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Muscular carnitine palmitoyltransferase II deficiency in infancy
Muscular Carnitine Palmitoyltransferase II Deficiency in Infancy Haggit Hurvitz, MD*, Aharon Klar, MD*, Isabelle Korn-Lubetzki†, MD, Ron J.A. Wanders, MD‡, and Orly N. Elpeleg, MD§ An 8-month-old female presented with febrile myoglobinuria. The activity of carnitine palmitoyltransferase (CPT) II was decreased to 16% of the control mean, and the oxidation of the long-chain fatty acids was reduced to 25% of the mean in the fibroblasts. Homozygosity for the common mutation, S113L, was identified in the CPT II gene. Residual CPT II activity of more than 10% of the mean and homozygosity for the common mutation S113L are usually associated with a milder reduction of long-chain fatty acid oxidation to about 80% of the control and with a later age of clinical onset. The early clinical presentation in the present patient is unique and was associated with a marked impairment of long-chain fatty acid oxidation, possibly because of other genetic factors. CPT II deficiency should be included in the differential diagnosis of isolated myoglobinuria in infancy. © 2000 by Elsevier Science Inc. All rights reserved. Hurvitz H, Klar A, Korn-Lubetzki I, Wanders RJA, Elpeleg ON. Muscular carnitine palmitoyltransferase II deficiency in infancy. Pediatr Neurol 2000;22:148-150.
Introduction The beta-oxidation of long-chain fatty acids (LCFAs) requires their import into the mitochondria. This process is carnitine dependent and is catalyzed by two carnitine
From the *Department of Pediatrics; Bikur Cholim General Hospital; Hebrew University-Hadassah Medical School; †Pediatric Neurology Unit; Bikur Cholim General Hospital; Jerusalem, Israel; ‡University Hospital Amsterdam; Academic Medical Center; Amsterdam, The Netherlands; and §Metabolic Disease Unit; Shaare-Zedek Medical Center; Jerusalem, Israel.
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palmitoyltransferases (CPTs) and carnitine-acylcarnitine translocase. The outer membrane CPT I is involved in the esterification of palmitoyl-coenzyme A (CoA) to yield palmitoyl carnitine. After translocation across the inner mitochondrial membrane the palmitoyl carnitine molecule is reconverted into carnitine and palmitoyl-CoA by the activity of CPT II [1]. Deficiency of CPT II typically manifests around puberty, with exercise intolerance and myoglobinuria [2]. In the few patients who presented with CPT II in infancy the clinical picture was dominated by encephalopathy, cardiomyopathy, and hepatomegaly and was associated with hypoglycemia and long-chain acylcarnitine accumulation [3-5]. An 8-month-old infant with CPT II deficiency who presented with myoglobinuria is reported.
Case Report An 8-month-old female was admitted to the hospital because of high fever and listlessness for 2 days after a diptheria, pertussis, tetanus vaccination. She is the firstborn of first-degree cousins of AshkenaziJewish origin. The pregnancy and delivery were uneventful, and her birth weight was 3,200 gm. Her psychomotor development was adequate for her age. On admission, she was responsive but looked pale and exhausted; a marked paucity of spontaneous movements was evident. Her weight, head circumference, temperature, blood pressure, pulse, and respiratory rate were 8,600 gm, 44 cm, 38.3°C, 80/55 mm Hg, 170 beats per minute, and 70 breaths per minute, respectively. Muscle tone was generally decreased, muscle mass was normal, and deep tendon reflexes were elicited. No dysphagia or ophthalmoplegia was present, and the strength of her sucking was normal. The liver was palpable 2 cm below the right costal margin. The rest of the physical examination was normal. Serum glucose and blood gases were normal. The serum creatine kinase (CK) level was 56,000 U/L (normal less than 150) and increased to a peak level of 140,000 U/L within several hours. The peak level of aspartate aminotransferase was 4,000 U/L (normal less than 56) and alanine aminotransferase was 800 U/L (normal less than 50). The prothrombin time was mildly prolonged, and the bilirubin was normal. The total serum carnitine level was 56.8 uM. The plasma acylcarnitine analysis by fast atom bombardment-mass spectrometry revealed reduced acetylcarnitine and elevated long-chain (C12:0-C18:1) species (Dr. S.G. Kahler, Duke University Medical Center, Durham, NC). Blood cultures were negative. The concentration of myoglobin in the urine was 9,830 ng/mL (control less than 5). Urinary organic acid analysis disclosed a normal profile. Echocardiographic, electroencephalographic, and abdominal ultrasound studies were normal. The patient was treated with intravenous fluids and alkalinization of the urine. A marked clinical improvement was evident within 2 days, and the CK returned to normal after 10 days. Myoglobinuria never recurred, and at 4 years, her psychomotor development was age appropriate.
