What we know that could influence future treatment of phenylketonuria

Sarkissian, Christineh N.; Gámez, Alejandra; Scriver, Charles R.

doi:10.1007/s10545-008-0917-7

Cited by 27 publications

(15 citation statements)

References 77 publications

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“…In fact, elevated tyrosine levels and any of its downstream effects on brain catecholamine levels or turnover can be ruled out contributing to hyperglycinemia. New treatment paradigms for PKU patients, in addition to Phe-restricted diet, are designed to target enzyme and cofactor deficiencies with gene, enzyme, or cofactor therapies, and with dietary supplementation with large neutral amino acids to compete with phenylalanine for uptake into brain and reduce brain Phe level while increasing the brain levels of neutral amino acids [84, 86, 87]. These approaches use modern techniques and are derived, in large part, from knowledge generated by many studies in various PKU animal models.…”

Section: Discussionmentioning

confidence: 99%

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

Dienel

Cruz

2015

Neurochem Res

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Phenylketonuria and hyperphenylalanemia are inborn errors in metabolism of phenylalanine arising from defects in steps to convert phenylalanine to tyrosine. Phe accumulation causes severe mental retardation that can be prevented by timely identification of affected individuals and their placement on a Phe-restricted diet. In spite of many studies in patients and animal models, the basis for acquisition of mental retardation during the critical period of brain development is not adequately understood. All animal models for human disease have advantages and limitations, and characteristics common to different models are most likely to correspond to the disorder. This study established similar levels of Phe exposure in developing rats between 3 and 16 days of age using three models to produce chronic hyperphenylalanemia, and identified changes in brain amino acid levels common to all models that persist for ~16h of each day. In a representative model, local rates of glucose utilization (CMRglc) were determined at 25–27 days of age, and only selective changes that appeared to depend on Phe exposure were observed. CMRglc was reduced in frontal cortex and thalamus and increased in hippocampus and globus pallidus. Behavioral testing to evaluate neuromuscular competence revealed poor performance in chronically-hyperphenylalanemic rats that persisted for at least three weeks after cessation of Phe injections and did not occur with mild or acute hyperphenylalanemia. Thus, the abnormal amino acid environment, including hyperglycinemia, in developing rat brain is associated with selective regional changes in glucose utilization and behavioral abnormalities that are not readily reversed after they are acquired.

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Section: Discussionmentioning

confidence: 99%

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

Dienel

Cruz

2015

Neurochem Res

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“…Numerous studies have reported a relationship between genotype and phenotype; however, given the complexity of the PKU phenotype [11] not all mutations follow the expected outcome [1, 12–14]. Based on the metabolic phenotype and genotype relationships observed in 184 subjects at 5 years of age, Guldberg et al [15] devised a classification system to determine an expected phenotype for 105 mutations.…”

Section: Introductionmentioning

confidence: 99%

Reassessment of phenylalanine tolerance in adults with phenylketonuria is needed as body mass changes

MacLeod

Gleason

Calcar

et al. 2009

Molecular Genetics and Metabolism

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Lifelong treatment of phenylketonuria (PKU) includes a phenylalanine (phe) restricted diet that provides sufficient phe for growth and maintenance plus phe-free amino acid formula to meet requirements for protein, energy and micronutrients. Phe tolerance (mg phe/kg body weight/day) is the amount of phe those with PKU can consume and maintain acceptable blood phe levels; it requires individual assessment because of varying phenylalanine hydroxylase activity. The objective was to reassess phe tolerance in 8 adults with PKU considering phe requirements, blood phe levels, genotype and phe tolerance at 5 years of age. Subjects had not received a personalized assessment of phe tolerance in several years, and 5 subjects were overweight, body mass index (BMI) 25-28. With the guidance of a metabolic dietitian, 7 subjects increased phe tolerance (by 15-173%) without significantly increasing blood phe concentration. Increased phe tolerance was associated with both improved dietary compliance and inadequate phe intake at the onset of the protocol compared with current requirements. Improved dietary compliance reflected increased consumption of protein equivalents from amino acid formula and increased frequency of formula intake, from 2.2 to 3 times per day. Predictors of higher final phe tolerance following reassessment included being male and having a lower BMI (R 2 =0.588). This suggests that the rising trend of overweight and obesity may affect assessment of phe tolerance in adults. Therefore, interaction with the metabolic dietitian to reassess phe tolerance in relation to body mass is essential throughout adulthood to insure adequate intake of phe to support protein synthesis and prevent catabolism.

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“…La importancia de los programas de tamización neonatal es evidente, pues permiten la detección temprana de la enfermedad y logran un cometido crucial en la medicina actual: evitar que se instauren secuelas irreversibles de enfermedades que pudieron haber sido tratadas y controladas si se hubieran diagnosticado en el momento del nacimiento (21,22).…”

Section: Discussionunclassified

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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What we know that could influence future treatment of phenylketonuria

Cited by 27 publications

References 77 publications

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

Reassessment of phenylalanine tolerance in adults with phenylketonuria is needed as body mass changes

Caracterización fenotípica y molecular de una familia colombiana con fenilcetonuria

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