Carnitine Palmitoyltransferase Ii Deficiency

Clinical characteristics.

Carnitine palmitoyltransferase II (CPT II) deficiency is a disorder of long-chain fatty-acid oxidation. The three clinical presentations are lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form (which is usually mild and can manifest from infancy to adulthood). While the former two are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death, the latter is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and the most frequent cause of hereditary myoglobinuria. Males are more likely to be affected than females.

Diagnosis/testing.

The diagnosis of CPT II deficiency is established in a proband by the finding of reduced CPT enzyme activity in muscle or the identification of biallelic pathogenic variants in CPT2 on molecular genetic testing.

Management.

Treatment of manifestations: High-carbohydrate (70%) and low-fat (<20%) diet to provide fuel for glycolysis; use of carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines; avoidance of known triggers.

Prevention of primary manifestations: Infusions of glucose during intercurrent infections to prevent catabolism; frequent meals; avoiding extended fasting and prolonged exercise.

Prevention of secondary complications: Providing adequate hydration during an attack of rhabdomyolysis and myoglobinuria to prevent renal failure.

Agents/circumstances to avoid: Valproic acid, general anesthesia, ibuprofen, and diazepam in high doses.

Evaluation of relatives at risk: If the pathogenic variants have been identified in an affected family member, molecular genetic testing of at-risk relatives can reduce morbidity and mortality through early diagnosis and treatment; if the pathogenic variants in the family are not known, screening for alterations in acylcarnitines may be of use in identifying other affected family members.

Genetic counseling.

CPT II deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are usually asymptomatic; however, manifesting carriers have been reported. Prenatal testing for a pregnancy at increased risk for one of the severe forms of the disease is possible either by molecular genetic testing of CPT2, if the two pathogenic variants in the family are known, or by assay of CPT II enzyme activity.

Suggestive Findings

Carnitine palmitoyltransferase II (CPT II) deficiency should be suspected in individuals with the following clinical features (by age) and supportive laboratory findings.

Clinical features (by age)

• Lethal neonatal form presents within days after birth. Characterized by:
  • Episodes of liver failure with hypoketotic hypoglycemia
  • Cardiomyopathy
  • Cardiac arrhythmias
  • Seizures and coma after fasting or infection
  • Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis)
• Severe infantile hepatocardiomuscular form presents in the first year of life. Characterized by:
  • Liver failure
  • Cardiomyopathy
  • Seizures
  • Hypoketotic hypoglycemia
  • Peripheral myopathy
  • Attacks of abdominal pain and headache
• Myopathic form has variable onset (1st to 6th decade). Characterized by:
  • Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress
  • Possible weakness during attacks
  • Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks

Supportive laboratory findings

• High-performance liquid chromatography tandem mass spectrometry of serum/plasma acylcarnitines (i.e, the acylcarnitine profile) that demonstrates an elevation of C12 to C18 acylcarnitines, notably of C16 and C18:1 (See Differential Diagnosis for other disorders with this acylcarnitine profile.)
  Note: CPT II deficiency cannot be excluded based on acylcarnitine quantification in dried blood spots alone and investigation of plasma is recommended [de Sain-van der Velden et al 2013].
• Serum CK concentration more than fivefold of normal when heart or brain disease is excluded
  • Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks.
  • Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [Wieser et al 2003].

Establishing the Diagnosis

The diagnosis of CPT II deficiency is established in a proband by the finding of reduced CPT enzyme activity in muscle or by the identification of biallelic pathogenic variants in CPT2 on molecular genetic testing (see Table 1).

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

• Single-gene testing. Sequence analysis of CPT2 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes CPT2 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.

Clinical Description

Three carnitine palmitoyltransferase II (CPT II) deficiency phenotypes are recognized: a lethal neonatal form; a severe infantile hepatocardiomuscular form; and a myopathic form, in which onset ranges from infancy to adulthood.

Genotype-Phenotype Correlations

A consistent genotype-phenotype correlation is found between CPT2 missense pathogenic variants (including the common p.Ser113Leu) and the myopathic form; these are referred to as pathogenic variants that cause "mild" form of the disease. CPT2 pathogenic null variants leading either to truncation of the protein or to mRNA degradation are referred to as pathogenic variants associated with the lethal neonatal form. However, several pathogenic variants are associated with both the mild and severe forms of CPT II deficiency, suggesting a role for other unknown modulators (intragenic variants; epigenetic or environmental factors) [Vladutiu et al 2000b, Musumeci et al 2007]. For a list of variants and their predicted phenotype, see Isackson et al [2008], Anichini et al [2011], and Fanin et al [2012].

