Glutaric acidaemia type 1 (GA1) is a rare hereditary metabolic disorder with an autosomal recessive mode of inheritance. GA1 has an estimated overall prevalence of 1 in 100,000 newborns and is caused by a deficiency of glutaryl-CoA dehydrogenase, a mitochondrial enzyme involved in the metabolism of lysine, hydroxylysine and tryptophan. Untreated, approximately 90% of the patients will develop a neurological disease during a finite period of brain development (age 3–-36 months) following an acute encephalopathic crisis often precipitated by gastroenteritis, intercurrent febrile illness, immunisation or surgical intervention. GA1 can also develop insidiously without clinically apparent crisis in 10 to 20% of the patients.
Presenting symptoms include macrocephaly at birth or shortly thereafter, psychomotor delay, dystonia and, later, spastic quadriparesis. Patients seem to have relatively normal cognition, respond to commands, but have trouble talking or performing tasks because of poor muscle coordination and severe spasticity. Also, mild cases causing only slight neurological complaints and/or fatigue have been described.
Brain imaging performed shortly after birth usually shows frontoparietal atrophy with widening of Sylvian fissures and arachnoid cysts. The brain is more vulnerable to head trauma which can lead to acute subdural or retinal haemorrhage.
The cerebral damage seen in GA1 is caused by the direct effect of glutaric acid or a related metabolite. Glutaric acid, 3-hydroxyglutaric acid, and glutaconic acid accumulate in the brain and lead to neuronal damage, lymphocyte infiltration, elevated concentrations of inflammatory cytokines and nitric oxide, glial proliferation, atrophy of striatal neurons and neurologic dysfunction.