2-Aminoadipic 2-Oxoadipic Aciduria

A number sign (#) is used with this entry because of evidence that 2-aminoadipic 2-oxoadipic aciduria (AMOXAD) is caused by compound heterozygous mutation in the DHTKD1 gene (614984) on chromosome 10p14.

Clinical Features

In the course of routine screening, Fischer et al. (1974) observed alpha-aminoadipic aciduria in 2 brothers, aged 9 and 10 years. They attributed it to a defect in lysine metabolism. One had slight mental retardation (IQ 86), but the authors doubted a relation to the metabolic variant. Alpha-aminoadipicacid is COOH-CH(NH2)3-COOH. See ketoadipic aciduria (245130). Lormans and Lowenthal (1974) described the same condition in a 6-year-old boy with mental retardation. Alpha-aminoadipic acid is an intermediate in the breakdown of lysine. It is metabolized to alpha-ketoadipic acid and ultimately to acetoacetyl CoA via glutaryl CoA. Fischer and Brown (1980) studied tryptophan and lysine metabolism.

Danhauser et al. (2012) stated that over 20 individuals with 2-aminoadipic 2-oxoadipic aciduria were known. More than half of them were asymptomatic, whereas others had mild to severe intellectual disability, muscular hypotonia, developmental delay, ataxia, and epilepsy, as reported by Przyrembel et al. (1975) and Duran et al. (1984). Danhauser et al. (2012) reported 2 additional individuals, unrelated girls born to nonconsanguineous parents after uneventful pregnancies and deliveries. The first patient had moderately delayed psychomotor development (sitting alone at 10 months and walking alone at 25 months) in infancy, which was improved with physiotherapy and occupational therapy. At 2 years of age she had elevated 2-oxoadipic acid (range, 10 to 120 mmol/mol creatinine) and 2-hydroxyadipic acid (range, 5 to 40 mmol/mol creatinine) in her urine. These metabolites are usually not present in urine. The plasma concentration of 2-aminoadipic acid was also elevated (120 mmol/mol per liter). A protein-restricted diet did not improve her course and MRI was normal. At the age of 8 testing showed an IQ of 117; at age 11 she was diagnosed with ADHD; and at 14 years of age she was in good health, attending regular school, and following a normal diet with a normal neurologic exam. The second individual presented with microcephaly, mild motor developmental delay (sitting alone at age 9 months and walking alone at the age 22 months), and prominent speech delay in early childhood. Her hearing was normal. At 2 years of age metabolic analysis of urine and plasma revealed the characteristic biochemical profile of 2-aminoadipic 2-oxoadipic aciduria (2-oxoadipate, 520-970 mmol/mol creatinine; 2-hydroxyadipate, 100-150 mmol/mol creatinine; 2-aminoadipate, elevated). Protein restriction did not affect the course. At the age of 12 years, she still had significant problems with expressive and receptive language (limited active and passive vocabulary, dyslalia, and dysgrammatism). Her IQ was 87. She had mild muscular hypotonia and an otherwise normal neurologic exam.

Molecular Genetics

Danhauser et al. (2012) performed whole-exome sequencing in a patient with 2-aminoadipic 2-oxoadipic aciduria and found her to be compound heterozygous for 2 mutations in the DHTKD1 (614984) gene. The first mutation was an A-to-G transition altering the methionine at codon 1, which the authors suggested might cause out-of-frame usage of an AUG triplet 160 nucleotides downstream (614984.0001). The second mutation was a missense mutation, gly729 to arg (614984.0002), which affected an amino acid residue evolutionarily conserved from Homo sapiens to C. elegans and D. melanogaster. This mutation was found with a minor allele frequency of 0.17%, corresponding to 19 heterozygous but no homozygous carriers among 5,379 individuals. In this patient the methionine mutation was present in her mother but the missense mutation occurred as a de novo event. In a second patient, Sanger sequencing detected the same G729R mutation as in the first patient and a nonsense mutation on the other allele, arg410 to ter (R410X; 614984.0003). Functional assays showed that reduced DHTKD1 activity was responsible for the 2-aminoadipic and 2-oxoadipic aciduria in the affected individuals.

History

Barshop et al. (2000) reported a patient who presented with 2-oxoadipic aciduria and 2-aminoadipic aciduria at 2 years of age with manifestations typical of organic acidemia and episodes of ketosis and acidosis, progressive to coma. This resolved and the key metabolites disappeared from the urine and blood. At 9 years of age, she developed typical Kearns-Sayre syndrome (530000) with complete heart block, retinopathy, and ophthalmoplegia. Southern blot revealed a deletion in the mitochondrial genome.