Glutaryl-CoA dehydrogenase deficiency

Glutaryl-CoA dehydrogenase deficiency, also known as glutaric aciduria type 1 (GA1) or glutaric acidemia type 1, is an inherited metabolic disorder caused by deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), which is essential for the breakdown of the amino acids lysine, hydroxylysine, and tryptophan. This deficiency leads to the accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutaconic acid in body fluids and tissues, particularly affecting the brain. The condition is caused by pathogenic variants in the GCDH gene located on chromosome 19p13.2. The hallmark clinical feature of GA1 is macrocephaly, which may be present at birth or develop in early infancy. Without treatment, affected children are at high risk of acute encephalopathic crises, typically triggered by febrile illnesses or other catabolic stress, most commonly occurring between 3 and 36 months of age. These crises cause acute striatal necrosis, leading to a severe dystonic-dyskinetic movement disorder that can be profoundly disabling. Subdural hemorrhages and retinal hemorrhages may also occur, sometimes leading to misdiagnosis of non-accidental injury. Some patients develop neurological symptoms insidiously without a recognizable acute crisis. Early diagnosis through newborn screening programs using tandem mass spectrometry has significantly improved outcomes. Treatment involves a lysine-restricted diet supplemented with a lysine-free, tryptophan-reduced amino acid formula, carnitine supplementation to prevent secondary carnitine deficiency, and aggressive emergency management during intercurrent illnesses to prevent catabolic crises. When treatment is initiated presymptomatically and maintained consistently, the majority of affected children can achieve normal or near-normal neurological development. However, once striatal injury has occurred, the resulting movement disorder is largely irreversible, though supportive therapies including physical therapy, occupational therapy, and medications for dystonia can help manage symptoms.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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