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Clinical Chemistry 47: 1763-1768, 2001;
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(Clinical Chemistry. 2001;47:1763-1768.)
© 2001 American Association for Clinical Chemistry, Inc.

Articles

Hepatic Carnitine Palmitoyltransferase I Deficiency: Acylcarnitine Profiles in Blood Spots Are Highly Specific

Ralph Fingerhut1a, Wulf Röschinger2, Ania C. Muntau2, Torsten Dame1, Jens Kreischer1, Ralf Arnecke1, Andrea Superti-Furga3, Heinz Troxler3, Bernhard Liebl4, Bernhard Olgemöller1 and Adelbert A. Roscher2

1 Labor Becker, Olgemöller & Kollegen, D-81671 Munich, Germany.

2 Dr. von Hauner Children’s Hospital, Department of Clinical Chemistry and Biochemical Genetics, Ludwig-Maximilians-University, D-80337 Munich, Germany.

3 University Children’s Hospital, CH-8032 Zurich, Switzerland.

4 Public Health Screening Center, D-80764 Oberschleissheim, Germany.

aAddress correspondence to this author at: Labor Becker, Olgemöller & Kollegen, Führichstrasse 70, D-81671 Munich, Germany. Fax 49-89-544-654-10; e-mail fingerhu{at}labor-bo.de.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: In carnitine palmitoyltransferase I (CPT-I) deficiency (MIM 255120), free carnitine can be increased with no pathologic acylcarnitine species detectable. As inclusion of CPT-I deficiency in high-risk and newborn screening could prevent potentially life-threatening complications, we tested whether CPT-I deficiency might be diagnosed by electrospray ionization-tandem mass spectrometry (ESI-MS/MS).

Methods: A 3.2-mm spot of whole blood dried on filter paper was extracted with 150 µL of methanol. After derivatization of carnitine and acylcarnitines to their butyl esters, the samples were analyzed by ESI-MS/MS with 37.5 pmol of L-[2H3]carnitine and 7.5 pmol of L-[2H3]palmitoylcarnitine as internal standards.

Results: In all dried-blood specimens from each of three patients with CPT-I deficiency, we found an invariably increased ratio of free carnitine to the sum of palmitoylcarnitine and stearoylcarnitine [C0/(C16 + C18)]. The ratio in patients was between 175 and 2000, or 5- to 60-fold higher than the ratio for the 99.9th centile of the normal newborn population in Bavaria (n = 177 842). No overlap with the values of children that were known to be supplemented with carnitine was detected [C0/(C16 + C18), 34 ± 30; mean ± SD; n = 27].

Conclusions: ESI-MS/MS provides a highly specific acylcarnitine profile from dried-blood samples. The ratio of free carnitine to the sum of palmitoylcarnitine and stearoylcarnitine [C0/(C16 + C18)] is highly specific for CPT-I deficiency and may allow presymptomatic diagnosis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In carnitine palmitoyltransferase I (CPT-I) 1 deficiency (MIM 255120), long-chain fatty acids are not transferred from CoA to carnitine to form acylcarnitines by palmitoyl-CoA:L-carnitine O-palmitoyltransferase (EC 2.3.1.21). Thus, they cannot enter the mitochondria for subsequent ß-oxidation (1). There are two distinct tissue-specific isoforms of the enzyme: the liver-type isoform (CPT-IA) and the muscle-type isoform (CPT-IB) (2)(3). The two isoforms are encoded by two different genes (4). Whereas CPT-IA is expressed in liver, kidney, and fibroblasts and CPT-IB is expressed in skeletal muscle, cardiac ventricular myocytes are the only cells known to express both isoforms. CPT-IA and CPT-IB are subject to different types of regulation. CPT-IA is inhibited by malonyl-CoA, whereas a high-fat diet increases CPT-IA expression specifically in the liver (5). Therefore, CPT-IA is the key enzyme in the regulation of fatty acid oxidation. Twenty-two patients with CPT-IA deficiency in 17 families have been reported to date. All patients have CPT-IA deficiency (6), which will subsequently be called "CPT-I". To date, there has been no report of a patient with CPT-IB deficiency. Children with CPT-I deficiency usually present with life-threatening attacks of fasting hypoketotic hypoglycemia and coma during the first 2 years of life. Persistent neurologic deficits are common. These children usually do not have cardiac or skeletal muscle involvement. However, four new cases were recently described that interestingly had myopathy with increased creatine kinase or cardiac symptoms in the neonatal period (7). Once diagnosed, patients can be treated by prevention of any period of fasting that would require the use of fatty acids as an energy source. In addition, because medium-chain fatty acids bypass the carnitine cycle and enter the midportion of the mitochondrial ß-oxidation spiral directly, dietary restriction of fat intake associated with supplementation with medium-chain triacylglycerols (MCTs) is considered to be helpful [for a review, see Ref. (8)].

