Tyrosinemia, Type Iii

A number sign (#) is used with this entry because tyrosinemia type III (TYRSN3) is caused by homozygous or compound heterozygous mutation in the HPD gene (609695), encoding 4-hydroxyphenylpyruvate dioxygenase, on chromosome 12q24. Heterozygous mutation in the HPD gene can cause hawkinsinuria (140350).

Description

Tyrosinemia type III is an autosomal recessive disorder caused by a deficiency in the activity of 4-hydroxyphenylpyruvate dioxygenase (HPD) and is characterized by elevated levels of blood tyrosine and massive excretion of its derivatives into urine. Patients with this disorder have mild mental retardation and/or convulsions, with the absence of liver damage (summary by Tomoeda et al., 2000).

Clinical Features

Giardini et al. (1983) described tyrosinemia without liver dysfunction due apparently to deficiency of 4-hydroxyphenylpyruvate dioxygenase (4HPPD). The patient, a 17-month-old girl, had acute intermittent ataxia and drowsiness. Her psychomotor development was normal. Protein restriction and vitamin C therapy failed to correct the biochemical abnormality. Liver biopsy was histologically normal. In liver biopsy tissue, obtained at 25 months of age, there was no detectable activity of 4HPPD, either in whole homogenate or cytosol fraction. Mixing experiments showed no inhibitor of either 4HPPD or tyrosine amino transferase (TAT).

In the infant offspring of a sib-sib mating, Endo et al. (1983) demonstrated hypertyrosinemia without hepatic dysfunction, with normal soluble tyrosine aminotransferase and fumarylacetoacetase. The activity of 4-hydroxyphenylpyruvic acid oxidase (EC 1.13.11.27) in the patient's liver was about 5% of controls; the enzyme had a high Km for 4-hydroxyphenylpyruvic acid. The clinical picture was that of mild mental retardation. The mother had mild mental retardation and elevated blood tyrosine level (6.1 mg/dl as compared with 11.6 mg/dl in the infant).

Cerone et al. (1997) reported the clinical and biochemical findings and the results of long-term follow-up in a new patient with this disorder presenting with severe mental retardation and neurologic abnormalities. They compared clinical phenotype with those reported in the 3 previously described patients.

Ellaway et al. (2001) reviewed 9 previously reported patients with type III tyrosinemia and reported 4 additional patients. Five of the patients were detected by neonatal screening, 1 had some jitteriness on handling, and 1 had neonatal hepatitis; the others were clinically normal. One patient died accidentally at 105 days of age. Of the 12 patients surviving beyond infancy, the most common long-term complication was intellectual impairment in 9 patients. Three of 5 patients diagnosed by neonatal screening had psychomotor retardation but not all were treated in infancy. Neurologic abnormalities had been observed in 7 of the 8 patients diagnosed beyond the neonatal period. It was not clear whether a strict low tyrosine diet alters the natural history of tyrosinemia type III, although there remained suspicion that treatment may be important, at least in infancy.

Molecular Genetics

In 3 unrelated families with tyrosinemia type III, Ruetschi et al. (2000) identified 4 presumed pathogenic mutations (2 missense and 2 nonsense) in the HPD gene (609695.0001-609695.0004). Four individuals were homozygous and 1 was compound heterozygous. No correlation of the severity of the mutation and enzyme deficiency and mental function was found; furthermore, the recorded tyrosine levels did not correlate with the clinical phenotype.

Animal Model

Endo et al. (1990, 1991) described a mouse strain with hypertyrosinemia associated with absent 4-hydroxyphenylpyruvate dioxygenase activity in the liver. The mutant mouse had a CRM-negative mutation. The disorder was autosomal recessive. All the animals were apparently healthy with no evidence of hepatorenal dysfunction. Fumarylacetoacetase and tyrosine aminotransferases (both cytosolic and mitochondrial) were normal in the mutant mice. Endo et al. (1995) reported a single-nucleotide substitution in the Hpd gene as the cause of the phenotype. The mutation was predicted to result in a premature termination codon in exon 7 of the gene and partial skipping of the exon.

History

Bloxam et al. (1960) found that 14 of 1,276 infants tested had large amounts of p-hydroxyphenylpyruvic acid, p-hydroxyphenylactic acid, and tyrosine in the urine. The infants were on normal diet. A delay in maturation of an enzyme was postulated. A genetic basis was presumed.