Abstract
Celia’s encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.
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Acknowledgements
We thank the patient and her parents for their cooperation and collaboration in this study. This work was supported by the Fundación Mutua Madrileña and by the Instituto de Salud Carlos III and the European Regional Development Fund, FEDER (PI13/00314). SR-G was awarded a Research Fellowship by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP). We thank Bristol-Myers-Squibb, AstraZeneca, and Aegerion Pharmaceuticals for providing metreleptin, Dr Jesús R Requena for the kind gift of SH-SY5Y cells, and David Araujo-Gonzalez for technical support in Tube-Video presentation.
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DA-V received an honorarium as an expert advisor from Aegerion Pharmaceuticals; the remaining authors declare that they have no conflict of interest.
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Araújo-Vilar, D., Domingo-Jiménez, R., Ruibal, Á. et al. Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia’s encephalopathy. Eur J Hum Genet 26, 396–406 (2018). https://doi.org/10.1038/s41431-017-0052-8
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DOI: https://doi.org/10.1038/s41431-017-0052-8
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