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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease 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 the CPT1A gene 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 accounts for 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 associated with CPT1A deficiency. For individuals with an enzymatically confirmed diagnosis of CPT1A deficiency, the mutation detection rate using sequence analysis is higher than 90%; molecular genetic testing of the CPT1A gene is clinically available.
Management. Treatment of manifestations: prompt treatment of hypoglycemia with intravenous 10% dextrose. Prevention of primary manifestations: To prevent hypoglycemia, adults need a high-carbohydate, 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 of related neurologic damage. Surveillance: Pregnant female carriers should be monitored for acute fatty liver of pregnancy. 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. Testing 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 mutations have been identified in the proband. 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. 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. Pregnant female carriers may be at risk of developing acute fatty liver of pregnancy. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible by biochemical testing or by molecular genetic testing if both disease-causing alleles of an affected family member have been identified.
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 depleted by fasting. 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.
Acute fatty liver of pregnancy. Fetal homozygosity for CPT1A deficiency has been associated with acute fatty liver of pregnancy.
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 ten times 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.
Other
Measurement of urine organic acids is more sensitive in the diagnosis of CPT1A deficiency than acylcarnitine measurement and can aid in the differential diagnosis of other fatty acid oxidation and organic acid defects.
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 [MJ 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 is clinically available.
The fatty acid pathway study using tandem mass spectrometry and measurement of accumulating acylcarnitine species may be normal.
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 diathisis.
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%.
Biochemical testing. For laboratories offering biochemical testing, see
.
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].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. CPT1A is the only gene associated with CPT1A deficiency.
Clinical testing
Sequence analysis. For individuals with an enzymatically confirmed diagnosis of CPT1A deficiency, the mutation detection rate is higher than 90% [Bennett et al 2004].
Targeted mutation analysis. Targeted mutation analysis for the p.Pro479Leu mutation is useful in populations with a very high frequency for the mutation, including infants who test positive for CPT1A deficiency in the state of Alaska newborn screening program and in Canadian First Nations. Most affected individuals in these populations are homozygous for p.Pro479Leu [Park et al 2006].
Deletion/duplication analysis. 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].
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|
| Sequence analysis | CPT1A sequence variants 1 | >90% 2 | Clinical
|
| Targeted mutation analysis | CPT1A p.Pro479Leu | ~100% in high-risk infants 3 | |
| Deletion/duplication analysis 4 | Partial- or whole-gene deletions/duplications | Unknown |
1. 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].
2. In individuals with enzymatic confirmation of CPT1A deficiency
3. Infants in the state of Alaska who test positive for CPT1A deficiency by expanded newborn screening
4. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation dependent probe amplification (MLPA), and array CGH may be used.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To confirm the diagnosis 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].
Confirm the enzyme defect in cultured skin fibroblasts.
Perform molecular genetic testing to confirm the enzymatic diagnosis.
Test Canadian First Nation and Inuit populations for p.Pro479Leu mutation [Park et al 2006].
To confirm the diagnosis in a clinically stable proband
Obtain plasma total and free carnitine and acylcarnitine profiles, which should be informative even if the markers of metabolic decompensation are normal.
Confirm the enzyme defect in cultured skin fibroblasts.
Perform the following molecular genetic testing to confirm the enzymatic diagnosis:
Targeted mutation analysis of p.Pro479Leu in individuals with an Inuit or Canadian First Nations background
Sequence analysis on all other enzymatically confirmed cases
Carrier 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 for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
No other phenotypes are associated with mutations in CPT1A.
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 mutation has been described [Brown et al 2001]. The clinical findings were recurrent episodes of activity-associated muscle pain with elevated serum CK concentration.
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 for developing this obstetric complication.
The only mutation for which a clear genotype-phenotype correlation exists is the p.Pro479Leu Inuit mutation, which has high residual enzymatic activity and an adult-onset myopathic presentation.
In all other individuals, the residual enzyme activity is between 0%-5% and mutations have been identified throughout.
The disorder has been previously described as nonketotic hypoglycemia and hepatic CPT deficiency.
CPT1A deficiency appears to be very rare in the general population, with fewer than 30 cases reported and fewer than 50 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]).
The carrier rate for the p.Pro479Leu sequence variant in the Inuit population is not yet known; preliminary population studies indicate that it may be a common sequence variant [Sinclair et al 2005]. It has been hypothesized that this sequence variant may reflect a positive selection to the ancient Inuit lifestyle [Gillingham et al 2006].
