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Article ; Online: Plasma metabolomic profile changes in females with phenylketonuria following a camp intervention.

Schoen, Meriah S / Singh, Rani H

The American journal of clinical nutrition

2021 Volume 115, Issue 3, Page(s) 811–821

Abstract: Background: There remains a limited understanding of the metabolic perturbations, beyond phenylalanine (Phe) metabolism, that contribute to phenotypic variability in phenylketonuria (PKU).: Objectives: This study aimed to characterize changes in the ... ...

Abstract	Background: There remains a limited understanding of the metabolic perturbations, beyond phenylalanine (Phe) metabolism, that contribute to phenotypic variability in phenylketonuria (PKU). Objectives: This study aimed to characterize changes in the PKU plasma metabolome following a 5-d metabolic camp intervention and to compare PKU profiles with those of matched healthy controls. Methods: In 28 females (aged 12-57 y), fasting plasma samples were collected on the first (day 1) and final (day 5) days of camp to measure metabolic control and to complete untargeted metabolomic profiling. Three-day dietary records were collected to assess changes in dietary adherence and composition. Univariate (Wilcoxon signed-rank and Mann-Whitney U test) and multivariate (random forest, hierarchical clustering) analyses were performed to identify clinical and metabolic features that were associated with the intervention and disease state. Results: Relative to healthy controls, Phe catabolites, ketones, and carnitine- and glycine-conjugated fatty acids were elevated in females with PKU at baseline, whereas fatty acylcholine metabolites were substantially lower. After the camp intervention, plasma Phe concentrations decreased [median change: -173 µmol/L (IQR: -325, -28 µmol/L)] and 70% of PKU participants demonstrated improved dietary adherence by decreasing Phe intake and/or increasing medical food consumption. This was accompanied by a shift in abundance for 223 metabolites (q < 0.05). Compounds associated with the metabolism of Phe, fatty acids, and choline contributed most to profile differences between camp days 1 and 5. Conclusions: In females with PKU, untargeted metabolomics identified prominent perturbations in amino acid and lipid metabolites associated with bioenergetic impairment and oxidative stress. Choline-conjugated lipids could have fundamental roles in these pathways and they have not been previously evaluated in PKU. A short-term camp intervention was effective for improving or fully normalizing the abundance of the identified discriminatory metabolites.
MeSH term(s)	Carnitine ; Choline ; Fatty Acids ; Female ; Humans ; Male ; Metabolomics ; Phenylketonurias
Chemical Substances	Fatty Acids ; Choline (N91BDP6H0X) ; Carnitine (S7UI8SM58A)
Language	English
Publishing date	2021-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.1093/ajcn/nqab400
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Article ; Online: The relationship between working memory and anxiety in individuals with early treated phenylketonuria (PKU).

Boland, Kelly M / Schoen, Meriah S / Singh, Rani H / Clocksin, Hayley E / Cissne, Mackenzie N / Christ, Shawn E

Neuropsychology

2024 Volume 38, Issue 4, Page(s) 368–378

Abstract: Objective: Although early diagnosis and treatment prevent the severe impairments associated with untreated phenylketonuria (PKU), individuals with early treated PKU (ETPKU) nonetheless experience significant neurocognitive and psychological sequelae, ... ...

