Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency

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, John

doi:10.1136/jmedgenet-2016-104289

Cited by 21 publications

(40 citation statements)

References 32 publications

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“…Both types of cases, clinical HT-1 ( FAH mutation) without circulating SA, and persistent SA due to maleylacetoacetic isomerase deficiency (mutation in GSTZ1 , not FAH ) without HT-1-like clinical symptoms, have recently been described. 48 , 49 …”

Section: Genotype/phenotypementioning

confidence: 99%

Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Chinsky

Singh

Fıçıcıoğlu

et al. 2017

Genetics in Medicine

177

222

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Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks for hepatocellular carcinoma. An effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.

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Section: Genotype/phenotypementioning

confidence: 99%

Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Chinsky

Singh

Fıçıcıoğlu

et al. 2017

Genetics in Medicine

177

222

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“…However, to date, clinical data are not sufficient to indicate a role for GSTZ1‐1 in inherited genetic disorders. Recently, six children with mild hypersuccinylacetonemia caused by sequence variants in GSTZ1 were reported; however, no evidence of liver dysfunction was detected (Yang et al , ).…”

Section: Discussionmentioning

confidence: 99%

GSTZ 1‐1 Deficiency Activates NRF 2/ IGF 1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone

Yang

Deng

et al. 2019

The EMBO Journal

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The IGF 1R signaling is important in the malignant progression of cancer. However, overexpression of IGF 1R has not been properly assessed in HCC . Here, we revealed that GSTZ 1‐1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC , and its expression was negatively correlated with IGF 1R. Mechanistically, GSTZ 1‐1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP 1, and NRF 2 activation, thus promoting IGF 1R transcription by recruiting SP 1 to its promoter. Moreover, inhibition of IGF 1R or NRF 2 significantly inhibited tumor‐promoting effects of GSTZ1 knockout in vivo . These findings establish succinylacetone as an oncometabolite, and GSTZ 1‐1 as an important tumor suppressor by inhibiting NRF 2/ IGF 1R axis in HCC . Targeting NRF 2 or IGF 1R may be a promising treatment approach for this subset HCC .

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“…The first three are reactive and labile, and have not been accurately measured in tyrosinemic liver. The relative toxicities of FAA and MAA are not known, but the clinical severity of classical HT1 [1] , [3] contrasts with the apparently mild natural history of MAAI deficiency [9] . By extension, FAA may be more toxic.…”

Section: Introductionmentioning

confidence: 99%

“…To date, two conditions that cause mild hypersuccinylacetonemia have been identified in individuals referred as “screen-positive” by the program. Some of these individuals have deficiency of maleylacetoacetate isomerase (MAAI), the enzyme preceding FAH in tyrosine degradation [9] .…”

Section: Introductionmentioning

confidence: 99%

Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles

Yang

Rossignol

Cyr

et al. 2018

Molecular Genetics and Metabolism Reports

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BackgroundA high level of succinylacetone (SA) in blood is a sensitive, specific marker for the screening and diagnosis of hepatorenal tyrosinemia (HT1, MIM 276700). HT1 is caused by mutations in the FAH gene, resulting in deficiency of fumarylacetoacetate hydrolase. HT1 newborns are usually clinically asymptomatic, but have coagulation abnormalities revealing liver dysfunction. Treatment with nitisinone (NTBC) plus dietary restriction of tyrosine and phenylalanine prevents the complications of HT1ObservationsTwo newborns screened positive for SA but had normal coagulation testing. Plasma and urine SA levels were 3–5 fold above the reference range but were markedly lower than in typical HT1. Neither individual received nitisinone or dietary therapy. They remain clinically normal, currently aged 9 and 15 years. Each was a compound heterozygote, having a splicing variant in trans with a prevalent “pseudodeficient” FAH allele, c.1021C > T (p.Arg341Trp), which confers partial FAH activity. All newborns identified with mild hypersuccinylacetonemia in Québec have had genetic deficiencies of tyrosine degradation: either deficiency of the enzyme preceding FAH, maleylacetoacetate isomerase, or partial deficiency of FAH itself.ConclusionCompound heterozygotes for c.1021C > T (p.Arg341Trp) and a severely deficient FAH allele have mild hypersuccinylacetonemia and to date they have remained asymptomatic without treatment. It is important to determine the long term outcome of such individuals.

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Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency

Abstract: MHSA can be caused by sequence variants in . Such individuals have thus far remained asymptomatic despite receiving no specific treatment.

Cited by 21 publications

References 32 publications

Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

GSTZ 1‐1 Deficiency Activates NRF 2/ IGF 1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone

Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles

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