PT  - JOURNAL ARTICLE
AU  - Hao Yang
AU  - Walla Al-Hertani
AU  - Denis Cyr
AU  - Rachel Laframboise
AU  - Guy Parizeault
AU  - Shu Pei Wang
AU  - Francis Rossignol
AU  - Marie-Thérèse Berthier
AU  - Yves Giguère
AU  - Paula J Waters
AU  - Grant A Mitchell
TI  - Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency
AID  - 10.1136/jmedgenet-2016-104289
DP  - 2017 Apr 01
TA  - Journal of Medical Genetics
PG  - 241--247
VI  - 54
IP  - 4
4099  - http://jmg.bmj.com/content/54/4/241.short
4100  - http://jmg.bmj.com/content/54/4/241.full
SO  - J Med Genet2017 Apr 01; 54
AB  - 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.