Abstract	Objective: Although early diagnosis and treatment prevent the severe impairments associated with untreated phenylketonuria (PKU), individuals with early treated PKU (ETPKU) nonetheless experience significant neurocognitive and psychological sequelae, including difficulties in working memory (WM) and increased risk of anxiety. The primary objective of the present study was to examine the extent to which anxiety may moderate the relationship between ETPKU and WM performance. Method: A sample of 40 adults with ETPKU and a demographically comparable sample of 40 healthy adults without PKU completed a comprehensive assessment of WM performance and anxiety symptomatology. Data were collected using a variety of remote assessment methods (e.g., web-based neurocognitive tests, semistructured interview, report-based measures). Results: The ETPKU group demonstrated significantly poorer WM performance as compared to the non-PKU group. The groups did not differ significantly in anxiety; however, high anxiety was more common in the ETPKU group (53% of sample) than the non-PKU group (33%). A significant interaction between anxiety, metabolic control (as reflected by Phe levels), and WM performance was observed for the ETPKU group. Individuals with high anxiety and/or high Phe levels (> 360 μmol/L) performed poorer than the non-PKU group. Individuals with low anxiety and relatively low Phe levels (< 360 μmol/L) performed comparably to the non-PKU group. Conclusions: Anxiety was found to moderate the relationship between Phe levels and WM performance in individuals with ETPKU. This finding underscores the importance of accounting for anxiety when evaluating neurocognitive performance in individuals with ETPKU whether for research or clinical purposes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
MeSH term(s)	Humans ; Phenylketonurias/psychology ; Phenylketonurias/complications ; Male ; Memory, Short-Term/physiology ; Female ; Adult ; Anxiety/etiology ; Young Adult ; Neuropsychological Tests ; Adolescent
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1042412-x
ISSN	1931-1559 ; 0894-4105
ISSN (online)	1931-1559
ISSN	0894-4105
DOI	10.1037/neu0000942
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Article ; Online: Characterization of Choline Nutriture among Adults and Children with Phenylketonuria.

Schoen, Meriah S / Ramakrishnan, Usha / Alvarez, Jessica A / Ziegler, Thomas R / Cui, Xiangqin / Singh, Rani H

Nutrients

2022 Volume 14, Issue 19

Abstract: Choline is an essential nutrient for brain development and function that is attained through high-protein foods, which are limited in the phenylalanine-restricted diet of people with phenylketonuria (PKU). This study compared choline consumption among ... ...

Abstract	Choline is an essential nutrient for brain development and function that is attained through high-protein foods, which are limited in the phenylalanine-restricted diet of people with phenylketonuria (PKU). This study compared choline consumption among individuals with PKU to a reference sample from the National Health and Nutrition Examination Survey (NHANES), and identified treatment and diet-related factors that may modulate choline needs. Participants were individuals with PKU (
MeSH term(s)	Adult ; Child ; Choline ; Female ; Folic Acid ; Humans ; Methionine ; Nutrition Surveys ; Phenylalanine ; Phenylketonurias ; Pregnancy ; Vitamin B 12 ; Vitamins
Chemical Substances	Vitamins ; Phenylalanine (47E5O17Y3R) ; Folic Acid (935E97BOY8) ; Methionine (AE28F7PNPL) ; Choline (N91BDP6H0X) ; Vitamin B 12 (P6YC3EG204)
Language	English
Publishing date	2022-09-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14194056
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Article ; Online: Total choline intake and working memory performance in adults with phenylketonuria.

Schoen, Meriah S / Boland, Kelly M / Christ, Shawn E / Cui, Xiangqin / Ramakrishnan, Usha / Ziegler, Thomas R / Alvarez, Jessica A / Singh, Rani H

Orphanet journal of rare diseases

2023 Volume 18, Issue 1, Page(s) 222

Abstract: Background: Despite early diagnosis and compliance with phenylalanine (Phe)-restricted diets, many individuals with phenylketonuria (PKU) still exhibit neurological changes and experience deficits in working memory and other executive functions. ... ...

