Lethal carnitine palmitoyltransferase (CPT) II deficiency in newborns: A molecular-genetic study

Journal Article · Thu Sep 01 04:00:00 EDT 1994 · American Journal of Human Genetics

OSTI ID:134341

Taroni, F; Gellera, C; Cavadini, P ^[1]

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1. Istituto Nazionale Meurologico, Milano (Italy); and others

Classically, CPT II deficiency presents in young adults with recurrent episodes of paroxysmal myoglobinuria triggered by prolonged exercise, cold, or fever. More severe forms of CPT II deficiency have recently been observed in children and newborns. Here, were present biochemical and molecular studies of lethal neonatal CPT II deficiency in a premature Haitian infant of nonconsanguineous parents. He presented at birth with severe respiratory distress, cardiac arrhythmia and heart failure. His condition worsened and he died on the 4th day of life. Postmortem examination showed hypertrophied, dilated heart, and lipid storage in liver, heart and kidney. An older sibling had died unexpectantly at 4 days of age with postmortem evidence of fatty infiltration of liver, kidney, heart and muscle. Biochemical study of cultured fibroblasts demonstrated dramatic reduction of palmitate oxidation (to < 3%) and very low residual CPT II activity ({le}15%). No CPT II protein was detected by Western blot analysis of fibroblasts. However, immunoprecitation of cells pulse-labeled with L-[{sup 35}S] methionine demonstrated normal amounts of newly synthesized CPT II, thus suggesting altered stability of the enzyme. To identify the molecular defect in his patient, individual CPT II exons were amplified by genomic PCR and directly sequenced. A missense mutation was found in exon 4, resulting in the nonconservative amino acid substitution at codon 227 (Pro227Leu). SSCP analysis of a genomic PCR fragment encompassing the mutation demonstrated that the patient was homozygous and the parents were heterozygous for this mutation. The mutation was detected neither in a large number of controls nor in other CPT II deficient patients. Finally, CPT II activity in COS-1 cells transfected with mutated CPT II cDNA was <8% than that in cells transfected with wild-type cDNA, thus demonstrating the pathogenic role of this mutation.

• OSTI ID: 134341
• Report Number(s): CONF-941009--
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACIDS
CARDIOVASCULAR DISEASES
CARNITINE
CONGENITAL MALFORMATIONS
DNA SEQUENCING
ENZYMES
EXONS
GENE MUTATIONS
GENES
HEREDITARY DISEASES
INFANTS
LETHAL MUTATIONS
METABOLIC DISEASES
PHENOTYPE
POLYMERASE CHAIN REACTION
STABILITY