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<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="pjr6IMLGSuK93ciOMJGFlrycwFfAZPgTG6bblCe2s5xDXDoEp2jHPz4Q4JXMSqOd">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="pjr6IMLGSuK93ciOMJGFlrycwFfAZPgTG6bblCe2s5xDXDoEp2jHPz4Q4JXMSqOd">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="pjr6IMLGSuK93ciOMJGFlrycwFfAZPgTG6bblCe2s5xDXDoEp2jHPz4Q4JXMSqOd">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="pjr6IMLGSuK93ciOMJGFlrycwFfAZPgTG6bblCe2s5xDXDoEp2jHPz4Q4JXMSqOd">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="pjr6IMLGSuK93ciOMJGFlrycwFfAZPgTG6bblCe2s5xDXDoEp2jHPz4Q4JXMSqOd">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="37688338">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://onlinelibrary.wiley.com/doi/10.1002/mgg3.2283"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3058&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=37688338&amp;db=pubmed&amp;nlmid=101603758"
title="See full text options at Wiley"
data-ga-category="full_text"
data-ga-action="Wiley"
data-ga-label="37688338"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--media.wiley.com-assets-7388-68-wiley-free-full-text.png" alt="Wiley full text link"><span class="text">
Wiley
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/37688338/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=37688338&amp;db=pubmed&amp;nlmid=101603758"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="37688338"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/37688338/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/37688338/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="37688338" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F37688338%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="pjr6IMLGSuK93ciOMJGFlrycwFfAZPgTG6bblCe2s5xDXDoEp2jHPz4Q4JXMSqOd"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
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Affiliations
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><sup class="key">1</sup> West Virginia School of Osteopathic Medicine, Lewisburg, West Virginia, USA.</li>
<li data-affiliation-id="short-view-affiliation-2"
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><sup class="key">2</sup> UPMC Children&#x27;s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.</li>
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><sup class="key">3</sup> Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.</li>
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Abstract
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<p>
<strong class="sub-title">
Background:
</strong>
Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial neurometabolic disorder of energy deficit, with incidence of about 1 in 42,000 live births annually in the USA. The median and mean ages of diagnosis of PDCD are about 12 and 31 months, respectively. PDCD is a major cause of primary lactic acidosis with concomitant elevation in blood alanine (Ala) and proline (Pro) concentrations depending on phenotypic severity. Alanine/Leucine (Ala/Leu) ≥4.0 and Proline/Leucine (Pro/Leu) ≥3.0 combination cutoff from dried blood spot specimens was used as a biomarker for early identification of neonates/infants with PDCD. Further investigations were needed to evaluate the sensitivity (SN), specificity (SP), and clinical utility of such amino acid (AA) ratio combination cutoffs in discriminating PDCD from other inborn errors of metabolism (IEM) for early identification of such patients.
</p>
<p>
<strong class="sub-title">
Methods:
</strong>
We reviewed medical records of patients seen at UPMC in the past 11 years with molecularly or enzymatically confirmed diagnosis. We collected plasma AA analysis data from samples prior to initiation of therapeutic interventions such as total parenteral nutrition and/or ketogenic diet. Conditions evaluated included organic acidemias, primary mitochondrial disorders (MtDs), fatty acid oxidation disorders (FAOD), other IEMs on current newborn screening panels, congenital cardiac great vessel anomalies, renal tubular acidosis, and non-IEMs. The utility of specific AA ratio combinations as biomarkers were evaluated using receiver operating characteristic curves, correlation analysis, principal component analysis, and cutoff SN, SP, and positive predictive value determined from 201 subjects with broad age range.
</p>
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<strong class="sub-title">
Results:
</strong>
Alanine/Lysine (Ala/Lys) and Ala/Leu as well as (Ala + Pro)/(Leu + Lys) and Ala/Leu ratio combinations effectively discriminated subjects with PDCD from those with other MtDs and IEMs on current newborn screening panels. Specific AA ratio combinations were significantly more sensitive in identifying PDCD than Ala alone or combinations of Ala and/or Pro in the evaluated cohort of subjects. Ala/Lys ≥3.0 and Ala/Leu ≥5.0 as well as (Ala + Pro)/(Leu + Lys) ≥2.5 and Ala/Leu ≥5.0 combination cutoffs identified patients with PDCD with 100% SN and ~85% SP.
