{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:53:22Z","timestamp":1790434402463,"version":"4.1.0"},"reference-count":15,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJNS"],"abstract":"<jats:p>Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine\/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and progression in myelination. Her clinical phenotype, including protein tolerance, correlated with intermediate MSUD. Molecular analysis of all three genes identified two variants of uncertain significance, c.434-15_434-4del and c.365A&gt;G (p. Tyr122Cys) in the DBT gene. The rate of leucine decarboxylation in fibroblasts was reduced, but not to the extent observed in classical MSUD patients, supporting an intermediate form of MSUD. Previously reported mRNA splicing studies supported a deleterious effect of the c.434-15_434-4del variant. This functional evidence and confirmation that the variants were in trans, permitted their reclassification as pathogenic and likely pathogenic, respectively, facilitating subsequent prenatal testing. This report highlights the challenges in identifying intermediate MSUD by newborn screening, reinforcing the importance of functional studies to confirm variant pathogenicity in this era of molecular diagnostics.<\/jats:p>","DOI":"10.3390\/ijns7020025","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T02:31:34Z","timestamp":1621218694000},"page":"25","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning"],"prefix":"10.3390","volume":"7","author":[{"given":"Mona","family":"Sajeev","sequence":"first","affiliation":[{"name":"Genetic Metabolic Disorders Service, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Chin","sequence":"additional","affiliation":[{"name":"Genetics and Molecular Pathology, SA Pathology at Women\u2019s and Children\u2019s Hospital, North Adelaide, SA 5006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gladys","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"},{"name":"Discipline of Genetic Medicine, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5598-0278","authenticated-orcid":false,"given":"Bruce","family":"Bennetts","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"},{"name":"Discipline of Genetic Medicine, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bindu Parayil","family":"Sankaran","sequence":"additional","affiliation":[{"name":"Genetic Metabolic Disorders Service, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"},{"name":"The Children\u2019s Hospital at Westmead Clinical School, Faculty of Medicine &amp; Health, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0457-113X","authenticated-orcid":false,"given":"Bea","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"NSW Biochemical Genetics Service, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beena","family":"Devanapalli","sequence":"additional","affiliation":[{"name":"NSW Biochemical Genetics Service, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adviye Ayper","family":"Tolun","sequence":"additional","affiliation":[{"name":"Discipline of Genetic Medicine, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"NSW Biochemical Genetics Service, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Wiley","sequence":"additional","affiliation":[{"name":"Discipline of Genetic Medicine, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"NSW Newborn Screening Programme, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","family":"Fletcher","sequence":"additional","affiliation":[{"name":"Genetics and Molecular Pathology, SA Pathology at Women\u2019s and Children\u2019s Hospital, North Adelaide, SA 5006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9092-8942","authenticated-orcid":false,"given":"Maria","family":"Fuller","sequence":"additional","affiliation":[{"name":"Genetics and Molecular Pathology, SA Pathology at Women\u2019s and Children\u2019s Hospital, North Adelaide, SA 5006, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanti","family":"Balasubramaniam","sequence":"additional","affiliation":[{"name":"Genetic Metabolic Disorders Service, Western Sydney Genetics Program, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"},{"name":"Discipline of Genetic Medicine, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"key":"ref_1","unstructured":"Strauss, K.A., Puffenberger, E.G., and Carson, V.J. 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Chem."}],"container-title":["International Journal of Neonatal Screening"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2409-515X\/7\/2\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:01:01Z","timestamp":1760162461000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2409-515X\/7\/2\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,14]]},"references-count":15,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijns7020025"],"URL":"https:\/\/doi.org\/10.3390\/ijns7020025","relation":{},"ISSN":["2409-515X"],"issn-type":[{"value":"2409-515X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,14]]}}}