Tyrosinemia, Type I

A number sign (#) is used with this entry because tyrosinemia type I (TYRSN1) is caused by homozygous or compound heterozygous mutation in the FAH gene (613871), encoding fumarylacetoacetate hydrolase, on chromosome 15q25.

Description

Hereditary tyrosinemia type I is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine degradation. The disorder is characterized by progressive liver disease and a secondary renal tubular dysfunction leading to hypophosphatemic rickets. Onset varies from infancy to adolescence. In the most acute form patients present with severe liver failure within weeks after birth, whereas rickets may be the major symptom in chronic tyrosinemia. Untreated, patients die from cirrhosis or hepatocellular carcinoma at a young age (summary by Bliksrud et al., 2005).

Genetic Heterogeneity of Hereditary Tyrosinemia

Tyrosinemia type II (TYRSN2; 276600), also known as Richner-Hanhart syndrome, is caused by mutation in the TAT gene (613018) on chromosome 16q22. Tyrosinemia type III (TYRNS3; 276710) is caused by mutation in the HPD gene (609695) on chromosome 12q24.

Clinical Features

Among the children of first-cousin parents, Lelong et al. (1963) observed 2 sons with cirrhosis, Fanconi renotubular syndrome, and marked increase in plasma tyrosine. In the sib most extensively observed, hepatosplenomegaly was discovered at 3 months of age and rickets at 18 months. Malignant changes developed in the liver, and death from pulmonary metastases occurred shortly before his 5th birthday. The author suggested that the basic defect concerns an enzyme involved with tyrosine metabolism. Earlier, Himsworth (1950) described a similar case. Zetterstrom (1963) studied 7 cases coming from an isolated area of southwestern Sweden. Halvorsen et al. (1966) gave details on 6 cases from Norway.

Perry et al. (1965) described 3 sibs (2 females and a male) in 1 sibship who died in the third month after an illness characterized by irritability and progressive somnolence, and terminally by a tendency to bleed and hypoglycemia. A peculiar odor was noted. Pathologic changes included hepatic cirrhosis, renal tubular dilatation, and pancreatic islet hypertrophy. Biochemical studies showed generalized amino aciduria, marked elevation of methionine in the serum, and a disproportionately high urinary excretion of methionine. Alpha-keto-gamma-methiolbutyric acid was present in the urine and may account for the peculiar odor. The hypertrophy of the islets of Langerhans was probably due to stimulation by methionine or one of its metabolites. It seems likely that the disorder in the patients of Perry et al. (1965) was tyrosinemia since hypermethioninemia occurs secondary to liver failure in that condition (Scriver et al., 1967; Gaull et al., 1970).

Gentz et al. (1965) described 7 patients in 4 families with multiple renal tubular defects like those of the de Toni-Debre-Fanconi syndrome, nodular cirrhosis of the liver, and impaired tyrosine metabolism. In the urine, p-hydroxyphenyllactic acid was excreted in unusually large amounts. A total lack of liver p-hydroxyphenylpyruvate oxidase activity was demonstrated. Tyrosine-alpha-ketoglutarate transaminase was normal.

Scriver et al. (1967) identified the disease in 35 French Canadian infants, of whom 16 were sibs (i.e., 2 or more in each of several families). Marked tyrosinemia and tyrosyluria were present. The urine contained parahydroxyphenylpyruvic acid (PHPPA) and lactic and acetic derivatives. Loading test with tyrosine and with PHPPA suggested deficient p-hydroxyphenylpyruvate oxidase activity, which was confirmed by assay of liver biopsy samples. In stage I, infants exhibit hepatic necrosis and hypermethioninemia. In stage II, nodular cirrhosis and chronic hepatic insufficiency without hypermethioninemia are found. In stage III, renal tubular damage (Baber syndrome), often with hypophosphatemic rickets, appears. Low tyrosine diet arrested progression of the disease.

Lindblad et al. (1987) suggested that cardiomyopathy, usually subclinical, is a frequent finding.

