Novel mutations associated with carnitine palmitoyltransferase II deficiency

Taggart, R. Thomas; Smail, David; Apolito, C.J.; Vladutiu, Georgirene D.

doi:10.1002/(sici)1098-1004(1999)13:3<210::aid-humu5>3.0.co;2-0

Cited by 81 publications

(48 citation statements)

References 33 publications

(48 reference statements)

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“…There are some case reports of children with this mutation who present with myopathic features of the adult form of the disease (Gempel et al, 2001). CPT II deficiency may manifest clinically even in a person heterozygous for the S113L mutation (Kaufmann et al, 1997;Taggart et al, 1999;Taroni et al, 1993). Compound heterozygosity may cause intermediate disease, as in the case of the S113L and the R631C (1897CϾT) causing earlier presentation of the adult myopathic type.…”

Section: Sigauke Et Almentioning

confidence: 99%

“…The R503C (1507CϾT), and G549D (1646GϾA) substitutions are located in highly conserved regions of all CPT genes. The R503C mutation, which is lethal in the homozygous state, is known to cause clinical symptoms in the simple heterozygous form (Taggart et al, 1999;Vladutiu et al, 2000).…”

Section: Sigauke Et Almentioning

confidence: 99%

“…The 413delAG-F448L haplotype is found predominantly in the Ashkenazi Jewish population and is associated with the antenatal presentation when homozygous (Elpeleg et al, 2001;Taggart et al, 1999). The fatal perinatal phenotype has been reported in five siblings in an isolated Moroccan family.…”

Section: Sigauke Et Almentioning

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: Sigauke Et Almentioning

confidence: 99%

Section: Sigauke Et Almentioning

confidence: 99%

See 1 more Smart Citation

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

Sigauke

Rakheja

Kitson

et al. 2003

Laboratory Investigation

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show abstract

“…Because the enzyme is ubiquitous, its deficiency in affected individuals can readily be demonstrated in skeletal muscle biopsy, leukocytes, or cultured skin fibroblasts with activity reduced to 8-18% of the normal reference mean. 4 The disorder is autosomalrecessively inherited and typically presents in early adulthood with pain and stiffness following prolonged, vigorous exercise and accompanied by myoglobinuria with lifethreatening kidney failure in severe cases. Other triggers include fasting, extremes in temperature, general anesthesia, viral infection, and sleep deprivation.…”

Section: Combined Biochemical and Molecular Diagnosis In Blood Of A Cmentioning

confidence: 99%

Cocaine-induced hypokalemic paralysis

2000

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“…Truncating CPT II mutations on both alleles are associated with the severe neonatal form of the disease, while homozygous and/or compound heterozygous "mild" missense mutations are often associated with the adult form of CPT II deficiency (Bonnefont et al 1999). In the case where a patient is compound heterozygous for a severe and a mild CPT II mutation, the data show that the presence of the mild one is often sufficient to expose the patient to a mild clinical phenotype (Taggart et al 1999;Thuillier et al 2000;Yang et al 1998). In our patients, the compound heterozygosity of the two mutations led to the severe neonatal form of CPT II deficiency, so we can conclude that both mutations are severe.…”

mentioning

confidence: 99%