{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:06:10Z","timestamp":1785323170127,"version":"3.55.0"},"reference-count":16,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Neonatal Screen.","IJNS"],"abstract":"<jats:p>Krabbe disease is an autosomal recessive leukodystrophy caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), responsible for the degradation of galactolipids, resulting in toxic psychosine accumulation and progressive demyelination of the central and peripheral nervous systems. Newborn screening (NBS) has increased recognition of later-onset Krabbe disease, although interpretation of complex GALC genotypes remains challenging, particularly in the presence of \u201cpseudodeficiency\u201d and modifier alleles. In this case report, we describe a child with late-infantile Krabbe disease identified through NBS with markedly reduced GALC activity and a homozygous GALC haplotype containing c.956A&gt;G (p.Tyr319Cys; Y319C) and c.1685T&gt;C (p.Ile562Thr; I562T), in addition to other benign variants. Retrospective analysis of the newborn screening specimen demonstrated mild psychosine elevation. Despite preserved neurodevelopment, longitudinal surveillance demonstrated progressive cerebral white matter abnormalities by 3 years and 9 months of age and psychosine elevation in erythrocytes (14 pmol\/g Hb; controls &lt; 5), prompting umbilical cord blood transplantation (UCBT). Following transplantation, GALC enzyme activity normalized, psychosine levels decreased, and serial neuroimaging demonstrated radiographic stability without neurologic regression at last follow-up (9 years old). This case expands the phenotypic spectrum associated with homozygosity for the p.Tyr319Cys variant and highlights the role of p.Ile562Thr in amplifying the pathogenic potential when in cis with p.Tyr319Cys. This GALC haplotype illustrates how \u201cpseudodeficiency\u201d and modifier alleles may collectively influence biochemical, radiologic, and clinical disease expression. These findings emphasize the importance of integrating genotype, psychosine, enzyme activity, and longitudinal neuroimaging when evaluating infants with NBS results positive for Krabbe disease.<\/jats:p>","DOI":"10.3390\/ijns12030059","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:13:47Z","timestamp":1785320027000},"page":"59","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Homozygosity for a Clinically Significant GALC Haplotype Associated with Late-Infantile Krabbe Disease Detected on Newborn Screening: Implications for Clinical Management and Genetic Counseling"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8662-912X","authenticated-orcid":false,"given":"Daniel R.","family":"Schecter","sequence":"first","affiliation":[{"name":"Department of Medical Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Center for AI in Children\u2019s Health, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6911-9427","authenticated-orcid":false,"given":"Colleen","family":"Donnelly","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8226-615X","authenticated-orcid":false,"given":"Amy","family":"White","sequence":"additional","affiliation":[{"name":"Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8522-5860","authenticated-orcid":false,"given":"Hillary","family":"Raynes","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9792-5699","authenticated-orcid":false,"given":"Gordon","family":"Heller","sequence":"additional","affiliation":[{"name":"Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Rajan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, UPMC Children\u2019s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos A.","family":"Saavedra-Matiz","sequence":"additional","affiliation":[{"name":"Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, NY 12203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7081-6027","authenticated-orcid":false,"given":"Joseph","family":"Orsini","sequence":"additional","affiliation":[{"name":"Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, NY 12203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaap-Jan","family":"Boelens","sequence":"additional","affiliation":[{"name":"Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"},{"name":"Department of Pediatrics, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6298-4138","authenticated-orcid":false,"given":"Dietrich","family":"Matern","sequence":"additional","affiliation":[{"name":"Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4527-1264","authenticated-orcid":false,"given":"Jaya","family":"Ganesh","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. 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Metab."}],"container-title":["International Journal of Neonatal Screening"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2409-515X\/12\/3\/59\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:45:32Z","timestamp":1785321932000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2409-515X\/12\/3\/59"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":16,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijns12030059"],"URL":"https:\/\/doi.org\/10.3390\/ijns12030059","relation":{},"ISSN":["2409-515X"],"issn-type":[{"value":"2409-515X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]}}}