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<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<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="66slgI9NriMNvW91BPOZbms1T6mzd3KinTcqTyC91TzhpnfRe8r1FuYFra4L6EiC">
<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="66slgI9NriMNvW91BPOZbms1T6mzd3KinTcqTyC91TzhpnfRe8r1FuYFra4L6EiC">
<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="66slgI9NriMNvW91BPOZbms1T6mzd3KinTcqTyC91TzhpnfRe8r1FuYFra4L6EiC">
<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="66slgI9NriMNvW91BPOZbms1T6mzd3KinTcqTyC91TzhpnfRe8r1FuYFra4L6EiC">
<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="66slgI9NriMNvW91BPOZbms1T6mzd3KinTcqTyC91TzhpnfRe8r1FuYFra4L6EiC">
<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="26715604">
<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://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awv371"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=7898&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=26715604&amp;db=pubmed&amp;nlmid=0372537"
title="See full text options at Silverchair Information Systems"
data-ga-category="full_text"
data-ga-action="Silverchair Information Systems"
data-ga-label="26715604"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--academic.oup.com-images-oup_pubmed.png" alt="Silverchair Information Systems full text link"><span class="text">
Silverchair Information Systems
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/26715604/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=26715604&amp;db=pubmed&amp;nlmid=0372537"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="26715604"
><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="/26715604/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/26715604/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="26715604" 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%2F26715604%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="66slgI9NriMNvW91BPOZbms1T6mzd3KinTcqTyC91TzhpnfRe8r1FuYFra4L6EiC"><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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Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism
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data-ga-label="Darius Ebrahimi-Fakhari">Darius Ebrahimi-Fakhari</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="1 The F.M. Kirby Neurobiology Centre, Department of Neurology, Boston Children&#x27;s Hospital, Harvard Medical School, Boston, MA, USA 2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany darius.ebrahimi-fakhari@childrens.harvard.edu." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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data-ga-label="Afshin Saffari">Afshin Saffari</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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data-ga-label="Lara Wahlster">Lara Wahlster</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany 3 Department of Haematology and Oncology, Stem Cell Program, Boston Children&#x27;s Hospital, Harvard Medical School, Boston, MA, USA." href="#short-view-affiliation-3" ref="linksrc=author_aff">
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data-ga-label="Jenny Lu">Jenny Lu</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="1 The F.M. Kirby Neurobiology Centre, Department of Neurology, Boston Children&#x27;s Hospital, Harvard Medical School, Boston, MA, USA." href="#short-view-affiliation-4" ref="linksrc=author_aff">
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data-ga-label="Susan Byrne">Susan Byrne</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="4 Department of Paediatric Neurology, Evelina&#x27;s Children Hospital, Guy&#x27;s and St. Thomas&#x27; Hospital NHS Foundation Trust, London, UK." href="#short-view-affiliation-5" ref="linksrc=author_aff">
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data-ga-label="Georg F Hoffmann">Georg F Hoffmann</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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><sup class="key">1</sup> 1 The F.M. Kirby Neurobiology Centre, Department of Neurology, Boston Children&#x27;s Hospital, Harvard Medical School, Boston, MA, USA 2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany darius.ebrahimi-fakhari@childrens.harvard.edu.</li>
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><sup class="key">2</sup> 2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.</li>
<li data-affiliation-id="short-view-affiliation-3"
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><sup class="key">3</sup> 2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany 3 Department of Haematology and Oncology, Stem Cell Program, Boston Children&#x27;s Hospital, Harvard Medical School, Boston, MA, USA.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> 1 The F.M. Kirby Neurobiology Centre, Department of Neurology, Boston Children&#x27;s Hospital, Harvard Medical School, Boston, MA, USA.</li>
<li data-affiliation-id="short-view-affiliation-5"
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><sup class="key">5</sup> 4 Department of Paediatric Neurology, Evelina&#x27;s Children Hospital, Guy&#x27;s and St. Thomas&#x27; Hospital NHS Foundation Trust, London, UK.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> 4 Department of Paediatric Neurology, Evelina&#x27;s Children Hospital, Guy&#x27;s and St. Thomas&#x27; Hospital NHS Foundation Trust, London, UK 5 Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King&#x27;s College London, London, UK 6 Department of Basic and Clinical Neuroscience, IoPPN, King&#x27;s College London, London, UK.</li>
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Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy-related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.
