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A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report.
Orphanet J Rare Dis 2009; 4:28OJ

Abstract

A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (<720), total bilirubin was 2.53 mg/dl (<1.0), ammonaemia 69 microM (<32), prothrombin time less than 10%, thromboplastin time >180 s (<60) and alpha-fetoprotein 29723 microg/L (<186). Plasma tyrosine (651 microM) and methionine (1032 microM) were strongly increased. In urine, tyrosine metabolites and 4-oxo-6-hydroxyheptanoic acid were increased, but succinylacetone and succinylacetoacetate--pathognomonic for tyrosinemia type I--were repeatedly undetectable. Delta-aminolevulinic acid was normal, which is consistent with the absence of succinylacetone. Abdominal ultrasound and brain CT were normal.Fumarylacetoacetase (FAH) protein and activity in cultured fibroblasts and liver tissue were decreased but not absent. 4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr). In vitro expression studies showed this mutation results in a strongly decreased FAH protein expression.Dietary treatment with phenylalanine and tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development.This is the first report of mild tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites succinylacetone and succinylacetoacetate.

Authors+Show Affiliations

Center for Metabolic Diseases, Leuven University Hospitals, Leuven, Belgium. david.cassiman@med.kuleuven.beNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20003495

Citation

Cassiman, David, et al. "A Novel Mutation Causing Mild, Atypical Fumarylacetoacetase Deficiency (Tyrosinemia Type I): a Case Report." Orphanet Journal of Rare Diseases, vol. 4, 2009, p. 28.
Cassiman D, Zeevaert R, Holme E, et al. A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report. Orphanet J Rare Dis. 2009;4:28.
Cassiman, D., Zeevaert, R., Holme, E., Kvittingen, E. A., & Jaeken, J. (2009). A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report. Orphanet Journal of Rare Diseases, 4, p. 28. doi:10.1186/1750-1172-4-28.
Cassiman D, et al. A Novel Mutation Causing Mild, Atypical Fumarylacetoacetase Deficiency (Tyrosinemia Type I): a Case Report. Orphanet J Rare Dis. 2009 Dec 15;4:28. PubMed PMID: 20003495.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report. AU - Cassiman,David, AU - Zeevaert,Renate, AU - Holme,Elisabeth, AU - Kvittingen,Eli-Anne, AU - Jaeken,Jaak, Y1 - 2009/12/15/ PY - 2009/10/12/received PY - 2009/12/15/accepted PY - 2009/12/17/entrez PY - 2009/12/17/pubmed PY - 2010/3/13/medline SP - 28 EP - 28 JF - Orphanet journal of rare diseases JO - Orphanet J Rare Dis VL - 4 N2 - A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (<720), total bilirubin was 2.53 mg/dl (<1.0), ammonaemia 69 microM (<32), prothrombin time less than 10%, thromboplastin time >180 s (<60) and alpha-fetoprotein 29723 microg/L (<186). Plasma tyrosine (651 microM) and methionine (1032 microM) were strongly increased. In urine, tyrosine metabolites and 4-oxo-6-hydroxyheptanoic acid were increased, but succinylacetone and succinylacetoacetate--pathognomonic for tyrosinemia type I--were repeatedly undetectable. Delta-aminolevulinic acid was normal, which is consistent with the absence of succinylacetone. Abdominal ultrasound and brain CT were normal.Fumarylacetoacetase (FAH) protein and activity in cultured fibroblasts and liver tissue were decreased but not absent. 4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr). In vitro expression studies showed this mutation results in a strongly decreased FAH protein expression.Dietary treatment with phenylalanine and tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development.This is the first report of mild tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites succinylacetone and succinylacetoacetate. SN - 1750-1172 UR - https://www.unboundmedicine.com/medline/citation/20003495/A_novel_mutation_causing_mild_atypical_fumarylacetoacetase_deficiency__Tyrosinemia_type_I_:_a_case_report_ L2 - https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-28 DB - PRIME DP - Unbound Medicine ER -