Plasma Tyrosine Levels Research Articles

Blood Levels of Monoamine Precursors and Smoking in Patients with Schizophrenia.

Smoking is highly prevalent in patients with schizophrenia and exerts a negative impact on cardiovascular mortality in these patients. Smoking has complex interactions with monoamine metabolism through the ability of cigarette smoke to suppress Type 1 T helper cell (Th1) type immunity, the immunophenotype that is implicated in phenylalanine hydroxylase (PAH) dysfunction and tryptophan (Trp) breakdown to kynurenine (Kyn) via indoleamine 2,3-dioxygenase. Nicotine also induces tyrosine hydroxylase (TH) gene expression, leading to increased synthesis of catecholamines. Furthermore, there is evidence for PAH dysfunction in schizophrenia. This study aimed to compare the plasma levels of selected monoamine precursors and their metabolites in smokers vs. non-smokers in a large sample of patients with schizophrenia. We measured plasma phenylalanine (Phe), tyrosine (Tyr), Trp, and Kyn levels using high-performance liquid chromatography and calculated Phe:Tyr and Kyn:Trp ratios in 920 patients with schizophrenia. Analysis of variance and linear regression analyses were used to compare these endpoints between three groups of patients with schizophrenia: (1) current smokers, (2) past smokers, and (3) non-smokers. There were significant differences among the three groups with regards to Tyr levels [F(2,789) = 3.77, p = 0.02], with current smokers having lower Tyr levels when compared with non-smokers (p = 0.02). Kyn levels and Kyn:Trp ratio were different among the three groups [F(2,738) = 3.17, p = 0.04, F(2,738) = 3.61, p = 0.03] with current smokers having lower Kyn levels (p = 0.04) and higher Kyn:Trp ratio (p = 0.02) when compared with past smokers. These findings need to be replicated with protocols that include healthy controls to further elucidate the neurobiological underpinnings of altered Tyr and Kyn levels in smokers. Results do suggest potential molecular links between schizophrenia and smoking that may represent biomarkers and treatment targets for reducing an important modifiable cause of general morbidity and mortality in patients with schizophrenia.

Metabolic Effects of Increasing Doses of Nitisinone in the Treatment of Alkaptonuria.

Alkaptonuria is an autosomal recessive disease involving a deficiency of the enzyme homogentisate dioxygenase, which is involved in the tyrosine degradation pathway. The enzymatic deficiency results in high concentrations of homogentisic acid (HGA), which results in orthopedic and cardiac complications, among other symptoms. Nitisinone (NTBC) has been shown to effectively treat alkaptonuria by blocking the conversion of 4-hydroxyphenylpyruvate to HGA, but there have been concerns that using doses higher than about 2mg/day could cause excessively high levels of tyrosine, resulting in crystal deposition and corneal pathology. We have enrolled seven patients in a study to determine whether higher doses of NTBC were effective at further reducing HGA levels while maintaining tyrosine at acceptable levels. Patients were given varying doses of NTBC (ranging from 2 to 8mg/day) over the course of between 0.5 and 3.5years. Urine HGA, plasma tyrosine levels, and plasma NTBC were then measured longitudinally at various doses. We found that tyrosine concentrations plateaued and did not reach significantly higher levels as NTBC doses were increased above 2mg/day, while a significant drop in HGA continued from 2 to 4mg/day, with no significant changes at higher doses. We also demonstrated using untargeted metabolomics that elevations in tyrosine from treatment resulted in proportional elevations in alternative tyrosine metabolic products, that of N-acetyltyrosine and γ-glutamyltyrosine.

Effects of dietary tryptophan and phenylalanine–tyrosine depletion on phasic alertness in healthy adults – A pilot study

