The neuropathological findings in 5 children and 1 adult (8 months-40 years of age) with glutaric acidemia type 1 (GA-1), all N American aboriginals with the same homozygous mutation, were studied at the Manitoba Institute of Child Health, Winnipeg, and University of Western Ontario, London, Ontario, Canada; and University Children’s Hospital, Heidelberg, Germany. Case 1, a male infant having 6 of 7 older siblings affected by GA-1, was jittery at birth, a seizure occurred at 3 months, and developmental delay, hypotonia and head bobbing were noted at 4 months, A CT at 6 months showed enlarged ventricles, wide frontal sulci, and fluid collections in the temporal fossae. He presented with vomiting, diarrhea, fever and dehydration at 8 months, becoming rapidly comatose. His head circumference was above the 99th percentile at birth and at 8 months. A repeat CT scan showed hemorrhage in the right temporoparietal region, and he died 3 days later. Autopsy revealed ischemic neuronal damage in the cerebrum and cerebellum, venous sinus thrombosis, dilated ventricles, and striatal, caudate and putamen atrophy, with neuron loss, astrocyte hypertrophy and microglial activation. Four of the 6 cases had macroencephaly, usually in infancy and at the time of the encephalopathic crises, all had striatal, caudate and putamen atrophy, and all brain regions demonstrated elevated GA and 3-OH-GA protein. The characteristic dystonia was reported in 3 patients. The neuropathological findings were similar to those described previously in 10 autopsied cases of other ethnic backgrounds. The role of organic acids as toxic and osmotic agents, and of dietary treatment of presymptomatic cases diagnosed by screening of populations at risk, is discussed. [1]

COMMENT. Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of amino acid metabolism caused by a deficiency of glutaryl-CoA dehydrogenase, and leading to accumulation of glutaric acid, 3-OH-GA and glutaconic acid in blood, urine, CSF and brain tissue. Characteristic clinical features include macrocephaly at, or soon after, birth, an abrupt onset of dystonia between 6 and 18 months of age, often with a febrile illness, and death in early childhood. Caudate and putamen atrophy with neuronal loss are always present, and white matter spongiform degeneration is a frequent finding.

Strauss KA, in a Commentary [2], stresses the clinician’s dilemma in predicting when basal ganglia injury will occur (the progress of the disease can be variable), and the lack of effective therapy once the encephalopathy ensues. Plasma and urine organic acid measurements are unreliable in predicting the time of onset of neurologic symptoms. The Canadian report confirms previous findings that brain GA is very high in these patients, exceeding plasma and CSF levels two-fold, an accumulation caused either by a selective blood-brain-barrier affinity for GA or by an excess brain tissue production of GA, arising from the enzymatic block in degradation of lysine and tryptophan in the brain. The risk of brain injury in GA-1 may be inversely related to the efficiency of brain organic acid clearance. The commentary emphasizes the need to consider inter-organ transport mechanisms for GA and the prevention of striatal necrosis.