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

Abstract

IntroductionTyrosinemia 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.AimsDescribe long-term neurocognitive outcome individuals with HT1 treated with nitisinone and protein restricted diet.MethodologyTwelve 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.ResultsDelayed 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).ConclusionSome 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.

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

“…The strong correlation between recent tyrosine concentrations and levels of inattention, and the even more robust correlation when correcting for age at diagnosis, support the notion that transient concentration of tyrosine could be more relevant for levels of inattention than long‐term concentrations, and that these effects are not directly attributed to nitisinone itself. Garcia, de la Parra, Arias, Arredondo, and Cabello () reported a decline in IQ (mean of 16.8 IQ points) over minimum 2 years in patients receiving a diagnosis before 8 months of age (with first symptom appearing between the first and third months). Bendadi et al () also found a decline in IQ in a group with HT‐1 who were 8 months or younger when receiving the diagnosis.…”

Development of Risk Prediction Equations for Incident Chronic Kidney Disease

“…In addition, we thank the physicians, nursing staff, and metabolic departments of all collaborating Academic Medical Center, Amsterdam, Netherlands. 9 The NIHR Great Ormond Street Hospital Biomedical Research Centre (BRC ), London, UK.…”

“…However, recent studies suggest that the neurocognitive outcome of NTBC-dietary-treated TT1 patients is suboptimal [5][6][7][8][9][10][11]. Lower IQ values have been observed along with impairment in various cognitive domains, including executive functioning and social cognition.…”

Discontinuation of NTBC after liver transplantation in tyrosinemia type 1

“…The management of hereditary tyrosinemia type 1 (HT1) has been revolutionized by the introduction of 2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1‐3‐cyclohexanedione (NTBC) . Continued NTBC treatment after liver transplantation (LT) has been suggested as a means of controlling renal succinylacetone (SA) production and hence improving long‐term renal function .…”

“…A factor to consider is that even low‐dose NTBC causes significantly raised tyrosine, raising the issue of whether reintroduction of dietary restriction would be necessary. Furthermore, some patients with HT1 treated with NTBC and protein‐restricted diet are at risk of developmental delay and impaired cognitive functioning . We describe here the case of a HT1 patient who was allowed an unrestricted diet without NTBC after living‐related donor LT.…”