Tyrosinemia type III (OMIM 276710) is an autosomal recessive disorder caused by the deficiency of
4-hydroxyphenylpyruvate dioxygenase (4-HPD). Few cases have been described with
mental retardation or neurological symptoms. Recently it has been demonstrated that 4-HPD participates to
nitric oxide (NO) intracellular sequestration in Pseudomonas aeruginosa. 4-HPD is an ubiquitous
enzyme with a prominent expression in neutrophils and neurons. In the nervous system NO has been perceived to be a potential
neuromodulator although prolonged excessive generation is detrimental. We analyzed NO release by neutrophils of a patient with
tyrosinemia type III in order to evaluate a possible influence of 4-HPD deficiency on this process. Our patient, previously described, is a 30-year-old women with persistent
tyrosinemia (450-680 micromol/l) and deficient activity of 4-HPD.
At 17 months of age she experienced an acute
ataxia and drowsiness lasting for 10 days, but further
clinical course showed persistent
tyrosinemia with normal growth and psychomotor development. Neutrophils isolated from our patient exhibited a NO release greatly higher in respect to the controls (mean+/-SEM 23.2+/-1.8 micromol/10(6) cells vs 3.5+/-0.5 micromol/10(6) cells). Clinical findings of
tyrosinemia type III include neurological symptoms and
mental retardation but no consistent phenotype has emerged. Therefore the pathogenesis of neurological involvement is yet not well understood. Our results suggest that an excessive neutrophils of NO release could reflect the lack of scavenging action of 4-HPD. Considering the prominent expression of this
enzyme in neurons, we hypothesize that excessive NO release could participate in neuronal damage explaining the neurological involvement described in patients with
tyrosinemia type III.