title: Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency.
abstract: A high level of succinylacetone (SA) in blood is a sensitive, specific newborn screening marker for hepatorenal tyrosinemia type 1 (HT1, MIM 276700) caused by deficiency of fumarylacetoacetate hydrolase (FAH). Newborns with HT1 are usually clinically asymptomatic but show liver dysfunction with coagulation abnormalities (prolonged prothrombin time and/or high international normalised ratio). Early treatment with nitisinone (NTBC) plus dietary restriction of tyrosine and phenylalanine prevents the complications of severe liver disease and neurological crises.
  
  
  
  Six newborns referred for hypersuccinylacetonaemia but who had normal coagulation testing on initial evaluation had sequence variants in theGSTZ1gene, encoding maleylacetoacetate isomerase (MAAI), the enzyme preceding FAH in tyrosine degradation. Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15). Four individuals were homozygous for c.449C>T (p.Ala150Val). One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant. In one, a single heterozygousGSTZ1sequence variant was identified, c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met revealed low MAAI activity. The six individuals with mild hypersuccinylacetonaemia (MHSA) were not treated with diet or nitisinone. Their clinical course has been normal for up to 13 years.
  
  
  
  MHSA can be caused by sequence variants inGSTZ1. Such individuals have thus far remained asymptomatic despite receiving no specific treatment.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, Québec, Canada.|College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Departments of Medical Genetics and Paediatrics, Cumming School of Medicine, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada.|Department of Medical Genetics, Centre universitaire de Santé McGill (CUSM), Québec, Canada.
authors.forename: Walla
authors.identifier: 0000-0001-8967-8640
authors.initials: W
authors.lastname: Al-Hertani
authors.affiliation: Service de Génétique médicale, Département de Pédiatrie, Centre hospitalier universitaire de Sherbrooke (CHUS), Sherbrooke, Québec, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Cyr
authors.affiliation: Service de Génétique médicale, Département de Pédiatrie, CHU de Québec-Centre hospitalier de l'Université Laval (CHUL), Québec City, Québec, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Laframboise
authors.affiliation: Département de Pédiatrie, Centre Hospitalier de la Sagamie, Sagamie, Québec, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Parizeault
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, Québec, Canada.
authors.forename: Shu Pei
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, Québec, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Rossignol
authors.affiliation: Programme québécois de Dépistage Néonatal Sanguin, CHU de Québec-Université Laval, Québec City, Québec, Canada.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Berthier
authors.affiliation: Programme québécois de Dépistage Néonatal Sanguin, CHU de Québec-Université Laval, Québec City, Québec, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Giguère
authors.affiliation: Service de Génétique médicale, Département de Pédiatrie, Centre hospitalier universitaire de Sherbrooke (CHUS), Sherbrooke, Québec, Canada.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Waters
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, Québec, Canada.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics*; D006537:Heptanoates / Q000097:blood; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006867:Hydrolases / Q000097:blood / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D014443:Tyrosine / Q000097:blood; D020176:Tyrosinemias / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: D006537:Heptanoates; D014443:Tyrosine; C020804:succinylacetone; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase; D006867:Hydrolases; C020156:fumarylacetoacetase
keywords: GSTZ1/MAAI; MHSA; Tyrosinemia; hypersuccinylacetonemia; nitisinone