Carnitine Palmitoyltransferase 1a Deficiency

Clinical characteristics.

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

Diagnosis.

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

Management.

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

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

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

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

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

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

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

Genetic counseling.

CPT1A deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic, although heterozygous pregnant women may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible by biochemical testing if the enzyme defect has been confirmed in an affected family member or by molecular genetic testing if both pathogenic variants have been identified in an affected family member.

Suggestive Findings

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

Prenatal history. Maternal acute fatty liver of pregnancy. CPT1A deficiency in a fetus can lead to the following maternal findings during pregnancy:

• Hypoglycemia
• Abnormal liver enzymes
• Hyperammonemia
• Abnormal hepatic synthetic function resulting in bleeding diathesis

Newborn screening results

• Increased ratio of free carnitine to the sum of C16:0 (palmitoylcarnitine) plus C18 acylcarnitines ( C18:1, oleic acid and C18:2 linoleic acid) on a newborn screen blood spot [Fingerhut et al 2001, Sim et al 2001]. See ACMG ACT Sheet.

Postnatal clinical findings

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

Supportive laboratory findings

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

Establishing the Diagnosis

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

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of CPT1A is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Note: Targeted analysis may be considered first for the following pathogenic variants:
  • p.Pro479Leu 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, the Canadian First Nations population in Nunavut (i.e., Inuit) [Collins et al 2010], the Greenland Inuit [Rajakumar et al 2009], and Siberians [Clemente et al 2014]. Most affected individuals in these populations are homozygous for this variant [Park et al 2006].
  • p.Gly710Glu, which is common in the Hutterite population [Prasad et al 2001]
• A multigene panel that includes CPT1A and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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

Clinical Description

Carnitine palmitoyltransferase I (CPT I) is a mitochondrial membrane protein that converts long-chain fatty acyl-CoA molecules to their corresponding acylcarnitine molecules. The resulting acylcarnitines are then available for transport into the mitochondrial matrix where they can undergo fatty acid oxidation. Mitochondrial fatty acid oxidation by the liver provides an alternative source of fuel when glycogen reserves are significantly reduced, most often due to fasting or other intercurrent illness. The pathway fuels ketogenesis for metabolism in peripheral tissues that cannot oxidize fatty acids.

Clinical symptoms usually occur in an individual with a concurrent febrile or gastrointestinal illness when energy demands are increased. The precipitating illness may be a relatively common infectious disease, but the onset of symptoms is usually rapid and should alert the clinician to the possibility of a fatty acid oxidation defect.

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

Fetal CPT1A deficiency has been associated with acute fatty liver of pregnancy [Innes et al 2000]. A heterozygous female carrying an affected fetus is at risk of developing this obstetric complication. A number of other fetal fatty acid oxidation defects also carry a similar risk to the heterozygous mother of developing acute fatty liver of pregnancy, typically in the third trimester, prompting further investigation of the newborn for a fatty acid oxidation defect in this situation.

Hepatic encephalopathy. Although some neonates present with "physiologic" hypoglycemia of the newborn, most individuals with CPT1A deficiency present with fasting-induced hepatic encephalopathy in early childhood. This is a potentially fatal presentation; children who recover are at risk for recurrent episodes of life-threatening illness.

Survival through infancy without symptoms has been reported; initial presentation may occur later in life with similar life-threatening acute hepatic illness. For example, death as a result of rapid-onset hepatic failure in CPT1A deficiency occurred in an individual age 17 years despite the early recognition of a fatty acid oxidation defect [Brown et al 2001].

Between episodes of metabolic decompensation, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage.

Recognition of CPT1A deficiency and initiating management to prevent lipolysis reduces the episodes of decompensation [Stoler et al 2004, Stanley et al 2014].

Long-term liver damage as a result of recurring hepatosteatosis has not been reported.

Some individuals with the hepatic encephalopathy phenotype have also had renal tubular acidosis.

