Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone.
OBJECTIVE
To examine cognitive functioning in patients with tyrosinemia type I treated with nitisinone and a protein-restricted diet.


METHODS
We performed a cross-sectional study to establish cognitive functioning in children with tyrosinemia type I compared with their unaffected siblings. Intelligence was measured using age-appropriate Wechsler Scales. To assess cognitive development over time, we retrieved sequential IQ scores in a single-center subset of patients. We also evaluated whether plasma phenylalanine and tyrosine levels during treatment was correlated with cognitive development.


RESULTS
Average total IQ score in 10 patients with tyrosinemia type I receiving nitisinone was significantly lower compared with their unaffected siblings (71 ± 13 vs 91 ± 13; P = .008). Both verbal and performance IQ subscores differed (77 ± 14 vs 95 ± 11; P < .05 and 70 ± 11 vs 87 ± 15; P < .05, respectively). Repeated IQ measurements in a single-center subset of 5 patients revealed a decline in average IQ score over time, from 96 ± 15 to 69 ± 11 (P < .001). No significant association was found between IQ score and either plasma tyrosine or phenylalanine concentration.


CONCLUSIONS
Patients with tyrosinemia type I treated with nitisinone are at risk for impaired cognitive function despite a protein-restricted diet.
Department of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
Fatiha
F
Bendadi
Department of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
Tom J
TJ
de Koning
Department of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
Gepke
G
Visser
Department of Medical Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Utrecht, The Netherlands.
Hubertus C M T
HC
Prinsen
Department of Medical Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Utrecht, The Netherlands.
Monique G M
MG
de Sain
Department of Medical Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Utrecht, The Netherlands.
Nanda
N
Verhoeven-Duif
Department of Pediatric Psychology, University Medical Center Utrecht, Utrecht, The Netherlands.
Gerben
G
Sinnema
Division of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, Groningen, The Netherlands.
Francjan J
FJ
van Spronsen
Department of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: p.vanhasselt@umcutrecht.nl.
Peter M
PM
van Hasselt
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors; D000293:Adolescent; D002648:Child; D002657:Child Development; D002675:Child, Preschool; D003071:Cognition / Q000502:physiology*; D060825:Cognitive Dysfunction / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology; D003430:Cross-Sectional Studies; D003512:Cyclohexanones / Q000627:therapeutic use*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D009426:Netherlands / Q000453:epidemiology; D009579:Nitrobenzoates / Q000627:therapeutic use*; D011379:Prognosis; D012307:Risk Factors; D020176:Tyrosinemias / Q000150:complications* / Q000188:drug therapy; D055815:Young Adult
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C077073:nitisinone
2-[2-nitro-4-trifluoromethylbenzoyl]-1, 3-cyclohexanedione; NTBC