Hepatic and Muscular Presentations of Carnitine Palmitoyl Transferase Deficiency: Two Distinct Entities

Bonnefont, Jean‐Paul; Mitchell, G. H.; Nguyen-Hoang, Nam; Pelet, Anna; Rimoldi, M.; Donato, Stefano Di; Saudubray, Jean Marie

doi:10.1203/00006450-198809000-00006

Cited by 127 publications

(68 citation statements)

References 9 publications

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“…The symptoms are usually precipitated by heavy exercise, and to a lesser extent, by cold, infection, emotional distress, and/or fasting. Renal failure may be a complication in some cases (Demaugre et al, 1988). The infantile form, which usually presents in early childhood with fasting-induced hypoketotic hypoglycemia, liver failure, cardiomyopathy, and peripheral neuropathy, is potentially fatal, although treatable if diagnosed early (Hug et al, 1991;Taroni et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…Serum myoglobin levels are elevated in some cases (Shintani et al, 1995). There may be elevated levels of serum creatinine and blood urea nitrogen, and acute renal failure may occur (Berkman et al, 1993;Demaugre et al, 1988;Kelly et al, 1989;Shintani et al, 1995;Villard et al, 1996). Hypocalcemia may occur because of muscle necrosis.…”

Section: Diagnosismentioning

confidence: 99%

“…Electromyography may demonstrate muscle injury; however, results can be normal in some cases (Kelly et al, 1989;Mongini et al, 1991). In the infantile form, marked hypoglycemia and hypoketonuria caused by deficient hepatic ketogenesis are common findings (Demaugre et al, 1988).…”

Section: Diagnosismentioning

confidence: 99%

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

Sigauke

Rakheja

Kitson

et al. 2003

Laboratory Investigation

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SUMMARY:Congenital deficiency of carnitine palmitoyltransferase (CPT) II has been known for at least 30 years now, and its phenotypic variability remains fascinating. Three distinct clinical entities have been described, the adult, the infantile, and the perinatal, all with an autosomal recessive inheritance pattern. The adult CPT II clinical phenotype is somewhat benign and requires additional external triggers such as high-intensity exercise before the predominantly myopathic symptoms are elicited. The perinatal and infantile forms involve multiple organ systems. The perinatal disease is the most severe form and is invariably fatal. The introduction of mass spectrometry to analyze blood acylcarnitine profiles has revolutionized the diagnosis of fatty acid oxidation disorders including CPT II deficiency. Its use in expanded neonatal screening programs has made presymptomatic diagnosis a reality. An increasing number of mutations are being identified in the CPT II gene with a distinct genotype-phenotype correlation in most cases. However, clinical variability in some patients suggests additional genetic or environmental modifiers. Herein, we present a new case of lethal perinatal CPT II deficiency with a rare missense mutation, R296Q (907GϾA) associated with a previously described 25-bp deletion on the second allele. We review the clinical features, the diagnostic protocol including expanded neonatal screening, the treatment, and the biochemical and molecular basis of CPT II deficiency. (Lab Invest 2003, 83:1543-1554.T he carnitine palmitoyltransferase (CPT) enzyme system, in association with acyl-coenzyme A (CoA) synthetase and the carnitine-acylcarnitine translocase (CACT), plays an important role in the transfer of long chain fatty acids (LCFA) from the cytosolic compartment to the mitochondrial matrix, where ␤-oxidation occurs (Bieber, 1988). Two genetically distinct mitochondrial membrane-bound enzymes make up the CPT system. CPT I is located on the inner aspect of the outer mitochondrial membrane. This enzyme is physiologically inhibited by the high levels of malonyl-CoA that occur postprandially and thus regulates the entry of LCFA into the mitochondria (McGarry and Brown, 1997). CPT II, which is not inhibited by malonyl-CoA, is situated on the inner aspect of the inner mitochondrial membrane (Murthy and Pande, 1987).CPT II deficiency was first reported by DiMauro and DiMauro (1973) in adults with exercise-induced rhabdomyolysis. It is an autosomal recessive disorder (Angelini et al, 1981;Meola et al, 1987) and is now regarded as one of the most common inherited disorders of lipid metabolism . Isolated presentation in two successive generations has been reported, indicating a possible dominant inheritance (Mongini et al, 1991). Partial CPT II deficiency with an autosomal dominant inheritance pattern has also been reported (Ionasescu et al, 1980). The molecular basis for this presentation was not elucidated.To date, three distinct CPT II-deficient phenotypes have been described in the literature, for wh...

