Alpha-aminoadipic and alpha-ketoadipic aciduria
Alpha-aminoadipic and alpha-ketoadipic aciduria or 2-Aminoadipic-2-oxoadipic aciduria is a rare autosomal recessive metabolic disorder characterized by an increased urinary excretion of alpha-ketoadipic acid and alpha-aminoadipic acid. It is caused by mutations in DHTKD1, which encodes the E1 subunit of the oxoglutarate dehydrogenase complex.
It is caused by defects in the degradation of the amino acids lysine and tryptophan. It is classified as an organic aciduria. The condition leads to the accumulation of these metabolites in blood and urine.
Genetics
The disorder stems from compound heterozygous mutation in the DHTKD1 gene, located on chromosome 10p14. These mutations disrupt the function of the mitochondrial 2-oxoadipate dehydrogenase complex, a multienzyme system critical for amino acid metabolism. This complex catalyzes the oxidative decarboxylation of 2-oxoadipate during lysine and tryptophan degradation. Its dysfunction leads to the accumulation of toxic intermediates, which impair mitochondrial function, causing oxidative stress and energy deficits. Inheritance follows an autosomal recessive pattern, meaning an individual must inherit defective copies of the gene from both parents to manifest the disease. While AMOXAD is extremely rare, many cases remain asymptomatic or are diagnosed later in life.Pathophysiology
The pathogenic mechanisms of AMOXAD are not fully elucidated. The lysine degradation pathway is a complex, multistep process involving mitochondrial, cytosolic, and peroxisomal enzymes. It begins with the conversion of lysine into saccharopine and subsequently into 2-aminoadipate-6-semialdehyde. This step is catalyzed by alpha-aminoadipic semialdehyde synthase. The semialdehyde is then converted to 2-aminoadipate, which is subsequently deaminatied into 2-oxoadipate. In the mitochondria, 2-oxoadipate is decarboxylated by the 2-oxoadipate dehydrogenase complex, which depends on DHTKD1. This reaction yields glutaryl-CoA, which can enter the tricarboxylic acid cycle after conversion to acetyl-CoA. Mutations in DHTKD1 disrupt this crucial decarboxylation step, causing an accumulation of upstream metabolites such as 2-aminoadipate and 2-oxoadipate. This leads to mitochondrial dysfunction, increased oxidative stress, and toxic effects that contribute to the symptoms of AMOXAD. The pathway also intersects with the degradation of hydroxylysine and tryptophan, converging at the intermediates 2-aminoadipate and 2-oxoadipate. The exact pathways through which these metabolites cause damage remain a focus of ongoing research.Clinical Symptoms
Over 20 cases of AMOXAD have been identified, with varying outcomes. While some patients remain asymptomatic, others experience a range of neurological and muscular symptoms, including:- Hypotonia
- Developmental delays or intellectual disabilities of varying severity
- Ataxia
- Seizures
- Behavioral abnormalities, such as attention deficit hyperactivity disorder