Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria

@article{Hagen2015GeneticBO,
  title={Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria},
  author={Jacob J. Hagen and Heleen te Brinke and Ronald J.A. Wanders and Alida C. Knegt and Esm{\'e}e Oussoren and A. Jeannette M. Hoogeboom and George J. G. Ruijter and Daniel Becker and Karl Otfried Schwab and Ingo Franke and Marinus Dur{\'a}n and Hans R Waterham and J{\"o}rn Oliver Sass and Sander M. Houten},
  journal={Journal of Inherited Metabolic Disease},
  year={2015},
  volume={38},
  pages={873-879}
}
Alpha-aminoadipic and alpha-ketoadipic aciduria is an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. [] Key Method We have now sequenced DHTKD1 in nine patients diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria as well as one patient with isolated alpha-aminoadipic aciduria, and identified causal mutations in eight. We report nine novel mutations, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and…
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References

SHOWING 1-10 OF 42 REFERENCES
Tryptophan and lysine metabolism in alpha-aminoadipic aciduria.
TLDR
Two brothers previously diagnosed as having alpha-aminoadipic aciduria (alpha-AA) were subjected to a tryptophan loading test to determine if their condition resulted from a defect in the alpha-aminationoadipate aminotransferase (kynurenine aminosferase) system, which suggested that the retardation may result from other causes.
Biochemical and clinical studies of a new case of alpha-aminoadipic aciduria.
TLDR
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, and dietary restriction of lysine and administration of vitamins B1 and B6 were unsuccessful in correcting the biochemical abnormality.
α-Ketoadipic Aciduria: A Description of a New Metabolic Error in Lysine-Tryptophan Degradation
TLDR
Evidence is presented that would suggest that in humans these may be separate enzymes, or that more than one form of the α-ketoglutaric acid dehydrogenase exists.
Biochemical and clinical studies of a new case of α-aminoadipic aciduria
TLDR
A mentally retarded, 10-year-old female with obesity, hypotonia, clumsiness and mild ocular abnormalities excreted in her urine large amounts of α-aminoadipic acid, and dietary restriction of lysine and administration of vitamins B1 and B6 were unsuccessful in correcting the biochemical abnormality.
α-Aminoadipic andα-ketoadipic aciduria: Detection of a new case by a screening program using two-dimensional thin layer chromatography of amino acids
TLDR
In patients with α-aminoadipic aciduria, conversion of 14C-labelled α-ketoadipate to 14CO2 was decreased, although glutaryl-CoA dehydrogenase activity was normal, and in one case (Przyrembel et al., 1975), Wendel etAl.
α-aminoadipic aciduria and persistence of fetal haemoglobin in an oligophrenic child
TLDR
The persistent HbF could be the result of stress on the erythropoiesis by a secondary induced defect in an early stage of haemoglobin synthesis in which α-amino-β-ketoadipic acid, a structural analogue of α-aminoadipi acid, is an intermediate.
Genetic basis of hyperlysinemia
TLDR
Novel causal mutations in AASS are found in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication, which illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.
Alpha-ketoadipic aciduria, a new inborn error of lysine metabolism; biochemical studies.
Identification ofN-acetyl-α-aminoadipic acid in the urine of a patient with α-aminoadipic and α-ketoadipic aciduria
TLDR
A 3.5-year-old Japanese boy with a mild speech disturbance excreted a large amount of α-aminoadipic acid into the urine, which suggested the presence of acetylated derivatives in the effluent and washwater fraction through cation exchange resin.
Identification of N-acetyl-alpha-aminoadipic acid in the urine of a patient with alpha-aminoadipic and alpha-ketoadipic aciduria.
TLDR
A 3.5-year-old Japanese boy with a mild speech disturbance excreted a large amount of alpha-aminoadipic acid into the urine, which suggested the presence of acetylated derivatives and the amino acid analysis using an amino acid analyser confirmed the presence in both urine and plasma.
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