Glutaric acidemia type 1

Abstract

Glutaric acidemias comprise different disorders resulting in an increased urinary excretion of glutaric acid. Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism caused by deficiency of glutaryl-CoA dehydrogenase. It results in the accumulation of 3-hydroxyglutaric and glutaric acid. Affected patients can present with brain atrophy and macrocephaly and with acute dystonia secondary to striatal degeneration in most cases triggered by an intercurrent childhood infection with fever between 6 and 18 months of age. This disorder can be identified by increased glutaryl (C5DC) carnitine on newborn screening. Urine organic acid analysis indicates the presence of excess 3-OH-glutaric acid, and urine acylcarnitine profile shows glutaryl carnitine as the major peak. Therapy consists in carnitine supplementation to remove glutaric acid, a diet restricted in amino acids capable of producing glutaric acid, and prompt treatment of intercurrent illnesses. Early diagnosis and therapy reduce the risk of acute dystonia in patients with GA-1.

Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening

“…Defects in GCDH are reponsible for glutaric acidemia type 1 (GA1), an inherited metabolic disorder which prevents the complete breakdown of lysine and tryptophan Goodman et al, 1998). This disease manifests as macrocephaly and bleeding abnormalities in newborns, as well as muscular rigidity, spastic paralysis and other progressive movement disorders in older individuals Hedlund et al, 2006). Treatments for this disease include intravenous delivery of carnitine, which is depleted as a secondary effect of GA1, and a restricted-protein diet to limit lysine and tryptophan buildup in the circulatory system.…”

Organic anion transporters OAT1 and OAT4 mediate the high affinity transport of glutarate derivatives accumulating in patients with glutaric acidurias

“…Glutaric aciduria type 1 (GA1) is caused by deficiency of glutaryl-CoA dehydrogenase (EC 1.3.99.7; GCDH), a mitochondrial enzyme involved in the degradation of tryptophan and lysine. Defective GCDH causes insufficient glutaryl-CoA breakdown and results in an accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3OHGA), glutaconate (GC), and glutarylcarnitine in tissues, plasma, cerebrospinal fluid, and urine [1][2][3][4]. During catabolic situations, GA1 patients are subject to the development of encephalopathic crises, leading to striatal degeneration with a subsequent irreversible dystonic-dyskinetic movement disorder.…”

“…Histopathological findings include neuronal loss and astrogliosis in the striatum, subdural hemorrhages, and spongiform vacuolation of the white matter. These symptoms and the associated histopathological changes in putamen and caudatum mainly occur between the 3rd and 36th month of age triggered by a nonspecific disease like fever, respiratory infection, or diarrhea [1][2][3][4][5].…”

Mitochondrial metabolites extend lifespan

“…It is unclear why glutarate would evolve to inhibit complex V activity, but one possibility is that if glutarate levels accumulate during severe starvation when fat supplies are exhausted, it might act to limit cachexia. Inhibition of complex V by glutarate has not been previously described, but it may help explain the mitochondrial pathology that accompanies glutaric acidemias (Hedlund et al ., 2006; Ferreira et al ., 2007). …”