Mitchell et al. (1990) pointed out the significance of neurologic crises in this disorder. They found that of 48 children with tyrosinemia identified on neonatal screening since 1970, 20 (42%) had neurologic crises that began at the mean age of 1 year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75%), vomiting or paralytic ileus (69%), muscle weakness (29%), and self-mutilation (8%). In 8 children, mechanical ventilation was required because of paralysis and 14 of the 20 children died. Between crises, most survivors regained normal function. They could identify no reliable biochemical marker for the crises. Urinary excretion of delta-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during both crises and asymptomatic periods. Electrophysiologic studies and neuromuscular biopsies showed axonal degeneration and secondary demyelination. Thus, they demonstrated that episodes of acute, severe, peripheral neuropathy are common in this disorder and resemble the crises of the neuropathic porphyrias.

Fumarylacetoacetase Pseudodeficiency

Kvittingen et al. (1985) described a family that may have had a pseudodeficiency gene. Presumed homozygotes for this gene had levels of fumarylacetoacetase activity only slightly higher than those in patients with tyrosinemia. No clinical abnormalities were observed. Kvittingen et al. (1992) studied a healthy 41-year-old female homozygous for the pseudodeficiency gene and 3 tyrosinemia families in which one or both parents were compound heterozygotes for the tyrosinemia and pseudodeficiency genes. Only 2 of 7 patients with typical chronic tyrosinemia had definite immunoreactivity in fibroblasts when bovine fumarylacetoacetase antibodies were used; none of the patients with the acute type had detectable immunoreactive protein in fibroblast extracts. Twenty-eight patients with hereditary tyrosinemia of various clinical phenotypes were tested. The pseudodeficiency gene product gave almost no detectable immunoreactivity in fibroblasts.

Biochemical Features

La Du and Gjessing (1972) discussed evidence against the hypothesis that tyrosinemia type I is a p-hydroxyphenylpyruvic acid oxidase deficiency. Lindblad et al. (1977) suggested that the primary defect is in fumarylacetoacetase (EC 3.7.1.2), which leads to accumulation of succinylacetone and succinylacetoacetate. Porphobilinogen synthetase is inhibited by these substances and the authors suggested that the severe liver and kidney damage of tyrosinemia is caused by accumulation of tyrosine metabolites. A puzzling feature of hereditary tyrosinemia has been episodes similar to acute hepatic porphyria, with excretion of 5-aminolevulinic acid in the urine. The inhibition of porphobilinogen synthase explains this feature. Fumarylacetoacetase is the enzyme primarily deficient; deficiency of parahydroxyphenylpyruvate oxidase is secondary (Scriver, 1982).

Tanguay et al. (1990) concluded that the acute form of hereditary tyrosinemia has absence of FAH enzyme protein, whereas the chronic form has presence of immunoreactive enzyme protein. They quoted the work of others supporting these findings.

Prieto-Alamo and Laval (1998) noted that the defect in FAH in tyrosinemia type I results in accumulation of succinylacetone (SA), which reacts with amino acids and proteins to form stable adducts via Schiff base formation, lysine being the most reactive amino acid. Patients with this disorder surviving beyond infancy are at considerable risk for the development of hepatocellular carcinoma, and a high level of chromosomal breakage is observed in tyrosinemia cells, suggesting a defect in the processing of DNA. Prieto-Alamo and Laval (1998) showed that the overall DNA-ligase activity is low in tyrosinemia cells (about 20% of normal) and that Okazaki fragments are rejoined at a reduced rate compared with normal fibroblasts. No mutation was found by sequencing the ligase I cDNA (LIG1; 126391) from tyrosinemia cells, and the level of expression of the ligase I mRNA was similar in normal and tyrosinemia fibroblasts, suggesting the presence of a ligase inhibitor. SA was shown to inhibit in vitro the overall DNA-ligase activity present in normal cell extracts. The activity of purified T4 DNA-ligase, whose active site is also a lysine residue, was inhibited by SA in a dose-dependent manner. These results suggested that accumulation of SA reduces the overall ligase activity in tyrosinemia cells and indicated that metabolic errors may play a role in regulating enzymatic activities involved in DNA replication and repair.

Pathogenesis

It had been postulated that the severe liver damage in tyrosinemia is the result of defective degradation of tyrosine. Hostetter et al. (1983) showed, however, that liver damage is prenatal in onset (as indicated by greatly elevated alpha-fetoprotein in cord blood) and that hypertyrosinemia developed only postnatally. Thus, therapy aimed at reduction of the elevated tyrosine level is unlikely to be of fundamental value.

