Pathogenesis of cognitive dysfunction in phenylketonuria: Review of hypotheses☆

Groot, Martijn J. de; Hoeksma, Marieke; Blau, Nenad; Reijngoud, Dirk-Jan; Spronsen, van FrancJan

doi:10.1016/j.ymgme.2009.10.016

Cited by 181 publications

(179 citation statements)

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“…For decades it has been hypothesized that PKU-related cognitive impairment is associated with dopamine deficiency (De Groot et al 2010), because elevations in Phe disrupt the neurochemical cascade by which Phe is converted to tyrosine, a precursor of dopamine, and other catecholaminergic neurotransmitters (Scriver 2007). Compromised white matter integrity in the brain, however, is another possible mechanism underlying PKU-related cognitive impairment and represents the focus of the current study.…”

Section: Introductionmentioning

confidence: 98%

“…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%

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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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Section: Introductionmentioning

confidence: 98%

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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“…The location and type of mutation within the gene determine the severity of the phenotype (Mallolas et al, 1999). A decrease of PAH concentration and/or lower enzyme activity results in persistent elevated Phe blood and tissue concentrations, with potential toxic effects, particularly for the developmental brain (Blau, van Spronsen, & Levy, 2010;de Groot, Hoeksma, Blau, Reijngoud, & van Spronsen, 2010;van Spronsen & Enns, 2010). Early diagnosis in the neonatal period, with a screening program (Blau, Hennermann, Langenbeck, & Lichter-Konecki, 2011), and prompt dietary treatment are essential to prevent severe mental retardation and to achieve a good patient prognosis de Groot et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Phenylketonuria: Protein content and amino acids profile of dishes for phenylketonuric patients. The relevance of phenylalanine

Pimentel¹,

Alves²,

Costa³

et al. 2014

Food Chemistry

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A B S T R A C TPhenylketonuria is an inborn error of metabolism, involving, in most cases, a deficient activity of phenylalanine hydroxylase. Neonatal diagnosis and a prompt special diet (low phenylalanine and natural-protein restricted diets) are essential to the treatment. The lack of data concerning phenylalanine contents of processed foodstuffs is an additional limitation for an already very restrictive diet.Our goals were to quantify protein (Kjeldahl method) and amino acid (18) content (HPLC/fluorescence) in 16 dishes specifically conceived for phenylketonuric patients, and compare the most relevant results with those of several international food composition databases.As might be expected, all the meals contained low protein levels (0.67-3.15 g/100 g) with the highest ones occurring in boiled rice and potatoes. These foods also contained the highest amounts of phenylal-anine (158.51 and 62.65 mg/100 g, respectively). In contrast to the other amino acids, it was possible to predict phenylalanine content based on protein alone. Slight deviations were observed when comparing results with the different food composition databases.

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“…En diversos estudios se ha demostrado que existe un desequilibrio en el transporte a través de la barrera hematoencefálica de la fenilalanina y de otros aminoácidos neutros largos, como la tirosina, el triptófano, la valina, la leucina, la isoleucina, la treonina, la metionina y la histidina, lo cual afecta la síntesis de otras aminas biógenas (dopamina, noradrenalina y serotonina) (4,5,8).…”

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“…Su prevalencia en la población caucásica fluctúa entre 1:4.000 y 21.000 recién nacidos, con un promedio de 1:10.000 nacidos vivos, dependiendo de la zona geográfica (1,4). Gracias al establecimiento de programas de tamización neonatal a nivel mundial, el cuadro típico de la fenilcetonuria clásica es poco común, ya que se inicia la restricción en la dieta y la administración de preparados de aminoácidos libres de fenilalanina desde el nacimiento (6,8). Sin embargo, es importante señalar que en Colombia aún no se cuenta con este tipo de programas.…”

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Caracterización fenotípica y molecular de una familia colombiana con fenilcetonuria

et al. 2016

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de las muestras, evaluación clínica de los pacientes, y análisis e interpretación de los datos Todos los autores participaron en la escritura del manuscrito. Caracterización fenotípica y molecular de una familia colombiana con fenilcetonuriaNancy Gélvez, Johanna Acosta, Greizy López, Derly Castro, Juan Carlos Prieto, Martha Bermúdez, Marta L. TamayoInstituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, D.C., ColombiaIntroducción. La fenilcetonuria es un trastorno metabólico caracterizado por un compromiso neurológico grave y por alteraciones del comportamiento. Su diagnóstico temprano permite establecer un tratamiento efectivo que evita las secuelas y modifica el pronóstico. Objetivo. Caracterizar a una familia con fenilcetonuria en Colombia, a nivel clínico, bioquímico y molecular. Materiales y métodos. Se estudió una población de siete individuos de una familia consanguínea en la que cuatro hijos presentaban signos clínicos sugestivos de fenilcetonuria. Una vez firmado el consentimiento informado, se tomaron muestras de sangre y orina para las pruebas colorimétricas, la cromatografía de capa fina y la cromatografía líquida de alta eficacia. Se extrajo el ADN y se secuenciaron los 13 exones del gen PAH de todos los sujetos estudiados. Se diseñaron iniciadores para cada exón con el programa Primer 3; la secuenciación automática se hizo con el equipo Abiprism 3100 Avant y, el análisis de las secuencias, con el programa SeqScape v2.0.Resultados. Se describieron las características clínicas y moleculares de una familia colombiana con fenilcetonuria en la que se identificó la mutación c.398_401delATCA; se presentó una correlación fenotipo-genotipo con una interesante variabilidad clínica entre los afectados, a pesar de tener la misma mutación. Conclusiones. Es importante el reconocimiento temprano de esta enfermedad para evitar sus secuelas neurológicas y psicológicas, pues los pacientes llegan a edades avanzadas sin diagnóstico ni tratamiento adecuados.Palabras clave: fenilcetonurias, fenilalanina hidroxilasa, discapacidad intelectual, mutación, genética, diagnóstico precoz, dieta. doi: http://dx.doi.org/10.7705/biomedica.v36i3.2639 Phenotypic and molecular characterization of a Colombian family with phenylketonuriaIntroduction: Phenylketonuria is a metabolic disorder characterized by severe neurological involvement and behavioral disorder, whose early diagnosis enables an effective treatment to avoid disease sequelae, thus changing the prognosis. Objective: To characterize a family with phenylketonuria in Colombia at clinical, biochemical and molecular levels. Materials and methods:The population consisted of seven individuals of a consanguineous family with four children with suggestive symptoms of phenylketonuria. After signing an informed consent, blood and urine samples were taken for colorimetric tests and high performance liquid and thin layer chromatographies. DNA extraction and sequencing of the 13 exons of the PAH gene were performed in all subjects. We designed prim...

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Pathogenesis of cognitive dysfunction in phenylketonuria: Review of hypotheses☆

Cited by 181 publications

References 59 publications

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

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

Phenylketonuria: Protein content and amino acids profile of dishes for phenylketonuric patients. The relevance of phenylalanine

Caracterización fenotípica y molecular de una familia colombiana con fenilcetonuria

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