</p>
<p>
<strong class="sub-title">
Conclusions:
</strong>
With the best predictor of survival and positive cognitive outcome in PDCD being age of diagnosis, PDCD patients would benefit from use of such highly SN and SP AA ratio combination cutoffs as biomarkers for early identification of at-risk newborns, infants, and children, for early intervention(s) with known and/or novel therapeutics for this disorder.
</p>
</div>
<p>
<strong class="sub-title">
Keywords:
</strong>
amino acid ratio combinations; biomarkers; inborn errors of metabolism; pyruvate dehydrogenase complex deficiency.
</p>
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© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors report no conflict of interest.</p>
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Figures
</h2>
<div class="figures-list" id="slides-container"
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<figure class="figure-item "
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itemprop="associatedMedia"
data-slide-index="0"
data-label-slug="figure-1">
<a class="figure-link"
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itemprop="contentUrl"
aria-describedby="figure-caption-0"
role="button"
data-image-width="709"
data-image-height="440"
data-image-alt="FIGURE 1"
data-pmc-id="PMC10767461"
data-figure-id="mgg32283-fig-0001">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-0"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf3/10767461/193b74870963/MGG3-12-e2283-g004.gif"
alt="FIGURE 1" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="709">
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="440">
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
<div class="caption-wrap">
<strong class="figure-label">
<p> FIGURE 1 </p>
</strong>
<div class="figure-caption-contents"><p> Box and Whisker plot analysis… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> FIGURE 1 </p>
</strong>
<div class="figure-caption-contents"><p> Box and Whisker plot analysis comparing PDCD to other disorders (IEMs and nonIEMs)… </p></div>
</div>
<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
FIGURE 1
</strong>
<div class="figure-caption-contents">Box and Whisker plot analysis comparing PDCD to other disorders (IEMs and nonIEMs) for Ala (a) and specific AA ratios (Ala/Lys, b; Ala/Leu, c; and Pro/Leu, d). Subjects (<i>n</i>=201) were <i>not</i> on total parenteral nutrition, ketogenic diet, or receiving AA supplements at time of blood collection for AA analysis. Sample size (<i>n</i>value) for Ala and specific AA ratios for each disorder is noted in figure, except for Pro/Leu where the <i>n</i>value for the MMA and FAOD cohorts were 17 and 38, respectively. AA, amino acid; CKD, chronic kidney disease; FAOD, fatty acid oxidation disorder; GAL, galactosemia; IEM, inborn error of metabolism; Leigh, Leigh syndrome (mainly those with electron transport chain dysfunction); MELAS, mitochondrial encephalopathy lactic acidosis and strokelike episodes; MERRF, myoclonus epilepsy with raggedred fibers; MMA, methylmalonic acidemia; PA, propionic acidemia; PDCD, pyruvate dehydrogenase complex deficiency; RTA, renal tubular acidosis; syn, syndrome; TGV, transposition of great vessels; and TYR1, tyrosinemia type 1.</div>
</figcaption>
</figure>
<figure class="figure-item "
itemscope itemtype="http://schema.org/ImageObject"
itemprop="associatedMedia"
data-slide-index="1"
data-label-slug="figure-2">
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itemprop="contentUrl"
aria-describedby="figure-caption-1"
role="button"
data-image-width="709"
data-image-height="515"
data-image-alt="FIGURE 2"
data-pmc-id="PMC10767461"
data-figure-id="mgg32283-fig-0002">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf3/10767461/02435d3bd2b2/MGG3-12-e2283-g002.gif"
alt="FIGURE 2" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="709">
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="515">
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
<div class="caption-wrap">
<strong class="figure-label">
<p> FIGURE 2 </p>
</strong>
<div class="figure-caption-contents"><p> Sensitivity and specificity of Ala/Leu… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> FIGURE 2 </p>
</strong>
<div class="figure-caption-contents"><p> Sensitivity and specificity of Ala/Leu and Ala/Lys at different cutoff for PDCD (a,… </p></div>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
FIGURE 2
</strong>
