The effects of high phenylalanine concentrations on serotinin and catecholamine metabolism in the human brain

McKean, Charles M.

doi:10.1016/0006-8993(72)90653-1

Cited by 219 publications

(117 citation statements)

References 19 publications

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“…Mitochondrialcytopathies, Lesch-Nyhan syndrome, and pontocerebellar hypoplasia basically represent neurometabolic diseases that cause significant disturbances in neurotransmission. In some of these disorders, dopamine metabolite disturbances have already been reported, such as the presence of low CSF HVA values in phenylketonuria 21,22 and Lesch-Nyhan disease. 23 In addition, these kinds of diseases that involve the brain in a diffuse manner are commonly associated with structural brain abnormalities.…”

Section: (3) Neurogenetic Conditionsmentioning

confidence: 99%

Secondary abnormalities of neurotransmitters in infants with neurological disorders

García‐Cazorla

Serrano

Pérez‐Dueñas

et al. 2007

Develop Med Child Neuro

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Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants (33 males, 23 females; mean age 5.8mo [SD 4.1mo] range 1d-1y) with neurological disorders whose aetiology was initially unknown. Patients were classified into three clinical phenotypes: epileptic encephalopathy, severe motor impairment, and non-specific manifestations. All patients showed normal results for screening of inborn errors of metabolism. We report clinical, neuroimaging, and follow-up data. Among the patients studied, 10 had low homovanillic acid (HVA) levels and in four patients, 5-hydroxyindoleacetic acid (5-HIAA) was also reduced. Patients with neonatal onset had significantly lower levels of HVA than a comparison group. HVA deficiency was also associated with severe motor impairment and the final diagnosis related to neurodegenerative disorders. 5-HIAA values tended to be decreased in patients with brain cortical atrophy. The possibility of treating patients with L-Dopa and 5-hydroxytryptophan, in order to improve their neurological function and maturation, may be considered.Brain neurotransmission is essential in young children, not only for interneuronal communication but also for differentiation, neuronal growth, and shaping and wiring of the nervous system. 1 Biogenic amines are the most representative group among brain neurotransmitters 2 and are composed of catecholamines (dopamine and norepinephrine) and serotonin. Within the central nervous system, the final metabolite for dopamine is homovanillic acid (HVA) and for serotonin, 5-hydroxyindoleacetic acid (HIAA). These metabolites can be measured in the cerebrospinal fluid (CSF). Low concentrations of biogenic amine metabolites in the CSF are mainly due to defects in their biosynthetic and catabolic pathways. Deficiencies of tyrosine hydroxylase, aromatic L-amino acid decarboxylase, guanosine triphosphate cyclohydrolase (GTPCH), and sepiapterin reductase, 3 (the last two enzymes contributing to the formation of tetrahydrobiopterin [BH4]), cause the main paediatric neurotransmitter diseases.Little is known about secondary causes of low CSF biogenic amine metabolites, and, to our knowledge, no study focusing on how diverse neurological disorders in infants could affect brain biogenic amines production has been described until now. There are a few studies that have looked at secondary reduction of HVA. It has been reported that epilepsy, 4,5 rapidonset dystonia-parkinsonism, 6 Huntington's disease, 7 and depression and dementia 8,9,10 are among those disorders characterized by secondary reduction of HVA. However, the results found in these studies are often contradictory and not specific to young children. Moreover, no study concerning possible factors that could be related to these secondary abnormalit...

