The neuropathology of phenylketonuria: human and animal studies

Huttenlocher, Peter R.

doi:10.1007/pl00014371

Cited by 142 publications

(88 citation statements)

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“…Our findings are in line with former investigations, demonstrating abnormalities in gray matter development and architecture as one of the two important neuropathological features in PKU (25), resulting in a reduced density of cortical neurons and a pertubated neuroanatomical structure of the cortex. These changes correspond to clinical key features of untreated PKU, i.e.…”

Section: Discussionsupporting

confidence: 93%

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Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

et al. 2006

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Classical phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase, resulting in an accumulation of its upstream metabolite phenylalanine in brain tissue and cerebrospinal fluid of PKU patients. PKU is neuropathologically characterized by reduced dendritic arborization, loss of synapses, and neurodegeneration. We investigated whether increased concentrations of phenylalanine cause reduced synaptic density and alter dendritic branching. We treated primary cortical neurons differentiated for 21 d in vitro with 5 mM phenylalanine in the presence of all essential amino acids. Immunocytochemical analysis of 12 and 21 d in vitro primary neurons revealed no changes of dendritic morphology or neuronal viability but a significant difference in synaptic density, suggesting that elevated concentrations of extracellular phenylalanine cause an impairment of synaptogenesis. Although impairment of cerebral energy metabolism has been identified as an important pathophysiological principal in many diseases, respiratory chain function has not been extensively studied in PKU before. We investigated whether phenylalanine inhibits respiratory chain complexes I-V. In vitro analysis revealed no inhibitory effect of phenylalanine on complexes I-V, but an inhibition of pyruvate kinase, a key enzyme of glycolysis, catalyzing the formation of pyruvate. Pyruvate kinase is part of the enzyme assay to investigate enzyme activity of mitochondrial complex V and it remains to be elucidated whether this finding is relevant in vivo. In conclusion, elevated concentrations of phenylalanine might be involved in mechanisms underlying impaired synaptogenesis in PKU, supporting the common therapeutic strategy to reduce phenylalanine concentrations in the brain to prevent neurodegeneration. (Pediatr Res 59: 544-548, 2006)

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Section: Discussionsupporting

confidence: 93%

“…These changes correspond to clinical key features of untreated PKU, i.e. mental retardation and seizures (25). Notably, such changes usually escape standard neuropathologic evaluation and can only be proven by subtle quantitative analyses as performed in our study (25).…”

Section: Discussionsupporting

confidence: 54%

Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

et al. 2006

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“…Food proteins contain different amount of Phe and consumption of correct amount is required for the proper protein synthesis, normal growth and development of the body and brain in growing children [2]. In PKU patients, the body fails to eliminate the excess Phe due to the defective enzyme Phenylalanine Hydroxylase (PAH) resulting in the elevated blood Phe level causing neurological damage [3]. Many therapies like gene therapy, enzyme substitution therapy, and protein hydrolysate diet have so far been implemented.…”

Section: Introductionmentioning

confidence: 99%

In silico Designing of Protein Rich in Large Neutral Amino Acids Using Bovine αs1 Casein for Treatment of Phenylketonuria

Appaiah¹,

Vasu²

2016

J Proteomics Bioinform

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“…Free radicals also provoke cell injury and death directly by breaking cell lipid membranes, destroying proteins, and oxidizing DNA (Halliwell, 2001;Halliwell and Gutteridge, 1989a). In some of these disorders, the toxic metabolites were thought to be organic acids such as the phenylketones in PKU (Huttenlocher, 2000).…”

Section: Introductionmentioning

confidence: 99%

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

et al. 2007

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Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah enu2 mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah enu2 mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah enu2 mice and corresponded to rapid reduction of serum Phe levels.

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The neuropathology of phenylketonuria: human and animal studies

Cited by 142 publications

References 0 publications

Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

In silico Designing of Protein Rich in Large Neutral Amino Acids Using Bovine αs1 Casein for Treatment of Phenylketonuria

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

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