Biochemical and clinical studies of a new case of α‐aminoadipic aciduria

Abstract

A mentally retarded, 10-year-old female with obesity, hypotonia, clumsiness and mild ocular abnormalities excreted in her urine large amounts of alpha-aminoadipic acid. Amino acid analyser studies and gas-liquid chromatography--mass spectrometry (GC--MS) confirmed the presence of alpha-aminoadipic acid in both urine and plasma but, in contrast to most other patients with this disorder, failed to demonstrate significant levels of alpha-ketoadipic acid in urine. Other known causes of alpha-aminoadipic aciduria were eliminated by showing that levels of lysine, saccharopine and pipecolic acid in plasma and urine were normal and that the activity of glutaryl-CoA dehydrogenase was also normal. Loading with L-lysine and L-tryptophan both increased the concentration of alpha-aminoadipic acid in blood and urine compatible with the primary deficiency of alpha-ketoadipate dehydrogenase, in spite of the absence of alpha-ketoadipic aciduria. Dietary restriction of lysine and administration of vitamins B1 and B6 were unsuccessful in correcting the biochemical abnormality.

?-aminoadipic aciduria and persistence of fetal haemoglobin in an oligophrenic child

“…The severely mentally retarded patient described above had a-AAA-uria without significant a-KAAuria as was reported previously by Casey et al [1], Gray et al [4] and possibly Lormans and Lowenthal [5]. This condition is apparently different from the patients studied by Przyrembel et al [6], Wilson et al [10] and Fischer et al [3] in whom a-KAA-uria was also present.…”

“…Clinically, most of the patients described have been mentally retarded [2,5,10,6,1]: one was reported to have an immunodeficiency [4]. Normal healthy sibs of patients have been reported to excrete similarly elevated levels of ~-AAA as their mentally retarded sibs [2,10].…”

“…c~-Aminoadipic aciduria (c~-AAA-uria) was first described independently by Lormans and Lowenthal [5] and by Fischer et al [2], and subsequently reported by several other authors [6,10,1,43]. In some of the patients c~-AAA-uria was associated with c~-ketoadipic aciduria (~-KAA-uria) [6,10,3] while in other patients c~-KAA levels were either normal [1,4] or not measured [5].…”

“…In some of the patients c~-AAA-uria was associated with c~-ketoadipic aciduria (~-KAA-uria) [6,10,3] while in other patients c~-KAA levels were either normal [1,4] or not measured [5].…”

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.…”