TwoCPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: Functional analysis and association with polymorphic haplotypes and two clinical phenotypes

Wataya, Kaoru; Akanuma, Jun; Cavadini, Patrizia; Aoki, Yoko; Kure, Shigeo; Invernizzi, Federica; Yoshida, Ichiro; Kira, Jun Ichi; Taroni, Franco; Matsubara, Yoichi; Narisawa, Kuniaki

doi:10.1002/(sici)1098-1004(1998)11:5<377::aid-humu5>3.0.co;2-e

Cited by 56 publications

(2 citation statements)

References 22 publications

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“…Typical presentations involve the liver in the form of acute liver failure and hypoglycemia precipitating seizures and coma, as well as the heart in the form of cardiomyopathies and arrhythmias [ 5 ]. Paroxysmal heartbeat disorders are thought to be the cause of sudden infant death during the first year of life [ 8 - 10 , 12 , 14 ]. This could explain the sudden deterioration in our patient's twin sister's health and her death at the age of 10 weeks of life.…”

Section: Discussionmentioning

confidence: 99%

A Case of Carnitine Palmitoyltransferase II Deficiency in Bahrain With a Novel Mutation

Alsahlawi¹,

Fadhul²,

Mahmood³

et al. 2022

Cureus

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Carnitine palmitoyltransferase II (CPT II) deficiency is a rare genetic metabolic disorder. Three forms of the disease have been described: the lethal neonatal form, the severe infantile hepatocardiomuscular form, and the myopathic form. We report a case of the infantile form of CPT II deficiency with a novel mutation. Our patient is a seven-year-old Bahraini male who was investigated by the pediatric metabolic team following the sudden death of his twin sister in infancy. A fatty acid metabolic disorder was suspected based on his echocardiogram and tandem mass spectrometry (TMS) findings. Genetic analysis was initially inconclusive. Nonetheless, he was started on a fat-free diet, L-carnitine, and medium-chain triglycerides (MCT). At nearly two years of age, the patient had a metabolic crisis precipitated by a viral illness. TMS during this time was consistent with CPT II deficiency. Sanger sequencing then identified the presence of the variant c.161T>G (p.ille54Ser) in a homozygous state, confirming the diagnosis. Although this mutation has not been reported before in previous literature concerning CPT II deficiency, it is extremely likely that this mutation is pathogenic. Although the initial work-up of the patient was inconclusive, our clinical judgment was paramount in managing the patient.

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Section: Discussionmentioning

confidence: 99%

A Case of Carnitine Palmitoyltransferase II Deficiency in Bahrain With a Novel Mutation

Alsahlawi¹,

Fadhul²,

Mahmood³

et al. 2022

Cureus

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“…‡ To whom correspondence and reprint requests should be addressed: (18,22,23). One missense mutation, S113L, accounts for ϳ60% of the mutant alleles responsible for the adult myopathic form of the disease (24,25).…”

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confidence: 99%

Identification by Mutagenesis of a Conserved Glutamate (Glu487) Residue Important for Catalytic Activity in Rat Liver Carnitine Palmitoyltransferase II

