Chronic Tyrosinemia Associated with 4-Hydroxyphenylpyruvate Dioxygenase Deficiency with Acute Intermittent Ataxia and without Visceral and Bone Involvement

Abstract

MATERIALS AND METHODSdrolase (EC 3.7.1.2) has been demonstrated in several patients (18) and is now felt to be the primary enzyme defect in this disease.Tyrosinemia type II has been described in over twenty patients, most of whom have manifest the Richner-Hanhart syndrome with severe persistent keratitis and more variable hyperkeratosis on the fmgers and palms of the hands and soles of the feet. These lesions respond completely to dietary tyrosine restriction. Blood tyrosine is greatly elevated and there is massive tyrosyluria. Absent activity of hepatic cytosol TAT has been demonstrated in two patients (9, 16) and a milder deficiency has been reported in two other patients, in liver (Il) and fibroblasts (4) respectively.Another form of tyrosinemia has been reported in two childrep. with severe metabolic acidosis who excreted the unusual tyrosine metabolites hawkinsin and cis-and trans-4-hydroxycyclohexylacetic acids in the urine (3,22,26). The' primary abnormality is thought to be in the rearrangement of an intermediate formed in the 4HPPD reaction.We now report a case of persistent tyrosinemia and tyrosyluria associated with deficient activity of 4HPPD in liver. The clinical picture was characterized by sporadic ataxia and drowsiness in a child who was otherwise normal. Summary SpeculationA 17-month-old girl, with acute intermittent ataxia and drowsiness, had hypertyrosinemia (serum tyrosine, 62 JLmole/dl) and phenolic aciduria in the absence of hepatic, renal, eye or skin lesions. Serum methionine and urinary~-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 JLmole/mg protein/h (control, 0.10-0.30 JLmole/mg protein/h; n = 5). In mitochondria, TAT was 0.24 JLmole/mg protein/h (control, 0.09-0.12 JLmole/mg protein/h; n = 3) whereas in cytosol fraction it was 0.23 JLmole/mg protein/h (control, 0.27-0.44 JLmole/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

Autoimmune thyroiditis in a case of tyrosinaemia type III

“…We have previously described a 17-month-old girt with acute intermittent ataxia and drowsiness due to a defect of 4-hydroxyphenylpyruvate dioxygenase (4HPPD; EC 1.13.11.27; McKusick 276710) (Giardini et al 1983). The biochemical investigations showed high serum levels of tyrosine and phenolic aciduria even in periods when the patient was clinically completely normal.…”

Hepatorenal tyrosinemia

“…It is interesting that soon after the primary enzyme defect in HRT was confirmed, two patients with a new form of hereditary tyrosinemia with primary 4-HPPD defect were identified in 1983 independently in the US 45) and Japan. 46) This disease was assigned MIM 276710 and called tyrosinemia type III.…”

Disorders of Tyrosine Metabolism

“…The patients described to date Disorders of Tyrosine Metabolism 191 have presented with various neurological symptoms or have been detected by the finding of a high tyrosine concentration on neonatal screening [31][32][33][34][35]. The patients described to date Disorders of Tyrosine Metabolism 191 have presented with various neurological symptoms or have been detected by the finding of a high tyrosine concentration on neonatal screening [31][32][33][34][35].…”