Communications should be addressed to: Dr. Hurvitz; Department of Pediatrics; Bikur Cholim General Hospital; PO Box 492; Jerusalem 91004, Israel. Received June 4, 1999; accepted October 7, 1999.
© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00125-3 ● 0887-8994/00/$20.00
Methods The oxidation of (9-10-3H) palmitic acid in fresh lymphocytes and cultured fibroblasts was essentially determined as previously described [6]. The activity of CPTs I and II in fibroblasts was determined according to Ijist et al. [7]. Genomic DNA was isolated from fibroblasts of the patient. The five exons of the CPT II gene and the exon-intron junctions were amplified using the oligonucleotide primers, as previously described [8]. Two additional primers within exon 4, CPT5 5⬘-TGAGGAGAGCCTGAGGAAAG-3⬘ and CPT6 5⬘-AATGGGGAAGTCATCTAGGC-3⬘ were used for sequence analysis. Direct sequencing was performed on an automatic sequencer (ABI Prism 377, Perkin-Elmer Norwalk, CT) using the Dye Terminator Cycle Sequencing Core Kit (Perkin-Elmer), according to the manufacturer’s instructions.
Table 1.
CPT II activity and LCFA oxidation in fibroblasts
Prominent Symptoms Infantile form Adolescent form Present patient
Liver failure, cardiomyopathy Myoglobinuria Myoglobinuria
CPT II Activity (% of Mean)
LCFA Oxidation (% of Mean)
4-10
⬍ 10
15-26 16.5
80 31
Data from Bonnefont et al. [12]. Abbreviations: CPT ⫽ Carnitine palmitoyltransferase LCFA ⫽ Long-chain fatty acid
Results The oxidation of (9,10-3H) palmitic acid in lymphocytes and in fibroblasts was 42 pmol/minute/mg protein (control 157.8 ⫾ 51) and 43 pmol/minute/mg protein (control 135.8 ⫾ 63), respectively. In the fibroblasts the activity of CPT I was 1.51 nmol/minute/mg protein (control 0.58 ⫾ 0.26); the activity of CPT II was 2.55 nmol/minute/mg protein (control 15.37 ⫾ 3.13). The entire coding region of the CPT II gene and its exon-intron junctions were sequenced. The homozygosity for the S113L mutation was identified. In addition the patient was homozygous for substitutions V368I and M647V. No other mutations were identified. Discussion This patient presented at 8 months of age with febrile myoglobinuria after a routine vaccination. Her heart, brain, and liver were clinically unaffected, and the serum glucose was normal. The differential diagnosis of infantile myoglobinuria includes infectious, toxic, ischemic, traumatic, and genetic conditions. Inborn errors of metabolism, such as myophosphorylase or phosphofructokinase deficiency, may also present in infancy [9], yet metabolic causes of myoglobinuria in the young are typically considered only when the liver, heart, or brain are concomitantly involved. The clinical onset of CPT II deficiency is usually around puberty, with muscle pain and elevated serum CK levels after prolonged exercise [2]. Clinical heterogeneity of this adolescent phenotype has been reported within families, ranging from a lack of symptoms to fatal myoglobinuria [10]. A small number of patients with CPT II deficiency presented in early infancy with encephalopathy, hypertrophic cardiomyopathy, and hepatocellular disease [3-5]. A newborn with CPT II deficiency presented antenatally with decreased fetal movements and polyhydramnios; at birth he had severe myopathy that led to fatal respiratory insufficiency [11]. The molecular basis of many patients with the infantile hepatocardiomuscular form and the adolescent myoglobinuric form has been elucidated [12-15]. The most common mutation among the alleles of the adolescent
form is a substitution of serine for leucine at codon 113 (S113L), which is carried by approximately 60% of the mutated alleles. This mutation was revealed by pulsechase experiments to interfere with the stability of the enzymatic protein [16]. The early onset in the present patient who presented with isolated myoglobinuria and was homozygous for the common S113L mutation is noteworthy. It is unlikely that her being homozygous for the V368I and M647V substitutions contributed to the early presentation. Homozygosity for these substitutions was observed in four of 59 clinically asymptomatic whites, indicating the benign nature of this variant [12]. These substitutions were harbored by all