Abstract	Background: Despite early diagnosis and compliance with phenylalanine (Phe)-restricted diets, many individuals with phenylketonuria (PKU) still exhibit neurological changes and experience deficits in working memory and other executive functions. Suboptimal choline intake may contribute to these impairments, but this relationship has not been previously investigated in PKU. The objective of this study was to determine if choline intake is correlated with working memory performance, and if this relationship is modified by diagnosis and metabolic control. Methods: This was a cross-sectional study that included 40 adults with PKU and 40 demographically matched healthy adults. Web-based neurocognitive tests were used to assess working memory performance and 3-day dietary records were collected to evaluate nutrient intake. Recent and historical blood Phe concentrations were collected as measures of metabolic control. Results: Working memory performance was 0.32 z-scores (95% CI 0.06, 0.58) lower, on average, in participants with PKU compared to participants without PKU, and this difference was not modified by total choline intake (F[1,75] = 0.85, p = 0.36). However, in a subgroup with complete historical blood Phe data, increased total choline intake was related to improved working memory outcomes among participants with well controlled PKU (Phe = 360 µmol/L) after adjusting for intellectual ability and mid-childhood Phe concentrations (average change in working memory per 100 mg change in choline = 0.11; 95% CI 0.02, 0.20; p = 0.02). There also was a trend, albeit nonsignificant (p = 0.10), for this association to be attenuated with increased Phe concentrations. Conclusions: Clinical monitoring of choline intake is essential for all individuals with PKU but may have important implications for working memory functioning among patients with good metabolic control. Results from this study should be confirmed in a larger controlled trial in people living with PKU.
MeSH term(s)	Humans ; Adult ; Child ; Memory, Short-Term ; Cross-Sectional Studies ; Cognition ; Phenylketonurias ; Choline
Chemical Substances	Choline (N91BDP6H0X)
Language	English
Publishing date	2023-07-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2225857-7
ISSN	1750-1172 ; 1750-1172
ISSN (online)	1750-1172
ISSN	1750-1172
DOI	10.1186/s13023-023-02842-y
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Article ; Online: How long bones grow children: Mechanistic paths to variation in human height growth.

Lampl, Michelle / Schoen, Meriah

American journal of human biology : the official journal of the Human Biology Council

2017 Volume 29, Issue 2

Abstract: Objectives: Eveleth and Tanner's descriptive documentation of worldwide variability in human growth provided evidence of the interaction between genetics and environment during development that has been foundational to the science of human growth. There ...

Abstract	Objectives: Eveleth and Tanner's descriptive documentation of worldwide variability in human growth provided evidence of the interaction between genetics and environment during development that has been foundational to the science of human growth. There remains a need, however, to describe the mechanistic foundations of variability in human height growth patterns. Methods: A review of research documenting cellular activities at the endochondral growth plate aims to show how the unique microenvironment and cell functions during the sequential phases of the chondrocyte lifecycle affect long bone elongation, a fundamental source of height growth. Results: There are critical junctures within the chondrocytic differentiation cascade at which environmental influences are integrated and have the ability to influence progression to the hypertrophic chondrocyte phase, the primary driver of long bone elongation. Phenotypic differences in height growth patterns reflect variability in amplitude and frequency of discretely timed hypertrophic cellular expansion events, the cellular basis of saltation and stasis growth biology. Conclusions: Final height is a summary of the dynamic processes carried out by the growth plate cellular machinery. As these cell-level mechanisms unfold in an individual, time-specific manner, there are many critical points at which a genetic growth program can be enhanced or perturbed. Recognizing both the complexity and fluidity of this adaptive system questions the likelihood of a single, optimal growth pattern and instead identifies a larger bandwidth of saltatory frequencies for "normal" growth. Further inquiry into mechanistic sources of variability acting at critical organizational points of chondrogenesis can provide new opportunities for growth interventions.
Language	English
Publishing date	2017-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1025339-7
ISSN	1520-6300 ; 1042-0533
ISSN (online)	1520-6300
ISSN	1042-0533
DOI	10.1002/ajhb.22983
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Article: Functional Biomarkers of Vitamin B12 Status, Diet, and Metabolic Control in Women with Phenylketonuria (P24-005-19)

Schoen, Meriah / Coakley, Kathryn / Douglas, Teresa / Singh, Rani

Current developments in nutrition. 2019 June 13, v. 3, no. Supplement_1

2019

Abstract: Metabolic control in Phenylketonuria (PKU) requires a protein-restricted diet, which elevates the risk of vitamin B12 deficiency. Neurological sequelae driven by suboptimal B12 status in PKU may be overlooked due to concomitant elevations in ... ...

