Persistent succinylacetone excretion after liver transplantation in a patient with hereditary tyrosinaemia type I

Tuchman, Mendel; Freese, Deborah K.; Sharp, Harvey L.; Whitley, Chester B.; Ramnaraine, Margaret L.; Ulstrom, Robert A.; Najarían, John S.; Ascher, Nancy L.; Buist, Neil R. M.; Terry, Annie

doi:10.1007/bf01805479

Cited by 21 publications

(7 citation statements)

References 12 publications

(9 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result was consistent with a previous report, in which SA levels in liver were measured in homozygous C 14C°S mice and found not to be elevated (Collins et al 1992). The relevance of this finding, however, was questionable, because it has been shown in human HT1 patients, that SA is often not elevated in liver, whereas it is easily detectable in plasma and urine in the same patient (Tuchman et al 1985). For this reason, SA analysis was also carried out in plasma.…”

Section: Homozygous Fah a S Mice Have Multiple Biochemical Absupporting

confidence: 92%

See 1 more Smart Citation

Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.

Grompe

Al‐Dhalimy

Finegold

et al. 1993

Genes & Development

335

297

View full text Add to dashboard Cite

Mice homozygous for the c 14c°s albino deletion die as neonates as a result of liver dysfunction. Previous mapping studies have associated this defect with a 310-kb fragment encoding the hepatocyte-specific developmental regulation locus (alf/hsdr-1). The gene encoding fumarylacetoacetate hydrolase (Fah), a metabolic enzyme that catalyzes the last step of tyrosine catabolism, also maps to the same deletion interval. To test whether the neonatal defects found in the albino deletion mutants are attributable to loss of Fah, and not to another gene mapping to the deletion, we have generated Fah mutant mice by gene targeting in embryonic stem cells. Fah-deficient mice die within 12 hr after birth from hypoglycemia and liver dysfunction. In addition, the same pattern of altered liver mRNA expression found in the albino deletion mutants was also found in affected animals. We conclude that the neonatal lethal and liver dysfunction phenotype of the alf/hsdr-1 deletion is entirely attributable to loss of Fah.

show abstract

Section: Homozygous Fah a S Mice Have Multiple Biochemical Absupporting

confidence: 92%

“…The failure to detect SA in the liver of Fah-deficient subjects is not unique to mice as it has been reported for HT1 patients as well (Tuchman et al 1985) and might be attributable to entrapment of available SA as a result of protein binding.…”

Section: Possible Mechanisms Of the Alf/hsdr-1 Phenotypementioning

confidence: 68%

Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.

Grompe

Al‐Dhalimy

Finegold

et al. 1993

Genes & Development

335

297

View full text Add to dashboard Cite

show abstract

“…It may also be that lethality and SA phenotype are related in a more complex way not addressed by the experiments reported here. Mice heterozygous for either mutation do not exhibit an increase in SA levels, confirming that a rise in SA accompanies the disease state (40).…”

Section: Sbmentioning

confidence: 71%

Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1

Aponte

Sega

Hauser

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hereditary tyrosinemia type 1 (HT1) is a severe autosomal recessive metabolic disease associated with point mutations in the human fumarylacetoacetate hydrolase (FAH) gene that disrupt tyrosine catabolism. An acute form of HT1 results in death during the first months of life because of hepatic failure, whereas a chronic form leads to gradual development of liver disease often accompanied by renal dysfunction, childhood rickets, neurological crisis, and hepatocellular carcinoma. Mice homozygous for certain chromosome 7 deletions of the albino Tyr; c locus that also 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. Here we report that two independent, postnatally lethal mutations induced by N-ethyl-N-nitrosourea and mapped near Tyr are alleles of Fah. The Fah 6287SB allele is a missense mutation in exon 6, and Fah 5961SB is a splice mutation causing loss of exon 7, a 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 the Fah 6287SB and Fah 5961SB mutants indicate that these mutations cause a decrease in Fah enzymatic activity. Thus, the neonatal phenotype present in both mutants is due to a deficiency in Fah caused by a point mutation, and we propose Fah 5961SB and Fah 6287SB as mouse models for acute and chronic forms of human HT1, respectively.

show abstract

“…However, the enzyme FAH is active not only in the liver but also in the kidney (Fellman et al 1972). Some years after the first liver transplantations in these patients, some reports focused on the renal problems after transplantation, showing that urinary succinylacetone excretion remained but that tubular function normalized (Flye et al 1990;Kvittingen et al 1986;Shoemaker et al 1992;Sokal et al 1992;Tuchman et al 1985Tuchman et al , 1987van Thiel et al 1986). Glomerular function usually improved.…”

Section: Introductionmentioning

confidence: 95%

Renal function in tyrosinaemia type I after liver transplantation: A long‐term follow‐up

Pierik

Spronsen

Bijleveld

et al. 2005

J of Inher Metab Disea

View full text Add to dashboard Cite

Hereditary tyrosinaemia type I is an autosomal recessive inborn error of tyrosine catabolism caused by a deficiency of the enzyme fumarylacetoacetase that results in liver failure, hepatocellular carcinoma, renal tubular dysfunction and acute intermittent porphyria. When treated with liver transplantation, tyrosinaemia type I was considered to be cured. Some years after the first liver transplantations in these patients, some reports focused on the renal function after transplantation. These reports showed that urinary succinylacetone excretion remained but that tubular function normalized. In this report we discuss the long-term renal follow-up (mean follow-up time 11 years, range 7-14 years) after liver transplantation in 9 patients with tyrosinaemia type I treated by liver transplantation in our centre. An evaluation was made of renal function and succinylacetone excretion in urine. In all patients we found a persistent excretion of succinylacetone in the urine. With respect to the glomerular function, we can conclude that there is no clear change in GFR. At the same time, tubulopathy persisted in some patients. We consider that excretion of metabolites such as succinylacetone will be an important contributing factor to tubular dysfunction after liver transplantation in patients with tyrosinaemia type I. Therefore, notwithstanding the major effect of liver transplantation on tyrosine metabolism, renal tubular dysfunction remains at risk and needs careful monitoring. Progressive tubular dysfunction can cause glomerular damage. The use of low-dose NTBC might be considered after liver transplantation in case of tubulopathy to prevent progression of tubular and glomerular dysfunction.

show abstract

Persistent succinylacetone excretion after liver transplantation in a patient with hereditary tyrosinaemia type I

Cited by 21 publications

References 12 publications

Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.

Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.

Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1

Renal function in tyrosinaemia type I after liver transplantation: A long‐term follow‐up

Contact Info

Product

Resources

About