Disorders of Leucine Metabolism
The inborn errors of L-leucine catabolism present biochemically with branched-chain amino and/or organic aciduria [1]. These disorders include maple syrup disease (MSD; branched-chain a-ketoacid dehydrogenase (BCKD) deficiency), isovaleric acidemia (isova
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Introduction
The inborn errors of L-Ieucine catabolism present biochemically with branched -chain amino and/or organic aciduria [1]. These disorders include maple syrup disease (MSD; branched-chain a-keto acid dehydrogenase (BCKD) deficiency), isovaleric acidemia (isovaleryl-coenzyme A (CoA) dehydrogenase deficiency), isolated 3-methylcrotonyl-CoA carboxylase deficiency, the 3-methylglutaconic acidurias (3-methylglutaconyl-CoA hydratase deficiency, Barth syndrome, and other disorders in which the primary defect has not been demonstrated), and 3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency). The prevalence of MSD is approximately 1 in 200000 persons and is most common among the Mennonites of North America where the incidence is 1 in 380. Although all three branched-chain amino acids, leucine, isoleucine, and valine and their respective a-keto acids are increased in blood, urine and cerebrospinal fluid [2], it is the elevated leucine levels that are responsible for the clinical pathogenesis of the disorder. There are four forms, which differ in the age and severity of onset, biochemical findings, and responsiveness to thiamin (vitamin Bj ), a cofactor for the BCKD complex. The classical form presents in the first week of life with poor feeding, irritability and lethargy with progressive central nervous system deterioration; the intermediate form presents at any age, infancy to adulthood, with failure to thrive, neurologic features and ketoacidosis; an intermittent form manifests episodic ataxia and ketoacidosis, often associated with increased protein consumption or intercurrent illness; and a 'thiamin-responsive form' exists in which metabolic abnormalities are ameliorated with large doses of thiamin. Urine spot testing with 2,4-dinitrophenylhydrazine (DNPH) and ferric chloride will indicate the presence of oxoacids, and the diagnosis is confirmed with plasma or serum quantitative amino acid and urine organic acid analysis. Newborn screening for the classical form of MSD, employing measurement of leucine levels in dried blood filter paper spots, is available in many locations. Although many patients have psychomotor handicaps, there are increasing reports of patients with normal development when treatment was started in the first few days of life. At-risk N. Blau et al. (eds.), Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases © Springer-Verlag Berlin Heidelberg 2003
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Disorders of Leucine Metabolism
neonates can be diagnosed between ages 12-24 hours by amino acid quantification using high-performance liquid chromatography (HPLC) or tandem mass spectrometry (MS/MS). After delivery in affected infants there is an increase in plasma leucine caused by postpartum endogenous protein catabolism and a characteristic decrease in plasma alanine. Affected neonates (n= 19) have serum or plasma leucine concentrations 233-733 ~mol/l (nl 43-186), alanine concentrations range from 35-285 ~mol!l (nl 206-545), with molar ratios of [Leu]/[Ala]
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