Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome.

Abstract

BACKGROUND:

Tyrosinemia type 1 (HT1) is a rare but treatable disease. The aim of the present study was to review the efficacy of long-term treatment of HT1 with nitisinone, expand knowledge about the clinical spectrum of the disease and assess a possible genotype-phenotype correlation.

METHODS:

A retrospective multicenter study was carried out based on questionnaires on genotype, phenotype, therapy and outcome in 34 Spanish patients with HT1.

RESULTS:

The main manifestations that led to the diagnosis were acute liver failure (55.8%), asymptomatic hepatomegaly (44.1%) and renal tubular dysfunction (29.4%). Laboratory analysis indicated a marked increase of α-fetoprotein and coagulopathy. The most common mutation was IVS6-1(G > T; 66.6% of 24/34 patients for whom mutation analysis was available) and these patients presented less nephrocalcinosis and more hepatomegaly at diagnosis; two novel mutations (c.974C>T, c.398A>T) were found. The mean duration of treatment was 6.73 years. Dietary compliance was very good in 47.1% and good in 20.6%; nitisinone treatment adherence was very good in 85.2% of cases. Mean dose of nitisinone was 0.87 mg/kg per day with average plasma levels of 45.67 µmol/L. Only one patient required liver transplantation after nitisinone and none had hepatocellular carcinoma.

CONCLUSIONS:

Treatment with nitisinone has improved the prognosis of HT1, and compliance is good. In Spain, screening for HT1 by plasma tyrosine and urine succinylacetone determination may be implemented with IVS6-1(G > T) mutational analysis. A correlation between low frequency of nephrocalcinosis and IVS6-1(G > T) mutation was observed.

• Authors: Maria Luz Couce, Jaime Dalmau, Mireia del Toro, Guillem Pintos-Morell, Luís Aldámiz-Echevarría, Spanish Working Group on Tyrosinemia type 1
• Journal: Pediatrics international : official journal of the Japan Pediatric Society (Pediatr Int) Vol. 53 Issue 6 Pg. 985-9 (Dec 2011) ISSN: 1442-200X [Electronic] Australia
• PMID: 21752152 (Publication Type: Journal Article, Multicenter Study)
• Copyright: © 2011 The Authors. Pediatrics International © 2011 Japan Pediatric Society.

Chemical References

• Cyclohexanones
• Enzyme Inhibitors
• Nitrobenzoates
• Tyrosine
• DNA
• 4-Hydroxyphenylpyruvate Dioxygenase
• nitisinone

Topics

• 4-Hydroxyphenylpyruvate Dioxygenase (antagonists & inhibitors)
• Child
• Child, Preschool
• Cyclohexanones (therapeutic use)
• DNA (genetics)
• DNA Mutational Analysis
• Enzyme Inhibitors (therapeutic use)
• Female
• Follow-Up Studies
• Genotype
• Humans
• Incidence
• Male
• Mutation
• Nitrobenzoates (therapeutic use)
• Retrospective Studies
• Spain (epidemiology)
• Time Factors
• Treatment Outcome
• Tyrosine (blood, genetics)
• Tyrosinemias (drug therapy, epidemiology, genetics)