Low Bone Strength Is a Manifestation of Phenylketonuria in Mice and Is Attenuated by a Glycomacropeptide Diet

Solverson, Patrick; Murali, Sangita G.; Litscher, Suzanne J.; Blank, Robert D.; Ney, Denise M.

doi:10.1371/journal.pone.0045165

Cited by 48 publications

(44 citation statements)

References 47 publications

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“…Phe was selected as the essential nutrient for study because Phe has 1) few metabolic products, 2) similar structure to a large number of dietary and environmental chemicals and 3) known adverse effects from insufficiency or excess plasma concentration. The mean plasma concentration in marmosets (270 ± 150 μmol/L) was substantially greater than adult human (mean, 57-87 μmol/L, Human Metabolome Database) or mouse concentrations (50-52 μmol/L; (Solverson et al 2012)). This could reflect species differences in dietary Phe intake and/or disposition.…”

Section: Discussionmentioning

confidence: 90%

“…2) and unanticipated. Previous research showed minor sex difference in plasma Phe in adult humans in response to Phe load (Stegink et al 1981) and no noteworthy differences in fasting levels in humans or mice (Solverson et al 2012; Stegink et al 1981). Additional studies will be needed to address whether this difference is due to unique physiology, dietary requirements or environmental influences.…”

Section: Discussionmentioning

confidence: 94%

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Metabolome-wide association study of phenylalanine in plasma of common marmosets

Walker

Soltow

et al. 2014

Amino Acids

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Little systematic knowledge exists concerning the impacts of cumulative lifelong exposure, termed the exposome, on requirements for nutrients. Phenylalanine (Phe) is an essential dietary amino acid with an aromatic ring structure similar to endogenous metabolites, dietary compounds and environmental agents. Excess plasma Phe in genetic disease or nutritional deficiency of Phe has adverse health consequences. In principle, structurally similar chemicals interfering with Phe utilization could alter Phe requirement at an individual level. As a strategy to identify components of the exposome that could interfere with Phe utilization, we tested for metabolites correlating with Phe concentration in plasma of a non-human primate species, common marmosets (Callithrix jacchus). The results of tests for more than 5000 chemical features detected by high-resolution metabolomics showed 17 positive correlations with Phe metabolites and other amino acids. Positive and negative correlations were also observed for 33 other chemicals, which included matches to endogenous metabolites and dietary, microbial and environmental chemicals in database searches. Chemical similarity analysis showed many of the matches had high structural similarity to Phe. Together, the results show that chemicals in marmoset plasma could impact Phe utilization. Such chemicals could contribute to early lifecycle developmental disorders when neurological development is vulnerable to Phe levels.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 94%

Metabolome-wide association study of phenylalanine in plasma of common marmosets

Walker

Soltow

et al. 2014

Amino Acids

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“…This question cannot be addressed in humans, since the low-phe AA diet must be followed for life to prevent neurologic sequelae including cognitive impairment. Evidence from a long-term factorial experiment in wild type and Pah enu2 mice answered this question – both the PKU genotype and the AA diet contribute to the PKU bone phenotype (23)**. Regardless of diet and sex, PKU mice showed global deficits in BMD and bone biomechanical performance resulting in brittle, weak femora compared to wild type littermates, Figure 3.…”

Section: Skeletal Fragility Is a Chronic Poorly Understood Complicatmentioning

confidence: 99%

“…The increased bone brittleness in murine PKU strongly suggests that the disease results in the production of abnormal bone matrix protein as well as abnormal mineralization. Moreover, the AA diet resulted in smaller femora with reduced cross-sectional area and reduced strength, reflected in reduced maximal load tolerated before fracture, in both PKU and wild type mice compared with the GMP diet (23). …”

Section: Skeletal Fragility Is a Chronic Poorly Understood Complicatmentioning

confidence: 99%

Advances in the nutritional and pharmacological management of phenylketonuria

Ney¹,

Blank²,

Hansen³

2013

Current Opinion in Clinical Nutrition and Metabolic Care

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Structural Abstract Purpose of review The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU). Recent findings Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phe intact protein that represents a new dietary alternative to synthetic amino acids (AAs) for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an AA diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin (BH4), acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral AAs (LNAA) inhibit phe transport across the intestinal mucosa and blood brain barrier; LNAA are most effective for individuals unable to comply with the low-phe diet. Summary Although a low-phe synthetic AA diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to AA formula that may improve bone health, and BH4 permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management.

