Molecular characterization of inherited carnitine palmitoyltransferase II deficiency.

Abstract

(6, 7). Although the enzyme defect is evident in tissues other than skeletal muscle (6,8), the disease usually presents only with the muscular symptomatology. More recently, though, CPTase II deficiency has been observed also in children and newborns presenting with hypoketotic hypoglycemia, cardiomyopathy, and sudden death (9-12).These observations indicate that CPTase II deficiency is a complex disorder with phenotypic heterogeneity that may reflect underlying heterogeneity at the molecular level. As a first step to understanding the molecular basis of CPTase deficiency, we have cloned the full-length cDNA of human CPTase II (13, 14). We now report the identification and characterization of the molecular defect in a patient with the early-onset form of CPTase II deficiency presenting with hypoketotic hypoglycemia and cardiomyopathy. 16.4%, 8.8%, and 6.6% of normal control in fibroblasts, lymphoblasts, and skeletal muscle, respectively (see Fig. 4A). Fibroblast CPTase II activity was also reduced by 40%o and 35% in the father and in the mother, respectively. PATIENTS AND METHODSAbbreviations: CPTase, carnitine palmitoyltransferase; nt, nucleotide(s).tTo whom reprint requests should be addressed. 8429The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

The Mitochondrial Carnitine Palmitoyltransferase System — From Concept to Molecular Analysis

“…What came as something of a surprise was the finding that in the rat, non-lipogenic tissues such as heart and skeletal muscle also contain malonyl-CoA and that its concentration in these sites fluctuates with feeding and fasting, just as in liver [9]. In addition, CPT I of heart and skeletal muscle mitochondria proved to be far more sensitive to malonyl-CoA and to have a much higher K,, for carnitine than the liver enzyme [9,101. These observations raised the possibility that a malonyl-CoA/CPT I interaction might be important in the function of some non-hepatic tissues.…”

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

“…Cardiac manifestations include dilated hypertrophic cardiomyopathy and arrhythmias (Demaugre et al, 1991;Taroni et al, 1992;VianeySaban et al, 1995). Other clinical and laboratory features may include episodic weakness, encephalopathy, seizures, respiratory distress, metabolic acidosis, increased serum aminotransferase and ammonia, and decreased serum carnitine (Elpeleg et al, 1993;Ross et al, 1996;Taroni et al, 1992). In this group of patients, CPT II activity in fibroblasts ranges from 4% to 10% of the activity in control fibroblasts (Demaugre et al, 1991;Elpeleg et al, 1993).…”

“…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). The perinatal form is the least common clinical presentation of CPT II deficiency and is almost universally and rapidly fatal (Elpeleg et al, 2001;Gellera et al, 1992 We report a new case of perinatal CPT II deficiency with a rare missense mutation and we review the current and expanding literature on CPT II deficiency.…”

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

“…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).…”