Except for increased free carnitine, the blood acylcarnitine profile from CPT-I-deficient individuals has been considered unremarkable, with no pathologic acylcarnitine species detectable (9)(10). One preliminary report has emphasized markedly reduced long-chain acylcarnitines in CPT-I deficiency (11).

Because CPT-I deficiency may be amenable to treatment, inclusion of new markers into electrospray ionization-tandem mass spectrometry (ESI-MS/MS)-based newborn screening is desirable, both to estimate its incidence and to allow for early diagnosis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
materials
L-[2H3]Carnitine and L-[2H3]palmitoylcarnitine from Cambridge Isotope Laboratories were obtained from Promochem. Filter paper (S&S 2992) was purchased from Schleicher & Schüell. Nunc 96-well microtiter plates were obtained from Labor Schubert. Methanol, acetonitrile, and formic acid (HPLC grade) were from Merck. Butanolic hydrochloric acid was prepared by saturating dry HPLC-grade 1-butanol with HCl gas.

instruments
The following devices were used: a BSD 200 automated punching device (BSD Technologies International); a Titramax 1000 orbital shaker (Heidolph); a Savant Model SC210 A SpeedVac Plus centrifugal evaporator (Life Sciences); and an API 365 ESI-MS/MS system equipped with a TurboIon spray device, Series 200 lp HPLC pump, and Series 200 autosampler (PE-SCIEX).

Instrument control and data acquisition were performed by the software LC sample control and LC tune 1.3 (PE-SCIEX) on a personal computer (Power Macintosh 9600/200). Signal intensities and the ratios of the analytes to their respective internal standards were calculated from the total-ion chromatograms by an Apple script that is part of the Mac System D1-7.5.5 Neonatal Script 1.1c.

Statistical analysis was performed with SPSS, Ver. 10.0.5 software (SPSS).

samples
Whole blood was drawn by heel prick or venipuncture and dried on filter paper. A total of 177 842 samples from the central Bavarian newborn-screening program were analyzed during 18 months, which accounted for >98% of the Bavarian newborn population of that time period. For participation in the Bavarian newborn-screening program covering an extended disease range, written consent of the parents is required. Blood sampling is recommended between 48 and 72 h of life: 50% of the samples were taken within that time period, and 96% of the samples were taken within the first 5 days of life. In addition, samples from two patients with CPT-I deficiency were analyzed, including the original newborn-screening filter cards.

methods
Free carnitine and acylcarnitines were analyzed by ESI-MS/MS (12) using a modification of the methods described by Chace et al. (13) and Millington et al. (14). From the dried-blood samples, 3.2-mm (1/8-inch) spots were punched out and transferred to a 96-well microtiter plate. To each spot, 50 µL of internal standard solution containing 37.5 pmol of L-[2H3]carnitine and 7.5 pmol of L-[2H3]palmitoylcarnitine was added. After 5 min, 150 µL of methanol was added. The plate was then covered and shaken for 30 min at room temperature on an orbital shaker; 150 µL of the methanolic extract was then transferred to a second microtiter plate and evaporated to dryness in a Teflon-lined centrifugal evaporator. The acylcarnitines and free carnitine were derivatized to their corresponding butyl esters with 50 µL of saturated butanolic hydrochloric acid. The plate was sealed with polystyrene-coated aluminum foil and heated at 65 °C for 20 min. After cooling, the solvent was evaporated in a centrifugal evaporator. The residue was redissolved in 100 µL of acetonitrile-water-formic acid (50:50:0.025 by volume) before analysis. A 35-µL aliquot of each sample was introduced at a flow rate of 100 µL/min into the ionization chamber. Free carnitine and acylcarnitines were measured by positive precursor ion scan of 85 Da (scan range, 200–500 Da) using the following settings: ion spray voltage, 5500 V; orifice voltage, 15 V; collision energy, 38 V. The collision gas was set to a pressure of 2.1 x 10-5 Torr. Mass fragment data were collected in a 2.5-min window. Mass resolution was defined by a step size of 1 atomic mass unit (amu) and a dwell time of 20 ms. For calculation of the concentration of stearoylcarnitine, L-[2H3]palmitoylcarnitine was used as reference.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
patients
Patient 1 was the fifth child of consanguineous parents. Two siblings had died at the 2nd and 5th day of life, respectively; therefore, newborn screening of this patient was performed at the age of 12 and 65 h. At admission to our hospital at the age of 65 h, the boy appeared clinically well. However, he developed generalized seizures a few hours later. The electroencephalogram (EEG) was abnormal. In addition, renal tubular acidosis was observed. At the time of transfer, plasma glucose, ammonia, aminotransferase activities, and creatine kinase were within the appropriate reference intervals. The patient was placed on a high-carbohydrate, low-fat diet with MCT supplementation. The EEG normalized, and anticonvulsive treatment could be withdrawn. Renal tubular acidosis resolved. At the age of 15 months, the boy showed normal neurologic development.