Lethal neonatal form. Homozygosity for the severe pathogenic variants p.Pro227Leu, p.Lys414ThrfsTer7, and p.Lys642ThrfsTer6 [Isackson et al 2008] is associated with the lethal neonatal form. This subtype of the disease is also described in compound heterozygous states in combination with a pathogenic variant usually associated with mild disease (c.[1737delC];[520G>A]) [Semba et al 2008].

Severe infantile hepatocardiomuscular form. Compound heterozygosity for pathogenic variants associated with mild and severe forms has been reported. A detailed analysis associated the following pathogenic variants with this type of the disease: p.Tyr120Cys, p.Arg151Gln, p.Asp328Gly, p.Arg382Lys, p.Arg503Cys, p.Tyr628Ser, and p.Arg631Cys [Vladutiu et al 2002b, Thuillier et al 2003, Isackson et al 2008, Fanin et al 2012].

Myopathic form. The variant p.Ser113Leu accounts for 60% of pathogenic alleles in the myopathic form of CPT II deficiency. In a series of 32 affected individuals, 14 were homozygous for this common allele [Wieser et al 2003]; 17 were compound heterozygous for this common pathogenic variant and a second pathogenic variant. Testing for the p.Ser113Leu variant alone would suggest the diagnosis in 31 out of 32 individuals.

In northern Europeans the pathogenic variants p.Ser113Leu, p.Pro50His, and p.Lys414ThrfsTer7 are most frequently found, whereas in the Japanese the variant p.Phe383Tyr appears to have the highest prevalence [Taggart et al 1999, Isackson et al 2008, Yasuno et al 2008].

Heterozygotes have a biochemically intermediate phenotype (with markedly reduced enzyme activity) but generally do not display symptoms. However, a few symptomatic heterozygotes have been reported [Taggart et al 1999, Olpin et al 2003, Rafay et al 2005, Fanin et al 2012]. Heterozygotes have also been shown to have impaired fat oxidation during exercise as compared to controls [Ørngreen et al 2005].

Histopathologic changes in asymptomatic carriers of CPT II deficiency (heterozygotes) and in affected individuals (homozygotes) are inconsistent. A recent study found histopathologic abnormalities quite frequently (in all but one heterozygote). Lipid accumulation, found in all homozygotes, was mild or absent in heterozygotes.

Prevalence

Some twenty families with the lethal neonatal form [Smeets et al 2003, Thuillier et al 2003, Isackson et al 2008, Semba et al 2008, Boemer et al 2016] have been described. Since pregnancies in which a fetus has severe cerebral malformations are frequently interrupted, CPT II deficiency or other fatty acid oxidation disorders may be missed and the prevalence higher than previously suspected.

Approximately 28 families with the severe infantile hepatocardiomuscular form have been described.

Since the first description of the myopathic form of CPT II deficiency by DiMauro & DiMauro [1973], findings in more than 300 cases have been published [Thuillier et al 2003, Bonnefont et al 2004, Isackson et al 2006, Fanin et al 2012, Joshi et al 2013]. Symptoms of the myopathic form can be mild and physical impairment may not occur; thus, this form of CPT II deficiency may be under-recognized.

Neonatal Form

Carnitine-acylcarnitine translocase (CACT) deficiency (OMIM 212138). The neonatal phenotype of CACT deficiency, one of the most severe and usually lethal mitochondrial fatty-acid oxidation abnormalities, is characterized by hypoketotic hypoglycemia, hyperammonemia, cardiac abnormalities, and early death. Tandem mass spectrometry shows increased concentration of 16-2 H3 palmitoylcarnitine, suggesting either CPT II deficiency or CACT deficiency. One report shows that heat-denaturing high-performance liquid chromatography (DHPLC) is of use for diagnosing CACT deficiency [Fukushima et al 2013]. CACT deficiency is an autosomal recessive condition caused by compound heterozygous or homozygous pathogenic variants in SLC25A20.

Note: The differentiation of CACT deficiency from CPT II deficiency continues to be difficult using current acylcarnitine profiling techniques either from plasma or blood spots, or in the intact cell system (fibroblasts/amniocytes). Specific enzyme assays are required to unequivocally differentiate CACT enzyme activity from CPT II enzyme activity [Roe et al 2006].

Alternatively, molecular genetic testing could be used to distinguish between these two conditions.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty-acid oxidation in which clinical symptoms usually occur with a concurrent febrile or gastrointestinal illness when energy demands are increased. The recognized phenotypes are: acute fatty liver of pregnancy, in which the fetus has biallelic pathogenic variants in CPT1A that cause 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.

