Executive function in early-treated phenylketonuria: Profile and underlying mechanisms☆☆☆

Christ, Shawn E.; Huijbregts, Stephan C. J.; Sonneville, Leo de; White, Desirée A.

doi:10.1016/j.ymgme.2009.10.007

Cited by 166 publications

(182 citation statements)

References 111 publications

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“…69 Notably, although studies have not been uniform, deficits in executive function in individuals with PAH deficiency are consistent enough to warrant special attention. 27,[72][73][74][75][76][77][78][79][80][81][82][83] …”

Section: Acmg Practice Guidelines Neurocognitive and Psychological Oumentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

540

443

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Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU) due to characteristic phenylketones accumulating in the urine of affected individuals, has a significant place in history as the first inborn error of metabolism identified through population-based screening, initiating a new era in the diagnosis and treatment of genetic disorders. PKU was first described in 1934 by the Norwegian physician Asbjörn Fölling, but it was not until the mid-1950s that a patient with PAH deficiency was treated with a low phenylalanine (PHE) diet. Although this first patient already had irreversible Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder.Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medica...

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Section: Acmg Practice Guidelines Neurocognitive and Psychological Oumentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

540

443

View full text Add to dashboard Cite

show abstract

“…As a consequence, the amino acid phenylalanine (Phe) is improperly metabolized, which leads to higher than normal Phe levels (De Groot et al 2010). Although serious cognitive sequelae are generally avoided through early detection and dietary treatment to limit Phe intake (Mitchell et al 2011;Paine 1957), individuals with early and continuously treated PKU often have lower than expected intellectual abilities (Waisbren et al 2007), as well as impairments in processing speed (Janos et al 2012) and executive abilities (Christ et al 2010;DeRoche and Welsh 2008).…”

Section: Introductionmentioning

confidence: 99%

“…In terms of relationships between white matter integrity, cognition, and Phe control in individuals with PKU, a number of studies have shown that higher Phe is associated with both decreases in MD (e.g., Vermathen et al 2007;Hood et al 2014a) and poorer cognition (e.g., Christ et al 2010;Weglage et al 2013). Our knowledge of relationships between DTI findings and cognition is quite limited, but the three relevant studies to date point to associations between MD across a range of brain regions and IQ (Peng et al 2004(Peng et al , 2013Antenor-Dorsey et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Brain White Matter Integrity Mediates the Relationship Between Phenylalanine Control and Executive Abilities in Children with Phenylketonuria

et al. 2016

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We tested the hypothesis that brain white matter integrity mediates the relationship between phenylalanine (Phe) control and executive abilities in children with phenylketonuria (PKU; N ¼ 36). To do so, we examined mean diffusivity (MD) from diffusion tensor imaging (DTI) in two white matter brain regions (posterior parietal-occipital, PPO; centrum semiovale, CSO) and lifetime phenylalanine (Phe) exposure; the executive abilities examined included verbal strategic processing, nonverbal strategic processing, and working memory. Mediation modeling showed that MD in the PPO and CSO mediated the relationship between Phe exposure and nonverbal strategic processing, MD in the CSO mediated the relationship between Phe exposure and verbal strategic processing, and MD in the PPO mediated the relationship between Phe exposure and working memory. These exploratory findings demonstrate the importance of using sophisticated modeling procedures to understand the interplay among metabolic control, neural factors, and functional outcomes in individuals with PKU.

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“…13,23 Scores in tests for executive functions have a negative relationship with plasma phenylalanine values. 24,25 Among our patients, a trend can be observed towards a negative relationship among most of the evaluated executive functions and concurrent phenylalanine values along patients' lives.…”

Section: Discussionmentioning

confidence: 99%

Neuropsychological assessment among children and adolescents with phenylketonuria and hyperphenylalaninemia and its relationship with plasma phenylalanine levels

et al. 2017

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Although with early treatment phenylketonuria patients may have average intelligence levels, it is important to optimize the nutritional management to maintain adequate phenylalanine levels, so that patients can develop their intellectual potential free of abnormalities in their daily activities due to deficits of cognitive executive functions. This study presents a series of 26 patients, diagnosed and treated early, who underwent a psychometric evaluation together with phenylalanine determinations along their lives, and at the time of doing the tests. A trend is observed towards a reverse relationship between IQ and concurrent phenylalanine concentration, phenylalanine median and phenylalanine/tyrosine ratio. Likewise, a trend towards a negative relationship is observed between executive functions and concurrent phenylalanine values along patients' lives.

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Executive function in early-treated phenylketonuria: Profile and underlying mechanisms☆☆☆

Cited by 166 publications

References 111 publications

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Brain White Matter Integrity Mediates the Relationship Between Phenylalanine Control and Executive Abilities in Children with Phenylketonuria

Neuropsychological assessment among children and adolescents with phenylketonuria and hyperphenylalaninemia and its relationship with plasma phenylalanine levels

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