Population Genetics

De Braekeleer and Larochelle (1990) estimated the prevalence of hereditary tyrosinemia at birth as 1/1,846 liveborn and the carrier rate as 1/20 inhabitants in the Saguenay-Lac-Saint-Jean region. The mean coefficient of inbreeding was only slightly elevated in the tyrosinemic group compared to a control group and was due to remote consanguinity. The mean kinship coefficient was 2.3 times higher in the tyrosinemic group than in the control group. This was interpreted as indicating founder effect.

Diagnosis

Prenatal diagnosis of tyrosinemia is possible either by the detection of succinylacetone in the amniotic fluid (Gagne et al., 1982) or by measurement of fumarylacetoacetase in cultured amniotic cells (Kvittingen et al., 1983). Holme et al. (1985) demonstrated the feasibility of enzymatic diagnosis in chorionic villus material. Also, they showed that normal red cells have fumarylacetoacetase activity. They proposed that studies of red cells permit rapid diagnosis and recognition of heterozygotes and that enzyme replacement by blood transfusion may help patients over acute metabolic crises and until such time as definitive therapy by orthotopic liver transplantation (Fisch et al., 1978; Gartner et al., 1984) can be performed.

Laberge et al. (1990) described an enzyme-linked immunosorbent assay (ELISA) to measure the deficient enzyme in dried blood spots in this disorder. As mean levels of blood tyrosine in newborn specimens have declined, probably as a result of dietary changes and early discharge from nurseries, the traditional approach to screening for tyrosinemia, which was based on the fluorometric determination of tyrosine on the first dried blood spot received by neonatal screening programs, has required replacement.

As an aid to early diagnosis for early institution of drug therapy, Holme and Lindstedt (1992) suggested a neonatal screening test based on the measurement of porphobilinogen synthase activity. Porphobilinogen synthase activity is always low in patients with tyrosinemia type I. Holme and Lindstedt (1992) were not aware of any drug used neonatally or of conditions that would interfere with the test or mimic porphobilinogen synthase activity to result in a false-normal test. Specificity of the test is not absolute because homozygous porphobilinogen synthase deficiency (125270) would be detected; in this disorder also, early diagnosis would presumably benefit the patients.

Tanguay et al. (1990) identified RFLPs for 4 restriction sites within the FAH gene and proposed the development of a carrier detection test by linkage analysis.

Clinical Management

Dehner et al. (1989) reviewed the pathologic findings in the liver on the basis of the findings in children undergoing liver transplant. They concluded that to preclude hepatocellular carcinoma, a liver replacement is necessary before the age of 2 years. In the view of Van Spronsen et al. (1989) also, orthotopic liver transplantation is the only definitive therapy for both the metabolic and the oncologic problem in this disorder.

Russo and O'Regan (1990) reviewed the pathologic findings in the liver and kidney. In the Hopital Sainte-Justine in Montreal, 16 patients had been evaluated for liver transplantation. Renal involvement was found to be 'more abnormal than expected.' The liver was transplanted in 7 patients of whom 2 also received kidney transplantation. Hepatocarcinoma was detected in 2 of 8 patients in whom the whole liver was examined. Of the 9 patients who did not receive transplants, 5 died; of the 7 transplant patients, 1 died in an instance of combined liver-kidney transplantation. The 6 patients who survived had normal liver function, normal growth, and no recurrence of neurologic crises on a normal diet.

Sokal et al. (1992) recommended orthotopic liver transplantation at an early stage. The procedure was performed in 4 children under 1 year of age, within 5 months of presentation and diagnosis. During the pretransplant period, intensive medical support and restriction of dietary tyrosine was initiated to improve the patient's condition and promote weight gain.

As an alternative to liver transplantation, Lindstedt et al. (1992) treated patients with type I tyrosinemia with a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPD; EC 1.13.11.27) to prevent the formation of maleylacetoacetate and fumarylacetoacetate and their saturated derivatives. The agent used in 1 acute and 4 subacute/chronic cases was 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Signs of improvement included decrease in several metabolites, correction of the almost complete inhibition of porphobilinogen synthase in erythrocytes, decrease in alpha-fetoprotein, improved liver and renotubular function, and regression of hepatic abnormalities by computed tomography. No side effects were encountered. Inhibition of 4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver cirrhosis and abolish or diminish the risk of liver cancer. Furthermore, normalization of porphyrin synthesis should eliminate the risk of porphyric crises.