S113L alleles in a large series of adult patients with the muscular phenotype. When associated with the S113L mutation, the substitutions were functionally inert and had no synergistic effect [12]. In line with the relatively late clinical onset of homozygotes for the S113L mutation the overall oxidation of LCFAs in their cells was only marginally decreased [12]. Thus despite the marked reduction of CPT II activity to 15-26% of the control, the LCFA oxidation, determined with [9,10-3H] myristate, was about 80% of the control [12]. This level stood in sharp contrast to the severely impaired (less than 10% of the control) LCFA oxidation in patients with the hepatocardiomuscular form, whose residual CPT II activity was 4-10% of the control [12]. Our patient differed from these two groups in that she had residual CPT II activity well within the adolescent range, which was associated with a markedly impaired LCFA oxidation capacity (Table 1). Therefore the early presentation could be attributed to an impaired activity of other enzymes of the beta-oxidation pathway in this member of a highly consanguineous family. CPT II deficiency should be included in the differential diagnosis of myoglobinuria in infancy, even in the absence of hepatic and cardiac involvement. The age of clinical onset of CPT II deficiency correlates not only with the genotype but also with the global function of the betaoxidation pathway.
Hurvitz et al: CPT II Deficiency in Infancy 149
References [1] McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Ann Rev Biochem 1980;49:395-420. [2] DiMauro S, DiMauro PMM. Muscle carnitine palmitoyl transferase deficiency and myoglobinuria. Science 1973;182:929-31. [3] Hug G, Bove KE, Soukup S. Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II. N Engl J Med 1991;325: 1862-4. [4] Demaugre F, Bonnefont JP, Colonna M, Cepanec C, Leroux JP, Sadubray JM. Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death. Physiopathological approach to carnitine palmitoyltransferase II deficiencies. J Clin Invest 1991;87:859-64. [5] Ross B, Zucherberg ALL, Geraghty MT. Carnitine palmitoyltransferase II (CPT II) deficiency presenting with hyperammonemia in an infant. Am J Hum Genet 1996;59 (Suppl):A379. [6] Manning NJ, Olpin SE, Pollitt RJ, Webley J. A comparison of [9,10-3H]palmitic and [9,10-3H]myristic acids for the detection of defects of fatty acid oxidation in intact cultured fibroblasts. J Inher Metab Dis 1990;13:58-68. [7] Ijist L, Mandel H, Oostheim W, Ruiter JP, Gutman A, Wander RJ. Molecular basis of hepatic carnitine palmitoyltransferase I deficiency. J Clin Invest 1998;102:527-31. [8] Verderio E, Cavadini P, Montermini L, et al. Carnitine palmitoyltransferase II deficiency: Structure of the gene and characterization of two novel disease causing mutations. Hum Mol Genet 1995;4:19-29.
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[9] DiMauro S, Hartlage PL. Fatal infantile form of muscle phosphorylase deficiency. Neurology 1978;28:1124-9. [10] Handig I, Dams E, Taroni F, Van Laere S, de Barsy T, Willems PJ. Inheritance of the S113L mutation within an inbred family with carnitine palmitoyltransferase enzyme deficiency. Hum Genet 1996;97: 291-3. [11] Land JM, Mistry S, Squier M, et al. Neonatal carnitine palmitoyltransferase-2 deficiency: A case presenting with myopathy. Neuromusc Dis 1995;5:129-37. [12] Bonnefont JP, Taroni F, Cavadini P, et al. Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomuscular expression. Am J Hum Genet 1996;58:971-8. [13] Tagart RT, Small D, Apolito C, Vladutiu GD. Novel mutations associated with carnitine palmitoyltransferase II deficiency. Hum Mutat 1999;13:210-20. [14] Wataya K, Akanuma J, Cavadini P, et al. Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: Functional analysis and association with polymorphic haplotypes and two clinical phenotypes. Hum Mutat 1998;11:377-86. [15] Yang BZ, Ding JH, Dewese T, et al. Identification of four novel mutations in patients with carnitine palmitoyltransferase II (CPT II) deficiency. Mol Genet Metab 1998;64:229-36. [16] Taroni F, Verderio E, Dworzak F, Willems PJ, Cavadini P, DiDonato S. Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet 1993;4:314-20.
