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Carnitine Palmitoyltransferase 1A Deficiency

Synonyms: CPT1A Deficiency, Hepatic CPT1, Hepatic Carnitine Palmitoyltransferase 1 Deficiency, L-CPT 1 Deficiency

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

Author Information
, PhD, FRCPath, DABCC
Professor of Pathology and Laboratory Medicine, University of Pennsylvania
Evelyn Willing Bromley Endowed Chair, Clinical Laboratories and Pathology
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
, PhD, FACMG
Department of Pathology and Laboratory Medicine
Molecular Diagnostics Laboratory
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania

Initial Posting: ; Last Update: March 7, 2013.

Summary

Clinical characteristics.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation. Clinical symptoms usually occur in an individual with a concurrent febrile or gastrointestinal illness when energy demands are increased; onset of symptoms is usually rapid. The three recognized phenotypes are hepatic encephalopathy, in which individuals (typically children) present with hypoketotic hypoglycemia and sudden onset of liver failure; adult-onset myopathy, seen in one individual of Inuit origin; and acute fatty liver of pregnancy, in which the fetus is homozygous for a pathogenic variant in CPT1A that causes CPT1A deficiency. Between episodes of hepatic encephalopathy, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage.

Diagnosis/testing.

Encephalopathy with hypoglycemia, absent or low levels of ketones, and elevated serum concentrations of liver transaminases, ammonia, and total carnitine are typical findings. In most affected individuals CPT I enzyme activity in cultured skin fibroblasts is 1%-5% of control activity. Screening for CPT1A deficiency by detecting an elevated ratio of free-to-total carnitine in serum or plasma on a blood spot is available in some state newborn screening programs. CPT1A is the only gene in which pathogenic variants are known to cause 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.

Prevention of primary manifestations: To prevent hypoglycemia, 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); 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.

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, ALP) 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 a combination of enzyme testing and molecular genetic testing if both pathogenic variants have been identified in the proband.

Pregnancy management: Pregnant female carriers should be monitored for acute fatty liver of pregnancy.

Other: Affected individuals, parents/guardians, and health care providers need to have readily available emergency treatment protocols for catastrophic metabolic crises.

Genetic counseling.

CPT1A deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic. Pregnant female carriers 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 disease-causing alleles have been identified in an affected family member.

Diagnosis

Clinical Diagnosis

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.

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 pathogenic variant, 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.

Testing

Hypoglycemia, 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 ACMG-ACT Sheet).

Other

  • Measurement 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 Testing

Gene. CPT1A is the only gene in which pathogenic variants are known to cause CPT1A deficiency.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Carnitine Palmitoyltransferase 1A Deficiency

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
CPT1ASequence analysis 4 / variant scanning 5Sequence variants>90% 6, 7
Targeted analysis for pathogenic variantsp.Pro479Leu
p.Gly710Glu 5, 8
~100% in high-risk infants 9
Deletion/duplication analysis 10Partial- or whole-gene deletionsUnknown 11, rare
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

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.

5.

Sequence analysis and scanning of the entire gene for pathogenic variants can have similar detection frequencies, although variant scanning detection rates may vary considerable between laboratories as that method is highly dependent on details of methodology employed.

6.

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

7.

In individuals with enzymatic confirmation of CPT1A deficiency

8.

Pathogenic variants tested may vary among laboratories.

9.

Infants in the state of Alaska who test positive for CPT1A deficiency by expanded newborn screening. Targeted analysis for the p.Pro479Leu pathogenic variant 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 pathogenic variant is common in the Hutterite population.

10.

Testing that identifies exon or whole-gene 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.

11.

Testing Strategy

To confirm/establish the diagnosis in a proband

In 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 variant [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 analysis for the p.Pro479Leu pathogenic variant in those of Inuit or Canadian First Nations ancestry
    • Sequence analysis on all others with an enzymatically confirmed diagnosis
    • Confirmation of the enzyme defect in cultured skin fibroblasts or white blood cells

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

Clinical Characteristics

Clinical Description

Carnitine 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 variant 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 Correlations

The 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 pathogenic variants have been identified throughout the gene.

Nomenclature

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

Prevalence

CPT1A deficiency, other than the p.Pro479Leu variant appears to be very rare in the general population, with fewer than 40 cases reported and fewer than 60 known cases [Bennett & Narayan, unpublished observations].

Improved detection of CPT1A deficiency in the newborn period may increase the detection rate for the disorder [Sim et al 2001].

The frequency of homozygosity for the p.Pro479Leu sequence variant is very high in the 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, homozygosity of p.Pro479Leu is usually non-pathogenic except perhaps in one patient with adult-onset myopathy.

The carrier rate for the p.Gly710Glu variant in the Hutterite population may be as high as one in 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
  • Medical genetics consultation

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 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 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, 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, each sib of a proband, regardless of age, should be evaluated for CPT1A deficiency by molecular genetic testing if both pathogenic variants have been identified in the proband. If the two known pathogenic variants in the family are not identified, the healthy sib is unaffected. If one of the known pathogenic variants is identified in the sib, he or she is heterozygous for CPT1A deficiency

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 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 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 child are obligate heterozygotes and therefore carry one mutant allele.
  • 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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic. Pregnant female carriers 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 of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible by molecular genetic testing if the pathogenic variants have been identified in an affected family member.

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

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing based on DNA analysis can be performed.

Biochemical testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of enzyme activity of cultured amniotic fluid cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or cultured chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation [Bennett & Narayan, unpublished observations].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like CPT1A deficiency) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

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 mutation 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.

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 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.

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.

Benign allelic variants. One putative benign 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].

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

Table 3.

Selected CPT1A Allelic Variants

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
Benignc.823G>Ap.Ala275ThrNM_001876​.3
NP_001867​.2
Pathogenicc.96T>Gp.Tyr32Ter
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 pathogenic 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.

References

Literature Cited

  1. Bennett MJ, Boriack RL, Narayan S, Rutledge SL, Raff ML. Novel mutations in CPT 1A define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency. Mol Genet Metab. 2004;82:59–63. [PubMed: 15110323]
  2. Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med. 2004;25:495–520. [PubMed: 15363638]
  3. 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]
  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]
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  6. Gessner BD, Gillingham MB., Birch S, Wood T, Koeller DM. Evidence for an associayion 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 DM2011Impaired fasting tolerance among alaska native children with a common carnitine palmitoyltransferase 1A sequence variant. Mol genet Metab 104261–4. [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. Greenberg CR, Dilling LA, Thompson GR, Seargeant LE, Haworth JC, Philips S, Chan A, Vallance HD, Waters PJ, Sinclair G, Lillquist Y.wanders RJA, Olpin SE2009The paradox of the carnitinr palmitoyltransferase type 1a P479L variantin Canadian Aboriginal populations. Mol Genet Metab 96201–7. [PubMed: 19217814]
  10. 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]
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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. Roe CR, Ding J. Mitochondrial fatty acid oxidation disorders. 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). New York, NY: McGraw-Hill. Chap 101. 2014. Available online. Accessed 10-21-15.
  4. 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

  • 7 March 2013 (me) 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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