{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:03:39Z","timestamp":1789833819407,"version":"4.0.1"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Infantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in\n                      <jats:italic>PLA2G6<\/jats:italic>\n                      , which encodes a calcium-independent phospholipase A2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      We comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of\n                      <jats:italic>PLA2G6<\/jats:italic>\n                      -associated neurodegeneration (PLAN) and a clinical history consistent with INAD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense\/truncating variants compared with missense\/in-frame deletions in the time of initial concern (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04), initial loss of language (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.001), initial loss of fine motor skills (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.009), and initial loss of bulbar skills (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.007).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>INAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-020-01355-2","type":"journal-article","created":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:17:11Z","timestamp":1588292231000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The natural history of infantile neuroaxonal dystrophy"],"prefix":"10.1186","volume":"15","author":[{"given":"Fadie D.","family":"Altuame","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen","family":"Foskett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paldeep S.","family":"Atwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Endemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Midei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Milner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa A.","family":"Salih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muddathir","family":"Hamad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Al-Muhaizea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mais","family":"Hashem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fowzan S.","family":"Alkuraya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,1]]},"reference":[{"key":"1355_CR1","doi-asserted-by":"crossref","unstructured":"Balsinde J, Balboa MAJCs. 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J Mol Biol. 2011;412(3):412\u201322.","DOI":"10.1016\/j.jmb.2011.07.034"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-020-01355-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-020-01355-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-020-01355-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T09:01:08Z","timestamp":1620032468000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-020-01355-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,1]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1355"],"URL":"https:\/\/doi.org\/10.1186\/s13023-020-01355-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.2.19797\/v2","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.19797\/v1","asserted-by":"object"}]},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,1]]},"assertion":[{"value":"25 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"An IRB-approved written informed consent was obtained from all patients and their parents enrolled in this study. The ethics committee at King Faisal Specialist Hospital and Research Centre, Riyadh (KFSHRC) and Quorum Review (RAC# 2121053, File #: 33273\/1; Protocol #: RT-INAD-NH001) specifically approved this study. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declarations of 1975, as revised in 2000 [\n                      \n                      ].","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"An IRB-approved written informed consent was obtained from all patients and their parents enrolled in this study with respect to publication. The ethics committee at King Faisal Specialist Hospital and Research Centre, Riyadh (KFSHRC) and Quorum Review (RAC# 2121053, File #: 33273\/1; Protocol #: RT-INAD-NH001) specifically approved this study. All subjects reported in this manuscript have provided consent for publication, although the reports are anonymous and does not contain personal information. Proof of informed consent is available upon request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Peter Milner, Sarah Endemann, Mark Midei, Paldeep Atwal, are employed by, and hold stock in Retrotope, Inc. All other authors have no potential conflicts of interest. All authors confirm that the content of the article has not been influenced by the sponsor.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"109"}}