Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease

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Downloaded from heart.bmj.com on September 8, 2014 - Published by group.bmj.com

Heart Online First, published on July 16, 2014 as 10.1136/heartjnl-2014-305616 Heart failure and cardiomyopathies


Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease Turid Apelland,1 Einar Gude,2 Erik H Strøm,3 Lars Gullestad,2 Kristin L Eiklid,4 Jan-Eric Månsson,5 Finn P Reinholt,3 Gunnar Houge,6 Christen P Dahl,2,7 Vibeke M Almaas,2 Arvid Heiberg4 1

Department of Internal Medicine, Baerum Hospital, Baerum, Norway 2 Department of Cardiology, Oslo University Hospital, Oslo, Norway 3 Department of Pathology, Oslo University Hospital, Oslo, Norway 4 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway 5 Laboratory of Medicine/ Clinical Chemistry, Neurochemistry, Sahlgrenska University Hospital, Molndal, Sweden 6 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway 7 Faculty of Medicine, K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway Correspondence to Dr Turid Apelland, Department of Internal Medicine, Baerum Hospital, Vestre Viken, Drammen 3004, Norway; [email protected] Received 31 January 2014 Revised 25 April 2014 Accepted 23 June 2014

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 singlenucleotide 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 endstage 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.

disease. The classical manifestation is early onset disease with progressive multiorgan failure already in early adulthood, but attenuated and late onset variants exist.1–11 Fabry disease is an X linked disorder caused by lack of α-galactosidase A activity.1 2 A hallmark of Fabry disease is accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in various tissues, particularly in the kidney.1 2 Some patients with Fabry disease have predominantly cardiac disease with LVH and increased risk of arrythmias.1–5 6 12 The diagnosis is based on measurement of cellular α-galactosidase A activity, Gb3 accumulation in plasma and tissues, and mutation analysis of the α-galactosidase A gene (GLA).1 2 Early diagnosis of Fabry disease is important since renal and cardiac disease may be prevented by enzyme replacement therapy.1–4 6 13 14 Until now, Fabry disease has been the only known Gb3 storage cardiomyopathy.1 2 Here we describe our findings in two unrelated families presenting with early adult onset unexplained LVH, arrhythmias and progressive heart failure due to a novel Gb3-associated cardiomyopathy mimicking Fabry disease.

METHODS Patient population We studied five patients from two unrelated families. The pedigrees of Family A (Patient 1–3) and Family B (Patient 4 and 5) are shown in figure 1. There are no other siblings in Family A. In Family B one brother has no evidence of structural heart disease. There was no family history of any genetic disorder or consanguinity present. All parents in the two families were ethnically Norwegian.

Clinical studies INTRODUCTION

To cite: Apelland T, Gude E, Strøm EH, et al. Heart Published Online First: [please include Day Month Year] doi:10.1136/heartjnl2014-305616

Unexplained left ventricular hypertrophy (LVH) may be caused by a variety of disorders.1–11 One of the most prevalent causes is hypertrophic cardiomyopathy, a sarcomere protein gene disorder. LVH may also be the initial and predominant manifestation of systemic disorders such as infiltrative diseases (ie, sarcoidosis and amyloidosis) and intracellular storage disorders. Cardiac affection is particularly important in glycogen storage diseases such as AMP-activated protein kinase γ2 (PRKAG2), Pompe and Danon disease, mucopolysaccharidoses and the glycosphingolipidosis Fabry

We performed clinical evaluation, ECG, echocardiography and coronary angiogram in all patients. X-rays of total skeleton were performed in Family A, ophthalmological examination in four out of five, and capillaroscopy in two patients (table 1). Myocardial MRI was not performed due to implanted pacemakers.

Morphological studies Endomyocardial biopsies were sampled from the RV of all patients during right sided heart catheterisation. Renal biopsies were taken from Patient 1 and Patient 5. Biopsies were studied by light and electron microscopy.

Apelland T, etArticle al. Heart 2014;0:1–6. doi:10.1136/heartjnl-2014-305616 1 Copyright author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BCS) under licence.

Downloaded from heart.bmj.com on September 8, 2014 - Published by group.bmj.com

Heart failure and cardiomyopathies

Figure 1 Pedigrees of Family A and Family B.

Biochemical studies Tissue aliquots from mid-ventricular left myocardium were obtained from still-beating hearts immediately on explantation

from the three patients undergoing heart transplantation. Mid-ventricular left myocardium was also obtained during surgery with basal septal myectomy from six control patients

Table 1 Clinical, morphological, biochemical and genetic findings of Family A (Patient 1–3) and Family B (Patient 4 and Patient 5) Characteristics and findings

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Sex Age of symptom onset (year) ECG-findings T inversions Short PR interval Bradyarrhythmias Age at implantation of pacemaker, years Atrial fibrillation Left ventricular hypertrophy Left ventricular wall thickness (end-diastolic, in mm) Mid-ventricular septum Posterior wall Coronary angiogram Cardiac transplantation (Age, years) Striking fatty distribution Capillaroscopy X-rays of total skeleton Ophthalmological examination Endomyocardial biopsy findings Renal biopsy findings Biopsy of skin (s) or fat (f) α-galactosidase A activity (22–36 mkat/kg protein) Myocardial Gb3 (55–64 nmol/g fresh tissue) Gb3/sphingomyelin ratio (0.03–0. 04) Gb3 plasma (1.6–3.3 mmol/L) Gb3 urine ratio Urinary protein: creatine ratio (
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