Acylcarnitine profiles in fibroblasts from patients with respiratory chain defects can resemble those from patients with mitochondrial fatty acid beta-oxidation disorders.
Mitochondrial fatty acid beta-oxidation (FAO) is coupled to the respiratory chain (RC). Functional defects of one pathway may lead to secondary alteration in flux through the other. We investigated the acylcarnitine profiles in cultured fibroblasts obtained from 14 healthy subjects, 31 patients with 8 different primary enzyme deficiencies of FAO, and 16 patients with primary RC defects including both isolated and multiple enzyme complex defects. Intact cells were incubated in media containing deuterium-labeled hexadecanoic acid and L-carnitine, and the acylcarnitines analysed using an electrospray tandem mass spectrometer. All FAO-deficient cell lines revealed disease-specific acylcarnitine profiles related to the sites of defects. Some cell lines from patients with RC defects showed profiles similar to those of controls, whereas others had abnormal profiles mimicking those found in FAO disorders. The acylcarnitine profiles of patients with RC enzyme defects were not predictable, and in some patients defects caused by mutations in either nuclear-encoded or mitochondrial DNA were associated with acylcarnitine abnormalities. While in vitro acylcarnitine profiling is useful for the diagnosis of FAO deficiencies, abnormal profiles do not exclusively indicate these disorders, and primary defects of the RC remain a possibility. Awareness of this diagnostic pitfall will aid in the selection of subsequent confirmatory tests and therapeutic options.
Sim
Keow Giak
KG
New South Wales Biochemical Genetics Service, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia.
Carpenter
Kevin
K
Hammond
Judith
J
Christodoulou
John
J
Wilcken
Bridget
B
D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism*; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D012016:Reference Values
D005227:Fatty Acids; C116917:acylcarnitine; D002331:Carnitine