title: Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease.
abstract: OBJECTIVE
  To characterise a globotriaosylceramide (Gb3) storage cardiomyopathy mimicking Fabry.
  
  
  METHODS
  We investigated five patients from two unrelated families with early adult onset unexplained left ventricular hypertrophy. Endomyocardial biopsy was performed in all patients and diagnostic kidney biopsies in two of them. We measured α-galactosidase A activity in all patients. Three patients were checked for LAMP1 or LAMP2 deficiency and screened for congenital disorders of glycosylation. Gb3 concentration was quantified in plasma, urinary sediment and cardiac muscle. We sequenced the Fabry and Danon genes and looked for other genetic causes by single-nucleotide polymorphism array haplotyping and whole exome sequencing.
  
  
  RESULTS
  Three patients had a striking fat distribution around the buttocks and upper thighs. All patients developed bradyarrhythmias and needed pacemakers. Cardiac transplantation was performed in three patients due to end-stage heart failure, one patient died before transplantation. The cardiomyocytes contained lysosomal vacuoles with lamellar myelin-like deposits. Interstitial cells had vacuoles containing granular material. Deposits were found in the kidneys without renal dysfunction. The histological pattern was atypical for Fabry disease. Biochemical studies revealed normal activity of α-galactosidase A and other relevant enzymes. There was a selective accumulation of Gb3 in cardiomyocytes, at levels found in patients with Fabry disease, but no mutations in the Fabry gene, and Fabry disease was excluded. Other known lysosomal storage diseases were also excluded. Single-nucleotide polymorphism array haplotyping and whole exome sequencing could not identify the genetic cause.
  
  
  CONCLUSIONS
  We describe a novel familial Gb3-associated cardiomyopathy. Autosomal recessive inheritance is likely, but the genetic and metabolic cause remains to be identified.
authors.affiliation: Department of Internal Medicine, Baerum Hospital, Baerum, Norway.
authors.forename: Turid
authors.initials: T
authors.lastname: Apelland
authors.affiliation: Department of Cardiology, Oslo University Hospital, Oslo, Norway.
authors.forename: Einar
authors.initials: E
authors.lastname: Gude
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Erik H
authors.initials: EH
authors.lastname: Strøm
authors.affiliation: Department of Cardiology, Oslo University Hospital, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Eiklid
authors.affiliation: Laboratory of Medicine/Clinical Chemistry, Neurochemistry, Sahlgrenska University Hospital, Molndal, Sweden.
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Månsson
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Finn P
authors.initials: FP
authors.lastname: Reinholt
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houge
authors.affiliation: Department of Cardiology, Oslo University Hospital, Oslo, Norway Faculty of Medicine, K.G.Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Christen P
authors.initials: CP
authors.lastname: Dahl
authors.affiliation: Department of Cardiology, Oslo University Hospital, Oslo, Norway.
authors.forename: Vibeke M
authors.initials: VM
authors.lastname: Almaas
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Arvid
authors.initials: A
authors.lastname: Heiberg
mesh_terms: D000328:Adult; D001707:Biopsy, Needle; D009202:Cardiomyopathies / Q000175:diagnosis / Q000235:genetics*; D003937:Diagnosis, Differential; D018450:Disease Progression; D000795:Fabry Disease / Q000175:diagnosis* / Q000473:pathology; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D006579:Heterozygote; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018570:Risk Assessment; D012494:Sampling Studies; D015996:Survival Rate; D014281:Trihexosylceramides / Q000235:genetics*
chemical_list: D014281:Trihexosylceramides; C018549:globotriaosylceramide
keywords: Genetics; Heart Failure