Zheng

Dai

Woldegiorgis

2002

Journal of Biological Chemistry

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Mammalian mitochondrial membranes express two active but distinct carnitine palmitoyltransferases: carnitine palmitoyltransferase I (CPTI), which is malonyl coA-sensitive and detergent-labile; and carnitine palmitoyltransferase II (CPTII), which is malonyl coA-insensitive and detergent-stable. To determine the role of the highly conserved C-terminal acidic residues glutamate 487 (Glu 487 ) and glutamate 500 (Glu 500 ) on catalytic activity in rat liver CPTII, we separately mutated these residues to alanine, aspartate, or lysine, and the effect of the mutations on CPTII activity was determined in the Escherichia coli-expressed mutants. Substitution of Glu 487 with alanine, aspartate, or lysine resulted in almost complete loss in CPTII activity. Because a conservative substitution mutation of this residue, Glu 487 with aspartate (E487D), resulted in a 97% loss in activity, we predicted that Glu 487 would be at the active-site pocket of CPTII. The substantial loss in CPTII activity observed with the E487K mutant, along with the previously reported loss in activity observed in a child with a CPTII deficiency disease, establishes that Glu 487 is crucial for maintaining the configuration of the liver isoform of the CPTII active site. Substitution of the conserved Glu 500 in CPTII with alanine or aspartate reduced the V max for both substrates, suggesting that Glu 500 may be important in stabilization of the enzyme-substrate complex. A conservative substitution of Glu 500 to aspartate resulted in a significant decrease in the V max for the substrates. Thus, Glu 500 may play a role in substrate binding and catalysis. Our site-directed mutagenesis studies demonstrate that Glu 487 in the liver isoform of CPTII is essential for catalysis.Carnitine palmitoyltransferase (CPT) 1 I and CPTII, in conjunction with carnitine translocase, transport long chain fatty acids from the cytoplasm to the mitochondrial matrix for ␤-oxidation (1, 2). Mammalian mitochondrial membranes express two active but distinct carnitine palmitoyltransferases (CPTI and CPTII), a malonyl CoA-sensitive, detergent-labile CPTI, and a malonyl-CoA-insensitive, detergent-stable CPTII. CPTI is an integral membrane enzyme located on the outer mitochondrial membrane, and CPTII is a membrane-associated enzyme loosely bound to the matrix side of the inner mitochondrial membrane. A current model for the membrane topology of CPTI predicts exposure of the N-and C-terminal domains crucial for activity and malonyl-CoA sensitivity on the cytosolic side of the outer mitochondrial membrane (3). As an enzyme that catalyzes the rate-limiting step in fatty acid oxidation, CPTI is tightly regulated by its physiologic inhibitor, malonylCoA, the first intermediate in fatty acid synthesis (1, 2). This is an important regulatory mechanism in fatty acid metabolism and suggests coordinated control of fatty acid oxidation and synthesis. Mammalian tissues express two isoforms of CPTI, a liver isoform of CPTI and a heart/skeletal muscle isoform of CPTI, that are 62% identical in amino ...

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Muscle Carnitine Palmitoyltransferase II Deficiency

Deschauer

Wieser²,

Zierz³

2005

Arch Neurol

116

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uscle carnitine palmitoyltransferase (CPT) II deficiency is an autosomal recessive disorder of fatty acid oxidation characterized by attacks of myalgia and myoglobinuria. This review summarizes the clinical features of this disease, analyzing data of 28 patients with biochemically and genetically confirmed CPT II deficiency. The review shows that exercise-induced myalgia is the most frequent symptom, whereas myoglobinuria, known as the clinical hallmark, is missing in 21% of the patients. Typically, myalgia starts in childhood, whereas attacks with myoglobinuria mostly emerge in adolescence or early adulthood. However, there are also patients with only myalgia, patients with attacks triggered by factors other than exercise, and patients with late-onset disease. Molecular or biochemical analysis is necessary for diagnosis, since no myopathologic hallmark exists. For screening patients, analysis of not only the common S113L mutation but also the P50H and Q413fs-F448L mutations is recommended. The phenotype of muscle CPT II deficiency might be influenced by the underlying mutation, and patients with a truncating mutation on 1 allele might be affected more severely.

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TwoCPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: Functional analysis and association with polymorphic haplotypes and two clinical phenotypes

Cited by 56 publications

References 22 publications

A Case of Carnitine Palmitoyltransferase II Deficiency in Bahrain With a Novel Mutation

A Case of Carnitine Palmitoyltransferase II Deficiency in Bahrain With a Novel Mutation

Identification by Mutagenesis of a Conserved Glutamate (Glu487) Residue Important for Catalytic Activity in Rat Liver Carnitine Palmitoyltransferase II

Muscle Carnitine Palmitoyltransferase II Deficiency

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