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 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. 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.

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 [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 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%.

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]. See National Newborn Screening Status Report (pdf).

Molecular Genetic Testing

Gene. CPT1A is the only gene associated with CPT1A deficiency.

Clinical testing

• Sequence analysis/mutation scanning. For individuals with an enzymatically confirmed diagnosis of CPT1A deficiency, the mutation detection rate is higher than 90% [Bennett et al 2004; Author, personal information].

• Targeted mutation analysis. Targeted mutation analysis for the p.Pro479Leu mutation is useful in populations with a very high frequency of this allele, including infants who test positive for CPT1A deficiency in the state of Alaska newborn screening program and in the Canadian First Nations population in Nunavut [Collins et al 2010]. Most affected individuals in these populations are homozygous for p.Pro479Leu [Park et al 2006]. The p.Gly710Glu mutation is common in the Hutterite population.

• 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]. Deletions in the CPT1A gene have been described as a rare cause of CPT1A deficiency; the frequency of this type of mutation is unknown.

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

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Gene Symbol		Test Method		Mutations Detected		Mutation Detection Frequency by Test Method 1		Test Availability
CPT1A		Sequence analysis/mutation scanning 2		Sequence variants 3		>90% 4, 5		Clinical
		Targeted mutation analysis		p.Pro479Leu p.Gly710Glu 2, 6		~100% in high-risk infants 7
		Deletion/duplication analysis 8		Partial- or whole-gene deletions/duplications		Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. 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.

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

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

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations.

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

5. In individuals with enzymatic confirmation of CPT1A deficiency

6. Mutations tested may vary among laboratories.

7. Infants in the state of Alaska who test positive for CPT1A deficiency by expanded newborn screening

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

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].

• 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].

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 and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in CPT1A.

Natural History

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. There is some doubt whether the myopathy in this individual was related to CPT1A sequence variation [Greenberg 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 for developing this obstetric complication.

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.

In all other individuals, the residual enzyme activity is between 0% and 5% and mutations have been identified throughout the gene.

Nomenclature

The disorder has been previously described as nonketotic hypoglycemia and hepatic CPT deficiency.

Prevalence

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 in Alaska indicate that it may be a common sequence variant [Sinclair et al 2005]. Recent prevalence studies in Canadian Aboriginal populations indicate that the allele frequencies are 0.02, 0.08, and 0.77 in Yukon, Northwest Territories, and Nanavut, respectively [Collins et al 2010]. It has been hypothesized that this sequence variant may reflect a positive selection to the ancient Inuit lifestyle [Gillingham et al 2006, Greenberg et al 2009].

The carrier rate for the p.Gly710Glu mutation in the Hutterite population may be as high as one in 16 [Prasad et al 2001].

Evaluations Following Initial Diagnosis

Affected individuals who have profound and/or prolonged exposure to hypoglycemia should undergo a complete neurologic evaluation to detect secondary neurologic damage.

Treatment of Manifestations

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.

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.

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 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.

Testing 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 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.

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.

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.

Other

Genetics clinics, staffed by genetics professionals, provide 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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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.

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 Detection

Carrier testing for at-risk family members is 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.

Related Genetic Counseling Issues

See Management, 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 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 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

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].

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.

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) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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.

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. CPT1A spans more than 60 kb of genomic DNA, of which 18 exons (2-19) are transcribed. One putative normal allelic variant has been described: c.823G>A, which results in p.Ala275Thr in exon 8, has a heterozygote frequency of 0.138. The functional significance (if any) of this change, which is within the large catalytic region, 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 (listed in Table 3) as well as insertions and deletions [Gobin et al 2002, Bonnefont et al 2004, Stoler et al 2004, Korman et al 2005]. Approximately 50% of individuals characterized to date are homozygous for a private mutation.

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 mutations result in very low to undetectable enzymatic activity and no detectable protein product [Brown et al 2001, Gobin et al 2002]. The p.Pro479Leu mutant allele has high residual activity and a detectable protein of normal size and amount on western blot analysis. It is believed that p.Pro479Leu affects malonyl-CoA interaction with CPT1A.

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. Britton CH, Schultz RA, Zhang B, Esser V, Foster DW, McGarry JD. Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene. Proc Natl Acad Sci U S A. 1995;92:1984–8. [PMC free article: PMC42407] [PubMed: 7892212]
4. 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]
5. 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]
6. 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]
7. Gillingham MB, Banta-Wright SA, Hermerath CA, Skeels MR, Bennett MJ, Narayan SB, Park J, Harding CO, Koeller DM. CPT1A P479L variant identified in Alaska native infants by expanded newborn screening. J Inherit Metab Dis. 2006;1:S84.
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. The paradox of the carnitinr palmitoyltransferase type 1a P479L variantin Canadian Aboriginal populations. Mol Genet Metab. 2009;96:201–7. [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]
11. 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]
12. McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997;244:1–14. [PubMed: 9063439]
13. Olpin SE, Allen J, Bonham JR, Clark S, Clayton PT, Calvin J, Downing M, Ives K, Jones S, Manning NJ, Pollitt RJ, Standing SJ, Tanner MS. Features of carnitine palmitoyltransferase type I deficiency. J Inherit Metab Dis. 2001;24:35–42. [PubMed: 11286380]
14. 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]
15. 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]
16. Price N, van der Leij F, Jackson V, Corstorphine C, Thomson R, Sorensen A, Zammit V. A novel brain-expressed protein related to carnitine palmitoyltransferase I. Genomics. 2002;80:433–42. [PubMed: 12376098]
17. 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]
18. Sinclair G, Waters PJ, Vallance H, MacLeod P, Chan AKJ, Bennett MJ et al. The dilemma of the CPT1 P479L mutation in Canadian Inuit and First Nations families. Abstract. Egmond aan Zee, Netherlands: 6th International Congress on Fatty Acid Oxidation; 2005.
19. 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]
20. Yamazaki N, Shinohara Y, Shima A, Yamanaka Y, Terada H. Isolation and characterization of cDNA and genomic clones encoding human muscle type carnitine palmitoyltransferase I. Biochim Biophys Acta. 1996;1307:157–61. [PubMed: 8679700]

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: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 101. Available at www.ommbid.com. Accessed 8-25-10.
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: McGraw-Hill; 2009.

Revision History

• 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