Serotonin and Dopamine Synthesis in Phenylketonuria

Curtius, Hans−Christoph; Niederwieser, A.; Viscontini, M.; Leimbacher, Walter; Wegmann, H. M.; Blehovà, B; Rey, Françoise; Schaub, J.; Schmidt, H

doi:10.1007/978-1-4684-3860-4_16

Cited by 58 publications

(29 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Curtius et al (34) described both decreased serotonin and dopamine synthesis in patients with high plasma phenylalanine concentrations caused by both phenylalanine hydroxylase deficiency and disorders in the tetrahydrobiopterin pathway. He also postulated competitive inhibition of both tyrosine and tryptophan hydroxylase by high phenylalanine at 1,500 and 600 gM concentrations, Phenylketonuria: a Modelfor Study ofPhenylalanine and Brain Function 25 25 test which required higher integrative function rather than fine 20 20 motor coordination.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man.

Krause¹,

Halminski²,

McDonald³

et al. 1985

J. Clin. Invest.

190

View full text Add to dashboard Cite

Phenylketonuria provides a human model for the study of the effect of phenylalanine on brain function. Although irreversible mental retardation is preventable through newborn diagnosis and dietary phenylalanine restriction, controversy exists regarding the effects of increased concentrations of phenylalanine in older patients. We have studied ten older, treated, phenylketonuric patients using a triple-blind, multiple trials, crossover design. Each patient was tested at the end of each of three 1-wk periods of high or low phenylalanine intakes. Tests included a repeatable battery of neuropsychological tests, analysis of plasma amino acids, and measurement of urine amino acids, phenyl organic acids, dopamine, and serotonin. In all 10 patients, plasma phenylalanine rose (9004,000 AM). In 9 of 10 patients there was an inverse relationship between plasma phenylalanine and urine dopamine excretion. When blood phenylalanine was elevated, these patients had prolonged performance times on neuropsychological tests of higher but not lower integrative function. Urinary serotonin fell during phenylalanine loading in six patients. The concentration of phenylacids in the urine was not proportional to the plasma phenylalanine at concentrations below 1.5 mM. In one patient, neither performance time nor dopamine excretion varied as blood phenylalanine rose or fell. We interpret these data as follows: blood phenylalanine above 13 mM impairs performance on neuropsychological tests of higher integrative function, this effect is reversible, and one mechanism may involve impaired biogenic amine synthesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man.

Krause¹,

Halminski²,

McDonald³

et al. 1985

J. Clin. Invest.

190

View full text Add to dashboard Cite

show abstract

“…Since a phenylalaninerestricted diet may sometimes cause poor patient compliance the question of cessation of dietary treatment has been raised [13]. It has been proposed that the dietary treatment could be terminated when the central nervous system is almost fully developed, The function of the central nervous system, however, should also be considered especially with respect to the biosynthesis of dopamine, noradrenaline and serotonin since the biosynthesis of these neurotransmitters is inhibited by phenylalanine [1,9,12,16,18,19,29].…”

Section: Offprint Requests To: C Lykkelundmentioning

confidence: 99%

Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine

Lykkelund¹,

Nielsen

et al. 1988

Eur J Pediatr

View full text Add to dashboard Cite

Seven phenylketonuria (PKU) patients aged 15-24 years were allowed unrestricted diet for 3 weeks. Three of these patients performed well on unrestricted diet according to visual reaction time variability (RTv 50-100 ms) and did not show significant changes when returning to the phenylalanine-restricted diet (RTv 70-100 ms). Neither did the concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) change significantly. Four of the patients, however, performed rather poorly (RTv 120-220 ms) on unrestricted diet and improved significantly (P less than 0.03) when the diet was restored (RTv 70-150 ms). The improvements were accompanied by significant (P less than 0.01 and P less than 0.02) increases (mean 52% and 109%) in CSF levels of HVA and 5-HIAA. Five PKU patients aged 15-23 years were allowed unrestricted diet or unrestricted diet supplemented with various amounts of tyrosine (106-194 mg/kg per 24 h). Two of these patients performed very well on unrestricted diet (RTv 60 ms) and showed little change when the unrestricted diet was supplemented with tyrosine (RTv 70 ms and 80 ms). The three other patients, who performed rather poorly (RTv 120-220 ms), improved significantly (P less than 0.03) when the unrestricted diet was supplemented with tyrosine (RTv 70-140 ms). HVA in CSF increased significantly (P less than 0.01) with the tyrosine supplement when the amount exceeded a threshold of approximately 80 mg/kg per 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

“…However, the pathophysiological mechanisms of brain injury in PKU seem to be multiple and still obscure. In this context, Phe disturbs the transport of various neutral amino acids into the brain, possibly reducing their availability for synthesis of protein and neurotransmitters including dopamine and noradrenalin (Hanley et al 2000;Curtius et al 1981;Araujo et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress in Phenylketonuria: What is the Evidence?

et al. 2011

View full text Add to dashboard Cite

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by severe deficiency of phenylalanine hydroxylase activity, leading to the accumulation of phenylalanine and its metabolites in blood and tissues of affected patients. Phenylketonuric patients present as the major clinical feature mental retardation, whose pathomechanisms are poorly understood. In recent years, mounting evidence has emerged indicating that oxidative stress is possibly involved in the pathology of PKU. This article addresses some of the recent developments obtained from animal studies and from phenylketonuric patients indicating that oxidative stress may represent an important element in the pathophysiology of PKU. Several studies have shown that enzymatic and non-enzymatic antioxidant defenses are decreased in plasma and erythrocytes of PKU patients, which may be due to an increased free radical generation or secondary to the deprivation of micronutrients which are essential for these defenses. Indeed, markers of lipid, protein, and DNA oxidative damage have been reported in PKU patients, implying that reactive species production is increased in this disorder. A considerable set of data from in vitro and in vivo animal studies have shown that phenylalanine and/or its metabolites elicit reactive species in brain rodent. These findings point to a disruption of pro-oxidant/antioxidant balance in PKU. Considering that the brain is particularly vulnerable to oxidative attack, it is presumed that the administration of appropriate antioxidants as adjuvant agents, in addition to the usual treatment based on restricted diets or supplementation of tetrahydrobiopterin, may represent another step in the prevention of the neurological damage in PKU.

show abstract

Serotonin and Dopamine Synthesis in Phenylketonuria

Cited by 58 publications

References 14 publications

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man.

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man.

Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine

Oxidative Stress in Phenylketonuria: What is the Evidence?

Contact Info

Product

Resources

About