The carrier rate for the p.Gly710Glu mutation in the Hutterite population may be as high as one in 16 [Prasad et al 2001].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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:
3-hydroxy-3-methylglutaryl (HMG)-CoA synthase deficiency
HMG-CoA lyase deficiency
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 acylcarnitine translocase (CACT) deficiency
Very-long-chain acyl-CoA dehydrogenase deficiency
Mitochondrial trifunctional protein deficiency
Urea cycle disorders (see Urea Cycle Disorders Overview)
Organic acidurias such as methylmalonic and propionic acidemia (see Organic Acidemias Overview)
Disorders of oxidative phosphorylation
Disorders of gluconeogenesis (e.g., glycogen storage disease type I)
Affected individuals who have profound and/or prolonged exposure to hypoglycemia should undergo a complete neurologic evaluation to detect secondary neurologic damage.
When individuals present with acute hypoglycemia, sufficient amounts of intravenous 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 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.
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.
Provision of approximately one-third of total calories as medium-chain triglycerides is recommended. 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 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 hypoglycemia reduces the risk of related neurologic damage.
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.
Prolonged fasting should be avoided, especially during a febrile illness 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.
Because presentation in later childhood is possible, each sib of a proband, regardless of age, should be evaluated for CPT1A deficiency by a combination of enzyme testing and molecular genetic testing if both mutations have been identified in the proband. If enzyme activity is normal, or if the two known disease-causing mutations in the family are not identified, the healthy sib is unaffected.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
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.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is inherited in an autosomal recessive manner.
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.
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.
Offspring of a proband
The offspring of an individual with CPT1A deficiency are obligate heterozygotes (carriers) for a disease-causing mutation 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 testing for at-risk family members is available on a clinical basis using either CPT1A enzymatic testing or molecular genetic testing once the disease-causing mutations have been identified in the proband.
See Testing of Relatives at Risk for information on testing 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 or at risk of being carriers.
DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
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 15-18 weeks' gestation or cultured chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation [Bennett & Narayan, unpublished observations].
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of fetal cells obtained by amniocentesis usually performed at approximately 15-18 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.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| CPT1A | 11q13 | Carnitine palmitoyltransferase I, liver |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 255120 | CARNITINE PALMITOYLTRANSFERASE I DEFICIENCY |
| 600528 | CARNITINE PALMITOYLTRANSFERASE I, LIVER; CPT1A |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| CPT1A | 1374 (MIM No. 600528) | CPT1A |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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.
CPT I is highly allosteric and is regulated by the cellular levels of malonyl-CoA. Malonyl-CoA levels rise postprandially and fall with fasting. High malonyl-CoA levels inhibit CPT I activity and impair fatty acid entry into the mitochondrion. Low malonyl-CoA levels, which result from fasting, reverse this inhibition. 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.
Three distinct genetic forms of CPT I are known:
CPT1A, expressed in liver, kidney, leukocytes, and skin fibroblasts [Britton et al 1995]
CPT1B, expressed in muscle [Yamazaki et al 1996]
CPT1C, which is brain specific [Price et al 2002]
Genetic defects of CPT1A alone have been described to date.
Normal allelic variants. The CPT1A gene spans more than 60 kb of genomic DNA, of which 18 exons (2-19) are transcribed. One putative polymorphism has been described; c.823G>A, which results in p.Ala275Thr in exon 8, is heterozygously present with a frequency of 0.138. The functional significance (if any) of this change, which is within the large catalytic region, is not 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: p.Pro123Cys, p.Cys304Trp, p.Thr314Ile, p. Arg316Gly, p.Phe343Val, p.Arg357Trp, p.Glu360Gly, p.Ala414Val, p.Asp454Gly, p.Gly465Trp, p.Pro479Leu, p.Leu484Pro, p.Tyr498Cys, p.Gly709Glu, p.Glu710Glu; seven nonsense mutations: p.Tyr32X, p.Gln100X, p.Arg160X, p.Trp475X, p.Tyr498X, p.Leu534fsX, p.Tyr579X; and insertion and deletion mutations [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.
Normal gene product. The CPT1A gene 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 mutation results in high residual activity and a detectable protein of normal size and amount on western blot analysis. It is believed that p.Pro479Leu affects malonyl-CoA interaction with CPT1A.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Carnitine palmitoyltransferase I deficiency
Children Living with Inherited Metabolic Diseases (CLIMB)
Climb Building
176 Nantwich Road
Crewe CW2 6BG
United Kingdom
Phone: 0800 652 3181 (toll free)
Email: info.svcs@climb.org.uk
www.climb.org.uk
FOD (Fatty Oxidation Disorder) Family Support Group
2041 Tomahawk
Okemos MI 48864
Phone: 517-381-1940
Email: deb@fodsupport.org
www.fodsupport.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
No specific guidelines regarding genetic testing for this disorder have been developed.
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
