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,
Urine organic acid analysis shows increased excretion of glutaric
and 3-hydroxyglutaric acids, and acylcarnitine analysis by tandem
mass spectrometry (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 ...