Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients

Abstract

BackgroundTreatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and dietary phenylalanine and tyrosine restriction improves physical health and life expectancy in Tyrosinemia type 1 (TT1). However, neurocognitive outcome is suboptimal. This study aimed to investigate behavior problems and health-related quality of life (HR-QoL) in NTBC-dietary-treated TT1 and to relate this to phenylalanine and tyrosine concentrations.ResultsThirty-one TT1 patients (19 males; mean age 13.9 ± 5.3 years) were included in this study. Emotional and behavioral problems, as measured by the Achenbach System of Empirically Based Assessment, were present in almost all domains. Attention and thought problems were particularly evident. HR-QoL was assessed by the TNO AZL Children’s and Adults QoL questionnaires. Poorer HR-QoL as compared to reference populations was observed for the domains: independent daily functioning, cognitive functioning and school performance, social contacts, motor functioning, and vitality. Both internalizing and externalizing behavior problems were associated with low phenylalanine (and associated lower tyrosine) concentrations during the first year of life. In contrast, high tyrosine (and associated higher phenylalanine) concentrations during life and specifically the last year before testing were associated with more internalizing behavior and/or HR-QoL problems.ConclusionsTT1 patients showed several behavior problems and a lower HR-QoL. Associations with metabolic control differed for different age periods. This suggests the need for continuous fine-tuning and monitoring of dietary treatment to keep phenylalanine and tyrosine concentrations within target ranges in NTBC-treated TT1 patients.

Type 1 tyrosinemia in Finland: a nationwide study

“…Neurological problems and poor growth were more common here, but the follow-up times of these earlier studies may have been too short to detect these late-appearing issues. The former have been suggested to be partially attributable to the side effects of nitisinone [34,35], but this is debatable [33,36] and here low levels seemed more harmful. However, early disease onset seems to increase the risk for neurological complications [6], again supporting the idea of in utero progression of TT1.…”

Long‐term low dose nitisinone therapy in adults with alkaptonuria shows no cognitive decline or increased severity of depression

“…It has been postulated in HT-1 that hypertyrosinaemia may be linked to the neurocognitive deficits observed, through altered neurotransmitter metabolism such as lower intelligence quotient; motor abilities, impaired executive functioning, and social cognition; and schooling problems. [17][18][19][20][21] A more recent study however 22 demonstrated no significant correlation between tyrosine and intelligence quotient at school age. In principle, alterations in neurotransmitter metabolism may also lead to changes in mood, although this has not been reported in HT-1 or AKU.…”

Preventive use of nitisinone in alkaptonuria

“…Nevertheless, some patients can tolerate plasma tyrosine levels over 1000 μmol/l without complications. From another defect in this cascade, TT1, it is known that increased tyrosine concentrations (as a consequence of nitisinone) may play a role in the risk of mental dysfunction in these patients [ 19 , 20 ], while in younger patients low phenylalanine concentrations rather than high tyrosine concentrations seem to be more dangerous [ 21 ]. So, while in young AKU patients an earlier start of nitisinone (including a diet restricting the phenylalanine and tyrosine intake) may lead to an improved long-term functional outcome, at the same time, nitisinone treatment at least should be carefully used and monitored for development of mental and cognitive disturbances.…”