BackgroundThe synthesis of the neurotransmitters serotonin (5-HT) and dopamine (DA) in the brain can be directly altered by dietary manipulation of their relevant precursor amino acids (AA). There is evidence that altered serotonergic and dopaminergic neurotransmission are both associated with impaired attentional control. Specifically, phasic alertness is one specific aspect of attention that has been linked to changes in 5-HT and DA availability in different neurocircuitries related to attentional processes. The present study investigated the impact of short-term reductions in central nervous system 5-HT and DA synthesis, which was achieved by dietary depletion of the relevant precursor AA, on phasic alertness in healthy adult volunteers; body weight–adapted dietary tryptophan and phenylalanine–tyrosine depletion (PTD) techniques were used.MethodsThe study employed a double-blind between-subject design. Fifty healthy male and female subjects were allocated to three groups in a randomized and counterbalanced manner and received three different dietary challenge conditions: acute tryptophan depletion (ATD, for the depletion of 5-HT; N=16), PTD (for the depletion of DA; N=17), and a balanced AA load (BAL; N=17), which served as a control condition. Three hours after challenge intake (ATD/PTD/BAL), phasic alertness was assessed using a standardized test battery for attentional performance (TAP). Blood samples for AA level analyses were obtained at baseline and 360 min after the challenge intake.ResultsOverall, there were no significant differences in phasic alertness for the different challenge conditions. Regarding PTD administration, a positive correlation between the reaction times and the DA-related depletion magnitude was detected via the lower plasma tyrosine levels and the slow reaction times of the first run of the task. In contrast, higher tryptophan concentrations were associated with slower reaction times in the fourth run of the task in the same challenge group.ConclusionThe present study is the first to demonstrate preliminary data that support an association between decreased central nervous system DA synthesis, which was achieved by dietary depletion strategies, and slower reaction times in specific runs of a task designed to assess phasic alertness in healthy adult volunteers; these findings are consistent with previous evidence that links phasic alertness with dopaminergic neurotransmission. A lack of significant differences between the three groups could be due to compensatory mechanisms and the limited sample size, as well as the dietary challenge procedures administered to healthy participants and the strict exclusion criteria used. The potential underlying neurochemical processes related to phasic alertness should be the subject of further investigations.

Plasma levels of lysine, tyrosine, and valine during pregnancy are independent risk factors of insulin resistance and gestational diabetes.

This study compared plasma concentrations of amino acids in pregnant women with and without gestational diabetes mellitus (GDM) and identified the association between plasma amino acid levels and GDM, insulin resistance, and insulin secretion at 24-28 weeks of pregnancy. Circulating amino acid levels were evaluated using high-performance liquid chromatography at 24-28 weeks of pregnancy in 25 non-GDM and 64 GDM women after adjusting for covariates such as maternal age, body mass index (BMI) before pregnancy, BMI and gestational age at screening GDM, and daily caloric intake. Backward stepwise logistic regression analysis was used to identify the predictors of developing GDM, and homeostatic model assessments for insulin resistance (HOMA-IR) and β-cell function (HOMA-B). Circulating levels of amino acids except threonine and tyrosine were significantly higher in GDM women than non-GDM women. Along with the intakes of energy, protein, and fat from animal sources, the intakes of each amino acid were significantly higher in the GDM group without a direct correlation to plasma amino acid levels. The variation in GDM development was explained by maternal age, diastolic blood pressure, and plasma lysine levels (R(2)=0.691). Height, BMI before pregnancy, systolic blood pressure, and plasma tyrosine and valine levels accounted for the variation in HOMA-IR (R(2)=0.589). The 53.3% variation of HOMA-B was explained by maternal age, BMI at GDM screening, plasma insulin level at 1 h during the oral glucose tolerance test (OGTT), and plasma valine level. Circulating concentrations of lysine, tyrosine, and valine were independently and positively associated with GDM through modifying insulin resistance and secretion.

ADHD impacted by sulfotransferase (SULT1A) inhibition from artificial food colors and plant-based foods

BackgroundFive recent reviews have analyzed trials on the association between artificial food colors and ADHD; the 50 underlying studies and the reviews in aggregate were inconclusive. Recent work has shown human in vivo SULT1A inhibition leading to incremental catecholamines, and an inverted-U relationship between brain catecholamines and proper functioning of the prefrontal cortex where ADHD behavior can arise. MethodThis study re-examined the same underlying trials for evidence that SULT1A inhibitors were in the placebos and other inactive foods, that these “inactive” materials were symptomatic, and that ADHD symptoms exhibited an inverted-U response to SULT1A inhibition. ResultsNearly all the underlying diets, and many placebos and delivery vehicles, were found to contain SULT1A inhibitors. Eight publications provided evidence of ADHD symptoms caused by the “inactive” materials containing SULT1A inhibitors. Ten studies showed additional SULT1A inhibitors reducing the symptoms of some subjects. ConclusionSULT1A inhibitors in foods, including natural substances and artificial food colors, have a role in ADHD that can both worsen or improve symptoms. Mechanistically, SULT1A enzymes normally deactivate catecholamines, especially dopamine formed in the intestines; SULT1A inhibition can influence brain catecholamines through the intermediary of plasma tyrosine levels, which are influenced by dopamine inhibition of intestinal tyrosine hydroxylase. Biochemical measurements focused on SULT1A activity and plasma tyrosine concentrations are proposed for future work.

