title: 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.affiliation: Unit for Diagnosis and Treatment of Metabolic Diseases, Department of Paediatrics, University Hospital of Santiago, Santiago de Compostela, Spain. maria.luz.couce.pico@sergas.es
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Couce
authors.forename: Jaime
authors.initials: J
authors.lastname: Dalmau
authors.forename: Mireia
authors.initials: M
authors.lastname: del Toro
authors.forename: Guillem
authors.initials: G
authors.lastname: Pintos-Morell
authors.forename: Luís
authors.initials: L
authors.lastname: Aldámiz-Echevarría
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors; D002648:Child; D002675:Child, Preschool; D003512:Cyclohexanones / Q000627:therapeutic use*; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D009154:Mutation; D009579:Nitrobenzoates / Q000627:therapeutic use*; D012189:Retrospective Studies; D013030:Spain / Q000453:epidemiology; D013997:Time Factors; D016896:Treatment Outcome; D014443:Tyrosine / Q000097:blood / Q000235:genetics*; D020176:Tyrosinemias / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*
chemical_list: D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D014443:Tyrosine; D004247:DNA; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C077073:nitisinone