Introduction The beta-oxidation of long-chain fatty acids (LCFAs) requires their import into the mitochondria. This process is carnitine dependent and is catalyzed by two carnitine
From the *Department of Pediatrics; Bikur Cholim General Hospital; Hebrew University-Hadassah Medical School; †Pediatric Neurology Unit; Bikur Cholim General Hospital; Jerusalem, Israel; ‡University Hospital Amsterdam; Academic Medical Center; Amsterdam, The Netherlands; and §Metabolic Disease Unit; Shaare-Zedek Medical Center; Jerusalem, Israel.
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palmitoyltransferases (CPTs) and carnitine-acylcarnitine translocase. The outer membrane CPT I is involved in the esterification of palmitoyl-coenzyme A (CoA) to yield palmitoyl carnitine. After translocation across the inner mitochondrial membrane the palmitoyl carnitine molecule is reconverted into carnitine and palmitoyl-CoA by the activity of CPT II [1]. Deficiency of CPT II typically manifests around puberty, with exercise intolerance and myoglobinuria [2]. In the few patients who presented with CPT II in infancy the clinical picture was dominated by encephalopathy, cardiomyopathy, and hepatomegaly and was associated with hypoglycemia and long-chain acylcarnitine accumulation [3-5]. An 8-month-old infant with CPT II deficiency who presented with myoglobinuria is reported.
Case Report An 8-month-old female was admitted to the hospital because of high fever and listlessness for 2 days after a diptheria, pertussis, tetanus vaccination. She is the firstborn of first-degree cousins of AshkenaziJewish origin. The pregnancy and delivery were uneventful, and her birth weight was 3,200 gm. Her psychomotor development was adequate for her age. On admission, she was responsive but looked pale and exhausted; a marked paucity of spontaneous movements was evident. Her weight, head circumference, temperature, blood pressure, pulse, and respiratory rate were 8,600 gm, 44 cm, 38.3°C, 80/55 mm Hg, 170 beats per minute, and 70 breaths per minute, respectively. Muscle tone was generally decreased, muscle mass was normal, and deep tendon reflexes were elicited. No dysphagia or ophthalmoplegia was present, and the strength of her sucking was normal. The liver was palpable 2 cm below the right costal margin. The rest of the physical examination was normal. Serum glucose and blood gases were normal. The serum creatine kinase (CK) level was 56,000 U/L (normal less than 150) and increased to a peak level of 140,000 U/L within several hours. The peak level of aspartate aminotransferase was 4,000 U/L (normal less than 56) and alanine aminotransferase was 800 U/L (normal less than 50). The prothrombin time was mildly prolonged, and the bilirubin was normal. The total serum carnitine level was 56.8 uM. The plasma acylcarnitine analysis by fast atom bombardment-mass spectrometry revealed reduced acetylcarnitine and elevated long-chain (C12:0-C18:1) species (Dr. S.G. Kahler, Duke University Medical Center, Durham, NC). Blood cultures were negative. The concentration of myoglobin in the urine was 9,830 ng/mL (control less than 5). Urinary organic acid analysis disclosed a normal profile. Echocardiographic, electroencephalographic, and abdominal ultrasound studies were normal. The patient was treated with intravenous fluids and alkalinization of the urine. A marked clinical improvement was evident within 2 days, and the CK returned to normal after 10 days. Myoglobinuria never recurred, and at 4 years, her psychomotor development was age appropriate.
