Rudolph's Pediatrics, 22nd Ed.

CHAPTER 140. Disorders of Metabolism of Lysine, Hydroxylysine, and Related Compounds

Stephen I. Goodman


Deficiency of the bifunctional protein alpha-aminoadipic semialdehyde synthase causes familial hyperlysinemia. The clinical significance of this enzyme deficiency is controversial. Psychomotor retardation has been reported in many, but not all, affected individuals.


Individuals who lack 2-ketoadipic acid dehydrogenase excrete large amounts of 2-ketoadipic acid and 2-hydroxy adipic acid in their urine. Although there are some reports of neurological disease in this condition, other patients have been clinically normal.


Glutaric acidemia type I (GA1) is caused by a defect in glutaryl-CoA dehydrogenase, a flavin adenine dinucleotide–containing enzyme that converts glutaryl-CoA—an intermediate in the oxidation of lysine, tryptophan, and hydroxylysine—to crotonyl-CoA. It is inherited as an autosomal recessive trait.1


Most patients with glutaric acidemia are born with macrocephaly and develop normally until they suddenly develop hypotonia and dystonia during or after an intercurrent infection; this usually occurs during the first 2 to 3 years of life. CT-MRI scans show frontal and cortical atrophy from birth and, after the onset of dystonia, degeneration of the caudate nucleus and putamen. Some patients gradually develop signs of striatal degeneration during the first years of life, and others, probably less than 5% of patients, remain asymptomatic. Metabolic acidosis, the usual indication for organic acid screening, is rare.


Urine organic acid analysis shows increased excretion of glutaric and 3-hydroxyglutaric acids, and acylcarnitine analysis by tandem mass spec-trometry (MS-MS) shows increased glutarylcarnitine. Some patients do not have prominent organic aciduria, and some individuals show it only when ill. Most patients have low serum-carnitine levels by the time they are diagnosed.

The enzyme defect can be demonstrated in many tissues, including leukocytes and cultured fibroblasts, and prenatal diagnosis of an affected fetus can be made by demonstrating enzyme deficiency in cultured amniocytes or chorionic villus cells, or by demonstrating increased glutaric acid concentrations in amniotic fluid. The gene encoding glutaryl-CoA dehydrogenase has been cloned and localized to chromosome 19 (19p.13.2), and many disease-causing mutations have been identified. Prenatal diagnosis can also be made on this basis when mutations in a particular family are known.


Treating symptomatic patients with a diet low in lysine and tryptophan, or with drugs such as Depakene and Lioresal, is of limited benefit. However, treatment with diet and L-carnitine before the onset of symptoms prevents striatal degeneration in many patients, especially if catabolism accompanying infection is minimized by prompt treatment with intravenous fluids and glucose. This in turn is why the condition is often screened for in newborns.


Two-hydroxyglutaric acid can exist as D- or L-isomers, and there are recessively inherited neurological disorders in which one isomer or both are increased in blood and urine. Disease-causing mutations have been identified in isomer-specific mitochondrial dehydrogenases that oxidize their substrates to 2-ketoglutaric acid, but some patients with D-2-hydroxyglutaric acidemia do not have detectable mutations in the corresponding enzyme.2


L-2-hydroxyglutaric acidemia typically presents in childhood or adult life with developmental delay and signs of cerebellar dysfunction such as ataxia and intention tremor. MRI scans show changes in subcortical white matter, cerebellar atrophy, and signal changes in the putamen and dentate nuclei. D-2-hydroxyglutaric acidemia usually presents with hypotonia, apnea, seizures, and developmental delay in infancy, but symptoms in some patients are milder and appear later. The most consistent MRI finding is enlargement of the lateral ventricles, especially in the occipital region. There is no treatment.

The few known patients with combined DL-2-hydroxyglutaric acidemia have had neonatal-onset encephalopathy and died in the first few years of life.


Urine organic acid analysis shows increased 2-hydroxyglutaric acid, but special methods are then required to determine its isomeric configuration. Prenatal diagnosis can often be made by measuring 2-hydroxyglutaric acid in amniotic fluid, but because amniotic fluid levels can be increased when the fetus is heterozygous, molecular analysis should also be performed whenever possible.