Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review

Sigauke, Ellen; Rakheja, Dinesh; Kitson, Kimberly; Bennett, Michael J.

doi:10.1097/01.lab.0000098428.51765.83

Cited by 93 publications

(84 citation statements)

References 112 publications

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“…Most reports also recommend early analgesia. 1,[6][7][8][9] The first case report of CPT II deficiency in pregnancy was published in 1994. 7 It describes the use of a 10% dextrose infusion and close monitoring of blood sugars in a woman with CPT II deficiency during labour.…”

Section: Discussionmentioning

confidence: 99%

Anesthetic management of a parturient with carnitine palmitoyltransferase ii deficiency

Lilker

Kasodekar

Goldszmidt

2006

Can J Anesth/J Can Anesth

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Purpose: To report the anesthetic management of a patient with carnitine palmitoyltransferase II deficiency who presented for labour and delivery. Clinical features:A 30-yr-old primiparous woman with known carnitine palmitoyltransferase II deficiency and a past history of exercise induced muscle pain, weakness and myoglobinuria presented in active labour. Management consisted of an early epidural for labour and continuous dextrose infusion with frequent blood sugar monitoring. She had an uneventful spontaneous vaginal delivery. She experienced a single asymptomatic episode of hypoglycemia on the first postpartum day. Her serum creatine kinase was six times normal at 24 hr postdelivery and remained elevated for three days without evidence of rhabdomyolysis. The remainder of her postpartum course was uneventful. Conclusion:Labour and delivery is a potential precipitant of rhabdomyolysis in patients with carnitine palmitoyltransferase II deficiency. The normal postpartum creatine kinase elevation (two to four times baseline at 24 hr) must be taken into account when monitoring these patients. On the basis of the physiologic principles, institution of early epidural analgesia to blunt the stress response to labour and delivery, continuous dextrose infusion and frequent glucose monitoring during labour and postpartum are the mainstays of management. Objectif

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Section: Discussionmentioning

confidence: 99%

Anesthetic management of a parturient with carnitine palmitoyltransferase ii deficiency

Lilker

Kasodekar

Goldszmidt

2006

Can J Anesth/J Can Anesth

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“…The CPT enzyme system consists of several mitochondrial membrane-bound enzymes: CPT I, CPT II (EC 2.3.1.21), and carnitine-acylcarnitine translocase. CPT II is located on the inner aspect of the inner mitochondrial membrane and converts long-chain acylcarnitines to long-chain acyl-CoAs [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

“…The neonatal form is more severe than the infantile form. Many sudden death cases are reported, most often during the first month of life [1][2][3]7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Various mutations of the CPT2 gene have been reported and some of the more severe mutations are fatal [1][2][3]. Carnitine palmitoyltransferase 2 gene polymorphisms have not been reported to affect enzyme activity, although a thermolabile phenotype of the CPT2 polymorphism (F352C) has been recently reported to reduce enzyme activity at high temperature [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Carnitine palmitoyltransferase 2 gene polymorphism is a genetic risk factor for sudden unexpected death in infancy

Yamamoto

Tanaka

Emoto

et al. 2014

Brain and Development

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Rationale: Carnitine palmitoyltransferase (CPT) II is one of a pivotal enzyme in mitochondrial fatty acid oxidation, which is essential for energy production during simultaneous glucose sparing and a requirement for major energy supply, such as prolonged fasting or exercise. When infants require more energy than provided by the glycolytic system, they rely on the mitochondrial fatty acid oxidation pathway.Mutations of the CPT2 gene have been reported to cause sudden unexpected death in infancy (SUDI). A thermolabile phenotype of a CPT2 polymorphism (F352C) has been recently reported to reduce CPT II enzyme activity. The F352C variant results in energy crisis at high temperature and is suspected as a risk factor for acute encephalopathy. However, a relationship between CPT2 gene polymorphism and SUDI has not been described. Methods: Single nucleotide polymorphisms of the CPT2 gene were investigated among 54 SUDI cases and 200 healthy volunteers.Results: The frequency of the C allele was significantly higher in the SUDI group than in the control group [25.0% vs 16.0%, odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.05-2.92, p = 0.030). The frequency of the F352C homozygote was significantly higher in the SUDI group than in control group (11.1% vs 3.5%, OR = 3 3.45, 95% CI = 1.11-10.73, p = 0.036). Conclusion: The F352C CPT2 variant might be a genetic risk factor for SUDI.

