GM3 synthase deficiency in non-Amish patients |
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Authors: | Solveig Heide Marie-Line Jacquemont David Cheillan Michel Renouil Marilyn Tallot Charles E. Schwartz Juliette Miquel Marc Bintner Diana Rodriguez Françoise Darcel Julien Buratti Damien Haye Sandrine Passemard Domitille Gras Laurence Perrin Yline Capri Bénédicte Gérard Amélie Piton Cyril Mignot |
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Affiliation: | 1. AP-HP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;2. Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;3. Unité fonctionnelle de Génétique Médicale, Centre Hospitalier Universitaire de La Réunion, Saint-Pierre, France;4. Service de Biochimie et Biologie Moléculaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France;5. Service de Pédiatrie, Centre Hospitalier Universitaire de La Réunion, Saint-Pierre, France;6. Greenwood Genetic Center, Greenwood, SC, USA;7. Unité Fonctionnelle de Dermatologie Pédiatrique, Centre Hospitalier Universitaire de La Réunion, Saint-Pierre, France;8. Service d’Imagerie Médicale, Centre Hospitalier Universitaire de La Réunion, Saint-Pierre, France;9. AP-HP.Sorbonne Université, Service de Neuropédiatrie & Centre de Référence de Neurogénétique, Hôpital Armand Trousseau, Paris, France;10. INSERM U1141, FHU I2-D2, Paris, France;11. Centre de Maladie Neurologiques Rares, Centre Hospitalier Universitaire de La Réunion, Saint-Pierre, France;12. Service de Neuropédiatrie, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Nord-Université de Paris, Paris, France;13. Service de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Nord-Université de Paris, Paris, France;14. Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France;15. Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l’Interrégion Est, Fédération Hospitalo-Universitaire Médecine TRANSLationnelle et Anomalies du Développement, Centre Hospitalier Universitaire Dijon, Equipe Genetics of Developmental Anomalies-INSERM UMR 1231, Dijon, France;16. Service de Médecine Physique, Hôpital d’enfants de Saint-Denis, Saint-Denis, France;17. Sorbonne Université, Institut du Cerveau, INSERM, Paris, France;18. EuroEPINOMICS RES Consortium;19. Centre of Developmental Epilepsy and Electroencephalography, San Paolo Hospital, Bari, Italy;20. Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children''s Hospital, University of Florence, Florence, Italy |
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Abstract: | PurposeBiallelic loss-of-function variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD) responsible for Amish infantile epilepsy syndrome. All Amish patients carry the homozygous p.(Arg288Ter) variant arising from a founder effect. To date only 10 patients from 4 non-Amish families have been reported. Thus, the phenotypical spectrum of GM3SD due to other variants and other genetic backgrounds is still poorly known.MethodsWe collected clinical and molecular data from 16 non-Amish patients with pathogenic ST3GAL5 variants resulting in GM3SD.ResultsWe identified 12 families originating from Reunion Island, Ivory Coast, Italy, and Algeria and carrying 6 ST3GAL5 variants, 5 of which were novel. Genealogical investigations and/or haplotype analyses showed that 3 of these variants were founder alleles. Glycosphingolipids quantification in patients’ plasma confirmed the pathogenicity of 4 novel variants. All patients (N = 16), aged 2 to 12 years, had severe to profound intellectual disability, 14 of 16 had a hyperkinetic movement disorder, 11 of 16 had epilepsy and 9 of 16 had microcephaly. Other main features were progressive skin pigmentation anomalies, optic atrophy or pale papillae, and hearing loss.ConclusionThe phenotype of non-Amish patients with GM3SD is similar to the Amish infantile epilepsy syndrome, which suggests that GM3SD is associated with a narrow and severe clinical spectrum. |
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Keywords: | Epilepsy GM3 synthase deficiency Intellectual disability Movement disorder |
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