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Volume 13
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Abnormal Splicing of GALC Transcripts Underlies Unusual Cases of Krabbe Disease

by
María Domínguez-Ruiz
1,2,†,
Juan Luis Chico
3,†,
Laura López-Marín
4,
Sinziana Stanescu
5,6,
Pablo Crujeiras
7,8,
Daniel Rodrigues
7,8,
María-Elena de las Heras-Alonso
9,
Rosana Torremocha
10,
María del Mar Meijón-Ortigueira
11,
Patricia Muñoz-Díez
11,
Val F. Lanza
12,13,
Cristóbal Colón
7,8,
Jesús Villarrubia
6,11,
Amaya Belanger
5,6 and
Francisco J. del Castillo
1,2,*
1
Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain
2
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28034 Madrid, Spain
3
Servicio de Neurología, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá de Henares, 28034 Madrid, Spain
4
Sección de Neuropediatría, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain
5
Servicio de Pediatría, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain
6
CSUR de Enfermedades Metabólicas, European Reference Network for Hereditary Metabolic Disorders (MetabERN), Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain
7
Congenital Metabolic Diseases Unit, Department of Neonatology, University Clinical Hospital of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago (IDIS), European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15706 Santiago de Compostela, Spain
8
Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), 15706 Santiago de Compostela, Spain
9
Servicio de Dermatología, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain
10
Unidad de Genómica, Fundación Parque Científico de Madrid, 28049 Madrid, Spain
11
Servicio de Hematología, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain
12
UCA de Genómica Traslacional y Bioinformática (UCA-GTB), Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain
13
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28034 Madrid, Spain
 
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*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomedicines 2025, 13(12), 3114; https://doi.org/10.3390/biomedicines13123114
Submission received: 12 November 2025 / Revised: 11 December 2025 / Accepted: 12 December 2025 / Published: 17 December 2025
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
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Abstract

Background/Objectives: Krabbe disease (KD) is a hereditary lysosomal disorder whose hallmark is progressive demyelination, with variable involvement of the central nervous system. It is caused by pathogenic variants in the GALC gene that disrupt the function of its gene product, the lysosomal enzyme galactosylceramidase. We analyzed two unrelated cases (one early infantile and one adult) with a clinical suspicion of KD. Methods: We used a combination of biochemical techniques (high-performance liquid chromatography–tandem mass spectrometry), NGS (resequencing gene panels), splicing assays, and molecular modeling to identify and analyze the pathogenicity of the variants underlying the disorder. Results: The two probands were compound heterozygotes for disease-causing variants in the GALC gene, encoding the lysosomal hydrolase galactosylceramidase. Three of the variants were novel and caused aberrant splicing, either by exon skipping (c.908+5G>A and c.1034-1G>C) or by inclusion of a cryptic, deep intronic pseudoexon (c.621+772G>C). The fourth variant was a known missense change (c.956A>G, p.(Tyr319Cys)) with conflicting interpretations of pathogenicity in the databases. Conclusions: We demonstrated the pathogenicity of the three novel splicing variants, all with strong impact on galactosylceramidase function. We also concluded that the c.956A>G missense variant is a hypomorph usually underlying the later-onset, milder phenotypes of KD. Our results stress the importance of integrated approaches combining clinical, biochemical, and genetic testing to obtain a definitive diagnosis of lysosomal diseases.
Keywords: rare diseases; lysosomal diseases; NGS; Krabbe disease; globoid cell leukodystrophy; functional assays; phenotypic variation; deep intronic variants rare diseases; lysosomal diseases; NGS; Krabbe disease; globoid cell leukodystrophy; functional assays; phenotypic variation; deep intronic variants
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MDPI and ACS Style

Domínguez-Ruiz, M.; Chico, J.L.; López-Marín, L.; Stanescu, S.; Crujeiras, P.; Rodrigues, D.; Heras-Alonso, M.-E.d.l.; Torremocha, R.; Meijón-Ortigueira, M.d.M.; Muñoz-Díez, P.; et al. Abnormal Splicing of GALC Transcripts Underlies Unusual Cases of Krabbe Disease. Biomedicines 2025, 13, 3114. https://doi.org/10.3390/biomedicines13123114

AMA Style

Domínguez-Ruiz M, Chico JL, López-Marín L, Stanescu S, Crujeiras P, Rodrigues D, Heras-Alonso M-Edl, Torremocha R, Meijón-Ortigueira MdM, Muñoz-Díez P, et al. Abnormal Splicing of GALC Transcripts Underlies Unusual Cases of Krabbe Disease. Biomedicines. 2025; 13(12):3114. https://doi.org/10.3390/biomedicines13123114

Chicago/Turabian Style

Domínguez-Ruiz, María, Juan Luis Chico, Laura López-Marín, Sinziana Stanescu, Pablo Crujeiras, Daniel Rodrigues, María-Elena de las Heras-Alonso, Rosana Torremocha, María del Mar Meijón-Ortigueira, Patricia Muñoz-Díez, and et al. 2025. "Abnormal Splicing of GALC Transcripts Underlies Unusual Cases of Krabbe Disease" Biomedicines 13, no. 12: 3114. https://doi.org/10.3390/biomedicines13123114

APA Style

Domínguez-Ruiz, M., Chico, J. L., López-Marín, L., Stanescu, S., Crujeiras, P., Rodrigues, D., Heras-Alonso, M.-E. d. l., Torremocha, R., Meijón-Ortigueira, M. d. M., Muñoz-Díez, P., Lanza, V. F., Colón, C., Villarrubia, J., Belanger, A., & Castillo, F. J. d. (2025). Abnormal Splicing of GALC Transcripts Underlies Unusual Cases of Krabbe Disease. Biomedicines, 13(12), 3114. https://doi.org/10.3390/biomedicines13123114

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