Alpha-aminoadipic and alpha-ketoadipic aciduria

Lore & Background

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 (OADHC), a multienzyme system critical for amino acid metabolism. This complex catalyzes the oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA 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.

Reader's Guide

The pathogenic mechanisms of AMOXAD are not fully elucidated. The lysine degradation pathway is a complex, multistep process involving mitochondrial, cytosolic, and peroxisomal enzymes. Mutations in DHTKD1 disrupt the 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. Over 20 cases have been identified, with varying outcomes. While some patients remain asymptomatic, others experience neurological and muscular symptoms including hypotonia, developmental delays, ataxia, seizures, and behavioral abnormalities such as ADHD. Diagnosis involves analyzing urinary organic acids using gas chromatography–mass spectrometry, with characteristic findings of elevated 2-oxoadipate and 2-hydroxyadipate in urine and 2-aminoadipate in blood. Molecular genetic testing can confirm mutations in DHTKD1. There is no specific cure; management focuses on symptomatic treatment and supportive care, including a low-lysine diet and antiepileptic drugs, though vigabatrin should be avoided. The prognosis depends on symptom severity.

Did You Know?

• AMOXAD is caused by mutations in the DHTKD1 gene on chromosome 10p14.
• The disorder leads to accumulation of alpha-aminoadipic acid and alpha-ketoadipic acid in blood and urine.
• Many cases of AMOXAD remain asymptomatic or are diagnosed later in life.
• Vigabatrin should be avoided in treatment because it may exacerbate underlying metabolic imbalances.