A comparison of phenylketonuria with attention deficit hyperactivity disorder: Do markedly different aetiologies deliver common phenotypes?

Stevenson, Matt P.; McNaughton, Neil

doi:10.1016/j.brainresbull.2013.10.003

Cited by 26 publications

(26 citation statements)

References 245 publications

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“…This may help to explain the hyperactivity seen in the PKU mice, based on increased open field movement time in association with reduced brain DA and NE content [52]. Human PKU is associated with ADHD and the potential dysregulation of the monoamine NTs with decreased availability of tyr and trp to the brain [53]. Ney et al found an inverse correlation between phe concentration in the cerebellum and plasma concentrations of threonine + valine + isoleucine in PKU mice fed the AA and GMP diets [33].…”

Section: Discussionmentioning

confidence: 99%

Differential effects of low-phenylalanine protein sources on brain neurotransmitters and behavior in C57Bl/6-Pahenu2 mice

Sawin

Murali

Ney

2014

Molecular Genetics and Metabolism

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Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase, which metabolizes phenylalanine (phe) to tyrosine. A low-phe diet plus amino acid (AA) formula is necessary to prevent cognitive impairment; glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to the AA formula. Our objective was to assess neurotransmitter concentrations in brain and the behavioral phenotype of PKU mice (Pahenu2 on the C57Bl/6 background) and how this is affected by low-phe protein sources. Wild type (WT) and PKU mice, both male and female, were fed high-phe casein, low-phe AA, or low-phe GMP diets between 3–18 weeks of age. Behavioral phenotype was assessed using the open field and marble burying tests, and brain neurotransmitter concentration measured using HPLC with electrochemical detection system. Data were analyzed by 3-way ANOVA with genotype, sex, and diet as the main treatment effects. Brain mass and the concentrations of catecholamines and serotonin were reduced in PKU mice compared to WT mice; the low-phe AA and GMP diets improved these parameters in PKU mice. Relative brain mass was increased in female PKU mice fed the GMP diet compared to the AA diet. PKU mice exhibited hyperactivity and impaired vertical exploration compared to their WT littermates during the open field test. Regardless of genotype or diet, female mice demonstrated increased vertical activity time and increased total ambulatory and horizontal activity counts compared with male mice. PKU mice fed the high-phe casein diet buried significantly fewer marbles than WT control mice fed casein; this was normalized in PKU mice fed the low-phe AA and GMP diets. In summary, C57Bl/6-Pahenu2 mice showed an impaired behavioral phenotype and reduced brain neurotransmitter concentrations that were improved by the low-phe AA or GMP diets. These data support lifelong adherence to a low-phe diet for PKU.

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Section: Discussionmentioning

confidence: 99%

Differential effects of low-phenylalanine protein sources on brain neurotransmitters and behavior in C57Bl/6-Pahenu2 mice

Sawin

Murali

Ney

2014

Molecular Genetics and Metabolism

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“…As symptoms of ADHD have been linked to low dopamine levels in prefrontal cortex, studies of metabolic disorders influencing the dopamine system have been of particular interest. Similarities in neurodevelopmental functioning have been found, for example, between treated phenylketonuria and ADHD (Stevenson & McNaughton, ), but also between ADHD and hereditary tyrosinemia Type 1 (HT‐1; OMIM 276700; Pohorecka et al, ).…”

Section: Introductionmentioning

confidence: 97%

“…Thus, in classical PKU, mutations in the PAH gene diminish PAH activity, resulting in low levels of tyrosine, which leads to decreased dopamine levels in PKU (Antshel & Waisbren, ). Although dietary treatment could prevent severe cognitive impairment, residual symptoms have been reported (Stevenson & McNaughton, ). This is supported by a study showing that 26% of children with treated PKU used central stimulants for attentional dysfunction, compared to 6.5% in a group with Type 1 diabetes mellitus (Arnold, Vladutiu, Orlowski, Blakely, & DeLuca, ).…”