Communications should be addressed to: Dr. Hurvitz; Department of Pediatrics; Bikur Cholim General Hospital; PO Box 492; Jerusalem 91004, Israel. Received June 4, 1999; accepted October 7, 1999.
© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00125-3 ● 0887-8994/00/$20.00
Methods The oxidation of (9-10-3H) palmitic acid in fresh lymphocytes and cultured fibroblasts was essentially determined as previously described [6]. The activity of CPTs I and II in fibroblasts was determined according to Ijist et al. [7]. Genomic DNA was isolated from fibroblasts of the patient. The five exons of the CPT II gene and the exon-intron junctions were amplified using the oligonucleotide primers, as previously described [8]. Two additional primers within exon 4, CPT5 5⬘-TGAGGAGAGCCTGAGGAAAG-3⬘ and CPT6 5⬘-AATGGGGAAGTCATCTAGGC-3⬘ were used for sequence analysis. Direct sequencing was performed on an automatic sequencer (ABI Prism 377, Perkin-Elmer Norwalk, CT) using the Dye Terminator Cycle Sequencing Core Kit (Perkin-Elmer), according to the manufacturer’s instructions.
Table 1.
CPT II activity and LCFA oxidation in fibroblasts
Prominent Symptoms Infantile form Adolescent form Present patient
Liver failure, cardiomyopathy Myoglobinuria Myoglobinuria
CPT II Activity (% of Mean)
LCFA Oxidation (% of Mean)
4-10
⬍ 10
15-26 16.5
80 31
Data from Bonnefont et al. [12]. Abbreviations: CPT ⫽ Carnitine palmitoyltransferase LCFA ⫽ Long-chain fatty acid
Results The oxidation of (9,10-3H) palmitic acid in lymphocytes and in fibroblasts was 42 pmol/minute/mg protein (control 157.8 ⫾ 51) and 43 pmol/minute/mg protein (control 135.8 ⫾ 63), respectively. In the fibroblasts the activity of CPT I was 1.51 nmol/minute/mg protein (control 0.58 ⫾ 0.26); the activity of CPT II was 2.55 nmol/minute/mg protein (control 15.37 ⫾ 3.13). The entire coding region of the CPT II gene and its exon-intron junctions were sequenced. The homozygosity for the S113L mutation was identified. In addition the patient was homozygous for substitutions V368I and M647V. No other mutations were identified. Discussion This patient presented at 8 months of age with febrile myoglobinuria after a routine vaccination. Her heart, brain, and liver were clinically unaffected, and the serum glucose was normal. The differential diagnosis of infantile myoglobinuria includes infectious, toxic, ischemic, traumatic, and genetic conditions. Inborn errors of metabolism, such as myophosphorylase or phosphofructokinase deficiency, may also present in infancy [9], yet metabolic causes of myoglobinuria in the young are typically considered only when the liver, heart, or brain are concomitantly involved. The clinical onset of CPT II deficiency is usually around puberty, with muscle pain and elevated serum CK levels after prolonged exercise [2]. Clinical heterogeneity of this adolescent phenotype has been reported within families, ranging from a lack of symptoms to fatal myoglobinuria [10]. A small number of patients with CPT II deficiency presented in early infancy with encephalopathy, hypertrophic cardiomyopathy, and hepatocellular disease [3-5]. A newborn with CPT II deficiency presented antenatally with decreased fetal movements and polyhydramnios; at birth he had severe myopathy that led to fatal respiratory insufficiency [11]. The molecular basis of many patients with the infantile hepatocardiomuscular form and the adolescent myoglobinuric form has been elucidated [12-15]. The most common mutation among the alleles of the adolescent
form is a substitution of serine for leucine at codon 113 (S113L), which is carried by approximately 60% of the mutated alleles. This mutation was revealed by pulsechase experiments to interfere with the stability of the enzymatic protein [16]. The early onset in the present patient who presented with isolated myoglobinuria and was homozygous for the common S113L mutation is noteworthy. It is unlikely that her being homozygous for the V368I and M647V substitutions contributed to the early presentation. Homozygosity for these substitutions was observed in four of 59 clinically asymptomatic whites, indicating the benign nature of this variant [12]. These substitutions were harbored by all S113L alleles in a large series of adult patients with the muscular phenotype. When associated with the S113L mutation, the substitutions were functionally inert and had no synergistic effect [12]. In line with the relatively late clinical onset of homozygotes for the S113L mutation the overall oxidation of LCFAs in their cells was only marginally decreased [12]. Thus despite the marked reduction of CPT II activity to 15-26% of the control, the LCFA oxidation, determined with [9,10-3H] myristate, was about 80% of the control [12]. This level stood in sharp contrast to the severely impaired (less than 10% of the control) LCFA oxidation in patients with the hepatocardiomuscular form, whose residual CPT II activity was 4-10% of the control [12]. Our patient differed from these two groups in that she had residual CPT II activity well within the adolescent range, which was associated with a markedly impaired LCFA oxidation capacity (Table 1). Therefore the early presentation could be attributed to an impaired activity of other enzymes of the beta-oxidation pathway in this member of a highly consanguineous family. CPT II deficiency should be included in the differential diagnosis of myoglobinuria in infancy, even in the absence of hepatic and cardiac involvement. The age of clinical onset of CPT II deficiency correlates not only with the genotype but also with the global function of the betaoxidation pathway.
