title: Long-term cognitive functioning in individuals with tyrosinemia type 1 treated with nitisinone and protein-restricted diet.
abstract: BACKGROUND
  Tyrosinemia Type 1 (HT1) is an autosomal recessive disorder caused by a defect in the enzyme fumarylacetoacetate hydroxylase in the tyrosine pathway. Implementation of nitisinone (NTBC) treatment has dramatically improved survival rate of individuals with HT1, yet recent reports on cognitive impairment in treated patients exist.
  
  
  OBJECTIVE
  Describe long-term neurocognitive outcome individuals with HT1 treated with nitisinone and protein restricted diet.
  
  
  METHODS
  Twelve individuals with HT1 were analyzed with respect to psychomotor development and cognitive functioning using standardized psychometric tests. Plasma tyrosine and phenylalanine concentrations were also collected and analyzed, as part of the regular HT1 follow up program in our clinic.
  
  
  RESULTS
  Delayed performance in Bayley scale mental developmental index (MDI) was identified in 29% to 38% of the patients assessed at different ages. At preschool age, mean full scale IQ (FSIQ) was 88 ± 16; six out of nine assessed children preformed within normal range, and one child presented with intellectual disability. At school age mean FSIQ was 79 ± 18, three out of nine children preformed within normal range and two showed intellectual disability. Repeated measures showed IQ decline over time in four out of eight patients, all of whom presented with symptoms in their first months of life. Patients that showed no progressive IQ decline were 8 months or older at diagnosis, with a mean age of 17 months. Significant correlation between Phe/Tyr ratio and FSIQ at school age was identified (r = - 0.689; p < 0.044).
  
  
  CONCLUSIONS
  Some patients with HT1 treated with nitisinone and protein restricted diet are at risk of presenting developmental delay and impaired cognitive functioning. Patients with early onset of symptoms could be at risk for progressive cognitive functioning decline over time.
authors.affiliation: Laboratory of Genetics and Metabolic Disease, INTA, University of Chile, Chile.
authors.forename: María Ignacia
authors.initials: MI
authors.lastname: García
authors.affiliation: Laboratory of Genetics and Metabolic Disease, INTA, University of Chile, Chile.
authors.forename: Alicia
authors.initials: A
authors.lastname: de la Parra
authors.affiliation: Laboratory of Genetics and Metabolic Disease, INTA, University of Chile, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Arias
authors.affiliation: Laboratory of Micronutrients, INTA, University of Chile, Chile.
authors.forename: Miguel
authors.initials: M
authors.lastname: Arredondo
authors.affiliation: Laboratory of Genetics and Metabolic Disease, INTA, University of Chile, Chile.
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: Cabello
keywords: Cognitive impairment; NTBC; Nitisinone; Tyrosine; Tyrosinemia type 1