Section: Introductionmentioning

confidence: 99%

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

Barone

Bliksrud

Elgen

et al. 2019

American J of Med Genetics Pt B

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Hereditary tyrosinemia Type 1 (HT-1) is a rare metabolic disease where the enzyme catalyzing the final step of tyrosine breakdown is defect, leading to accumulation of toxic metabolites. Nitisinone inhibits the degradation of tyrosine and thereby the production of harmful metabolites, however, the concentration of tyrosine also increases. We investigated the relationship between plasma tyrosine concentrations and cognitive functions and how tyrosine levels affected enzyme activities of human tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2). Eight Norwegian children between 6 and 18 years with HT-1 were assessed using questionnaires measuring Attention Deficit Hyperactivity Disorder (ADHD)-symptoms and executive functioning. Recent and past levels of tyrosine were measured and the enzyme activities of TH and TPH2 were studied at conditions replicating normal and pathological tyrosine concentrations. We observed a significant positive correlation between mean tyrosine levels and inattention symptoms. While TH exhibited prominent substrate inhibition kinetics, TPH2 activity also decreased at elevated tyrosine levels.Inhibition of both enzymes may impair syntheses of dopamine, noradrenaline, and serotonin in brain tissue. Inattention in treated HT-1 patients may be related to decreased production of these monoamines. Our results support recommendations of strict guidelines on plasma tyrosine levels in HT-1. ADHD-related deficits, particularly inattention, should be monitored in HT-1 patients to determine whether intervention is necessary. K E Y W O R D SADHD, dopamine, hereditary tyrosinemia Type 1, inattention, serotonin

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“…The prefrontal dysfunction hypothesis is consistent with disorders observed in pathologies with frontal lobe damages, like in frontal lobe epilepsy, including impaired attention and executive functions. Moreover, executive function disorders are also reported in the attention-deficit/hyperactivity disorder (ADHD) (Cortese et al 2015) and a parallel has been made between ADHD and PKU (Stevenson and McNaughton 2013). Strong similarities between the two disorders were noted, particularly prefrontal dysfunction of the behavioural inhibition system.…”

Section: Discussionmentioning

confidence: 99%

Neurocognitive profiles in MSUD school‐age patients

Bouchereau

Leduc-Leballeur

Pichard

et al. 2017

J of Inher Metab Disea

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Maple syrup urine disease (MSUD), an inborn error of amino acids catabolism is characterized by accumulation of branched chain amino acids (BCAAs) leucine, isoleucine, valine and their corresponding alpha-ketoacids. Impact on the cognitive development has been reported historically, with developmental delays of varying degree. Currently, earlier diagnosis and improved management allow a better neurodevelopment, without requirement of special education. However, specific impairments can be observed, and so far, results of detailed neurocognitive assessments are not available. The aim of this study was to analyse neurocognitive profiles of French MSUD patients. This was a multicentre retrospective study on MSUD patients who underwent neurocognitive evaluation at primary school age. Twenty-one patients with classical neonatal onset MSUD were included. The patients' mean age at the time of evaluation was 8.7 years. The mean intellectual quotient (IQ) score was in the normal range (95.1 ± 12.6). In a subset of eight patients, a consistent developmental pattern of higher verbal than performance IQ was observed (mean of the difference 25.7 ± 8.7, p < 0.0001). No correlation could be established between this pattern and long-term metabolic balance (BCAA blood levels), or severity of acute metabolic imbalances, or leucine blood levels at diagnosis and time to toxin removal procedure. These data show that some MSUD patients may exhibit an abnormal neurocognitive profile with higher verbal than performance abilities. This might suggest an executive dysfunction disorder that would need to be further investigated by specialized testing. This pattern is important to detect in MSUD, as appropriate neuropsychological treatment strategies should be proposed.

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A comparison of phenylketonuria with attention deficit hyperactivity disorder: Do markedly different aetiologies deliver common phenotypes?

Cited by 26 publications

References 245 publications

Differential effects of low-phenylalanine protein sources on brain neurotransmitters and behavior in C57Bl/6-Pahenu2 mice

Differential effects of low-phenylalanine protein sources on brain neurotransmitters and behavior in C57Bl/6-Pahenu2 mice

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

Neurocognitive profiles in MSUD school‐age patients

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