Glutaric acidemia type 1 (GA1), one of the more common organic acidemias, was first described in 1975 by Dr. Stephen I. Goodman, MD (Goodman et al., 1975). The condition is due to deficiency of glutaryl-Coenzyme A dehydrogenase, a mitochondrial enzyme that converts gutaryl-CoA, an intermediate in the oxidation of lysine), tryptophan and hydroxylysine, to crotonyl-CoA.
The condition is inherited as an autosomal recessive trait and the gene encoding glutaryl-Coenzyme A dehydrogenase is located on chromosome 19 (19p13.2). Many disease-causing mutations have been identified, but none is common except in inbred populations (Goodman et al., 1998).
Most patients with GA1 are born with relative macrocephaly, and suddenly develop hypotonia and dystonia during or after a relatively minor infection between the ages of six months and three years. Seizures, abnormal movements, hypoglycemia, hepatomegaly and acidosis may be noted during the episode, and CT or MRI scans show acute Striatal degeneration, with shrinkage of the caudate and putamen. Less common is a more chronic course in which dystonia and athetosis develop gradually during the first years of life (hoffman et al., 1996). Fatty changes in the viscera, and gliosis and neuronal loss in the putamen and lateral aspects of the caudate, have been described at autopsy (Goodman et al., 1977). Perhaps 5% of enzyme-deficient individuals remain asymptomatic.
In most instances glutaric and 3-hydroxyglutaric acids are increased in urine, acylcarnitine analysis by tandem mass spectrometry (MS/MS) shows increased glutarylcarnitine (C5 dicarboxylic carnitine ester), and serum carnitine is low. Some patients have easily detectable abnormal organic aciduria only when they are ill; and a few have so little glutaric aciduria even when they are ill that they are very difficult to detect with organic acid and/or acylcarnitine analysis. Diagnosis of such patients may require measurement of glutaric and 3-hydroxyglutaric acid in serum or urine by stable isotope dilution GC/MS, assay of enzyme activity in leukocytes or cultured fibroblasts, or mutation analysis. Prenatal diagnosis is possible by enzyme assay in cultured amniocytes or chorionic villus samples (Christensen, 1994), by mutation analysis, or by demonstrating large amounts of glutaric acid in amniotic fluid (Goodman et al., 1980).
Treatment of neurologically-impaired patients is not usually effective, but treatment begun before the onset of symptoms appears to prevent damage in 75-80% of cases. Treatment involves preventing catabolism during fasting and/or infections with intravenous fluids, electrolytes, glucose and insulin if necessary, and oral carnitine (Hoffman et al., 1996). Protein (or lysine) restriction is less well established in preventing symptoms, but should probably be tried. Lioresal, the p-chlorophenyl analog of GABA, has improved some patients with symptoms (brandt et al., 1976), but has had no effect on others.