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“…Inherited mutational defects of these enzymes are the cause of many human diseases (2,3). CPT-I deficiency is linked to serious episodes of hypoketonic hypoglycemia, whereas autosomal recessive deficiency of CPT-II is one of the most common inherited muscle lipid metabolism disorders (6). Both missense and deletion mutations have been described for these enzymes, and the defect of the mutated enzymes is most often caused by their reduced catalytic activity.…”

mentioning

confidence: 99%

Crystal Structure of Mouse Carnitine Octanoyltransferase and Molecular Determinants of Substrate Selectivity*[boxs]

Jogl

Hsiao

Tong

2005

Journal of Biological Chemistry

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Carnitine acyltransferases have crucial functions in fatty acid metabolism. Members of this enzyme family show distinctive substrate preferences for short-, medium-or long-chain fatty acids. The molecular mechanism for this substrate selectivity is not clear as so far only the structure of carnitine acetyltransferase has been determined. To further our understanding of these important enzymes, we report here the crystal structures at up to 2.0-Å resolution of mouse carnitine octanoyltransferase alone and in complex with the substrate octanoylcarnitine. The structures reveal significant differences in the acyl group binding pocket between carnitine octanoyltransferase and carnitine acetyltransferase. Amino acid substitutions and structural changes produce a larger hydrophobic pocket that binds the octanoyl group in an extended conformation. Mutation of a single residue (Gly-553) in this pocket can change the substrate preference between short-and medium-chain acyl groups. The side chains of Cys-323 and Met-335 at the bottom of this pocket assume dual conformations in the substrate complex, and mutagenesis studies suggest that the Met-335 residue is important for catalysis.Carnitine acyltransferases catalyze the reversible transfer of acyl groups between carnitine and coenzyme A (see Fig. 1A) (1-4). Members of this family of enzymes include carnitine palmitoyltransferases (CPTs) 1 I and II (CPT-I, CPT-II), carnitine octanoyltransferase (CrOT), and carnitine acetyltransferase (CrAT) with substrate preferences for long-chain, medium-chain, and short-chain acyl groups, respectively. The catalytic domains of these enzymes contain about 600 amino acid residues (see Fig. 1B), and share ϳ30% amino acid sequence identity (see supplemental Fig. 1).Carnitine acyltransferases are of crucial importance for the transport of fatty acids among different cellular compartments (2-4). The CPTs are associated with the mitochondrial compartment and are essential for the import of long-chain fatty acids into the mitochondria for ␤-oxidation. The CoA esters of long-chain fatty acids are impermeable to the mitochondrial membrane. They must first be converted to carnitine esters by CPT-I, which is integrally associated with the outer membrane of the mitochondria through a unique N-terminal segment (see Fig. 1B) (5). Upon transport into the mitochondria, the carnitine esters are converted back to CoA esters by CPT-II, which is located in the mitochondrial matrix. The CoA esters can then undergo ␤-oxidation for energy production.The CPTs are therefore key enzymes for the transport of longchain fatty acids. Inherited mutational defects of these enzymes are the cause of many human diseases (2, 3). CPT-I deficiency is linked to serious episodes of hypoketonic hypoglycemia, whereas autosomal recessive deficiency of CPT-II is one of the most common inherited muscle lipid metabolism disorders (6). Both missense and deletion mutations have been described for these enzymes, and the defect of the mutated enzymes is most often caused by their reduce...

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Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review

Cited by 93 publications

References 112 publications

Anesthetic management of a parturient with carnitine palmitoyltransferase ii deficiency

Anesthetic management of a parturient with carnitine palmitoyltransferase ii deficiency

Carnitine palmitoyltransferase 2 gene polymorphism is a genetic risk factor for sudden unexpected death in infancy

Crystal Structure of Mouse Carnitine Octanoyltransferase and Molecular Determinants of Substrate Selectivity*[boxs]

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