Increase of CSF tyrosine and impaired serotonin turnover in tyrosinemia type I.
OBJECTIVE
Psychomotor impairment has been described in hypertyrosinemia types II and III (HT III). Only recently cognitive deficits have also been reported in hypertyrosinemia type I (HT I). The pathogenic mechanisms responsible are unknown. Since implementation of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, Nitisinone (Swedish Orphan International)) in the treatment of HT I, plasma tyrosine elevation is a common finding as known from the other hypertyrosinemias.


METHODS
With elevated tyrosine as suspected pathogenic factor in the development of cognitive deficits, we here investigated tyrosine in the cerebrospinal fluid (CSF) and serotonergic and dopaminergic neurotransmitter levels in three patients with HT I during long-term treatment with Nitisinone. In addition, Nitisinone concentrations in plasma and CSF were measured. We also assessed psychomotor and cognitive development by standardized test systems and brain morphology by magnetic resonance imaging.


RESULTS
All patients presented with high tyrosine concentrations in CSF correlating with increased plasma tyrosine levels and a reduced CSF serotonin turnover. MRI revealed no structural abnormalities in the brain. All patients presented with either impaired cognitive development or behavioural abnormalities.


CONCLUSIONS
We here outline the need to further study the exact pathogenic mechanisms responsible for the neurotransmitter changes observed in HT type I in order to possibly prevent cognitive dysfunction. Nitisinone has significantly improved outcome and quality of life in HT type I; however, it is also accompanied by elevated plasma and CSF tyrosine. Further studies are essential to identify the necessary dietary tyrosine restriction and the optimal Nitisinone dose.
Department of General Pediatrics, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, Düsseldorf, Germany. Eva.Thimm@med.uni-duesseldorf.de
Eva
E
Thimm
Diran
D
Herebian
Birgit
B
Assmann
Dirk
D
Klee
Ertan
E
Mayatepek
Ute
U
Spiekerkoetter
D001921:Brain / Q000033:anatomy & histology; D002648:Child; D003512:Cyclohexanones / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D008297:Male; D009579:Nitrobenzoates / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D011597:Psychomotor Performance; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D014443:Tyrosine / Q000097:blood / Q000134:cerebrospinal fluid*; D020176:Tyrosinemias / Q000188:drug therapy* / Q000201:enzymology*
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D012701:Serotonin; D014443:Tyrosine; C077073:nitisinone