Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency. Issue 4 (22nd November 2016)

• Record Type: Journal Article
• Authors: Yang, Hao; Al-Hertani, Walla; Cyr, Denis; Laframboise, Rachel; Parizeault, Guy; Wang, Shu Pei; Rossignol, Francis; Berthier, Marie-Thérèse; Giguère, Yves; Waters, Paula J; Mitchell, Grant A
• Other Names: author non-byline.; Alvarez Fernando author non-byline.; Brunel-Guitton Catherine author non-byline.; Buhas Daniela author non-byline.; Dubois Josée author non-byline.; Gosselin Martyne author non-byline.; Halac Ugur author non-byline.; Maranda Bruno author non-byline.; Mitchell John author non-byline.; Turcotte Jean-François author non-byline.; Gagnon Tommy author non-byline.; MacArthur Daniel author non-byline.
• Is Part Of: Journal of medical genetics. Volume 54:Issue 4(2017)
• Page Start: 241
• Page End: 247
• Publication Date: 2016-11-22
• Subjects: Tyrosinemia -- hypersuccinylacetonemia -- MHSA -- GSTZ1/MAAI -- nitisinone; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2016-104289
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.