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Clinical course, diagnostic and therapeutic management, and neurodevelopmental outcome were evaluated in 11 patients with glutaryl-coenzyme A dehydrogenase deficiency. In 9 patients macrocephalus was present at or shortly after birth and preceded the neurological disease. In 7 children an acute illness resembling encephalitis appeared after a period of normal development; 2 had developmental delay and progressive "dystonic cerebral palsy." Later, all 9 displayed typical signs of a disorder of the basal ganglia. In 1 patient with macrocephalus the disorder was diagnosed before the onset of neurological disease; in another it was diagnosed prenatally. Computed tomography and magnetic resonance imaging scans revealed severe generalized cerebral atrophy, most striking in the frontal and temporal lobes in 10 patients. Further deterioration was halted after initiation of treatment consisting of low-protein diets, special formulas low in lysine and tryptophan, and supplements of riboflavin and L-carnitine. Only 1 patient showed a slight clinical improvement. Later, dietary therapy was discontinued in 2 older patients and relaxed in a third without observed adverse effects. Two patients in whom treatment could be initiated before the onset of neurological symptoms have developed normally. However, duration of follow-up (6 and 29 months) does not yet allow classification of glutaryl-coenzyme A dehydrogenase deficiency as a treatable disorder. Total body production of glutaric acid, reflected in the daily urinary output, was efficiently reduced by therapeutic measures. Levels of glutaric acid in plasma and cerebrospinal fluid remained unchanged, which may in part explain the overall unsatisfactory outcome. All patients presented with a severe secondary deficiency of carnitine. L-Carnitine appears to play an important pathobiochemical role in the pathogenesis of the disorder. It is concluded that glutaryl-coenzyme A dehydrogenase deficiency is an acute to subacute neuropathic disorder of infancy or early childhood. Later in the course of the disease further deterioration appears to subside. The lack of significant metabolic derangements may cause this disorder to remain frequently undiagnosed. Glutaryl-coenzyme A dehydrogenase deficiency should have high priority in the differential diagnosis of any child with acute profound dyskinesia, subacute motor delay accompanied by increasingly severe choreoathetosis, and dystonia. It should especially be considered when there is macrocephalus in an infant together with progressive atrophic changes on computed tomography or nuclear magnetic resonance imaging, as neurological handicap can potentially still be prevented.