Hurvitz et al: CPT II Deficiency in Infancy 149
References [1] McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Ann Rev Biochem 1980;49:395-420. [2] DiMauro S, DiMauro PMM. Muscle carnitine palmitoyl transferase deficiency and myoglobinuria. Science 1973;182:929-31. [3] Hug G, Bove KE, Soukup S. Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II. N Engl J Med 1991;325: 1862-4. [4] Demaugre F, Bonnefont JP, Colonna M, Cepanec C, Leroux JP, Sadubray JM. Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death. Physiopathological approach to carnitine palmitoyltransferase II deficiencies. J Clin Invest 1991;87:859-64. [5] Ross B, Zucherberg ALL, Geraghty MT. Carnitine palmitoyltransferase II (CPT II) deficiency presenting with hyperammonemia in an infant. Am J Hum Genet 1996;59 (Suppl):A379. [6] Manning NJ, Olpin SE, Pollitt RJ, Webley J. A comparison of [9,10-3H]palmitic and [9,10-3H]myristic acids for the detection of defects of fatty acid oxidation in intact cultured fibroblasts. J Inher Metab Dis 1990;13:58-68. [7] Ijist L, Mandel H, Oostheim W, Ruiter JP, Gutman A, Wander RJ. Molecular basis of hepatic carnitine palmitoyltransferase I deficiency. J Clin Invest 1998;102:527-31. [8] Verderio E, Cavadini P, Montermini L, et al. Carnitine palmitoyltransferase II deficiency: Structure of the gene and characterization of two novel disease causing mutations. Hum Mol Genet 1995;4:19-29.
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[9] DiMauro S, Hartlage PL. Fatal infantile form of muscle phosphorylase deficiency. Neurology 1978;28:1124-9. [10] Handig I, Dams E, Taroni F, Van Laere S, de Barsy T, Willems PJ. Inheritance of the S113L mutation within an inbred family with carnitine palmitoyltransferase enzyme deficiency. Hum Genet 1996;97: 291-3. [11] Land JM, Mistry S, Squier M, et al. Neonatal carnitine palmitoyltransferase-2 deficiency: A case presenting with myopathy. Neuromusc Dis 1995;5:129-37. [12] Bonnefont JP, Taroni F, Cavadini P, et al. Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomuscular expression. Am J Hum Genet 1996;58:971-8. [13] Tagart RT, Small D, Apolito C, Vladutiu GD. Novel mutations associated with carnitine palmitoyltransferase II deficiency. Hum Mutat 1999;13:210-20. [14] Wataya K, Akanuma J, Cavadini P, et al. Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: Functional analysis and association with polymorphic haplotypes and two clinical phenotypes. Hum Mutat 1998;11:377-86. [15] Yang BZ, Ding JH, Dewese T, et al. Identification of four novel mutations in patients with carnitine palmitoyltransferase II (CPT II) deficiency. Mol Genet Metab 1998;64:229-36. [16] Taroni F, Verderio E, Dworzak F, Willems PJ, Cavadini P, DiDonato S. Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet 1993;4:314-20.