title: Intrauterine onset of acute neuropathic type 2 Gaucher disease: identification of a novel insertion sequence.
abstract: A subset of patients with type 2 Gaucher disease is characterized by intrauterine onset of rapidly progressive neuropathic disease, arthrogryposis, hydrops fetalis and in some cases restrictive dermopathy. beta-Glucocerebrosidase (beta-glucosidase) activity is usually low or undetectable. In most cases death ensues either in-utero or within hours or days after birth. We report on an infant born to non-consanguineous parents of Caucasian origin presenting at birth with hydrops, arthrogryposis, severe respiratory distress, hepatosplenomegaly, and liver failure. Death occurred within several hours after delivery and autopsy revealed typical Gaucher cells in multiple organs in combination with severe apoptotic neurodegeneration throughout the brain. beta-Glucocerebrosidase activity was 1% of the norm in fibroblasts and a novel heterozygous insertion c.1515_1516insAGTGAGGGCAAT was identified by genomic sequencing and an insertion-specific seminested PCR. In addition, molecular studies revealed a previously described in type 1 Gaucher disease missense mutation c.476G --> A which results in a heterozygous substitution of R120Q. Our observations confirm considerable genotypic heterogeneity in patients with type 2 Gaucher disease. The transheterozygous combination of a mutation, previously described in type 1 Gaucher disease, together with a newly identified insertion may result in this severe phenotype.
authors.affiliation: Department of Neonatology, Charité, Campus Virchow Klinikum, Berlin, Germany. ursula.felderhoff@charite.de
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Mueser
authors.forename: Johannes
authors.initials: J
authors.lastname: Uhl
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Frank
authors.initials: F
authors.lastname: Van Landeghem
authors.forename: Martin
authors.initials: M
authors.lastname: Vogel
authors.forename: Michael
authors.initials: M
authors.lastname: Obladen
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kopitz
mesh_terms: D017668:Age of Onset; D017209:Apoptosis; D001176:Arthrogryposis / Q000235:genetics; D001344:Autopsy; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005776:Gaucher Disease / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005962:Glucosylceramidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D017093:Liver Failure / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D047928:Premature Birth; D012313:RNA / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013997:Time Factors
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D012313:RNA; D004247:DNA; D005962:Glucosylceramidase