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“…Specifically, chronic ingestion of the AA diet significantly increased renal mass, water intake and urine output (Solverson et al 2012a) and also significantly reduced bone size and strength (Solverson et al 2012b) in both Pah enu2/enu2 and wild type littermates compared with the GMP diet. PKU subjects fed the AA diet in an inpatient metabolic study showed significantly lower plasma AA concentrations, higher blood urea nitrogen concentrations, and lower carbon dioxide at 2.5 h after a meal compared with the GMP diet (van Calcar et al 2009).…”

mentioning

confidence: 96%

Does the PKU diet contribute to impaired renal function?

Ney

2013

J of Inher Metab Disea

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The recent report by Hennermann et al provides novel evidence of impaired renal function, proteinuria and arterial hypertension in adolescent and adult PKU patients (median age 24 years) treated lifelong with the low-phe, amino acid (AA)-based diet (Hennermann et al 2012). I wish to call attention to our recent research publications (not cited by the authors) that support their findings and highlight the need for additional research to elucidate the contribution of the PKU diet to impaired renal function.Briefly, impaired renal function was observed in 19 % of subjects (11 out of 59) based on a glomerular filtration rate (GFR, measured by 51 Cr-EDTA) that was below the normal range and associated with longer lifelong years of diet time and greater proteinuria compared to subjects with a normal GFR (Supplementary Table 2, Hennermann et al 2012). Lifelong plasma phe concentration did not correlate with GFR and total dietary protein intake was within the range of a typical Western diet (0.75-1.14 g pro/kg/day). Given that the majority of nitrogen is provided by a mixture of AAs rather than intact dietary protein in the PKU diet, evidence presented by Hennermann et al suggests that the low-phe AA diet may contribute to alterations in renal function that warrant prospective, controlled investigation to identify the underlying pathophysiology.Our recent studies comparing low-phe diets comprised of AAs versus primarily intact protein from glycomacropeptide (GMP) in murine and human PKU are consistent with the potential for the AA-based PKU diet to impair renal function. Specifically, chronic ingestion of the AA diet significantly increased renal mass, water intake and urine output and wild type littermates compared with the GMP diet. PKU subjects fed the AA diet in an inpatient metabolic study showed significantly lower plasma AA concentrations, higher blood urea nitrogen concentrations, and lower carbon dioxide at 2.5 h after a meal compared with the GMP diet (van Calcar et al 2009). These changes suggest that the AA diet provides a high dietary acid load and invokes greater renal workload, due to rapid absorption of AAs followed by subsequent degradation to urea, compared with the low-phe GMP diet.The low-phe, AA-based diet implemented in infancy has shown tremendous success in preventing severe cognitive impairment due to PKU. Unfortunately, there is evidence of suboptimal health outcomes in PKU subjects treated with the AA diet including neurocognitive/psychosocial issues, oxidative stress, skeletal fragility (Enns et al 2010), and now, the potential for impaired renal function. In order to develop improved treatments that minimize these chronic complications associated with PKU, additional research with controlled dietary treatments is needed.

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Low Bone Strength Is a Manifestation of Phenylketonuria in Mice and Is Attenuated by a Glycomacropeptide Diet

Cited by 48 publications

References 47 publications

Metabolome-wide association study of phenylalanine in plasma of common marmosets

Metabolome-wide association study of phenylalanine in plasma of common marmosets

Advances in the nutritional and pharmacological management of phenylketonuria

Does the PKU diet contribute to impaired renal function?

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