The ratio of free-to-total carnitine in serum or plasma on a newborn screen bloodspot may be elevated in CPT1A deficiency. CPT1 enzyme activity on cultured skin fibroblasts is 1%-5% of normal in most affected individuals. In individuals with an enzymatically confirmed diagnosis of CPT1A deficiency, the CPT1A pathogenic variant detection frequency using sequence analysis is greater than 90%. Inheritance is autosomal recessive.

Myopathic Form

The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and is the most frequent cause of hereditary myoglobinuria. If clinical history is suggestive of a metabolic myopathy, routine laboratory tests including measurement of concentrations of lactate, pyruvate, creatine kinase, amino acids, and free acylcarnitine in blood should be performed. Careful family history should be taken. In early reports, elevation of acylcarnitines, notably C16 and C18:1, suggestive of a defect in mitochondrial β-oxidation, was detected by screening for acylcarnitines [Chace 2001]. Differential diagnosis of this finding includes CPT II deficiency, glutaricacidemia II (OMIM 231680), carnitine-acylcarnitine translocase deficiency (OMIM 212138), and TANGO2-related metabolic encephalopathy and arrhythmias (a condition characterized by metabolic encephalomyopathic crises, rhabdomyolysis, cardiac arrhythmias, and neurodegeneration and caused by pathogenic variants in TANGO2). Unlike CPT II deficiency, TANGO2-related metabolic encephalopathy and arrhythmias is frequently accompanied by cardiac arrhythmias, cognitive impairment, epilepsy, spasticity, and brain atrophy. Additional tests are necessary to reach a definite diagnosis [Albers et al 2001].

Rhabdomyolysis and/or myoglobinuria. Rhabdomyolysis is etiologically heterogeneous, most cases being apparently acquired – for example, as a result of mechanical or vascular damage. Recurrent rhabdomyolysis preceded by exercise or infection is more likely to have an underlying metabolic defect, and strategic diagnostic procedures are warranted. History and physical examination are likely to identify the acquired and drug-related forms. However, one has to bear in mind that sometimes myoglobinuria with episodes of dark urine is ignored, and pronounced muscle pain after only light exercise is not considered a sign of disease. Screening for metabolic disorders (carnitine profile, amino acids, tandem mass spectrometry) may point in specific directions. Muscle biopsy for histologic and biochemical analysis should be performed. However, in a significant proportion of individuals, no cause of rhabdomyolysis can be identified.

Acquired causes of rhabdomyolysis

• Excessive use of muscle force (e.g., sports, seizures, dystonia)
• Muscle damage (e.g., crush, cold, ischemia, embolism)
• Infections (bacterial/viral/fungal)
• Temperature changes
• Inflammatory myopathies (polymyositis, vasculitis)

Drug-related causes of rhabdomyolysis

• Induction of an autoimmune reaction (e.g., cyclosporine, penicillamine)
• Hypokalemia (amphotericin, caffeine)
• Membrane disruption (cemitidin, colchicine)
• Disturbance of Na/K ATPase (antidepressants, arsen, azathioprine, bezafibrates)
• Neuroleptic syndrome (all neuroleptics, lithium)
• Serotonergic syndrome (amphetamines, MAO-inhibitor, SSRI)

Metabolic-toxic causes of rhabdomyolysis

• Defects of glucose/glycogen metabolism (e.g., McArdle disease, Tarui disease [OMIM 232800]). Deficiencies of the six enzymes involved in glycogen breakdown (phosphorylase, phosphorylase kinase, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase) result in exercise intolerance and recurrent rhabdomyolysis.
• Defects of lipid metabolism (carnitine deficiency). Mitochondrial β-oxidation of long-chain fatty acids is a major source of energy production, particularly at times of stress or fasting. Skeletal muscle can use carbohydrates or lipids as fuel, depending on the degree of activity. At rest or during prolonged low-intensity exercise, approximately 70% of the energy requirement is met by the oxidation of long-chain fatty acids. Two defects of lipid metabolism primarily affecting the skeletal muscle are known: carnitine palmitoyltransferase II deficiency and systemic primary carnitine deficiency characterized by progressive proximal weakness and cardiomyopathy.
• Defects of oxidative phosphorylation (complex II deficiency, complex III defect, cytochrome c oxidase deficiency) (See Mitochondrial Disorders Overview.)
• TANGO2-related encephalopathy and arrhythmias
• Malignant hyperthermia (See Malignant Hyperthermia Susceptibility.)
• Dystrophinopathies (Duchenne muscular dystrophy, Becker muscular dystrophy)
• Myoadenylate deaminase deficiency (MAD) (OMIM 615511)

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with carnitine palmitoyltransferase II (CPT II) deficiency, the following are recommended:

• Neurologic examination
• Strength testing
• Review of dietary association of symptoms
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Current treatment for long-chain fatty-acid oxidation disorders:

• Avoid known triggers.
• Reduce the amount of long-chain dietary fat while covering the need for essential fatty acids.
• Provide carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines.
• Provide a large fraction of calories as carbohydrates to reduce body fat utilization and prevent hypoglycemia.
• Provide approximately one third of the calories as even-chain medium chain triglycerides (MCT). Metabolism of the eight to ten carbon fatty acids in MCT oil, for example, is independent of CPT I, carnitine/acylcarnitine translocase, CPT II, very-long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein, and long-chain hydroxy-acyl-CoA dehydrogenase deficiency (LCHAD) enzyme activities.