Abstract	Metabolic control in Phenylketonuria (PKU) requires a protein-restricted diet, which elevates the risk of vitamin B12 deficiency. Neurological sequelae driven by suboptimal B12 status in PKU may be overlooked due to concomitant elevations in phenylalanine and B12 monitoring techniques that lack sensitivity. The aim of this analysis was to assess the effectiveness of functional biomarkers of B12 status, methylmalonic acid (MMA) and total homocysteine (tHcy), in the early identification of B12 deficiency in PKU. Diet and blood measures (plasma amino acids, B6; serum B12, folate, MMA, tHcy) were assessed in 31 females with PKU who attended the Emory Metabolic Camp in 2012 (N = 14) or 2018 (N = 17). The prevalence of functional B12 deficiency (MMA > 378 nmol/L and B12 < 914 pg/mL) was determined, and Spearman rank correlations between dietary intake, metabolic control, and biochemical indicators of B12 status were assessed (SAS 9.4, α = 0.05). All characteristics were similar for 2012 and 2018 participants except tHcy, which was higher among females in 2012 (P = 0.01). Median age was 20 years (IQR: 16–24) and mean BMI was 29.6 ± 8.3 kg/m2. Of the 31 participants, 13 (41.9%) were on a phenylalanine-lowering medication (Kuvan). Five females (16%) had low B12 concentrations (<230 pg/mL), and one of these five had elevated MMA. Dietary consumption of B12 was below the RDA in seven females (22.6%), five of which also had suboptimal consumption of B6 and folate. Low B12 was associated with increased MMA (r = −0.49, P = 0.01) and tHcy (r = −0.42, P = 0.02) levels. Whereas, higher serum B12 was associated with elevated plasma B6 (r = 0.86, P < 0.01), dietary compliance (r = 0.41, P = 0.03), and increased intake of B12 (r = 0.63, P < 0.01), B6 (r = 0.47, P = 0.01), folate (r = 0.46, P = 0.01), and total protein (r = 0.43, P = 0.02). Vitamin B12 has a moderate correlation with MMA and tHcy in females with PKU. Functional B12 deficiency, however, is not prevalent in this sample. This may reflect the regular consumption of fortified medical food among the females in this sample. Monitoring MMA and tHcy, regardless of B12 levels, may still have utility in this population for the detection of early deficiency. National Center for Advancing Translational Sciences of the NIH, private donations.
Keywords	biomarkers ; blood serum ; body mass index ; compliance ; complications (disease) ; drug therapy ; females ; folic acid ; food intake ; homocysteine ; methylmalonic acid ; monitoring ; nutrition risk assessment ; phenylalanine ; phenylketonuria ; protein content ; vitamin B12 ; women
Language	English
Dates of publication	2019-0613
Publishing place	Oxford University Press
Document type	Article
ISSN	2475-2991
DOI	10.1093/cdn/nzz044.P24-005-19
Database	NAL-Catalogue (AGRICOLA)

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Article: Promoting Healthy Growth or Feeding Obesity? The Need for Evidence-Based Oversight of Infant Nutritional Supplement Claims.

Lampl, Michelle / Mummert, Amanda / Schoen, Meriah

Healthcare (Basel, Switzerland)

2016 Volume 4, Issue 4

Abstract: The Developmental Origins of Health and Disease (DOHaD) model recognizes growth in infancy and childhood as a fundamental determinant of lifespan health. Evidence of long-term health risks among small neonates who subsequently grow rapidly poses a ... ...

Abstract	The Developmental Origins of Health and Disease (DOHaD) model recognizes growth in infancy and childhood as a fundamental determinant of lifespan health. Evidence of long-term health risks among small neonates who subsequently grow rapidly poses a challenge for interventions aiming to support healthy growth, not merely drive weight gain. Defining healthy growth beyond "getting bigger" is essential as infant and young child feeding industries expand. Liquid-based nutritional supplements, originally formulated for undernourished children, are increasingly marketed for and consumed by children generally. Clarifying the nature of the evidentiary base on which structure/function claims promoting "healthy growth" are constructed is important to curb invalid generalizations. Evidence points to changing social beliefs and cultural practices surrounding supplementary feeding, raising specific concerns about the long-term health consequences of an associated altered feeding culture, including reduced dietary variety and weight gain. Reassessing the evidence for and relevance of dietary supplements' "promoting healthy growth" claims for otherwise healthy children is both needed in a time of global obesity and an opportunity to refine intervention approaches among small children for whom rapid subsequent growth in early life augments risk for chronic disease. Scientific and health care partnerships are needed to consider current governmental oversight shortfalls in protecting vulnerable populations from overconsumption. This is important because we may be doing more harm than good.
Language	English
Publishing date	2016-11-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2721009-1
ISSN	2227-9032
ISSN	2227-9032
DOI	10.3390/healthcare4040084
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Article ; Online: Maternal FADS2 single nucleotide polymorphism modified the impact of prenatal docosahexaenoic acid (DHA) supplementation on child neurodevelopment at 5 years: Follow-up of a randomized clinical trial.