Laine et al. (1995) studied renal function after orthotopic liver transplantation and found that the patients had normal glomerular filtration rates but showed signs of tubular dysfunction 18 to 36 months after operation.

Holme and Lindstedt (1998) stated that since the first trial of NTBC treatment for type I tyrosinemia in 1991, over 220 patients had been treated by the drug using a protocol that included regular follow-up with reports of clinical and laboratory investigations. Only 10% of the patients had not responded clinically to NTBC treatment. In half of these patients, successful liver transplantation had been performed, which further reduced the mortality rate during infancy to 5%. The data indicated a decreased risk for early development of hepatocellular carcinoma in patients who started treatment at an early age. Of the 101 patients aged 2 to 8 years who had started NTBC treatment before 2 years of age, no patient developed cancer after 2 years of age.

Molecular Genetics

Grompe et al. (1994) found that 100% of patients with tyrosinemia type I from the Saguenay-Lac-Saint-Jean region of Quebec and 28% of TYRSN1 patients from other regions of the world carry a splice donor site mutation in intron 12 of the FAH gene (613871.0003). Of 25 patients from the Saguenay-Lac-Saint-Jean region, 20 were homozygous. The frequency of carrier status, based on screening of blood spots from newborns, was about 1 per 25 in that region of Quebec and about 1 per 66 overall in Quebec. Using cDNA probes for the FAH gene, Demers et al. (1994) identified 10 haplotypes with 5 RFLPs in 118 normal chromosomes from the French Canadian population. Among 29 children with hereditary tyrosinemia, haplotype 6 was found to be strongly associated with disease, at a frequency of 90% as compared with approximately 18% in 35 control individuals. This frequency increased to 96% in the 24 patients originating from the Saguenay-Lac-Saint-Jean region. Most patients were found to be homozygous for a specific haplotype in this population. Analysis of 24 tyrosinemia patients from 9 countries gave a frequency of approximately 52% for haplotype 6, suggesting a relatively high association worldwide.

Kvittingen et al. (1994) demonstrated a mosaic pattern of immunoreactive FAH protein in liver tissue from 15 of 18 tyrosinemia type I patients of various ethnic origins. One additional patient had variable levels of FAH enzyme activity in liver tissue. In 4 patients exhibiting mosaicism of FAH protein, analysis for the tyrosinemia-causing mutations was performed in immunonegative and immunopositive areas of liver tissue by restriction digestion analysis and direct DNA sequencing. In all 4 patients, the immunonegative liver tissue contained the FAH mutations demonstrated in fibroblasts of the patients. In the immunopositive nodules of regenerating liver tissue, one of the mutated alleles apparently had reverted to the normal genotype. This genetic correction was observed for 3 different tyrosinemia-causing mutations. In each case, a mutant AT nucleotide pair was reverted to a normal GC pair. One of the mutations that showed reversion was the splice site mutation described in 613871.0003. Another was the glu357-to-ter mutation due to a G-to-T transversion at nucleotide 1069, which is described in 613871.0004. In a compound heterozygous patient, the same mutation was reverted to wildtype in all 4 nodules investigated. A gene conversion event or mitotic recombination between homologous chromosomes could theoretically explain the appearance of a normal allele in a compound heterozygote. Two of the patients with reverted mutations, however, were homozygous for their mutations, and no pseudogenes for FAH, for contribution of wildtype sequences, are known. Early embryonic mutation with selective growth of the mutated cells could account for the mosaicism, but a high incidence of such an event would indicate a precipitating factor. Chemical mutagenesis, reverting the disease-causing mutation, could result from the metabolites accumulating in tyrosinemia. Even if the metabolites are not direct mutagens, the compounds are toxic and induce cell necrosis with a subsequent accelerated regeneration of hepatocytes. Rapidly replicating cells are generally prone to mutations. Reversion of the genetic defect resulting from accelerated cell regeneration should be sought in other genetic diseases in tissues with an induced, or naturally high, rate of cell replication.