Prevention of Primary Manifestations

Appropriate measures include the following:

• Infusions of glucose during intercurrent infections to prevent catabolism
  Note: Oral glucose cannot achieve this effect.
• High-carbohydrate (70%) and low-fat (<20%) diet to provide fuel for glycolysis
• Frequent meals and avoidance of extended fasting
• Avoidance of prolonged exercise and other known triggers

Prevention of Secondary Complications

The most important aim while treating an individual with CPT II deficiency is to prevent renal failure during an episode of rhabdomyolysis and myoglobinuria. Therefore, sufficient hydration and, if necessary, dialysis must be performed immediately when renal failure is imminent.

Surveillance

Annual or more frequent monitoring to regulate medication and diet is indicated.

Agents/Circumstances to Avoid

Extended fasting and prolonged exercise are to be avoided.

Reports of medication-induced side effects in individuals with CPT II deficiency are rare. Relying mostly on case reports, the following agents should be avoided:

• Valproic acid [Kottlors et al 2001]
• General anesthesia
• Ibuprofen
• Diazepam in high doses [Bonnefont et al 1999]

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk relatives so that morbidity and mortality can be reduced by early diagnosis and treatment. In addition, predictive testing for at-risk asymptomatic family members may be advisable before general anesthesia. Complications of general anesthesia (including rhabdomyolysis and suxamethonium hypersensitivity in individuals with a variety of neuromuscular diseases and renal post-anesthetic failure in individuals with CPT II deficiency in particular) have been observed [Katsuya et al 1988, Wieser et al 2008].

• Molecular genetic testing is appropriate if the pathogenic variants in the family are known.
• If the pathogenic variants in the family are not known, screening for alterations in acylcarnitines may be of use to identify other affected family members.

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

Pregnancy Management

While a variety of maternal complications have been observed in association with other fatty acid oxidation disorders (severe preeclampsia; acute fatty liver of pregnancy; maternal liver disease; and hemolysis, elevated liver enzymes, and low platelets), none of these complications has been associated with CPT II deficiency [Preece & Green 2002, Shekhawat et al 2005].

Therapies Under Investigation

Promising results have been obtained with treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using anaplerotic odd-chain triglycerides [Roe et al 2002]. These results were confirmed in seven individuals with CPT II deficiency, who avoided rhabdomyolysis or hospitalization while on the triheptanoin (anaplerotic) diet. Affected individuals returned to normal physical activity including strenuous sports [Roe et al 2008].

Fibrates are a class of hypolipidemic drugs that increase high-density lipoprotein levels by mRNA upregulation of many lipid-metabolism genes through interaction with the steroid/thyroid transcription factor PPARa. Studies have demonstrated that bezafibrate increases CPT2 mRNA and normalizes enzyme activity in mild forms of CPT II-deficient cultured fibroblasts and myoblasts [Bonnefont et al 2009]. In a trial including six affected individuals treated with bezafibrate, the level of fatty acid oxidation in muscle biopsies was elevated, accompanied by a significant increase in palmitoyl-L-carnitine oxidation, increased CPT2 mRNA, and increased translated protein. A reduction of episodes of rhabdomyolysis could be observed, as well as amelioration of quality of life (measured by SF-36) as shown by an increase in physical activity and a decline in muscular pain [Bonnefont et al 2009, Bonnefont et al 2010]. Another study did not show beneficial effects of bezafibrate on fatty acid oxidation and other disease manifestations; this study, however, was heavily criticized for methodologic shortcomings [Ørngreen et al 2014, Bastin et al 2015]

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Other

Carnitine supplementation is essentially a cure for the carnitine membrane transporter defect. While oral carnitine supplementation of 50 mg/kg/d is often prescribed in the treatment of other fat oxidation disorders, controlled trials of its effectiveness in CPT II deficiency are lacking. In addition, carnitine administration is controversial, given the possibility of accumulation of acyl-CoAs and consequent depletion of free CoA in the mitochondria [Yoshino et al 2003]. In acutely ill infants aggressive treatment with IV glucose and cardiac support is critical, and should be complemented with L-carnitine supplementation.