Patient 2 was the first child of nonconsanguineous parents. The boy had been clinically asymptomatic until the age of 9 months. He came to medical attention during an episode of somnolence attributable to mild nonketotic hypoglycemia (glucose, 2 mmol/L). After 5 days of encephalopathy with depressed EEG activity, the patient fully recovered. Aminotransferase activities were increased (aspartate aminotransferase, 275 U/L; alanine aminotransferase, 362 U/L), whereas creatine kinase and ammonia were within the appropriate reference intervals. The patient remained well on a low long-chain fat diet supplemented with MCTs.

Patient 3 was the product of an incestuous relationship in a family of Asian origin. Neonatal adaptation was uneventful. The child was admitted to the hospital for failure to thrive at age 2 months, but no specific diagnosis was made and the child was discharged. At age 5 months, he was found in a comatose state without preceding illness. While being taken to the emergency department, he had generalized convulsions. The liver was moderately enlarged. Severe nonketotic hypoglycemia was found (<0.5 mmol/L). The child recovered consciousness over several days, but the EEG showed persistence of epileptic discharges. The child was placed on a MCT-enriched diet. There was sporadic recurrence of seizures for a few months followed by complete remission. Psychomotor development was, however, moderately delayed. Under the MCT-enriched diet, the child’s physical growth was good with catch-up growth, and he was in excellent physical condition at age 18 months.

CPT-I deficiency was confirmed by enzyme assay in cultured skin fibroblasts from all three patients: CPT-I activity was 0.00 nmol/min · mg protein in patient 1, 0.04 nmol/min · mg protein in patient 2, and 0.00 nmol/min · mg protein in patient 3. The mean (± SD) activity in cultured skin fibroblasts from 12 controls was 0.58 ± 0.26 nmol/min · mg protein.

linearity
For the determination of linearity, precision, and recovery, blood from a healthy volunteer was supplemented with increasing amounts of free carnitine, palmitoylcarnitine, and stearoylcarnitine. For regression analysis, the ratio of the analyte signal vs internal standard signal was plotted against the analyte concentration. Values from 10 consecutive days were calculated. The mean slope, y-intercept, and coefficient of linear regression (r2) were 0.05, 3.29 µmol/L, and 0.955 for free carnitine (C0); 0.082, 0.20 µmol/L, and 0.980 for palmitoylcarnitine (C16); and 0.085, 0.13 µmol/L, and 0.975 for stearoylcarnitine (C18), respectively. The calibration curves were linear at least up to 192 µmol/L (C0), 26 µmol/L (C16), and 25 µmol/L (C18), respectively.

precision and recovery
The intraassay precision was determined with 20 repeat samples in one analytical run. The mean ± SD concentrations (CVs) were 48.4 ± 3.16 µmol/L (6.5%) for free carnitine (C0), 10.5 ± 0.67 µmol/L (6.4%) for palmitoylcarnitine (C16), and 0.42 ± 0.04 µmol/L (9.5%) for stearoylcarnitine (C18), respectively. The interassay precision and recovery data (on 20 consecutive days) were determined at two different concentrations for each analyte. The mean ± SD concentrations (CVs) were 17.0 ± 2.7 (16%) and 57.3 ± 8.0 µmol/L (14%) for free carnitine (C0), 0.60 ± 0.10 (17%) and 8.2 ± 1.6 µmol/L (19%) for palmitoylcarnitine (C16), and 0.52 ± 0.07 (13%) and 8.4 ± 1.0 µmol/L (12%) for stearoylcarnitine (C18), respectively. The mean recoveries were 92.9% for free carnitine (C0), 82.6% for palmitoylcarnitine (C16), and 97.3% for stearoylcarnitine (C18), respectively.

