MR imaging and spectroscopy in PKU

Moats, Rex; Scadeng, Miriam; Nelson, Marvin D.

doi:10.1002/(sici)1098-2779(1999)5:2<132::aid-mrdd7>3.0.co;2-m

Cited by 10 publications

(3 citation statements)

References 34 publications

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“…Magnetic resonance spectroscopy analysis showed that the highscoring patients had undetectable elevations of phenylalanine in the brain compartment, whereas the low-scoring subjects had pathological elevated phenylalanine levels in their brains [Weglage et al, 1998a]. Further studies in additional patients measured brain phenylalanine content and flux rates of phenylalanine at the blood brain barrier between vascular and brain spaces [Weglage et al, 1998b;Moller et al, 1998;Moats et al, 1999]; the latter corroborated the initial observations. The findings suggest an effect of allelic variation (perhaps polymorphic) on a high-Km L-type transporter for large neutral amino acids shared by phenylalanine.…”

Section: A Modi¢er Locus Acting As a ''Protector''mentioning

confidence: 78%

ThePAH gene, phenylketonuria, and a paradigm shift

2007

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“Inborn errors of metabolism,” first recognized 100 years ago by Garrod, were seen as transforming evidence for chemical and biological individuality. Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype, was identified in 1934 by Asbjörn Fölling. It is a disease with impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (HPA). Its metabolic phenotype is accountable to multifactorial origins both in nurture, where the normal nutritional experience introduces L‐phenylalanine, and in nature, where mutations (>500 alleles) occur in the phenylalanine hydroxylase gene (PAH) on chromosome 12q23.2 encoding the L‐phenylalanine hydroxylase enzyme (EC 1.14.16.1). The PAH enzyme converts phenylalanine to tyrosine in the presence of molecular oxygen and catalytic amounts of tetrahydrobiopterin (BH4), its nonprotein cofactor. PKU is among the first of the human genetic diseases to enter, through newborn screening, the domain of public health, and to show a treatment effect. This effect caused a paradigm shift in attitudes about genetic disease. The PKU story contains many messages, including: a framework on which to appreciate the complexity of PKU in which phenotype reflects both locus‐specific and genomic components; what the human PAH gene tells us about human population genetics and evolution of modern humans; and how our interest in PKU is served by a locus‐specific mutation database (http://www.pahdb.mcgill.ca; last accessed 20 March 2007). The individual Mendelian PKU phenotype has no “simple” or single explanation; every patient has her/his own complex PKU phenotype and will be treated accordingly. Knowledge about PKU reveals genomic components of both disease and health. Hum Mutat 28(9), 831–845, 2007. Published 2007 Wiley‐Liss, Inc.

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Section: A Modi¢er Locus Acting As a ''Protector''mentioning

confidence: 78%

ThePAH gene, phenylketonuria, and a paradigm shift

2007

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“…While this interpretation is tempting given that the majority of this population displays WMAs (Bick et al, 1991;Cleary et al, 1994;Pietz, Kreis et al, 1996;Thompson et al, 1993), most investigators believe that these white matter lesions have minimal, if any, adverse consequences (Cleary & Walter, 2001;Moats, Scadeng, & Nelson, 1999). This view is based on studies that have reported a non-significant relationship between WMAs and general intelligence (Bick et al, 1993;Pearsen, Gean-Marton, Levy, & Davis, 1990;Thompson et al, 1993;Weglage et al, 1995).…”

Section: White Matter Abnormalities (Wma)mentioning

confidence: 93%

“…While our rate of pathology was slightly below that reported in other studies (Bick et al, 1991;Cleary et al, 1994;Pietz, Kreis et al, 1996;Thompson et al, 1993), our sample was significantly younger. In the past this pathology has been considered to have minimal, if any, clinical significance (Cleary & Walter, 2001;Moats et al, 1999), however we propose that severity of pathology may need to reach a certain threshold before decrements in neuropsychological functioning are observable. When we differentiated the PKU group according to severity of WM pathology, we found that the group of children with abnormalities extending into subcortical and/or frontal regions (Moderate WMA group) exhibited significant impairments in attention, processing efficiency, memory and learning, and executive dysfunction.…”

Section: Relative Impact Of White Matter Abnormalities and Dopamine Dmentioning

confidence: 99%

Are Neuropsychological Impairments in Children with Early-Treated Phenylketonuria (PKU) Related to White Matter Abnormalities or Elevated Phenylalanine Levels?

Anderson

Wood

Francis

et al. 2007

Developmental Neuropsychology

120

101

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This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.

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Magnetic Resonance Spectroscopy: Basic Principles and Application in White Matter Disorders

Knaap¹,

Pouwels²

2005

Magnetic Resonance of Myelination and Myelin Disorders

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MR imaging and spectroscopy in PKU

Cited by 10 publications

References 34 publications

ThePAH gene, phenylketonuria, and a paradigm shift

ThePAH gene, phenylketonuria, and a paradigm shift

Are Neuropsychological Impairments in Children with Early-Treated Phenylketonuria (PKU) Related to White Matter Abnormalities or Elevated Phenylalanine Levels?

Magnetic Resonance Spectroscopy: Basic Principles and Application in White Matter Disorders

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