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Section: Discussionmentioning

confidence: 99%

Section: Diagnosismentioning

confidence: 99%

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

Sigauke

Rakheja

Kitson

et al. 2003

Laboratory Investigation

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“…Available evidence indicates that mitochondrial CPT deficiency in humans manifests itself as two distinct phenotypes, the "muscle" and "hepatic" forms of the disease (10)(11)(12)(13). Fibroblasts from patients with the "muscle" presentation express normal levels of CPT I but are variably deficient in CPT II (10,13 (10,12); yet the same patients show no abnormality of CPT I in skeletal muscle (11). A reasonable interpretation of these findings is that, since CPT II appears to be the same protein body-wide (13,18), its deficiency in fibroblasts reflects the same problem in other tissues including muscle.…”

Section: Methodsmentioning

confidence: 99%

“…Because of its pivotal role in lipid metabolism, CPT I has attracted attention as a potential site for pharmacological intervention in diabetes mellitus, where fatty acid oxidation is excessive and interferes with glucose homeostasis (8,9). In addition, inherited defects in CPT I or CPT II form the basis of serious, and sometimes fatal, disturbances in fatty acid oxidation, although precisely which enzyme and which tissues are affected often remain unsettled (10)(11)(12)(13).…”

mentioning

confidence: 99%

Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene.

Britton

Schultz

Zhang

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

131

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Using the cDNA for rat liver mitochondrial carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21) as a probe, we isolated its counterpart as three overlapping clones from a human liver cDNA library. Both the nucleotide sequence of the human cDNA and the predicted primary structure of the protein (773 aa) proved to be very similar to those of the rat enzyme (82% and 88% identity, respectively). The CPT I mRNA size was also found to be the same (-4.7

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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

et al. 1998

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Carnitine palmitoyltransferase II (CPT II) deficiency manifests as two different clinical phenotypes: a muscular form and a hepatic form. We have investigated three nonconsanguineous Japanese patients with CPT II deficiency. Molecular analysis revealed two missense mutations, a glutamate (174)‐to‐lysine substitution (E174K) and a phenylalanine (383)‐to‐tyrosine substitution (F383Y) in the CPT II cDNA. Transfection experiments in COS‐1 cells demonstrated that the two mutations markedly decreased the catalytic activity of mutant CPT II. Case 1 (hepatic form) was homozygous for the F383Y mutation, whereas case 3 (muscular form) was homozygous for the E174K mutation. Case 2 and her brother, who were compound heterozygotes for E174K and F383Y, exhibited the hepatic phenotype. We also identified a novel polymorphism in the CPT2 gene, a phenylalanine (352)‐to‐cysteine substitution (F352C), which did not alter CPT II activity in transfected cells. It was present in 21 out of 100 normal alleles in the Japanese population, but absent in Caucasian populations. Genotyping with the F352C polymorphism and the two previously reported polymorphisms, V368I and M647V, allowed normal Japanese alleles to be classified into five haplotypes. In all three families with CPT II deficiency, the E174K mutation resided only on the F1V1M1 allele, whereas the F383Y mutation was observed on the F2V2M1 allele, suggesting a single origin for each mutation. Hum Mutat 11:377–386, 1998. © 1998 Wiley‐Liss, Inc.

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Hepatic and Muscular Presentations of Carnitine Palmitoyl Transferase Deficiency: Two Distinct Entities

Cited by 127 publications

References 9 publications

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

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

Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene.

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

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