Impaired Cognitive Functioning in Patients with Tyrosinemia Type I Receiving Nitisinone

To examine cognitive functioning in patients with tyrosinemia type I treated with nitisinone and a protein-restricted diet. 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. 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. Patients with tyrosinemia type I treated with nitisinone are at risk for impaired cognitive function despite a protein-restricted diet.

Biological System Responses to Zearalenone Mycotoxin Exposure by Integrated Metabolomic Studies

This study aims to investigate the effect of zearalenone supplementation on rat metabolism. Rats received biweekly intragastric administration of zearalenone mycotoxin (3 mg/kg body weight) for 2 weeks. Urine and plasma samples after zearalenone administration were analyzed by NMR-based metabolomics. Zearalenone exposure significantly elevated the plasma levels of glucose, lactate, N-acetyl glycoprotein, O-acetyl glycoprotein, and propionate but reduced the plasma levels of tyrosine, branched-chain amino acids, and choline metabolites. Zearalenone supplementation decreased the urine levels of butyrate, lactate, and nicotinate. However, it increased the urine levels of allantoin, choline, and N-methylnicotinamide at 0-8 h after the last zearalenone administration and those of 1-methylhistidine, acetoacetate, acetone, and indoxyl sulfate at 8-24 h after the last zearalenone administration. These results suggest that zearalenone exposure can cause oxidative stress and change common systemic metabolic processes, including cell membrane metabolism, protein biosynthesis, glycolysis, and gut microbiota metabolism.

Plasma amino acid profiles are associated with biomarkers of breast cancer risk in premenopausal Japanese women

Recently, profiles of plasma amino acids have been utilized to detect diseases including breast cancer. However, there is a possibility that the amino acid status may be associated with the risk of breast cancer. We investigated the relationship of plasma levels of amino acids with levels of sex hormones and insulin-like growth factor (IGF)-1, which are relevant to the etiology of premenopausal breast cancer, in normal premenopausal women. Participants were 350 Japanese women who had regular menstrual cycles less than 40-day long. Fasting plasma samples were assayed for estradiol, testosterone, dehydroepiandrosterone sulfate, sex-hormone-binding globulin (SHBG), and IGF-1. A total of 20 amino acids in plasma were quantified by liquid chromatography-mass spectrometry. Information on lifestyle and reproductive factors was obtained using a self-administered questionnaire. The plasma arginine level was significantly inversely correlated with plasma levels of total and free estradiol and IGF-1 after adjusting for age, body mass index, and phase of the menstrual cycle. Plasma leucine and tyrosine levels were significantly positively correlated with the free testosterone level. The ratio of plasma asparagine to the total amino acids was significantly positively correlated with SHBG level. Plasma levels of some specific amino acids, such as arginine, leucine, tyrosine, and asparagine, were associated with the levels of sex hormones, SHBG, or IGF-1 in premenopausal women. However, the present cross-sectional study cannot provide a cause-effect relation. The implication of amino acids in the etiology of breast cancer needs to be addressed in future studies.

155. Correlation of elevated MIF and tyrosine plasma levels in pregnancy

A cross-sectional, correlational pilot study evaluating macrophage migration inhibitory factor (MIF) in plasma samples collected at early second trimester from 40 healthy pregnant women found a positive correlation between plasma MIF (ELISA) and plasma tyrosine (HPLC) ( r = 0.43, p < 0.008) levels. MIF functions as a proinflammatory cytokine, participates in glucocorticoid (e.g. cortisol) regulation via the MIF/glucocorticoid dyad, and is an increasingly important small molecule involved in modulation of neuroendocrine-immune crosstalk. Tyrosine motifs participate extensively in scaffolding phosphorylation and receptor/nonreceptor signaling; furthermore, nonreceptor tyrosine kinases have been shown to be activated by CD44, the signaling component of the MIF-CD74 complex. Potential key aspects of a correlation between MIF and tyrosine may be their mutual involvement in the persistence of B cells (a Th2 immune hallmark) with related survival signaling (e.g. MIF-CD74 induction), equilibrium in MIF glucocorticoid regulation, and a possible role in the Type 1 to Type 2 immune shift during pregnancy with resulting altered homeostasis and inflammation. Research suggests MIF and tyrosine levels may have a role in TLR-induced signaling directly bridging the innate to adaptive immune response (e.g. DAMP). Seemingly these factors also could demonstrate further significance when assessing pregnancy outcomes. In addition, expanded assessment of this correlation may illuminate specific mechanisms by which MIF and tyrosine in the periphery may cross the BBB and/or have a role in modulating neuroendocrine-immune interactions in the CNS.

