Long-term cognitive functioning in individuals with tyrosinemia type 1 treated with nitisinone and protein restricted diet

Abstract

Introduction: 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 individualswith HT1, yet recent reports on cognitive impairment in treated patients exist. Aims: Describe long-term neurocognitive outcome individuals with HT1 treated with nitisinone and protein restricted diet. Methodology: Twelve individualswith 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 scalemental 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 agemean FSIQwas 79±18, three out of nine children preformedwithin normal range and two showed intellectual disability. Repeatedmeasures showed IQ decline over time in four out of eight patients, all ofwhompresented with symptoms in their firstmonths of life. Patients that showed no progressive IQ decline were 8months or older at diagnosis,with amean age of 17months. Significant correlation between Phe/Tyr ratio and FSIQ at school age was identified (r= −0.689; p b 0.044). Conclusion: 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.