{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:23:20Z","timestamp":1760149400088,"version":"build-2065373602"},"reference-count":21,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T00:00:00Z","timestamp":1691712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Glycogen storage disease type IV (GSD IV) (OMIM #232500) is an autosomal recessive disorder caused by deficiency of the glycogen-branching enzyme. Here, we report a patient presenting with prematurity and severe hypotonia resulting from a complicated pregnancy with polyhydramnios. During her stay in the neonatal unit, the infant remained dependent on a ventilator, and her movements were mostly absent, except for occasional small movements of her fingers. A spontaneous fracture of femur shaft occurred in the postnatal fourth week. Whole-exome sequencing of DNA from the patient revealed a homozygous missense variant in the GBE1 gene (c.1693C&gt;T, p.Arg565Trp). The variation detected in the index case was also confirmed by Sanger sequencing in the patient and respective parents. This study showed that the neuromuscular subtypes of GSD-IV should be considered as a possible differential diagnosis in severe neonatal hypotonia cases.<\/jats:p>","DOI":"10.3390\/children10081375","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T10:20:16Z","timestamp":1691749216000},"page":"1375","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Unusual Case of Neonatal Hypotonia and Femur Fracture: Neuromuscular Variant of Glycogen Storage Disease Type IV"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5720-7104","authenticated-orcid":false,"given":"Handan","family":"Bezirganoglu","sequence":"first","affiliation":[{"name":"Division of Neonatology, Trabzon Kanuni Training and Research Hospital, Trabzon 61080, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0201-6877","authenticated-orcid":false,"given":"Kubra","family":"Adanur Saglam","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Karadeniz Technical University Medical Faculty, Trabzon 61080, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.3748\/wjg.v13.i18.2541","article-title":"Glycogen storage diseases: New perspectives","volume":"13","author":"Ozen","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/BF00294181","article-title":"Neonatal hyopotonia and cardiomyopathy secondary to type IV glycogenosis","volume":"87","author":"Tang","year":"1994","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.2174\/1566524024605815","article-title":"The Variable Presentations of Glycogen Storage Disease Type IV: A Review of Clinical, Enzymatic and Molecular Studies","volume":"2","author":"Moses","year":"2002","journal-title":"Curr. Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"992406","DOI":"10.3389\/fgene.2022.992406","article-title":"A novel approach to characterize phenotypic variation in GSD IV: Reconceptualizing the clinical continuum","volume":"13","author":"Kiely","year":"2022","journal-title":"Front. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/jp.2011.178","article-title":"Neonatal presentation of lethal neuromuscular glycogen storage disease type IV","volume":"32","author":"Escobar","year":"2012","journal-title":"J. Perinatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.nmd.2010.07.275","article-title":"Branching enzyme deficiency\/glycogenosis storage disease type IV presenting as a severe congenital hypotonia: Muscle biopsy and autopsy findings, biochemical and molecular genetic studies","volume":"20","author":"Taratuto","year":"2010","journal-title":"Neuromuscul. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.nmd.2012.11.005","article-title":"Whole exome sequencing in foetal akinesia expands the genotype-phenotype spectrum of GBE1 glycogen storage disease mutations","volume":"23","author":"Ravenscroft","year":"2013","journal-title":"Neuromuscul. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41436-019-0680-1","article-title":"The genomic and clinical landscape of fetal akinesia","volume":"22","author":"Pergande","year":"2020","journal-title":"Genet. Med."},{"key":"ref_9","unstructured":"Shen, F., and Sergi, C. (2023). StatPearls, StatPearls Publishing. Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK559250\/."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Venselaar, H., Beek, T.A.T., Kuipers, R.K., Hekkelman, M.L., and Vriend, G. (2010). Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-548"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5667","DOI":"10.1093\/hmg\/ddv280","article-title":"Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design","volume":"24","author":"Froese","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.humpath.2011.10.001","article-title":"Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: A case report and review","volume":"43","author":"Magoulas","year":"2012","journal-title":"Hum. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ymgmr.2018.09.001","article-title":"Analysis of GBE1 mutations via protein expression studies in glycogen storage disease type IV: A report on a non-progressive form with a literature review","volume":"17","author":"Iijima","year":"2018","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/MCD.0000000000000248","article-title":"Novel pathogenic variants in GBE1 causing fetal akinesia deformation sequence and severe neuromuscular form of glycogen storage disease type IV","volume":"28","author":"Radhakrishnan","year":"2019","journal-title":"Clin. Dysmorphol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S83","DOI":"10.1007\/s10545-009-9026-5","article-title":"Glycogen storage disease type IV: Novel mutations and molecular characterization of a heterogeneous disorder","volume":"33","author":"Li","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_16","first-page":"75","article-title":"Neuromuscular forms of glycogen branching enzyme deficiency","volume":"26","author":"Bruno","year":"2007","journal-title":"Acta Myol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1212\/01.WNL.0000138429.11433.0D","article-title":"Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV)","volume":"63","author":"Bruno","year":"2004","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107525","DOI":"10.1016\/j.ymgme.2023.107525","article-title":"Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource","volume":"138","author":"Koch","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1177\/088307380201700916","article-title":"Spinal muscular atrophy with congenital fractures: Postmortem analysis","volume":"17","author":"Davies","year":"2002","journal-title":"J. Child. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1080\/pdp.21.6.569.584","article-title":"Infant with high arched palate, bell-shaped chest, joint contractures, and intrauterine fractures","volume":"21","author":"Lacson","year":"2002","journal-title":"Pediatr. Pathol. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1002\/ajmg.a.38383","article-title":"Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy","volume":"173","author":"Abbott","year":"2017","journal-title":"Am. J. Med. Genet. 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