55–63. [PubMed: 11350183]
  14. Rajakumar C, Ban MR, Cao H, Young TK, Bjerregaard P, Hegele RA. Carnitine palmitoyltransferase 1A polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-1. J Lipid Res. 2009;50:1223–8. [PMC free article: PMC2681405] [PubMed: 19181627]
  15. Rinaldi C, Schmidt T, Situ AJ, Johnson JO, Lee PR, Chen KL, Bott LC, Fadó R, Harmison GH, Parodi S, Grunseich C, Renvoisé B, Biesecker LG, De Michele G, Santorelli FM, Filla A, Stevanin G, Dürr A, Brice A, Casals N, Traynor BJ, Blackstone C, Ulmer TS, Fischbeck KH. Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia. JAMA Neurol. 2015;72:561–70. [PubMed: 25751282]
  16. Sim KG, Wiley V, Carpenter K, Wilcken B. Carnitine palmitoyltransferase I deficiency in neonate identified by dried blood spot free carnitine and acylcarnitine profile. J Inherit Metab Dis. 2001;24:51–9. [PubMed: 11286383]
  17. Stanley CA, Palmieri F, Bennett MJ. Disorders of the mitochondrial carnitine shuttle. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 101a. New York, NY: McGraw-Hill; 2014. Available online.
  18. Stoler JM, Sabry MA, Hanley C, Hoppel CL, Shih VE. Successful long-term treatment of hepatic carnitine palmitoyltransferase I deficiency and a novel mutation. J Inherit Metab Dis. 2004;27:679–84. [PubMed: 15669684]

Suggested Reading

  1. Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006;142C:77–85. [PMC free article: PMC2557099] [PubMed: 16602102]
  2. Rinaldo P, Matern D, Bennett MJ. Fatty acid oxidation disorders. Annu Rev Physiol. 2002;64:477–502. [PubMed: 11826276]
  3. Strauss AW, Andresen BS, Bennett MJ. Mitochondrial fatty acid oxidation defects. In: Sarafoglou K, Hoffmann GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. New York, NY: McGraw-Hill; 2009.

Chapter Notes

Author History

Michael J Bennett, PhD, FRCPath, DABCC (2005-present)
Srinivas B Narayan, PhD, DABCC; Children’s Hospital of Philadelphia (2005-2013)
Avni B Santani, PhD, FACMG (2005-present)

Revision History

  • 17 March 2016 (ma) Comprehensive update posted live
  • 7 September 2010 (me) Comprehensive update posted live
  • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically
  • 24 September 2007 (me) Comprehensive update posted to live Web site
  • 27 July 2005 (ca) Review posted to live Web site
  • 14 January 2005 (mb) Original submission
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