Abstract
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 HT1 ObservationsTwo 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 15years. 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.
Highlights
A marked increase in succinylacetone (SA) is regarded as pathognomonic for hepatorenal tyrosinemia [1,2], a severe autosomal recessive disease that causes hepatic failure, cirrhosis, liver cancer, renal tubulopathy, rickets and severe porphyria-like neurological crises
Medical treatment of HT1 is highly effective. All of these complications are preventable by diagnosis and treatment with nitisinone (NTBC) plus dietary therapy, if this treatment is started in the first month of life [3]
Sanger sequencing of all exons and flanking intronic sequences of fumarylacetoacetate hydrolase (FAH) in certified commercial laboratories showed that both individuals are compound heterozygotes
Summary
A marked increase in succinylacetone (SA) is regarded as pathognomonic for hepatorenal tyrosinemia (tyrosinemia type I, HT1, MIM 276700) [1,2], a severe autosomal recessive disease that causes hepatic failure, cirrhosis, liver cancer, renal tubulopathy, rickets and severe porphyria-like neurological crises. Medical treatment of HT1 is highly effective. Sensitive newborn screening is essential for optimal treatment of HT1. SA is a sensitive and specific marker for the screening and diagnosis of HT1 [4]. The longest-running neonatal screening program for HT1 is in Québec, Canada, where HT1 is prevalent because of a genetic founder effect [8]. 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].
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