Gonzalez Casanova, Ines / Schoen, Meriah / Tandon, Sonia / Stein, Aryeh D / Barraza Villarreal, Albino / DiGirolamo, Ann M / Demmelmair, Hans / Ramirez Silva, Ivonne / Feregrino, Raquel Garcia / Rzehak, Peter / Stevenson, India / Standl, Marie / Schnaas, Lourdes / Romieu, Isabelle / Koletzko, Berthold / Ramakrishnan, Usha

Clinical nutrition (Edinburgh, Scotland)

2021 Volume 40, Issue 10, Page(s) 5339–5345

Abstract: Background: Variability in the FADS2 gene, which codifies the Delta-6 Desaturases and modulates the conversion of essential n-3 and n-6 fatty acids into long-chain polyunsaturated fatty acids, might modify the impact of prenatal supplementation with n-3 ...

Abstract	Background: Variability in the FADS2 gene, which codifies the Delta-6 Desaturases and modulates the conversion of essential n-3 and n-6 fatty acids into long-chain polyunsaturated fatty acids, might modify the impact of prenatal supplementation with n-3 docosahexaenoic acid (DHA) on neurodevelopment. Objective: To assess if maternal FADS2 single nucleotide polymorphisms (SNPs) modified the effect of prenatal DHA on offspring development at 5 years. Design: We conducted a post-hoc interaction analysis of the POSGRAD randomized controlled trial (NCT00646360) of prenatal supplementation with algal-DHA where 1094 pregnant women originally randomized to 400 mg/day of preformed algal DHA or a placebo from gestation week 18-22 through delivery. In this analysis, we included offspring with information on maternal genotype and neurodevelopment at 5 years (DHA = 316; Control = 306) and used generalized linear models to assess interactions between FADS2 SNPs rs174602 or rs174575 and prenatal DHA on neurodevelopment at 5 years measured with McCarthy Scales of Children's Abilities (MSCA). Results: Maternal and offspring characteristics were similar between groups. At baseline, mean (±standard deviation) maternal age was 26 ± 5 years and schooling was 12 ± 4 years. Forty-six percent (46%) of the children were female. Maternal minor allele frequencies were 0.37 and 0.33 for SNPs rs174602 and rs174575, respectively. There were significant variations by SNP rs174602 and intervention group (p for interactions <0.05) where children in the intervention group had higher MSCA scores on the quantitative (DHA: mean ± SEM = 22.6 ± 0.9 vs. Control = 19.1 ± 0.9, mean difference (Δ) = 3.45; p = 0.01) and memory (DHA = 27.9 ± 1.1 vs. Control = 23.7 ± 1.1, Δ = 4.26; p = 0.02) scales only among offspring of TT (minor allele homozygotes). Conclusions: Maternal FADS2 SNP rs174602 modified the effect of prenatal DHA on cognitive development at 5 years. Variations in the genetic make-up of target populations could be an important factor to consider for prenatal DHA supplementation interventions.
MeSH term(s)	Adult ; Child Development/drug effects ; Child, Preschool ; Cognition/drug effects ; Dietary Supplements ; Docosahexaenoic Acids/pharmacology ; Fatty Acid Desaturases/genetics ; Female ; Follow-Up Studies ; Humans ; Male ; Maternal Nutritional Physiological Phenomena/genetics ; Polymorphism, Single Nucleotide ; Prenatal Care ; Young Adult
Chemical Substances	Docosahexaenoic Acids (25167-62-8) ; Fatty Acid Desaturases (EC 1.14.19.-) ; FADS2 protein, human (EC 1.14.19.3)
Language	English
Publishing date	2021-09-11
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604812-2
ISSN	1532-1983 ; 0261-5614
ISSN (online)	1532-1983
ISSN	0261-5614
DOI	10.1016/j.clnu.2021.08.026
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Article: Maternal FADS2 single nucleotide polymorphism modified the impact of prenatal docosahexaenoic acid (DHA) supplementation on child neurodevelopment at 5 years: Follow-up of a randomized clinical trial

