Effect of Maternal Blood Phenylalanine Level on Mouse Maternal Phenylketonuria Offspring

Cho, Sangbun; McDonald, J. David

doi:10.1006/mgme.2001.3255

Cited by 12 publications

(8 citation statements)

References 64 publications

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“…In addition, we also note, similar to human, pregnancy loss when maternal serum Phe levels are high, and a dose dependent response of near term (E18.5) fetal weight. We have also defined the serum Phe level in the fetus at E18.5, providing an indication of the Phe level required in the developing fetus to cause cardiac defects, confirming earlier data [34]. This information will be crucial for design of cellular assays of Phe teratogenicity.…”

Section: Discussionsupporting

confidence: 80%

Cardiac teratogenicity in mouse maternal phenylketonuria: Defining phenotype parameters and genetic background influences

Seagraves

McBride

2012

Molecular Genetics and Metabolism

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Maternal phenylketonuria (MPKU) is a syndrome including cardiovascular malformations (CVMs), microcephaly, intellectual impairment, and small for gestational age, caused by in-utero exposure to elevated serum phenylalanine (Phe) due to PKU in the mother. It is becoming a public health concern as more women with PKU reach child bearing age. Although a mouse model of PKU, BTBR Pahenu2, has been available for 20 years, it has not been well utilized for studying MPKU. We used this model to delineate critical parameters in Phe cardiovascular teratogenicity and study the effect of genetic background. Dosing and timing experiments were performed with the BTBR Pahenu2 mouse. A dose response curve was noted, with CVM rates at maternal serum Phe levels <360 μM (control), 360 – 600 μM (low), 600 – 900 μM (mid), and >900μM (high) of 11.86%, 16.67%, 30.86%, and 46.67% respectively. A variety of CVMs were noted on the BTBR background, including double outlet right ventricle (DORV), aortic arch artery (AAA)abnormalities, and ventricular septal defects (VSDs). Timed exposure experiments identified a teratogenic window from embryonic day 8.5-13.5, with higher rates of conotruncal and valve defects occurring in early exposure time and persistent truncus arteriosus (PTA) and aortic arch branching abnormalities occurring with late exposure. Compared to the BTBR strain, N10+ Pahenu2 congenics on the C3H/HeJ background had higher rates of CVMs in general and propensity to left ventricular outflow tract (LVOT) malformations, while the C57B/L6 background had similar CVM rates but predominately AAA abnormalities. We have delineated key parameters of Phe cardiovascular teratogenicity, demonstrated the utility of this MPKU model on different mouse strains, and shown how genetic background profoundly affects the phenotype.

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Section: Discussionsupporting

confidence: 80%

Cardiac teratogenicity in mouse maternal phenylketonuria: Defining phenotype parameters and genetic background influences

Seagraves

McBride

2012

Molecular Genetics and Metabolism

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“…First, the results exclude inconclusive analyses comparing phenylalanine levels collected during the trial and inattention subscale scores. Previous research indicates that elevated levels of phenylalanine may cause frontal system dysfunction and symptoms consistent with ADHD [47,48]. The specific mechanism leading to the presence of these ADHD symptoms in persons with PKU is currently unknown; however, it may be caused by a direct toxic effect of phenylalanine levels.…”

Section: Discussionmentioning

confidence: 97%

Evaluation of Neuropsychiatric Function in Phenylketonuria: Psychometric Properties of the ADHD Rating Scale-IV and Adult ADHD Self-Report Scale Inattention Subscale in Phenylketonuria

Wyrwich

Auguste

et al. 2015

Value in Health

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“…Because of excessive blood phenylalanine concentration in the pregnant PKU homozygous female Pah enu2 mothers, their offspring have severe problems, such as growth failure, heart defects, mental retardation, and stillbirth (7, 18, 25). This suggests that the offspring of PKU mother treated with rAAV2/8-hPAH gene therapy could be free from the effect of maternal PKU.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Recombinant Adeno-Associated Virus 2/8-Mediated Gene Therapy from the Maternal Hyperphenylalaninemia in Offsprings of a Mouse Model of Phenylketonuria

Jung

Park

et al. 2008

J Korean Med Sci

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Phenylketonuria (PKU) is an autosomal recessively inherited metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine leads to severe mental and psychomotor retardation, and the fetus of an uncontrolled pregnant female patient presents with maternal PKU syndrome. We have reported previously on the cognitive outcome of biochemical and phenotypic reversal of PKU in a mouse model, Pahenu2, by the AAV serotype 2-mediated gene delivery of a human PAH transgene. However, the therapeutic efficacy had been limited to only male PKU mice. In this study, we generated a pseudotyped recombinant AAV2/8-hPAH vector and infused it into female PKU mice through the hepatic portal vein or tail vein. Two weeks after injection, complete fur color change to black was observed in female PKU, as in males. The PAH activity in the liver increased to 65-70% of the wild-type activity in female PKU mice and to 90% in male PKU mice. Plasma phenylalanine concentration in female PKU mice decreased to the normal value. In addition, the offsprings of the treated female PKU mice can rescue from the harmful effect of maternal hyperphenylalaninemia. These results indicate that recombinant AAV2/8-mediated gene therapy is a potential therapeutic strategy for PKU.

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Effect of Maternal Blood Phenylalanine Level on Mouse Maternal Phenylketonuria Offspring

Cited by 12 publications

References 64 publications

Cardiac teratogenicity in mouse maternal phenylketonuria: Defining phenotype parameters and genetic background influences

Cardiac teratogenicity in mouse maternal phenylketonuria: Defining phenotype parameters and genetic background influences

Evaluation of Neuropsychiatric Function in Phenylketonuria: Psychometric Properties of the ADHD Rating Scale-IV and Adult ADHD Self-Report Scale Inattention Subscale in Phenylketonuria

Protective Effect of Recombinant Adeno-Associated Virus 2/8-Mediated Gene Therapy from the Maternal Hyperphenylalaninemia in Offsprings of a Mouse Model of Phenylketonuria

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