Alpha-ketoadipic aciduria, a new inborn error of lysine metabolism; biochemical studies

Abstract

SummaryInvestigation of a psychomotodcally retardcd girl showed excretion of abnormal amounts of alpha-ketoadipic acid, alpha-hydroxyadipic acid, alphaaminoadipic acid, 1,2-butenedicarboxylic acid and elevation of plasma alphaaminoadipic acid levels. T}-e identity of these metabolites was established by various methods. The excretion oi alpha-aminoadipic acid correlated to the lysine intake. Degradation studies with cultured fibroblasts indicate a defect in the oxidative decarboxyla:ion of alpha-ketoadipic acid (see Clin. Chim. Acta, 58 (1975) 271).

New Cases of DHTKD1 Mutations in Patients with 2-Ketoadipic Aciduria

“…The subsequent conversion of 2-ketoadipic acid to glutaryl-CoA, which is common to all three pathways and has long been assumed to involve a multienzyme complex similar to those that act on pyruvate, branched-chain keto acids and 2-ketoglutarate; indeed, the activities of the 2-ketoglutarate and 2-oxoadipic dehydrogenases in porcine heart could not be separated (Hirashima et al 1967). Several subjects have been described with 2-ketoadipic aciduria, including a 14-month-old girl with hypotonia, intermittent metabolic acidosis, and developmental delay (Przyrembel et al 1975), a 14-year-old retarded boy and his intellectually normal sister (Wilson et al 1975), a 9-yearold boy with a mild learning disability and his normal brother (Fischer et al 1974;Fischer and Brown 1980), a 10-year-old retarded girl (Casey et al 1978), a 9-year-old retarded boy with a history of seizures (Duran et al 1984), a 7-year-old girl with cerebellar ataxia (Vianey-Liaud et al 1985), two unrelated children with developmental delay (Danhauser et al 2012), and three apparently normal siblings detected by a newborn screening program in Australia (Wilcken et al 1980;Wilcken 2014, personal communication), whose genetic findings and outcome are presented here. Evidence for defects in the metabolism of 2-ketoadipic acid in these patients have included increased excretion of 2-ketoadipic and/or 2-hydroxyadipic acid in urine, often together with 2-aminoadipic acid, and delayed clearance of 2-aminoadipic and 2-hydroxyadipic after an oral lysine load.…”

“…To date over 20 individuals have been reported, about half of whom were asymptomatic (Przyrembel et al 1975;Fischer and Brown 1980;Duran et al 1984;Danhauser et al 2012). With no known genetic etiology, 2-ketoadipic aciduria was thought to represent ascertainment bias with clinical symptoms being coincidental findings (Duran et al 1984;Danhauser et al 2012;Saudubray et al 2012).…”

A study on α-ketoadipic aciduria by gas chromatographic-mass spectrometry

“…α-ketoadipic aciduria was first described by Przyrembel et al in 1975 since then 7 cases have been reported [1][2][3][6][7][8][9] using GC/MS or other analytical methods, and some subjects with α-ketoadipic aciduria were found by reexamination [3] . In addition to symptomatic cases, 6 asymptomatic cases have also been reported [2][3][4][5]10] .…”

“…α-ketoadipic aciduria (Mckusick 245130) is a rare inborn error in the metabolism of α-KA to glutaryl-CoA and is characterized by the increased excretion of α-KA, α-aminoadipate (α-AA) and α-hydrocyadipate (α-HAA). Since Przyrembel et al firstdescribed it in 1975 [1] , only 13 cases of α-ketoadipic aciduria have been reported over the past 25 years, including 7 symptomatic, and 6 asympotmaticones even in the symptomatic siblings with α-ketoadipic aciduria [1][2][3][4][5][6][7][8][9][10] . The clinical manifestations of this metabolic disorder showed heterogeneity.…”

Fluorometric Determination of 2-Oxoadipic Acid, a Common Metabolite of Tryptophan and Lysine, by High-Performance Liquid Chromatography with Pre-Chemical Derivatization

“…We have confirmed that urinary excretion of tryptophan catabolites such as kynurenic acid and xanthurenic acid reflect the intake of tryptophan. 6) Hence, we did quantitative analyses of 2-OAA, and learned that 2-oxoadipic aciduria, a rare congenital condition, was present, as first reported in 1975 by Przyrember et al 7) Since that report, there have been seven reported cases, 8) found mainly by employing organic solvent extraction and GC-MS techniques, 9) but the GC-MS technique is not a practical measurement method for the detection of 2-OAA. Nakamura et al 10) reported an attractive chemical derivatization method for 2-oxo acids with DMB.…”