Neurocognitive outcome in tyrosinemia type 1 patients compared to healthy controls

Abstract

BackgroundHereditary Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the enzyme Fumarylacetoacetate Hydrolase. Due to this defect, toxic products accumulate which, in turn, cause liver and kidney dysfunction. Treatment with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and diet has diminished these problems, but recent data indicate that HT1 patients have neurocognitive problems. However, the neuropsychological profile of these patients is unknown. Therefore, this study aimed to investigate this neuropsychological profile by comparing HT1 patients with healthy controls.MethodsNeurocognitive testing was performed in a heterogeneous group of 19 NTBC and dietary treated HT1 patients (five female, fourteen male; mean age 12.9 ± 4.8 years; range 7.9–23.6 years) and 19 age and gender matched controls (five female, fourteen male; mean age 13.2 ± 4.6 years; range 8.1–24.8 years). IQ scores were estimated and all participants performed the Amsterdam Neuropsychological Tasks, measuring executive functions (inhibition, cognitive flexibility and working memory) and social cognition (face recognition and identification of facial emotions).ResultsHT1 patients showed poorer estimated IQ, executive functioning (working memory and cognitive flexibility), and social cognition compared to healthy controls. Lower IQ scores in HT1 patients were mostly unrelated to scores on executive function- and social cognition tasks and therefore did not account for group differences in these domains. Further analyses within the HT1 patient group (comparing different groups of patients based on the age at diagnosis and the clinical symptoms at diagnosis) did not reveal any significant results. The duration of NTBC treatment was negatively correlated with IQ.ConclusionsDespite the heterogeneity of the patient group, these data clearly show that IQ, executive functioning and social cognition are affected in HT1 patients, and that IQ screening is not sufficient for cognitive monitoring of these patients. Further research should focus on the underlying pathophysiological mechanisms of these impairments to consequently try to improve treatment strategies.

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

“…In patients with tyrosinemia Type III with similar concentrations of tyrosine as treated HT‐1 patients, and in tyrosinemia Type II, with even higher levels of tyrosine, neurocognitive difficulties are prominent (G. A. Mitchell, Grompe, Lambert, & Tanguay, ; Natt, Kida, Odievre, Di Rocco, & Scherer, ). This is in accordance with studies showing learning difficulties (Masurel‐Paulet et al, ), lower IQ (Thimm et al, ), suboptimal motor function (Thimm et al, ), difficulties with social cognition (van Ginkel et al, ), inattentiveness (Pohorecka et al, ), and difficulties with working memory (van Ginkel et al, ) among treated HT‐1 patients. See Figure for information about the catabolic pathways for the different types of tyrosinemia and nitisinone.…”

Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria

“…Metabolites of these neurotransmitters have previously been shown to significantly alter with nitisinone treatment in AKU patients . Similarly, numerous reports and studies document impaired cognitive function in HT‐1 patients that have been treated long‐term with nitisinone and protein restriction . These neurodevelopmental effects however could be due to either nitisinone‐induced tyrosinemia or severe liver failure experienced before diagnosis and subsequent initiation of nitisinone treatment.…”

“…13 Similarly, numerous reports and studies document impaired cognitive function in HT-1 patients that have been treated long-term with nitisinone and protein restriction. 9,14,15 These neurodevelopmental effects however could be due to either nitisinone-induced tyrosinemia or severe liver failure experienced before diagnosis and subsequent initiation of nitisinone treatment. With the cause of impaired cognition in HT-1 remaining to be elucidated, the off-license use of nitisinone has been restricted to ≥16 years in AKU.…”

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

“…An average drop of 27 IQ points was observed. Also poorer executive functioning (working memory and cognitive flexibility) and social cognition compared to healthy controls has been reported [15].…”