Tyrosinemia: a report of three cases from India

Tyrosinemia has rarely been reported from India due to lack of diagnostic facilities. We present three children, two boys and one girl, who presented with rickets and hepatomegaly. They had increased plasma and urine tyrosine levels, renal tubular acidosis, large kidneys, elevated urine succinylacetone, and chronic liver disease. Two patients also had elevated alpha-fetoprotein but no evidence of hepatocellular carcinoma. All patients are on low tyrosine-phenylalanine diet and on regular follow up.

Effect of Hyperalimentation and Insulin‐Treated Hyperglycemia on Tyrosine Levels in Very Preterm Infants Receiving Parenteral Nutrition

Hyperalimentation describes the increase in glucose, amino acids (AAs), and lipid intake designed to overcome postnatal growth failure in preterm infants. Preterm infants are dependent on phenylalanine metabolism to maintain tyrosine levels because of tyrosine concentration limits in parenteral nutrition (PN). We hypothesized that hyperalimentation would increase individual AA levels when compared with the control group but avoid high phenylalanine/tyrosine levels. To compare the plasma AA profiles on days 8-10 of life in preterm infants receiving a hyperalimentation vs a control regimen. Infants <29 weeks' gestation were randomized to receive hyperalimentation (30% more PN macronutrients) or a control regimen. Data were collected to measure macronutrient (including protein) intake and PN intolerance, including hyperglycemia, insulin use, urea, and AA profile. Plasma profiles of 23 individual AA levels were measured on days 8-10 using ion exchange chromatography. One hundred forty-two infants were randomized with 118 AA profiles obtained on days 8-10. There were no differences in birth weight or gestation between groups. There was an increase (P < .05) in 8 of 23 median individual plasma AA levels when comparing hyperalimentation (n = 57) with controls (n = 61). Only tyrosine levels (median; interquartile range) were lower with hyperalimentation: 27 (15-52) µmol/L vs 43 (24-69) µmol/L (P < .01). Hyperalimentation resulted in more insulin-treated hyperglycemia. No difference between the groups was apparent in tyrosine levels when substratified for insulin-treated hyperglycemia. All insulin vs no insulin comparisons showed lower tyrosine levels with insulin treatment (P < .01). Hyperalimentation can result in paradoxically low plasma tyrosine levels associated with an increase in insulin-treated hyperglycemia.

Hyperalimentation results in paradoxical fall in tyrosine levels in very preterm infants receiving parenteral nutrition: Abstract G72 Table 1

<h3>Background</h3> Hyperalimentation describes the increase in glucose, amino acid and lipid intake designed to overcome postnatal growth failure in preterm infants. Preterm infants are dependent on phenylalanine metabolism to maintain tyrosine levels because of tyrosine concentration limits in parenteral nutrition (PN). Phenylalanine hydroxylase activity is increased by increasing phenylalanine intake (preterm infants), steroids and diabetes (animal models). The latter is reversed by insulin administration. Hyperalimentation increases hyperglycaemia requiring insulin treatment1. <h3>Aim</h3> To compare the plasma amino acid profiles in preterm infants receiving a hyperalimentation versus a control PN regimen. <h3>Methods</h3> Infants &lt;29 weeks gestation were randomised to receive hyperalimentation (25% more glucose, 4 g/kg/day versus 3 g/kg/day protein/lipid) or a control regimen within 5 days of birth with head growth as the primary outcome1. Metabolic markers of PN “intolerance” including hyperglycaemia, insulin use, urea and amino acid profiles and hyperlipidaemia were collected from routine laboratory testing and the electronic patient database. Amino acid levels were measured on day 9 (ion exchange chromatography). <h3>Results</h3> 142 infants were randomised with 118 amino acid profiles obtained on day 8-10. There were no differences in birthweight or gestation between groups. Of the 22 individual plasma amino acid levels, 14 showed a rise (p&lt;0.05) and 7 no change (p&gt;0.05) when comparing hyperalimentation (n=57) with controls (n=61). Median (IQR) phenylalanine levels increased from 72 (63-79) mmol/l to 80 (65-89) mmol/l (p=0.03). Only tyrosine levels fell (p&lt;0.01) with hyperalimentation resulting in suboptimal tyrosine levels (normal range 33-75 mmol/l). This was associated with the increase in insulin-treated hyperglycaemia seen in this group (table 1; all insulin versus no insulin comparisons: p&lt;0.001). <h3>Conclusion</h3> Hyperalimentation results in a paradoxical fall in plasma tyrosine levels associated with an increase in insulin-treated hyperglycaemia. We propose that insulin administration inhibits phenylalanine hydroxylase activity preventing the PN dependent preterm infant maintaining adequate tyrosine levels.

