Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease

Heart. 2014 Nov;100(22):1793-8. doi: 10.1136/heartjnl-2014-305616. Epub 2014 Jul 16.

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.

Keywords: Genetics; Heart Failure.

MeSH terms

  • Adult
  • Biopsy, Needle
  • Cardiomyopathies / diagnosis
  • Cardiomyopathies / genetics*
  • Diagnosis, Differential
  • Disease Progression
  • Fabry Disease / diagnosis*
  • Fabry Disease / pathology
  • Female
  • Heart Failure / diagnosis
  • Heart Failure / genetics
  • Heart Failure / mortality
  • Heterozygote*
  • Humans
  • Hypertrophy, Left Ventricular / diagnosis
  • Hypertrophy, Left Ventricular / genetics*
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Risk Assessment
  • Sampling Studies
  • Survival Rate
  • Trihexosylceramides / genetics*

Substances

  • Trihexosylceramides
  • globotriaosylceramide