<div class="figure-caption-contents">Sensitivity and specificity of Ala/Leu and Ala/Lys at different cutoff for PDCD (a, b) Receiver operating characteristic (ROC) curves for Ala/Leu and Ala/Lys shown in the inset of (a) and (b), respectively. Scatter plot of Pro/Leu ≥3.0 OR Ala/Leu ≥4.0 (c), and Ala/Lys ≥3.0 AND Ala/Leu ≥5.0 (d) ratio combinations, with beige shaded areas corresponding to the areas covered by the combination ratio cutoffs. PDCD only (red dots; <i>n</i>=13) and all subjects (ALL, <i>n</i>=201; red and blue dots) are noted. Other disorders identified in the upper right quadrant of the scatter plots for Pro/Leu ≥3.0 AND Ala/Leu ≥4.0, and Ala/Lys ≥3.0 AND Ala/Leu ≥5.0 are detailed (as true positive; TP) in Table S4 and Table 3 (or Figure 4), respectively, and determination of sensitivity using these combination ratios for the other disorders evaluated besides PDCD. Ala, alanine; Leu, leucine; Lys, lysine; PDCD, pyruvate dehydrogenase complex deficiency; and Pro, proline.</div>
</figcaption>
</figure>
<figure class="figure-item "
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data-slide-index="2"
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itemprop="contentUrl"
aria-describedby="figure-caption-2"
role="button"
data-image-width="709"
data-image-height="623"
data-image-alt="FIGURE 3"
data-pmc-id="PMC10767461"
data-figure-id="mgg32283-fig-0003">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf3/10767461/08c0942285d3/MGG3-12-e2283-g005.gif"
alt="FIGURE 3" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="709">
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="623">
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
<div class="caption-wrap">
<strong class="figure-label">
<p> FIGURE 3 </p>
</strong>
<div class="figure-caption-contents"><p> Correlation and principal component analyses… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> FIGURE 3 </p>
</strong>
<div class="figure-caption-contents"><p> Correlation and principal component analyses of AA ratios. (a) Correlation analysis of AA… </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
FIGURE 3
</strong>
<div class="figure-caption-contents">Correlation and principal component analyses of AA ratios. (a) Correlation analysis of AA ratio averages for the evaluated conditions. Color scale shows degree of correlation, with darker red (and numerical values closer to 1.0) being highly correlated. (b) Principal component analysis applied using AA ratios Ala/Leu, Ala/Lys, Pro/Leu, Pro/Lys, and (Ala+Pro)/(Leu+Lys) for condition pairs (1) PDCD and MELAS, (2) PDCD and FAOD, (3) PDCD and PA, (4) PDCD and nonIEM, and (5) PDCD and MMA. All conditions used for principal component analysis had <i>n</i>&gt;10 for subject cohort count. AA, amino acid; Ala, alanine; FAOD, fatty acid oxidation disorder; IEM, inborn error of metabolism; Leu, leucine; Lys, lysine; MELAS, mitochondrial encephalopathy lactic acidosis and strokelike episodes; MMA, methylmalonic acidemia; PA, propionic acidemia; and PDCD, pyruvate dehydrogenase complex deficiency.</div>
</figcaption>
</figure>
<figure class="figure-item "
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itemprop="associatedMedia"
data-slide-index="3"
data-label-slug="figure-4">
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itemprop="contentUrl"
aria-describedby="figure-caption-3"
role="button"
data-image-width="709"
data-image-height="493"
data-image-alt="FIGURE 4"
data-pmc-id="PMC10767461"
data-figure-id="mgg32283-fig-0004">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aaf3/10767461/50646dfe4bd4/MGG3-12-e2283-g003.gif"
alt="FIGURE 4" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="709">
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="493">
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
<div class="caption-wrap">
<strong class="figure-label">
<p> FIGURE 4 </p>
</strong>
<div class="figure-caption-contents"><p> Distribution of PDCD subjects and… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> FIGURE 4 </p>
</strong>
<div class="figure-caption-contents"><p> Distribution of PDCD subjects and subjects with other disorders when Ala/Lys ≥3.0 AND… </p></div>
</div>
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
FIGURE 4
</strong>
