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Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease
  1. Turid Apelland1,
  2. Einar Gude2,
  3. Erik H Strøm3,
  4. Lars Gullestad2,
  5. Kristin L Eiklid4,
  6. Jan-Eric Månsson5,
  7. Finn P Reinholt3,
  8. Gunnar Houge6,
  9. Christen P Dahl2,7,
  10. Vibeke M Almaas2,
  11. Arvid Heiberg4
  1. 1Department of Internal Medicine, Baerum Hospital, Baerum, Norway
  2. 2Department of Cardiology, Oslo University Hospital, Oslo, Norway
  3. 3Department of Pathology, Oslo University Hospital, Oslo, Norway
  4. 4Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  5. 5Laboratory of Medicine/Clinical Chemistry, Neurochemistry, Sahlgrenska University Hospital, Molndal, Sweden
  6. 6Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  7. 7Faculty of Medicine, K.G.Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway
  1. Correspondence to Dr Turid Apelland, Department of Internal Medicine, Baerum Hospital, Vestre Viken, Drammen 3004, Norway; turid.apelland{at}vestreviken.no

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-assoociated cardiomyopathy. Autosomal recessive inheritance is likely, but the genetic and metabolic cause remains to be identified.

  • Heart Failure
  • Genetics

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