analytical sensitivity and detection limit
The detection limit (signal + 3 SD of a sample free of analyte) of the assay was 1.15 µmol/L for free carnitine (C0), 0.03 µmol/L for palmitoylcarnitine (C16), and 0.01 µmol/L for stearoylcarnitine (C18). The quantification limit (signal + 6 SD of a sample free of analyte) was 1.92 µmol/L for free carnitine (C0), 0.05 µmol/L for palmitoylcarnitine (C16), and 0.02 µmol/L for stearoylcarnitine (C18).

diagnostic specificity
During 18 months, we analyzed samples from 177 842 newborns from the Bavarian newborn-screening program. We diagnosed a patient with CPT-I deficiency, who was the first to be detected prospectively by ESI-MS/MS newborn screening. In addition, samples from two patients with CPT-I deficiency found in high-risk screening were analyzed (samples at the time of diagnosis and the original newborn-screening filter cards retrospectively). Free carnitine (C0), palmitoylcarnitine (C16), and stearoylcarnitine (C18) are measured routinely within the newborn-screening program. As a potential marker for CPT-I deficiency, the ratio of free carnitine to the sum of palmitoylcarnitine and stearoylcarnitine [C0/(C16 + C18)] was also evaluated. Incidences of decreased concentrations of palmitoylcarnitine and stearoylcarnitine (<0.1th centile) were still above the quantification limit and could thus be quantified reliably. For the C0/(C16 + C18) ratio, no significant difference was detected between boys (n = 69 796) and girls (n = 64 782; means, 4.62 and 4.56, respectively; P = 0.576; age at sampling, 2–5 days; birth weight >2500 g). However, the ratio is dependent on birth weight and age. There was a significant steady decrease from newborns with a birth weight <1000 g (n = 369) to newborns with a birth weight >2500 g (n = 110 580; age at sampling 2–5 days). The mean values were 10.03 and 4.55, respectively (P <0.001; see Fig. 1 ). The ratio also decreased significantly after 24 h of age [mean, 5.66 at age <1 day (n = 1653) and 4.59 at age 1–4 days (n = 143 185); P <0.001] and increased strongly in the age group 5–15 days [mean, 4.59 at age 1–4 days (n = 143 185) and 15.84 at age >15 days (n = 1027); P < 0.001; Fig. 2 ].



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  		Figure 1. Mean values for the C0/(C16 + C18) ratio for different birth weight classes.

Age, 2–5 days. The boxes represent the interquartile range (25th–75th centiles); the horizontal black bar represents the median; the error bars indicate the 95% confidence interval of the mean.



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  		Figure 2. Mean values for the C0/(C16 + C18) ratio for different age groups.

Birth weight >2500 g. The boxes represent the interquartile range (25th–75th centiles); the horizontal black bar represents the median; the error bars represent the 95% confidence interval of the mean.

The frequencies of abnormal concentrations of free carnitine, palmitoylcarnitine, stearoylcarnitine, and the C0/(C16 + C18) ratio are shown in Table 1 . Of a total of 177 842 samples, there were 164 with isolated decreased palmitoylcarnitine concentrations or decreased palmitoyl- and stearoylcarnitine concentrations. In addition, we found increased concentrations of free carnitine in 27 samples from children with known carnitine supplementation, in 1 postoperative sample, in 1 sample from a child with kidney agenesis, in 1 sample from a child with mitochondrial DNA depletion syndrome, in 2 samples from the newborn period of the first CPT-I patient to be detected prospectively by ESI-MS/MS newborn-screening, and in 4 samples of two cases of prediagnosed CPT-I deficiency. The frequency distributions for the Bavarian newborn population of free carnitine, palmitoylcarnitine, and the ratio C0/(C16 + C18) are shown in Fig. 3 . For the assessment of reliable criteria and cutoff values for the detection of patients with CPT-I deficiency, we retrospectively calculated the specificity (number of true negatives/sum of true negatives and false positives), the sensitivity (number of true positives/sum of true positives and false negatives), and the positive predictive value (number of true positives/sum of true positives and false positives) for various markers and combinations (Table 2 ).


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  		Table 1. Concentrations and ranges (0.1–99.9th centile) for free carnitine (C0), palmitoylcarnitine (C16), stearoylcarnitine (C18), and the ratio C0/(C16 + C18) in the total screening population, in children with known carnitine supplementation, in patients with CPT-I deficiency, and in selected cases.



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  		Figure 3. Frequency distributions of free carnitine (A), palmitoylcarnitine (B), and the C0/(C16 + C18) ratio (C).