<div class="figure-caption-contents">Distribution of PDCD subjects and subjects with other disorders when Ala/Lys ≥3.0 AND Ala/Leu ≥5.0 combination ratios applied, with beige shaded areas corresponding to the cutoffs. MELAS and MERRF (a), Leigh syndrome and FAOD (b), PA and MMA (c), Barth syndrome, TYR1 and classic GAL (d), nonIEM (e), and TGV and RTA/CKD (f) compared with PDCD (red dots) in each scatter plot. Blue dots correspond to distribution of all subjects (<i>n</i>=201). Ala, alanine; CKD, chronic kidney disease; FAOD, fatty acid oxidation disorder; GAL, galactosemia; IEM, inborn error of metabolism; Leigh, Leigh syndrome (mainly those with electron transport chain dysfunction); Leu, leucine; Lys, lysine; MELAS, mitochondrial encephalopathy lactic acidosis and strokelike episodes; MERRF, myoclonus epilepsy with raggedred fibers; MMA, methylmalonic acidemia; PA, propionic acidemia; PDCD, pyruvate dehydrogenase complex deficiency; RTA, renal tubular acidosis; syn, syndrome; TGV, transposition of great vessels; and TYR1, tyrosinemia type 1.</div>
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Proline
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</div>
<div id="substances" class="substances keywords-section">
<h2 class="title">
Substances
</h2>
<ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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ref="linksrc=search_in_pubmed_keyword_link&amp;keyword=&quot;Amino Acids&quot;[nm]"
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Leucine
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href="/?term=%22Leucine%22%5Bnm%5D&amp;sort=date&amp;sort_order=desc"
data-href="/?term=%22Leucine%22%5Bnm%5D&amp;sort=date&amp;sort_order=desc"
ref="linksrc=search_in_pubmed_keyword_link&amp;keyword=&quot;Leucine&quot;[nm]"
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data-ga-label="&quot;Leucine&quot;[nm]"
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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Alanine
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aria-label="Dropdown menu for keyword Alanine"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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data-href="/?term=%22Alanine%22%5Bnm%5D&amp;sort=date&amp;sort_order=desc"
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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Proline
</button><div id="keyword-actions-substances-3"
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aria-label="Dropdown menu for keyword Proline"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
href="/?term=%22Proline%22%5Bnm%5D&amp;sort=date&amp;sort_order=desc"
data-href="/?term=%22Proline%22%5Bnm%5D&amp;sort=date&amp;sort_order=desc"
ref="linksrc=search_in_pubmed_keyword_link&amp;keyword=&quot;Proline&quot;[nm]"
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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data-ga-label="&quot;Proline&quot;[nm]"
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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Biomarkers
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ref="linksrc=search_in_pubmed_keyword_link&amp;keyword=&quot;Biomarkers&quot;[nm]"
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data-search-term="&quot;Biomarkers&quot;[nm]"
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data-ga-label="&quot;Biomarkers&quot;[nm]"
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</div>
<div id="related-links" class="related-links">
<h2 class="title">
Related information
</h2>
<ul class="related-links-list"><li><a title="Clinical variations associated with publication" href="https://www.ncbi.nlm.nih.gov/clinvar?linkname=pubmed_clinvar&amp;from_uid=37688338"
ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=37688338&ordinalpos=1&linkpos=1">
ClinVar
</a></li><li><a title="Related information in MedGen" href="https://www.ncbi.nlm.nih.gov/medgen?linkname=pubmed_medgen&amp;from_uid=37688338"
ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=37688338&ordinalpos=1&linkpos=2">
MedGen
</a></li><li><a title="Related PubChem Compound via MeSH" href="https://www.ncbi.nlm.nih.gov/pccompound?linkname=pubmed_pccompound_mesh&amp;from_uid=37688338"
ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=37688338&ordinalpos=1&linkpos=3">
PubChem Compound (MeSH Keyword)
</a></li></ul>
</div>
<div id="grants" class="grants">
<h2 class="title">
Grants and funding
</h2>
<div class="grants-list"><ul id="grants-head-list"><li class="grant-item"><a
title="All articles for grant R01 DK109907/DK/NIDDK NIH HHS/United States"
href="/?term=R01+DK109907%2FDK%2FNIDDK+NIH+HHS%2FUnited+States%5BGrants+and+Funding%5D&amp;sort=date&amp;sort_order=desc"
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</a></li><li class="grant-item"><a
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