Chronic tyrosinemia associated with 4-hydroxyphenylpyruvate dioxygenase deficiency with acute intermittent ataxia and without visceral and bone involvement

Abstract

A 17-month-old girl, with acute intermittent ataxia and drowsi-ness, had hypertyrosinemia (serum tyrosine, 62 µmole/di) and phenolic aciduria in the absence of hepatic, renal, eye or skin lesions. Serum methionine and urinary 3-aminolevulinic acid concentrations were normal. Her psychomotor development was also normal. Protein restriction and vitamin C therapy failed to correct the biochemical abnormality. Liver biopsy was histologically normal. Analysis of the enzymes in the liver biopsy, taken at 25 months of age, showed no detectable activity of 4-hydroxyphenylpyruvate dioxygenase (4HPPD), either in whole homogenate or cytosol fraction. Mixing experiments revealed no inhibitor of either 4HPPD or tyrosine aminotransferase (TAT). TAT in unfractionated liver was 0.23 /imole/mg protein/h (control, 0.10-0.30 µmole/mg protein/h; n = 5). In mitochondria, TAT was 0.24 jwnole/mg protein/h (control, 0.09-0.12 µmole/mg protein/h; if = 3) whereas in cytosol fraction it was 0.23 µmole/mg protein/h (control, 0.27-0.44 /imole/mg protein/h; n = 3). Glutamate dehydrogenase activity appeared in the cytosol fraction suggesting some rupture of mitochondria during fractionation of the patient’s liver and indicating that true cytosol TAT might be somewhat lower than indicated; however, the kinetics of the patient’s cytosol TAT were normal: Km for tyrosine, 4.5 X 10-3 M (control, 4.0 X 10-3 M); Km for a-ketoglutarate, 98 X 10-6 M (control, 75 X 10-6 M); approximate Km for pyridoxal phosphate, 2.1 x 10-6 M (control, 4.0 X 10-6 M). Vmax in patient liver was 0.37 µmole/mg protein/h (control, 0.88 µmole/mg protein/h). These data argue against a primary abnormality of TAT but are consistent with a defect of 4HPPD; thus, this patient appears to represent a previously undescribed form of tyrosinemia. Speculation : Demonstration of deficient activity of 4-hydroxyphenylpyruvate dioxygenase in a patient with a unique form of tyrosinemia raises the possibility that a similar defect may be present in several other patients with atypical forms of tyrosinemia. © 1983 International Pediatric Research Foundation, Inc.