A novel splice site mutation in neonatal carnitine palmitoyl transferase II deficiency

Smeets, Roel; Smeitink, Jan A.M.; Semmekrot, B.A.; Scholte, H.R.; Wanders, Ronald J. A.; Heuvel, L.P.W.J. van den

doi:10.1007/s100380300001

Cited by 22 publications

(11 citation statements)

References 15 publications

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“…This presentation is fatal, leading to death in the neonatal period as was observed in our case (Albers et al, 2001a;Elpeleg et al, 2001;Gellera et al, 1992;Hug et al, 1991;Land et al, 1995;North et al, 1995;Pierce et al, 1999;Sharma et al, 2003;Smeets et al, 2003;Taroni et al, 1994;Vladutiu et al, 2002b;Witt et al, 1991;Zinn et al, 1991). Pregnancy may be complicated by oligohydramnios, and prenatal screening may show malformations including large ventricles, agenesis of the corpus callosum, intraventricular calcifications, and cystic dysplasia of the brain and the kidneys (Elpeleg et al, 2001;North et al, 1995).…”

Section: Clinical and Metabolic Features Of Cpt II Deficiencymentioning

confidence: 76%

“…Genomic studies showed compound heterozygosity for the 534T ins/del 25 mutation and a GϾA splice mutation. This mutation, which is located in the intron 2 splice-acceptor site, was the first of its kind to be reported (Smeets et al, 2003). The L302fs (907_918ins) results in premature termination of the protein and truncation by about 350 amino acids and is also associated with the perinatal phenotype .…”

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: Clinical and Metabolic Features Of Cpt II Deficiencymentioning

confidence: 76%

Section: Sigauke Et Almentioning

confidence: 99%

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

Sigauke

Rakheja

Kitson

et al. 2003

Laboratory Investigation

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show abstract

“…The neonatal onset form of CPT2 deficiency appears to be markedly more severe than the infantile onset form of the disease. Sixteen unrelated patients have been reported to date Elpeleg et al, 2001;Vladutiu et al, 2002a,b;Sharma et al, 2003;Smeets et al, 2003). 11 siblings were reported to have suddenly died most often during the first month of life.…”

Section: Cpt2 Deficienciesmentioning

confidence: 96%

Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects

Bonnefont

Djouadi

Prip‐Buus

et al. 2004

Molecular Aspects of Medicine

515

411

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“…Recently [9] the same mutation was described in a Moroccan family in which four out of five children, heterozygous for the mutation, died from the neonatal phenotype.…”

Section: Discussionmentioning

confidence: 78%

A case of CPT deficiency, homoplasmic mtDNA mutation and ragged red fibers at muscle biopsy

Sciacco

Prelle

Fagiolari

et al. 2005

Journal of the Neurological Sciences

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A novel splice site mutation in neonatal carnitine palmitoyl transferase II deficiency

Abstract: at the mRNA level in cases where a mutation leads to aberrant splicing or nonsense-mediated messenger decay.

Cited by 22 publications

References 15 publications

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

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

Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects

A case of CPT deficiency, homoplasmic mtDNA mutation and ragged red fibers at muscle biopsy

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