Gonzalez Casanova, Ines / Schoen, Meriah / Tandon, Sonia / Stein, Aryeh D. / Barraza Villarreal, Albino / DiGirolamo, Ann M. / Demmelmair, Hans / Ramirez Silva, Ivonne / Feregrino, Raquel Garcia / Rzehak, Peter / Stevenson, India / Standl, Marie / Schnaas, Lourdes / Romieu, Isabelle / Koletzko, Berthold / Ramakrishnan, Usha

Clinical nutrition. 2021 Oct., v. 40, no. 10

2021

Abstract: Variability in the FADS2 gene, which codifies the Delta-6 Desaturases and modulates the conversion of essential n-3 and n-6 fatty acids into long-chain polyunsaturated fatty acids, might modify the impact of prenatal supplementation with n-3 ... ...

Abstract	Variability in the FADS2 gene, which codifies the Delta-6 Desaturases and modulates the conversion of essential n-3 and n-6 fatty acids into long-chain polyunsaturated fatty acids, might modify the impact of prenatal supplementation with n-3 docosahexaenoic acid (DHA) on neurodevelopment.To assess if maternal FADS2 single nucleotide polymorphisms (SNPs) modified the effect of prenatal DHA on offspring development at 5 years.We conducted a post-hoc interaction analysis of the POSGRAD randomized controlled trial (NCT00646360) of prenatal supplementation with algal-DHA where 1094 pregnant women originally randomized to 400 mg/day of preformed algal DHA or a placebo from gestation week 18–22 through delivery. In this analysis, we included offspring with information on maternal genotype and neurodevelopment at 5 years (DHA = 316; Control = 306) and used generalized linear models to assess interactions between FADS2 SNPs rs174602 or rs174575 and prenatal DHA on neurodevelopment at 5 years measured with McCarthy Scales of Children's Abilities (MSCA).Maternal and offspring characteristics were similar between groups. At baseline, mean (±standard deviation) maternal age was 26 ± 5 years and schooling was 12 ± 4 years. Forty-six percent (46%) of the children were female. Maternal minor allele frequencies were 0.37 and 0.33 for SNPs rs174602 and rs174575, respectively. There were significant variations by SNP rs174602 and intervention group (p for interactions <0.05) where children in the intervention group had higher MSCA scores on the quantitative (DHA: mean ± SEM = 22.6 ± 0.9 vs. Control = 19.1 ± 0.9, mean difference (Δ) = 3.45; p = 0.01) and memory (DHA = 27.9 ± 1.1 vs. Control = 23.7 ± 1.1, Δ = 4.26; p = 0.02) scales only among offspring of TT (minor allele homozygotes).Maternal FADS2 SNP rs174602 modified the effect of prenatal DHA on cognitive development at 5 years. Variations in the genetic make-up of target populations could be an important factor to consider for prenatal DHA supplementation interventions.
Keywords	algae ; alleles ; children ; clinical nutrition ; cognitive development ; docosahexaenoic acid ; females ; homozygosity ; memory ; neurodevelopment ; placebos ; pregnancy ; randomized clinical trials ; single nucleotide polymorphism
Language	English
Dates of publication	2021-10
Size	p. 5339-5345.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	604812-2
ISSN	1532-1983 ; 0261-5614
ISSN (online)	1532-1983
ISSN	0261-5614
DOI	10.1016/j.clnu.2021.08.026
Database	NAL-Catalogue (AGRICOLA)

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