Tyrosinemia Type III detected via neonatal screening: management and outcome.

Tyrosinemia Type III is caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), an enzyme involved in the catabolic pathway of tyrosine. To our knowledge, only a few patients presenting with this disease have been described in the literature, and the clinical phenotype remains variable and unclear. We report the case of a boy with tyrosinemia Type III detected using neonatal screening, who is homozygous for the splice donor mutation IVS11+1G>A in intron 11 of the HPD gene. At the age of 30 months, the boy's outcome under mild protein restriction was characterized by normal growth and psychomotor development.

Increased nitric oxide release by neutrophils of a patient with tyrosinemia type III.

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.

Manifestation of hawkinsinuria in a patient compound heterozygous for hawkinsinuria and tyrosinemia III.

Mutations in the gene for 4-hydroxyphenylpyruvic acid dioxygenase (HPD) cause either autosomal recessive tyrosinemia type III or autosomal dominant hawkinsinuria. We report a 6-month-old Indian infant who is compound heterozygous for both alleles and who has hawkinsinuria but not tyrosinemia type III based on biochemical investigations. The HPD gene was directly sequenced in the proband and both parents. The mechanistic model of the enzymatic function was built using the known structure of rat HPD. We identified a novel hawkinsinuria mutation, Asn241Ser, and a known tyrosinemia type III mutation, Ile335Met, in trans configuration. The structural analysis of the active site revealed that the IIe335Met mutation is situated in the close vicinity of one of the two highly conserved Phe rings which stack with the phenol ring of the substrate. The Asn241Ser mutation is situated further away from the 4-hydroxyphenylpyruvate binding pocket. Assuming that Asn241Ser causes hawkinsinuria, we propose positioning the dioxygen molecule in the HPD-catalyzed reaction as a novel role for the Asn residue. The IIe335Met allele is equivalent to a null mutation while the Asn241Ser allele results in a partially active enzyme with an uncoupled turnover causing hawkinsinuria.

Brain magnetic resonance imaging in tyrosinemia.

A 3.5-year-old girl with tyrosinemia is reported. A computed tomography scan of the abdomen revealed multiple hepatic nodules. Brain magnetic resonance imaging revealed bilateral high-signal changes confined to the globus pallidus on T2-weighted images. Globus pallidus lesions likely represented neuropathologic changes such as astocytosis, delayed myelination, and status spongiosus (myelin splitting and vacuolation).

Animal models reveal pathophysiologies of tyrosinemias.

The activity of the enzyme 4-hydroxyphenylpyruvic acid dioxygenase (HPD) is regulated by transcription factors. Mutations in the HPD locus are related to two known distinct diseases: hereditary tyrosinemia type 3 and hawkinsinuria. HPD-deficient mice are a good model with which to examine the biological effects of 4-hydroxyphenylpyruvic acid, which is a keto acid that causes no apparent visceral damage. In contrast, hereditary tyrosinemia type 1, a genetic disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH), induces severe visceral injuries. Mice with FAH deficiency are lethal after birth; thus, efforts to elucidate the mechanisms of the disease process have been impeded. The use of Fah(-/-) Hpd(-/-) double-mutant mice has enabled studies on tyrosinemias, and essential features of visceral injury have been reveale.

Outcome of tyrosinaemia type III.

Tyrosinaemia type III is a rare disorder caused by a deficiency of 4-hydroxyphenylpyruvate dioxygenase, the second enzyme in the catabolic pathway of tyrosine. The majority of the nine previously reported patients have presented with neurological symptoms after the neonatal period, while others detected by neonatal screening have been asymptomatic. All have had normal liver and renal function and none has skin or eye abnormalities. A further four patients with tyrosinaemia type III are described. It is not clear whether a strict low tyrosine diet alters the natural history of tyrosinaemia type III, although there remains a suspicion that treatment may be important, at least in infancy.

Tyrosinemia type III: diagnosis and ten-year follow-up.

Tyrosinemia type III, caused by deficiency of 4-hydroxyphenylpyruvate dioxygenase, is a rare disorder of tyrosine catabolism. Primary 4-hydroxyphenylpyruvate dioxygenase deficiency has been described in only three patients. The biochemical phenotype shows hypertyrosinemia and elevated urinary excretion of 4-hydroxyphenyl derivatives. We report 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 neurological abnormalities. The clinical phenotype is compared with those reported in the three previously described patients.

In vivo correction with recombinant adenovirus of 4-hydroxyphenylpyruvic acid dioxygenase deficiencies in strain III mice.

