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Celia’s encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant

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Abstract

Celia’s encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia’s encephalopathy, with variable phenotypic expression.

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Acknowledgements

We are indebted to the patients and their parents for their collaboration in this study. Control 18F-FDG PET brain of subject at 7 years of age was a courtesy of A. Niñerola-Baizán and X. Setoain from Hospital Clínic Barcelona.

Funding

This work was supported by the Instituto de Salud Carlos III and the European Regional Development Fund, FEDER (grant numbers PI10/02873 and PI13/00314), by the Consellería de Industria, Xunta de Galicia (grant numbers 10PXIB208013PR and ED341b 2017/19), and by Fundación Mutua Madrileña (Call 2015). S.S-I was awarded a Research Fellowship, granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP). Evaluation of case 2 was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases.

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Authors and Affiliations

  1. Thyroid and Metabolic Diseases Unit, Biomedical Research Institute (CIMUS)-IDIS, School of Medicine, Universidade de Santiago de Compostela, Santiago, Spain

    Sofía Sánchez-Iglesias, Antía Fernández-Pombo & David Araújo-Vilar

  2. Boston Children’s Hospital, Harvard University, Cambridge, MA, USA

    Melissa Crocker

  3. Servicio de Neurología, Hospital Sant Joan de Déu, Barcelona, Spain

    Mar O’Callaghan, Alejandra Darling & Angels García-Cazorla

  4. Section of Neuropediatrics, Division of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain

    Rosario Domingo-Jiménez

  5. Division of Endocrinology and Nutrition, Hospital Clínico Universitario de Santiago de Compostela, Santiago, Spain

    Ana Castro, Antía Fernández-Pombo & David Araújo-Vilar

  6. Division of Nuclear Medicine, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain

    Álvaro Ruibal, Pablo Aguiar & Miguel Garrido-Pumar

  7. Molecular Imaging and Medical Physics, Universidade de Santiago de Compostela. IDIS, Santiago, Spain

    Álvaro Ruibal, Pablo Aguiar & Miguel Garrido-Pumar

  8. Pediatric Intensive Care Unit, Pediatric Area, Hospital Clínico Universitario de Santiago de Compostela, Santiago, Spain

    Antonio Rodríguez-Núñez

  9. Anesthesia and Reanimation Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago, Spain

    Julián Álvarez-Escudero

  10. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Rebecca J. Brown

  11. U.E.T.eM. CIMUS.|, University of Santiago de Compostela, Avda. de Barcelona 3, 15707, Santiago de Compostela, Spain

    David Araújo-Vilar

Authors
  1. Sofía Sánchez-Iglesias
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  2. Melissa Crocker
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  14. Rebecca J. Brown
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  15. David Araújo-Vilar
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Corresponding author

Correspondence to David Araújo-Vilar.

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The regional IRBs approved this study, which was conducted according to the ethical guidelines of the Helsinki Declaration.

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Sánchez-Iglesias, S., Crocker, M., O’Callaghan, M. et al. Celia’s encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant. Neurogenetics 20, 73–82 (2019). https://doi.org/10.1007/s10048-019-00574-5

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