Isolated Corneal Pseudodendrites as the Initial Manifestation of Tyrosinemia Type II in Monozygotic Twins

Fifteen-month-old twins presented with photophobia and bilateral corneal pseudodendrites, and tyrosinemia type II was suspected. Plasma tyrosine levels were elevated. After therapy with tyrosine-restricted diet, corneal lesions resolved. Bilateral pseudodendritic keratitis may be the initial or only manifestation of tyrosinemia type II.

Application of LC-MS/MS analysis of plasma amino acids profiles in children with autism

Autism is a neurodevelopmental disability that is usually diagnosed before age 3 years.(1) The need to understand the causes of autism and the underlying pathophysiology has become more acute since the number of diagnosed cases has risen markedly.(2) Several recent research studies lend support to the hypothesis that abnormalities involving the plasma Amino Acids profiles have been implicated in the etiology of autism.(3,4) We designed a preliminary prospective cohort study to test plasma amino acids profiles in blood samples from patients with autism and normal cases whose age and gender matched. Twenty nonconsecutive patients admitted at 2 hospitals with a diagnosis of autism confirmed by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). All enrolled patients with autism were newly diagnosed. Twenty nonconsecutive control subjects were randomly selected from the eligible outpatients. All the eligible control subjects were defned as children 2–6 years old who were not known to be autistic or to have any other neurodevelopmental that could be related to autism. The Ethics Committee of China Rehabilitation Research Center, China, approved the trial protocol. All subjects’ parents provided informed consent. Fasting blood samples were drawn on days 1 (admission) and then were immediately centrifuged and stored at −80°C. The plasma amino acids profiles were assayed using aTRAQTM Kits by Liquid chromatography-tandem mass spectrometry. Plasma neurotransmitter (including dopamine, noradrenalin and adrenalin) were also tested using radioimmunoassay. Results were presented as means ± standard deviation (SD). Student’s unpaired t test was used to compare the values in normal and autistic children. Statistical significance was defined as p<0.05. The mean age of the 20 patients was 3.46 ± 0.56 years; 17 were boy. Three patients had family history of autism. The median length of hospital stay was 86 days (18–321 days). The mean hospitalization expense was 64.6 ± 5.8 US dollars per day. On admission, the results indicated that the mean plasma lysine, glutamic acid and homocysteine levels were significantly (p<0.05) higher in autism as compared to controls while plasma leucine, tryptophan, valine, taurine, tyrosine and glutamine levels were lower in autism than control group (p<0.05) (Table 1). However, there was no difference in plasma other amino acids levels between autism and control group. In addition, we observed that the plasma dopamine, noradrenalin and adrenalin were significantly higher in the autistic group compared to controls (p<0.05). Table 1. Table 1 Plasma amino acids profiles and neurotransmitter in children with autism and normal These preliminary results confirm an important conclusion: children with autism are significantly more likely to have abnormal in amino acids metabolim. Those may be caused by gastrointestinal problems as well as picky eating and selective eating in their children.(5) This raises serious concerns regarding the long term effects of supervised restricted diets or nutritional supplement in children with autism. Whiteley et al.(6) reported that dietary intervention may positively affect developmental outcome for some children diagnosed with autism. Thus, further investigation in Chinese autism required to measure the effectiveness of diet related treatments on improving the clinical symptoms of autism. In addition, elevated levels of various neurotransmitters (including dopamine, noradrenalin and adrenalin) have been observed in autistic group compared to controls. The relationships between autism and plasma neurotransmitter should be further explored.

