Background 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.
Methods and results Six newborns referred for hypersuccinylacetonaemia but who had normal coagulation testing on initial evaluation had sequence variants in the GSTZ1 gene, 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 heterozygous GSTZ1 sequence 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.
Conclusions MHSA can be caused by sequence variants in GSTZ1. Such individuals have thus far remained asymptomatic despite receiving no specific treatment.
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WA-H and DC contributed equally.
Collaborators Active members of the Québec NTBC Study Group who read and approved the manuscript: Fernando Alvarez, Catherine Brunel-Guitton, Daniela Buhas, Josée Dubois, Martyne Gosselin, Ugur Halac, Rachel Laframboise, Bruno Maranda, John Mitchell, Guy Parizeault and Jean-François Turcotte. We thank Martyne Gosselin for coordinating the Québec NTBC Study; Mélanie Beaucage for facilitating the sampling of several participants; Tommy Gagnon and Patrick Bherer for expert analytical contributions; Daniel MacArthur, Harvard Medical School, for help with interrogating the ExAC database; Reuben Matalon for updating patient data and André Imbeau for financial support. Data from this article were presented in part at the TYROSINÉMIE2015 Symposium in Chicoutimi, Québec, Canada, on 25 September 2015.
Contributors HY performed expression experiments and wrote part of the manuscript; WA-H contributed patient data; DC devised and performed SA measurements; RL contributed patient data; GP contributed patient data; SPW cloned MAAI and supervised enzymatic studies; FR interpreted molecular analyses; M-TB and YG reviewed the newborn screening data; PJW supervised analysis of SA and wrote part of the article and GAM supervised clinical, molecular and enzymatic investigations and wrote part of the article. All of the above authors and participating Québec NTBC Study members (Fernando Alvarez, Catherine Brunel-Guitton, Daniela Buhas, Josée Dubois, Martyne Gosselin, Ugur Halac, Bruno Maranda, John Mitchell, Jean-François Turcotte) reviewed, criticized the data and approved the article.
Funding This work was funded in part from account FHSJ-AI-TYROSINEMIE-G. Mitchell.
Competing interests None.
Ethics approval Approved as a clinical report by the Research Ethics Board of CHU Sainte-Justine.
Provenance and peer review Not commissioned; externally peer reviewed.