Strategies for the diagnosis of mitochondrial fatty acid beta-oxidation disorders.
Mitochondrial fatty acid beta-oxidation disorders (FAOD) are a group of clinically and biochemically heterogeneous inherited metabolic defects. The spectrum of phenotypes has expanded from hepatic encephalopathy to encompass myopathy, cardiomyopathy, peripheral neuropathy, sudden death and pregnancy complicated by fetal FAOD. Pre-symptomatic diagnosis is important to prevent morbidity and this is now achievable through newborn screening using tandem mass spectrometry (MS/MS). Moreover, most of the diagnosed defects are treatable and the prognosis is generally favourable. This article reviews the features of FAOD, critically evaluates methods of investigation including metabolite analyses in body fluids, in vitro oxidation rates and acylcarnitine profiling studies, enzymatic and mutational tests, and discusses genotype-phenotype correlation, treatment and monitoring options. Based on this knowledge, strategies for the biochemical investigation and differential diagnosis of patients presenting clinically, asymptomatic neonates detected by newborn screening, infants born after complications during late pregnancy, and cases of sudden death with suspected FAOD are presented. Laboratory investigation commonly begins with a search for diagnostic metabolites in physiological fluids, followed by in vitro functional studies if the initial findings are inconclusive, and confirmation by enzymology and molecular analyses. Occasionally a stress test in vivo may be required. At other times there may be no firm diagnosis achieved.
New South Wales Biochemical Genetics Service, The Children's Hospital at Westmead, Sydney, Australia. keows@chw.edu .au
Keow G
KG
Sim
Judith
J
Hammond
Bridget
B
Wilcken
D003937:Diagnosis, Differential; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism* / Q000652:urine; D013058:Mass Spectrometry; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D015997:Neonatal Screening; D010084:Oxidation-Reduction; D010641:Phenotype
D005227:Fatty Acids