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

Genotype-Phenotype Correlations

The p.Pro479Leu pathogenic variant observed in the Inuit, which has high residual enzymatic activity (15%-20%), does not appear to cause acute hepatic failure as do the other pathogenic variants associated with the more severe phenotype [Brown et al 2001]. However, evidence suggests that infants who are homozygous for the variant have impaired fasting tolerance [Gillingham et al 2011] and increased risk of infant mortality [Gessner et al 2010]. In a study using whole-genome high-coverage sequence data of Arctic populations, this CPT1A variant was identified as deleterious and associated with increased infant mortality in circum-Arctic populations [Clemente et al 2014].

Nomenclature

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

Prevalence

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

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

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

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with carnitine palmitoyltransferase 1A (CPT1A) deficiency, the following evaluations are recommended:

• In affected individuals who have profound and/or prolonged exposure to hypoglycemia: a complete neurologic evaluation to detect secondary neurologic damage
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Guidelines for the treatment of CPT1A deficiency can be found at newbornscreening.info and ghr.nlm.nih.gov.

When individuals present with acute hypoglycemia, sufficient amounts of intravenous fluid containing 10% dextrose should be provided as quickly as possible to correct hypoglycemia and to prevent lipolysis and subsequent mobilization of fatty acids into the mitochondria.

Because individuals presenting with profound hypoglycemia have little to no residual hepatic glycogen, treating physicians should continue the glucose infusion beyond the time that blood glucose concentration has normalized in order to provide sufficient substrate for glycogen synthesis.

A letter should be provided to affected individuals (or their parents/guardians) and involved health care providers alerting them to the potentially catastrophic metabolic crises for which these individuals are at risk and explaining the appropriate emergency treatment.

Prevention of Primary Manifestations

A high-carbohydrate diet (70% of calories) that is low in fat (<20% of calories) is generally recommended to provide a constant supply of carbohydrate energy, particularly during illness. Restriction of dietary fat intake is somewhat controversial when affected individuals are well. If the physician chooses to recommend a low-fat diet when the affected individual is well, supplementation with essential fatty acids is necessary.

Provision of approximately one third of total calories as medium-chain triglycerides is recommended during periods of illness. C6-C10 fatty acids do not require the carnitine shuttle for entry into the mitochondrion.

Frequent feeding is recommended, particularly for infants, given their limited glycogen reserves. Cornstarch feedings given overnight provide a constant source of slow-release carbohydrate to prevent hypoglycemia during sleep.

Older children should not fast for more than 12 hours and for a shorter time if evidence of a febrile or gastrointestinal illness exists.

Adults should be aware of the risks of fasting and they and their primary care physician should be aware of the risks during surgery when both metabolic stress and fasting occur.

Brief hospital admission for administration of intravenous dextrose-containing fluid should be considered in individuals with known CPT1A deficiency who are required to fast more than 12 hours because of illness or surgical or medical procedures.

Prevention of Secondary Complications

Prevention of hypoglycemia reduces the risk of related neurologic damage.

Surveillance

At clinic appointments and during periods of reduced caloric intake and febrile illness that could precipitate metabolic decompensation, individuals with CPT1A deficiency should undergo liver function testing whether they are symptomatic or not. Tests should include liver enzymes, AST, ALT, alkaline phosphatase (ALP), and functional liver tests (including the blood-clotting tests PT and PTT).

Agents/Circumstances to Avoid

Prolonged fasting should be avoided, especially during a febrile or gastrointestinal illness.

Potentially hepatotoxic agents such as valproate and salicylate should not be given, even though adverse effects of pharmacologic agents have not been reported in individuals with CPT1A deficiency.

Evaluation of Relatives at Risk

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

Evaluations can include:

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

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

Pregnancy Management

Although data are limited, it is prudent to counsel unaffected female carriers regarding the risk for obstetric complications.

Women who have had one child with CPT1A deficiency following an uneventful pregnancy remain at risk for acute fatty liver of pregnancy in subsequent pregnancies with an affected fetus.

Pregnant females who are heterozygous for a CPT1A pathogenic variant should be monitored for acute fatty liver of pregnancy. In any pregnancies that follow identification of a child with CPT1A deficiency, liver function testing should be performed at each prenatal visit during the first two trimesters and more frequently during the third trimester when the risk for acute fatty liver of pregnancy is greatest. Management by a team comprising a maternal-fetal medicine specialist and a medical/biochemical geneticist is highly recommended.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.