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Keywords:
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autophagy; inborn errors of metabolism; mammalian target of rapamycin (mTOR); neurodegeneration; neurodevelopment.
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<div class="figure-caption-contents"><p> Mutations in autophagy genes cause childhood-onset multisystem… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<div class="figure-caption-contents"><p> Mutations in autophagy genes cause childhood-onset multisystem diseases with predominant nervous system involvement and provide… </p></div>
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<div class="figure-caption-contents">Mutations in autophagy genes cause childhood-onset multisystem diseases with predominant nervous system involvement and provide a genetic window into autophagy's role in neurobiology and disease. In this review, Ebrahimi-Fakhari <i>et al</i>. examine the clinical and molecular spectrum of congenital disorders of autophagy, a novel class of inborn errors of metabolism.</div>
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da55/5841365/0c1acee66f47/awv371f1p.gif"
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<strong class="figure-label">
<p> Figure 1 </p>
</strong>
<div class="figure-caption-contents"><b> The three main subtypes of… </b></div>
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<p> Figure 1 </p>
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<div class="figure-caption-contents"><b> The three main subtypes of autophagy and their implications for multiple tissues and… </b></div>
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Figure 1
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<div class="figure-caption-contents"><b>The three main subtypes of autophagy and their implications for multiple tissues and organ systems.</b> Autophagy mainly comprises of three subtypes: microautophagy, chaperone-mediated autophagy and macroautophagy. These are distinguished based on the route and mechanism of cargo delivery to lysosomes, the final degrading organelles. Research over the last decades has elucidated a number of cell and tissue-specific functions that depend on or are critically influenced by autophagy. These functions are present in many organ systems, including the nervous system. The variety of functions of autophagy in different organ systems under physiological conditions is emphasized by the broad clinical manifestations in congenital disorders of autophagy, which manifest as multisystem diseases with prominent CNS pathology. CMA = chaperone-mediated autophagy.</div>
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<p> Figure 2 </p>
</strong>
<div class="figure-caption-contents"><b> Macroautophagy: an overview of the… </b></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 2 </p>
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<div class="figure-caption-contents"><b> Macroautophagy: an overview of the molecular pathway and mutations associated with congenital disorders… </b></div>
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Figure 2
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<div class="figure-caption-contents"><b>Macroautophagy: an overview of the molecular pathway and mutations associated with congenital disorders of autophagy.</b> Macroautophagy is a step-wise process resulting in the formation of double-membrane-bound autophagic vesicles that engulf their cargo before fusing with lysosomes. The principle stages of macroautophagy include: (I) initiation; (II) nucleation of an isolation membrane (also called phagophore); (III) elongation of evolving autophagic vesicles; (IV) engulfment of cargo and closure of the autophagosomal membrane; (V) autophagosome maturation; (VI) fusion with late endosomes or lysosomes; and finally (VII) degradation of cargo through lysosomal hydrolases. The last step yields basic metabolites that are then recycled. Mutations in congenital disorders of autophagy and single gene disorders associated with deficits in the regulation of autophagy impair different stages of the pathway. Through interfering with the beclin 1 complex, hereditary spastic paraplegia-associated recessive mutations in <i>ZFYVE26</i> (SPG15) impair early stages such as the formation of the isolation membrane. Mutations in <i>TECPR2</i> (SPG49) were recently shown to be critically involved in maintaining endoplasmic reticulum exit sites that may serve as scaffolds for the formation of early autophagosome intermediates. X-linked <i>WDR45</i> mutations cause beta-propeller protein-associated neurodegeneration (BPAN) and have been found to potentially interfere with the elongation of nascent autophagic vesicles. Autosomal-recessive <i>EPG5</i> mutations in Vici syndrome as well as <i>SNX14</i> mutations in <i>SNX14</i>-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome impact the late stages of the autophagy pathway through impairing autophagosome-lysosome fusion. Mutations in <i>SPG11</i> (SPG11) lead to a defect in autophagic lysosome reformation. Autophagy-associated diseases also affect different stages of autophagy regulation. An example for mTOR-associated neurodevelopmental diseases, loss-of-function mutations in <i>TSC1</i> or <i>TSC2</i> in tuberous sclerosis complex lead to constitutive activation of mTORC1 and thus block autophagic flux at multiple stages. Locating the defect to the late stages of the pathway, lysosomal storage diseases impact lysosomal metabolism and thus block upstream steps in the autophagy pathway. Impaired crosstalk between the lysosomal pathway and autophagosome biogenesis might also impact the coordinated regulation of both compartments. AR-CAID = autosomal-recessive cerebellar ataxia and intellectual disability syndrome; LSD = lysosomal storage disease; TSC = tuberous sclerosis complex.</div>
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<p> Figure 3 </p>
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<div class="figure-caption-contents"><b> Vici syndrome: a multisystem disease.… </b></div>
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<strong class="figure-label">
<p> Figure 3 </p>
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<div class="figure-caption-contents"><b> Vici syndrome: a multisystem disease. </b> Mutations in the autophagy gene <i> EPG5 </i> cause Vici…</div>
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Figure 3
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<div class="figure-caption-contents"><b>Vici syndrome: a multisystem disease.</b> Mutations in the autophagy gene <i>EPG5</i> cause Vici syndrome, a paradigm for multisystem diseases associated with defective autophagy. The eight cardinal features of Vici syndrome consist of agenesis of the corpus callosum, acquired microcephaly, bilateral cataracts, hypertrophic or dilated cardiomyopathy, combined immunodeficiency, and skin, hair or retinal hypopigmentation, failure to thrive and profound developmental delay. CNS manifestations are manifold and include congenital brain malformations such as agenesis of the corpus callosum with colpocephaly, cerebellar hypoplasia, hypoplasia/atrophy of the brainstem, abnormalities of the septum pellucidum, opercular hypoplasia and probably age-dependent abnormal T<sub>2</sub> signal in the thalami. Dysgenesis of the falx, non-lissencephalic cortical dysplasia, polymicrogyria of the cerebral hemispheres, or bilateral schizencephaly have also been reported in a few individuals. Delayed myelination and diffuse white matter atrophy are commonly reported. Pointing to the potential presence of a neurodegenerative phenotype in addition to prominent deficits in brain development, dilated ventricles, Purkinje cell loss, and diffuse cerebral atrophy have been described in a subset of patients.</div>
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<p> Figure 4 </p>
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<div class="figure-caption-contents"><b> BPAN: natural history of a… </b></div>
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<p> Figure 4 </p>
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<div class="figure-caption-contents"><b> BPAN: natural history of a biphasic disease. </b> Patients with <i> WDR45 </i> -mutation associated BPAN…</div>
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Figure 4
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<div class="figure-caption-contents"><b>BPAN: natural history of a biphasic disease.</b> Patients with <i>WDR45</i>-mutation associated BPAN commonly present with a distinct biphasic clinical course. Initial manifestations in infancy or early childhood consist of global developmental delay, intellectual disability, and seizures, which tend to progress in the later stages of the disease. Cerebellar ataxia, spasticity, Rett-like hand stereotypies, and autistic features have also been reported in a subset of patients. The disease advances in adolescence or early adulthood when dystonia, parkinsonism, and progressive cognitive decline become prominent. Other manifestations often include bladder and bowel incontinence, disordered sleep, and visual and auditory deficits.</div>
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