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Lysine is an essential amino acid that can be degraded via 2 alternative pathways. The predominant route is via the saccharopine pathway, with the peroxisomal pipecolic acid pathway playing a relatively minor role. Degradation of lysine through either pathway leads to the formation of α-aminoadipic semialdehyde, which is catabolized to acetyl-coenzyme A (CoA) and enters the tricarboxylic acid (TCA) cycle.


The first 2 steps in the saccharopine pathway of lysine degradation are catalyzed by α-aminoadipic semialdehyde synthase (AASS), a bifunctional enzyme with both lysine-ketoglutarate reductase and saccharopine dehydrogenase activities. Mutations in the AASS gene that affect both activities result in hyperlysinemia type 1, whereas mutations that primarily affect saccharopine dehydrogenase activity result in hyperlysinemia type 2. Types 1 and 2 hyperlysinemia are both associated with a marked elevation of serum lysine and significant lysinuria. Type 2 patients also have elevated urinary saccharopine. Another biochemical feature of hyperlysinemia is elevation of serum and urinary pipecolic acid. Elevation of pipecolic acid also occurs in disorders of peroxisome biogenesis, but in those disorders, there is no associated elevation of lysine. Hyperlysinemia was first identified in patients being evaluated for neurodevelopmental problems but has subsequently been observed in asymptomatic family members and other normal individuals, leading to a consensus that isolated hyperlysinemia does not cause symptoms.


The degradation pathways for lysine, hydroxylysine, and tryptophan converge with the formation of 2-oxoadipic acid, which is converted to glutaryl-CoA by 2-oxoadipic acid dehydrogenase. Mutations in the gene for 2-oxoadipic acid dehydrogenase (DHTKD1) result in the accumulation of 2-oxoadipic acid and its transamination product 2-aminoadipic acid. The diagnosis is based on the presence of both 2-oxoadipic and 2-aminoadipic acid in the urine, which are normally present in only trace amounts. It is a very rare disorder, with only 20 to 30 patients reported. Some patients were reported to have significant neurodevelopmental impairment, but the majority have been developmentally normal, suggesting that it is a biochemical abnormality that, like hyperlysinemia, does not cause symptoms.


Glutaric acidemia type I (GA-I) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism that can result in significant neurologic impairment. GA-I results from mutations in the GCDH gene that encodes glutaryl-CoA dehydrogenase (GCDH), a mitochondrial matrix enzyme that catalyzes the conversion of glutaryl-CoA to crotonyl-CoA. The loss of GCDH activity in GA-I results in the accumulation of the neurotoxic metabolites glutaric acid and 3-OH glutaric acid in the blood, urine, and cerebrospinal fluid.


Patients with GA-I are often macrocephalic at birth and initially show nearly normal achievement of early developmental milestones. However, untreated patients usually develop progressive dystonia and dyskinesia within the first 3 years of life. Symptoms may have a gradual onset and progression, ...

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