Tyrosinemia type 3, caused by a genetic deficiency of 4-hydroxyphenylpyruvic acid dioxygenase (HPD) in tyrosine catabolism, is characterized by convulsion, ataxia, and mental retardation. The III mouse is a model of tyrosinemia type 3. HPD activity and protein are defective in the liver and its blood tyrosine levels are elevated, the range being between 1,100 and 1,656 microM. We constructed a recombinant adenoviral vector bearing the human HPD cDNA (AdexCAGhHPD), which is expressed under the control of a potent CAG promoter. III mice were injected with 1.0 x 10(8) to 1.0 x 10(9) pfu of AdexCAGhHPD through the tail vein. When 3.0 x 10(8) - 1.0 x 10(9) pfu were injected, blood tyrosine levels decreased within 3 hr, reached a normal range (under 300 microM), and remained at a low level for 2-6 weeks. Hepatic HPD activities also increased as early as 3 hr after the injection of 5.0 x 10(8) pfu, reached the levels comparable to the control mice in 3-7 days, and then decreased, and correlated well to blood tyrosine. Hepatic HPD expression was confirmed by Northern blot and immunoblot analyses. Histology revealed no difference (gross or microscopic) between the liver injected with AdexCAGhHPD and the control. No significant changes in blood tyrosine levels were noted after the second injection of 5.0 x 10(8) pfu of AdexCAGhHPD. Thus, the intravenous administration of the adenoviral vector bearing a foreign gene seems suitable for transient, early gene transfer into the liver.

A murine model for type III tyrosinemia: lack of immunologically detectable 4-hydroxyphenylpyruvic acid dioxygenase enzyme protein in a novel mouse strain with hypertyrosinemia.

We have characterized a new mutant strain of mouse that has hypertyrosinemia. The blood tyrosine level was persistently high, and increased amounts of 4-hydroxyphenylpyruvic acid and its derivatives were excreted into the urine. Succinylacetone was not detected in urine samples from these mice. All the animals were apparently healthy, and there was no evidence of hepatorenal dysfunction. The hypertyrosinemia was transmitted through an autosomal recessive inheritance. Analyses of hepatic enzymes related to tyrosine metabolism revealed that 4-hydroxyphenylpyruvic acid dioxygenase activity was virtually absent, while fumarylacetoacetase and tyrosine aminotransferases (cytosolic and mitochondrial forms) were normal in these mutant mice. Immunoblot analysis of 4-hydroxyphenylpyruvic acid dioxygenase protein in the liver indicated that the subunit protein of the enzyme was absent. It would appear that hypertyrosinemia in this mutant strain was caused by a genetic defect in 4-hydroxyphenylpyruvic acid dioxygenase. These features are similar to type III tyrosinemia in humans. Analysis of this mutant strain of mouse is expected to provide valuable information on the pathogenesis of human type III tyrosinemia and can also serve as a useful system for studies on tyrosine metabolism.

Hereditary tyrosinemia type I--an overview.

Hereditary tyrosinemia type I is a metabolic disorder of autosomal recessive inheritance. The disorder is characterized by progressive liver disease and renal tubular defects with accompanying hypophosphatemic rickets. It occurs in an acute and a chronic form. Hepatocellular carcinoma is frequently encountered in the chronic form of the disorder. The primary enzyme defect is a deficiency of fumarylacetoacetase (FAH) (EC 3.7.1.2), the last enzyme in the degradation of tyrosine. The enzyme defect results in accumulation of fumaryl- and maleyl-acetoacetate which are thought to cause the cellular damage in tyrosinemia. Fumaryl- and maleyl-acetoacetate are reactive compounds and have not been identified in tyrosinemia patients. Succinylacetone, however, presumably derived from these metabolites by reduction and decarboxylation, is elevated in serum and urine from the patients. The diagnosis of tyrosinemia can be established by determination of succinylacetone in urine or serum and by assay of FAH in lymphocytes and fibroblasts. Heterozygotes for FAH can be identified by fumarylacetoacetase analysis in lymphocytes and fibroblasts. Prenatal diagnosis of tyrosinemia is possible by analysis of succinylacetone in amniotic fluid supernatant and by assay of FAH in cultured amniotic fluid cells or chorionic villus material. Genetic variants of FAH may interfere in the prenatal diagnosis of tyrosinemia by the FAH assay and in the detection of the carrier state. Immunoblotting technique has shown absence of immunoreactive protein in liver tissue from tyrosinemia patients. Liver transplantation is as yet the only definite treatment of the disorder.

Enzyme defect in a case of tyrosinemia type I, acute form.

We determined the activities of tyrosine aminotransferase (TAT, EC 2.6.1.5), p-hydroxyphenylpyruvate oxidase (p- HPPA oxidase, EC 1.14.2.2) and fumarylacetoacetate fumarylhydrolase ( FAH , EC 3.7.12) in cytosol of the liver and kidney tissues obtained at autopsy from a case of hereditary tyrosinemia type I. Values were compared with those from a control group of autopsied tissues from three adults and six children, who had died of other causes. In tyrosinemia, these three hepatic enzyme activities were all decreased: TAT showed approximately 35%, p- HPPA oxidase 11%, and FAH 60% of the corresponding control values. On the other hand, kidney enzymes in tyrosinemia revealed that FAH was most significantly decreased to approximately 14% of the control activity. Km values for substrate--determined for p- HPPA oxidase and FAH --were not different between the patient and controls, suggesting no altered properties of these enzymes. We conclude that in the present case of hereditary tyrosinemia type I, the activities of p- HPPA oxidase in liver and FAH in kidney were most strikingly affected. This fact may in part explain the deteriorated metabolism of tyrosine observed in this patient.