Hahn et al. (1995) reviewed 7 previously reported mutations in tyrosinemia type I and added 2 more identified in a compound heterozygote.

Timmers and Grompe (1996) reported 6 new mutations in the FAH gene in patients with hereditary tyrosinemia type I: 2 splice mutations, 3 missense mutations, and 1 nonsense mutation.

Rootwelt et al. (1996) classified 62 hereditary tyrosinemia type I patients of various ethnic origins clinically into acute, chronic, or intermediate phenotypes and screened for the 14 published causal mutations in the FAH gene. Restriction analysis of PCR-amplified genomic DNA identified 74% of the mutated alleles. The IVS12+5G-A mutation (613871.0003), which is predominant in French Canadian tyrosinemia type I patients, was the most common mutation being present in 32 alleles in patients from Europe, Pakistan, Turkey, and the United States. The IVS6-1G-T mutation (613871.0010), encountered in 14 alleles, was common in central and western Europe. There was an apparent 'Scandinavian' 1009G-to-A combined splice and missense mutation (12 alleles), a 'Pakistani' 192G-to-T splice mutation (11 alleles), a 'Turkish' D233V mutation (6 alleles), and a 'Finnish' or northern European W262X (613871.0009) mutation (7 alleles). Rootwelt et al. (1996) commented that some of the mutations seemed to predispose for acute and others for more chronic forms of tyrosinemia type I, although no clear-cut genotype/phenotype correlation could be established.

According to the review of St-Louis and Tanguay (1997), 26 mutations in the FAH gene had been reported in type I tyrosinemia. All consisted of single-base substitutions resulting in 16 amino acid replacements, 1 silent mutation causing a splicing defect, 5 nonsense codons, and 4 putative splicing defects. The mutations were spread over the entire FAH gene, with a particular clustering between amino acid residues 230 and 250.

Arranz et al. (2002) determined the FAH genotype in a group of 29 patients, most of them from the Mediterranean area, with hereditary tyrosinemia type I. They identified 7 novel mutations and 2 previously described mutations. At least one splice site mutation was found in 92.8% of patients, with IVS6-1G-T (613871.0010) accounting for 58.9% of the total number of alleles. The group of patients with splice mutations showed heterogeneous phenotypic patterns ranging from the acute form, with severe liver malfunction, to chronic forms, with renal manifestations and slow progressive hepatic alterations. Despite the high prevalence of the IVS12+5G-A mutation (613871.0003) in the northwestern European population, Arranz et al. (2002) found only 2 patients with this mutation from the group of 29 patients. One patient, who was a double heterozygote for a nonsense and a frameshift mutation, showed an atypical clinical picture of hypotonia and repeated infections.

Bliksrud et al. (2005) described revertant mosaicism in a patient with type I tyrosinemia.

Fumarylacetoacetase Pseudodeficiency

Rootwelt et al. (1994) presented evidence for the existence of a 'pseudodeficiency' FAH allele. In an individual homozygous for pseudodeficiency of FAH and in 3 hereditary tyrosinemia type I families also carrying the pseudodeficiency allele, Western blotting of fibroblast extracts showed that the pseudodeficiency allele gave very little immunoreactive FAH protein, whereas Northern blot analysis revealed a normal amount of FAH mRNA. All the pseudodeficiency alleles were found to carry a 1021C-T transition, predicting an arg341-to-trp substitution (R341W; 613871.0006). Site-directed mutagenesis and expression in a rabbit reticulocyte lysate system demonstrated that the arg341-to-trp mutation gave reduced FAH activity and reduced amounts of the full-length protein. The normal and the mutated sequences could be distinguished by BsiEI restriction digestion of PCR products. Among 516 healthy volunteers of Norwegian origin, the R341W mutation was found in 2.2% of alleles. Testing for this specific mutation may solve the problem of prenatal diagnosis and carrier detection in families with compound heterozygote genotypes for type I tyrosinemia and pseudodeficiency.