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Section: (3) Neurogenetic Conditionsmentioning

confidence: 99%

Secondary abnormalities of neurotransmitters in infants with neurological disorders

García‐Cazorla

Serrano

Pérez‐Dueñas

et al. 2007

Develop Med Child Neuro

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“…Indeed, reductions in tyrosine that have little or no effect on dopamine systems in much of the brain, profoundly reduce the amount of dopamine metabolized in prefrontal cortex (e.g., Bradberry et al, 1989). In addition, dopamine synthesis can also be affected by the competitive inhibition exerted by high levels of Phe on tyrosine hydroxylase activity (Levitt et al, 1965;Ikeda et al, 1967;McKean, 1972).…”

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confidence: 99%

An animal model of early-treated PKU

et al. 1994

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Phenylketonuria (PKU) is a genetic disorder in which the hydroxylation of phenylalanine (Phe) to tyrosine is severely disrupted. If PKU is left untreated, severe mental retardation results. The accepted treatment is to restrict dietary intake of Phe. It has generally been thought that cognitive impairments are prevented if levels of Phe in plasma are maintained at or below five times the normal level. However, we recently documented that children treated early and continuously for PKU or children mildly hyperphenylalaninemic, who have levels of Phe in plasma approximately three to five times normal, still have cognitive impairments. These impairments are specific to the functions of frontal cortex (A. Diamond, W. Hurwitz, E. Lee, W. Grover, and C. Minarcik, unpublished observations). To investigate the mechanism underlying these cognitive deficits, an animal model of this condition was developed and characterized. Thirty-six rat pups were divided into three groups. The first group was treated pre- and postnatally with Phe and alpha-methylphenylalanine (a phenylalanine hydroxylase inhibitor). The second group was injected postnatally with Phe and alpha- methylphenylalanine. The third group received postnatal control injections. The mild plasma Phe elevations in the two experimental groups produced significant behavioral and neurochemical effects. Both experimental groups were impaired on a task dependent on frontal cortex, delayed alternation. Levels of dopamine, homovanillic acid (HVA), norepinephrine, and 5-hydroxyindole acetic acid (5-HIAA) were measured in medial prefrontal cortex, anterior cingulate cortex, striatum, and nucleus accumbens. The largest neurochemical reductions observed were in HVA and were in the two frontal cortical areas (medial prefrontal cortex and anterior cingulate cortex). There were modest reductions in HVA in the nucleus accumbens but no significant changes in HVA, or in any other metabolite or neurotransmitter, in the striatum. The levels of 5-HIAA were also reduced in all brain regions examined. There was no effect on norepinephrine in any of the four regions examined. Reduced levels of HVA in medial prefrontal cortex were the only neurochemical effect that significantly correlated with every measure of performance on the delayed alternation task. This study provides evidence of deleterious effects from mild elevations in the levels of Phe in plasma previously considered small enough to be safe. These effects include impaired performance on a cognitive task dependent on frontal cortex and reduced HVA levels in frontal cortex.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…McKean found low levels of DA in brain tissue at autopsy. An inverse relation between plasma levels of Phe and HVA in the CSF was also found (McKean 1972). However, a DA deficiency in PKU, as shown above, does not lead to overt parkinsonism in all cases, and reports of clear parkinsonism in PKU are rare.…”

Section: Discussionmentioning

confidence: 63%

Parkinsonism in Phenylketonuria: A Consequence of Dopamine Depletion?

et al. 2014

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Phenylketonuria (PKU) is caused by a deficiency or inactivity of the enzyme phenylalanine hydroxylase that converts phenylalanine (Phe) to tyrosine (Tyr). It has been proposed that a reduction of brain Tyr levels, as well as reduced activity of the key regulatory enzyme of dopamine (DA) synthesis tyrosine hydroxylase, leads to a depletion in DA activity in patients with PKU. We report a case of a 56-year-old woman with an intellectual disability due to late diagnosis of PKU and parkinsonism, with a modest clinical response to levodopa therapy.We hypothesize that the signs of parkinsonism might be caused by the depletion of DA activity in the brain. Clinicians should be alert on parkinsonian symptoms in patients with PKU, particularly in those treated with agents that negatively influence DA transmission.

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The effects of high phenylalanine concentrations on serotinin and catecholamine metabolism in the human brain

Cited by 219 publications

References 19 publications

Secondary abnormalities of neurotransmitters in infants with neurological disorders

Secondary abnormalities of neurotransmitters in infants with neurological disorders

An animal model of early-treated PKU

Parkinsonism in Phenylketonuria: A Consequence of Dopamine Depletion?

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