title: ALG3-CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation.
abstract: Congenital disorders of glycosylation (CDG) are a group of inborn errors of metabolism presenting with heterogeneous multisystemic clinical manifestations. To date, more than 60 different types of CDG have been reported. ALG3-CDG is very rare, with only nine patients described so far. We report two affected siblings presenting prenatally with skeletal abnormalities associated with dysmorphic features, cerebellar vermis hypoplasia, corpus callosum agenesis, hepatic fibrosis and poor prognosis. This is the first detailed report of an affected fetus including clinical, radiographic and pathological findings. The patients showed some clinical features previously unreported in ALG3-CDG, such as bone dysplasia, cataract, corneal opacities, and pons hypoplasia. Both patients were homozygous for the previously unreported p.Gly96Arg mutation of the ALG3 gene. One patient showed chondrodysplasia punctata (CDP), which has not been previously reported in CDG. An exhaustive genetic and metabolic assessment, performed in order to rule out other possible causes of CDP, showed abnormally raised levels of anti-nuclear antibodies in the mother who, nevertheless, did not show any clinical sign of autoimmune disease during a 7 years follow-up. We speculate that the observed CDP may be explained by the maternal anti-nuclear antibodies; alternatively, a possible link to the underlying metabolic disorder cannot be ruled out. In conclusion, we report the clinical, pathological, biochemical and molecular characterization of two further patients affected by ALG3-CDG, expanding the phenotypic spectrum of this very rare disease.
authors.affiliation: Centre de Référence des Anomalies du Développement, Service de Génétique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.
authors.forename: Laureline
authors.initials: L
authors.lastname: Lepais
authors.affiliation: Service des Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France.|INSERM U1060/Université Lyon-1, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Cheillan
authors.affiliation: Service d'Anatomie Pathologique, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France.|Université Lyon 1, Lyon, France.
authors.forename: Sophie Collardeau
authors.initials: SC
authors.lastname: Frachon
authors.affiliation: Service de Réanimation Néonatale et Néonatologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hays
authors.affiliation: Center for Human Genetics, UZ Gasthuisberg, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Service Epilepsie, Sommeil, Explorations Fonctionnelles Neuropédiatriques (ESEFNP), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.
authors.forename: Eleni
authors.initials: E
authors.lastname: Panagiotakaki
authors.affiliation: Centre de Référence des Anomalies du Développement, Service de Génétique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Abel
authors.affiliation: Centre de Référence des Anomalies du Développement, Service de Génétique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.|Université Lyon 1, Lyon, France.|INSERM U1028, CNRS UMR5292, CRNL TIGER Team, Bron, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Edery
authors.affiliation: Centre de Référence des Anomalies du Développement, Service de Génétique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.|INSERM U1028, CNRS UMR5292, CRNL TIGER Team, Bron, France.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Rossi
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D015153:Blotting, Western; D001921:Brain / Q000002:abnormalities; D018981:Congenital Disorders of Glycosylation / Q000000981:diagnostic imaging / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D011247:Pregnancy; D011859:Radiography; D035781:Siblings; D014168:Transferrin / Q000378:metabolism
chemical_list: D014168:Transferrin
keywords: ALG3; CDG; EEG; chondrodysplasia punctata; glycosylation; prenatal