Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency
| Autor: | Hao Yang, Paula J. Waters, Denis Cyr, Grant A. Mitchell, Walla Al-Hertani, Shu Pei Wang, Marie-Thérèse Berthier, Francis Rossignol, Rachel Laframboise, Guy Parizeault, Yves Giguère |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Nitisinone Maleylacetoacetate isomerase Adolescent Hydrolases Biology GSTZ1 Compound heterozygosity Asymptomatic Tyrosinemia 03 medical and health sciences Liver disease 0302 clinical medicine Internal medicine Genetics medicine Humans Child Genetics (clinical) Glutathione Transferase Tyrosinemias Infant Newborn Genetic Variation High-Throughput Nucleotide Sequencing Infant medicine.disease Heptanoates 030104 developmental biology Endocrinology Liver 030220 oncology & carcinogenesis Child Preschool Fumarylacetoacetate hydrolase Tyrosine Female medicine.symptom medicine.drug |
| Zdroj: | Journal of medical genetics. 54(4) |
| ISSN: | 1468-6244 |
| Popis: | 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 ( 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. |
| Databáze: | OpenAIRE |
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