Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma

Patrick R. Blackburn, Raymond D. Hickey, Rebecca A. Nace, Nasra H. Giama, Daniel L. Kraft, Andrew J. Bordner, Roongruedee Chaiteerakij, Jennifer McCormick, Maja Radulovic, Rondell P. Graham, Michael S. Torbenson, Silvia Tortorelli, C. Ronald Scott, Noralane M. Lindor, Dawn S. Milliner, Devin Oglesbee, Wafa'a Al-Qabandi, Markus Grompe, Dimitar K. Gavrilov, Mounif El-Youssef & 5 others Karl J. Clark, Paldeep S. Atwal, Lewis R. Roberts, Eric W. Klee, Stephen C. Ekker

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.

Original languageEnglish (US)
Pages (from-to)1097-1105
Number of pages9
JournalHuman Mutation
Volume37
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Tyrosinemias
Liver Cirrhosis
Tyrosine
Hepatocellular Carcinoma
Fibrosis
Exome
Routine Diagnostic Tests
succinylacetone
fumarylacetoacetase
Newborn Infant
Enzymes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Blackburn, P. R., Hickey, R. D., Nace, R. A., Giama, N. H., Kraft, D. L., Bordner, A. J., ... Ekker, S. C. (2016). Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma. Human Mutation, 37(10), 1097-1105. https://doi.org/10.1002/humu.23047
Blackburn, Patrick R. ; Hickey, Raymond D. ; Nace, Rebecca A. ; Giama, Nasra H. ; Kraft, Daniel L. ; Bordner, Andrew J. ; Chaiteerakij, Roongruedee ; McCormick, Jennifer ; Radulovic, Maja ; Graham, Rondell P. ; Torbenson, Michael S. ; Tortorelli, Silvia ; Scott, C. Ronald ; Lindor, Noralane M. ; Milliner, Dawn S. ; Oglesbee, Devin ; Al-Qabandi, Wafa'a ; Grompe, Markus ; Gavrilov, Dimitar K. ; El-Youssef, Mounif ; Clark, Karl J. ; Atwal, Paldeep S. ; Roberts, Lewis R. ; Klee, Eric W. ; Ekker, Stephen C. / Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma. In: Human Mutation. 2016 ; Vol. 37, No. 10. pp. 1097-1105.
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abstract = "Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.",
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Blackburn, PR, Hickey, RD, Nace, RA, Giama, NH, Kraft, DL, Bordner, AJ, Chaiteerakij, R, McCormick, J, Radulovic, M, Graham, RP, Torbenson, MS, Tortorelli, S, Scott, CR, Lindor, NM, Milliner, DS, Oglesbee, D, Al-Qabandi, W, Grompe, M, Gavrilov, DK, El-Youssef, M, Clark, KJ, Atwal, PS, Roberts, LR, Klee, EW & Ekker, SC 2016, 'Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma', Human Mutation, vol. 37, no. 10, pp. 1097-1105. https://doi.org/10.1002/humu.23047

Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma. / Blackburn, Patrick R.; Hickey, Raymond D.; Nace, Rebecca A.; Giama, Nasra H.; Kraft, Daniel L.; Bordner, Andrew J.; Chaiteerakij, Roongruedee; McCormick, Jennifer; Radulovic, Maja; Graham, Rondell P.; Torbenson, Michael S.; Tortorelli, Silvia; Scott, C. Ronald; Lindor, Noralane M.; Milliner, Dawn S.; Oglesbee, Devin; Al-Qabandi, Wafa'a; Grompe, Markus; Gavrilov, Dimitar K.; El-Youssef, Mounif; Clark, Karl J.; Atwal, Paldeep S.; Roberts, Lewis R.; Klee, Eric W.; Ekker, Stephen C.

In: Human Mutation, Vol. 37, No. 10, 01.10.2016, p. 1097-1105.

Research output: Contribution to journalArticle

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T1 - Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma

AU - Blackburn, Patrick R.

AU - Hickey, Raymond D.

AU - Nace, Rebecca A.

AU - Giama, Nasra H.

AU - Kraft, Daniel L.

AU - Bordner, Andrew J.

AU - Chaiteerakij, Roongruedee

AU - McCormick, Jennifer

AU - Radulovic, Maja

AU - Graham, Rondell P.

AU - Torbenson, Michael S.

AU - Tortorelli, Silvia

AU - Scott, C. Ronald

AU - Lindor, Noralane M.

AU - Milliner, Dawn S.

AU - Oglesbee, Devin

AU - Al-Qabandi, Wafa'a

AU - Grompe, Markus

AU - Gavrilov, Dimitar K.

AU - El-Youssef, Mounif

AU - Clark, Karl J.

AU - Atwal, Paldeep S.

AU - Roberts, Lewis R.

AU - Klee, Eric W.

AU - Ekker, Stephen C.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.

AB - Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.

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