Animal Model

Mice homozygous for an FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction. Grompe et al. (1995) demonstrated that treatment of affected animals with NTBC abolished neonatal lethality, corrected liver function, and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged life span of affected animals resulted in a phenotype analogous to human tyrosinemia type I, including hepatocellular carcinoma. These animals will serve as a useful model for studies of the pathophysiology and treatment of hereditary tyrosinemia type I as well as hepatic cancer.

In mice deficient in FAH through targeted disruption of the Fah gene, Overturf et al. (1996) found that as few as 1,000 transplanted wildtype hepatocytes were able to repopulate mutant liver, demonstrating their strong competitive growth advantage. Mutant hepatocytes corrected in situ by retroviral gene transfer were also positively selected. In mutant animals treated by multiple retrovirus injections, more than 90% of hepatocytes became FAH positive and liver function was restored to normal. These studies were prompted by a number of observations including the finding that the livers of patients with hereditary tyrosinemia frequently contained discrete nodules with FAH enzyme activity, due to a somatic reversion event (Kvittingen et al., 1993). Wilson (1996) commented on the significance of these results for the liver gene therapy for genetic diseases in general. He stated that, based on the encouraging data in the mouse model, it would seem reasonable to evaluate this approach in patients with hereditary tyrosinemia. A similar approach might be considered for other liver metabolic diseases in which genetically corrected hepatocytes would have a selective advantage over degenerating mutant cells. Wilson (1996) suggested that a useful extension of this approach might be to introduce into the vector a gene that confers upon the hepatocyte a selective advantage such as resistance to a hepatotoxic drug. This concept was being developed in bone marrow using the multidrug resistance (MDR) gene (171050).

Overturf et al. (1997) injected Fah-deficient mice with a first-generation adenoviral vector expressing the human FAH gene and followed them for up to 9 months. Nontreated FAH mutant control mice died within 6 weeks from fulminant liver failure, whereas FAH adenovirus-infected animals survived until sacrifice at 2 to 9 months. Hepatocellular cancer developed in 9 of 13 virus-treated animals. Immunohistochemical analysis revealed a mosaic of FAH-deficient and FAH-positive cells in all animals and liver function tests were improved compared to controls. Even mice harvested 9 months after viral infection had more than 50% FAH-positive cells. These results demonstrated a strong selective advantage of FAH-expressing cells in an FAH-deficient liver but also illustrated the danger of carcinomas arising from FAH-deficient hepatocytes in this disorder.

The 'albino lethal' mouse, first described by Gluecksohn-Waelsch (1979), has a large deletion on chromosome 7, including the albino locus and the Fah gene. Another Fah-deficient mouse was generated by targeted disruption of the Fah gene (Grompe et al., 1995). Endo et al. (1997) generated mice with disruption of both the Fah gene and the Hpd gene, which encodes 4-hydroxyphenylpyruvate dioxygenase at a step earlier in the metabolic pathway. This doubly mutant tyrosinemic mouse model showed apoptosis of hepatocytes and acute onset of liver failure after administration of homogentisic acid (HGA), the intermediate metabolite between the enzymes HPD and FAH (Kubo et al., 1998). Cytochrome c was released from mitochondria prior to liver failure in the double-mutant mice after administration of HGA. In a cell-free system, the addition of fumarylacetoacetate induced release of cytochrome c from the mitochondria. Kubo et al. (1998) also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double-mutant mice. Therefore, fumarylacetoacetate apparently induces the release of cytochrome c, which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type I.

Mice homozygous for certain chromosome 7 deletions that include Fah die perinatally as a result of liver dysfunction and exhibit a complex syndrome characterized by structural abnormalities and alterations in gene expression in the liver and kidney. Aponte et al. (2001) showed that 2 independent, postnatally lethal mutations induced by N-ethyl-N-nitrosourea were alleles of Fah. One was a missense mutation in exon 6, and the other a splice mutation causing loss of exon 7, with subsequent frameshift in the resulting mRNA, and a severe reduction of Fah mRNA levels. Increased levels of the diagnostic metabolite succinylacetone in the urine of both mutants indicated that these mutations cause a decrease in Fah enzymatic activity. The mutants were proposed as mouse models for acute and chronic forms of human hepatorenal tyrosinemia.

History

Malpuech et al. (1981) described tyrosinemia in a child with partial monosomy 4p-. The parents were not consanguineous and were chromosomally normal.