Six samples from the three CPT-I-deficient patients (•) and samples from individuals on carnitine supplementation (x) are specially depicted (see also Table 1Up ). P1a and P1b, samples from patient 1 taken at 2 h and on 3rd day, respectively; P2a and P2b, samples from patient 2 taken at 5th day and 12 months, respectively; P3a and and P3b, samples from patient 3 taken at 5th day and 7 months, respectively


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  		Table 2. Recalculated values for specificity, sensitivity, and positive predictive value for markers for CPT-I deficiency.1


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In CPT-I deficiency, the conjugation of long-chain acyl-CoA substrates to carnitine is absent. The major deviation to be expected in the metabolic pattern is decreased long-chain acylcarnitines, especially palmitoylcarnitine and stearoylcarnitine. Because of the impaired conjugation of fatty acids with carnitine, the concentrations of both free and total carnitine increase. The muscle is quantitatively responsible for a high proportion of total ß-oxidation of fatty acids in the body. Therefore, muscle CPT-I might contribute to the generation of substantial amounts of, e.g., palmitoylcarnitine. However, data from Al Aqeel and Rashed (11) and Sim et al. (15) as well as our observations support the hypothesis that muscle CPT-I does not significantly influence blood concentrations of palmitoylcarnitine. It has recently been hypothesized that the higher expression of the liver isoform of CPT-I in fetal heart compared with the expression of the muscle isoform of CPT-I may lead to cardiac problems in the neonate with CPT-I deficiency (16). An increased concentration of plasma free carnitine has been thought to be the only diagnostic marker metabolite for CPT-I deficiency (17). Sim et al. (15) correctly suggested in a recently published report that an isolated increase in free carnitine in an apparently healthy term neonate warrants further investigation to exclude CPT-I deficiency. However, our data show that in the newborn period free carnitine concentrations in CPT-I-deficient patients can still be within the interval reference (Table 1Up ). It needs to be emphasized that quantification of free carnitine in blood spots is not reliable because of the various decomposition characteristics of acylcarnitines, in particular of acetylcarnitine as recently described by Johnson (18), who showed that 30% of acetylcarnitine, 8% of decanoylcarnitine, and 6% of octadecanoylcarnitine butanolyze in 15 min when the dried extracts are heated in 3 mol/L HCl in n-butanol at 65 °C. Even taking into account the hydrolysis of labeled and unlabeled acylcarnitines, the applied ratio of C0/(C16 + C18) is sensitive enough to define cutoff values and to reliably allow for diagnosis of CPT-I deficiency.

In healthy individuals, carnitine status is dependent on nutritional state, age, and birth weight (19)(20)(21). Significantly increased serum free carnitine has been observed in patients with idiopathic hypertrophic cardiomyopathy attributable to decreased myocardial uptake (22). Therefore, increased free carnitine alone is not a specific feature suitable for the detection of patients with CPT-I deficiency. Long-chain acylcarnitines seem to be a better marker because they are already decreased in CPT-I patients at birth (Table 1Up ). As shown in Tables 1Up and 2Up and in Fig. 3Up , use of the ratio of free carnitine to the sum of palmitoylcarnitine and stearoylcarnitine [C0/(C16 + C18)] strongly increases specificity and especially the positive predictive value. When decreased concentrations of long-chain acylcarnitines are used as a single marker, exact birth weight- and age-related cutoff values need to be established to maintain acceptable sensitivity and specificity.

The reliability of the ratio C0/(C16 + C18) is dependent on the accurate measurement of low concentrations of long-chain acylcarnitines (especially palmitoyl- and stearoylcarnitine). With the cutoff value set to 100, the C0/(C16 + C18) ratio can reliably distinguish between samples from CPT-I-deficient patients on the one hand and samples from healthy individuals, samples from patients on carnitine supplementation, and samples from patients with severe diseases that potentially affect carnitine and/or fatty acid metabolism on the other hand. Early detection of CPT-I by newborn screening might prevent both a neonatal life-threatening metabolic decompensation and commonly observed neurologic deficits.


   Acknowledgments
 
We wish to thank Dr. R.J.A. Wanders (University Hospital Amsterdam, Laboratory for Genetic Metabolic Diseases, Amsterdam, The Netherlands) for assaying CPT-I in cultured skin fibroblasts. We thank Dr. E. Lainka (University Childrens’ Hospital, Essen, Germany) for kindly providing the blood samples and clinical information of one patient included in this study.


   Footnotes
 
1 Nonstandard abbreviations: CPT-I, carnitine palmitoyltransferase I; MCT, medium-chain triacylglycerol; ESI-MS/MS, electrospray ionization-tandem mass spectrometry; and EEG, electroencephalogram.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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