Heterogeneity of follow‐up procedures in French and Belgian patients with treated hereditary tyrosinemia type 1: results of a questionnaire and proposed guidelines

The 1991 introduction of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) as a treatment for hereditary tyrosinemia type 1 (HT-1), a disorder of tyrosine catabolism, has radically modified the natural history of this disorder. Despite the dramatic improvements in survival, outcomes and quality of life seen with NTBC treatment, HT-1 remains a chronic disorder with several long-term complications, including, a persistent (albeit low) risk of hepatocellular carcinoma and suboptimal neuropsychological outcomes. There remain unsolved key-questions concerning the long-term outcomes of patients with HT-1, which closely depend on the quality of follow-up in these patients. In the absence of published guidelines, we investigated the follow-up methods used for French and Belgian patients with HT-1. A simple questionnaire providing a rapid overview of follow-up procedures was sent to the 19 physicians in charge of HT-1 patients treated with NTBC and low-tyrosine diet in France and Belgium. Several areas of heterogeneity (especially liver imaging, slit lamp examination, neuropsychological evaluation and maximal plasma tyrosine level accepted) were observed. In an attempt to improve long-term management and outcome of patients with HT-1, we proposed follow-up recommendations.

Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism

Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by hypopigmentation of the skin, hair, and eyes. Affected individuals experience reduced visual acuity and substantially increased skin cancer risk. There are four major types of OCA (OCA1-OCA4) that result from disruption in production of melanin from tyrosine. Current treatment options for individuals with OCA are limited to attempts to correct visual problems and counseling to promote use of sun protective measures. However, Onojafe et al., reporting in this issue of the JCI, provide hope for a new treatment approach for OCA, as they demonstrate that treating mice that model OCA-1b with nitisinone, which is FDA approved for treating hereditary tyrosinemia type 1, elevates plasma tyrosine levels, and increases eye and hair pigmentation.

Neuropsychological outcome of NTBC-treated patients with tyrosinaemia type 1

Corinne De Laet, Vanessa Terrones Munoz, Jaak Jaeken, Baudouin FranAois, Dietbrandt Carton, Etienne M Sokal, Bernard Dan, Philippe J Goyens 1 Nutrition and Metabolism Unit, H pital Universitaire des Enfants Reine Fabiola, Universit Libre de Bruxelles (ULB), Brussels, Belgium. 2 Centre for Metabolic Diseases, University Hospital Gasthuisberg, Leuven, Belgium. 3 Pinocchio Centre for Inborn Metabolic Diseases, Esperance Hospital, Li ge, Belgium. 4 Centre for Metabolic Diseases, Ghent University Hospital, Ghent, Belgium. 5 Paediatric Department, St Luc Clinics, Brussels, Belgium. Correspondence to: corinne.delaet@huderf.be

A large TAT deletion in a tyrosinaemia type II patient

A girl, born to unrelated Spanish parents, presented at 6months of age with photophobia, keratitis, palmar hyperkeratosis and high plasma tyrosine levels, indicative of tyrosinaemia type II. Analysis of the tyrosine aminotransferase (TAT) gene revealed a paternally inherited frameshift mutation c.1213delCinsAG at codon 405 causing a premature stop codon, and a maternally inherited deletion of 193kb encompassing the complete TAT gene and three neighbouring genes. This is the first complete TAT deletion in tyrosinaemia type II described so far.

Maternal and fetal tyrosinemia type I

A 22 year-old woman with tyrosinemia type I (HT1) married her first cousin who is heterozygous for the same FAH mutation for which the patient is homozygous. During her pregnancy she was treated with diet (prescribed tyrosine intake 300 mg/day), and nitisinone (60 mg/day). Median plasma tyrosine levels were 560 μmol/L (range: 375-838, n = 21) and nitisinone 51 μmol/L (range: 41-57, n = 3) during pregnancy. She gave birth to a clinically healthy girl affected with tyrosinemia type 1. Birth was normal (birth weight 2615 g) and the baby had normal liver function, normal plasma alpha-fetoprotein concentrations, low urinary excretion of phenolic acids and no detectable succinylacetone. At birth, the baby had hypertyrosinemia (860 μmol/L in blood cord) and nitisinone levels of 14 μmol/L. Following molecular confirmation of the diagnosis of HT1 specific treatment began on day 15 by which time she had detectable urinary succinylacetone.

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. Patients and 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.