Journal List > Korean Circ J > v.49(5) > 1122181

Kwon, Lee, Park, Kim, Kim, Cho, Seong, and Sohn: Fabry Disease that Phenocopies Hypertrophic Cardiomyopathy: a thorough Genetic ‘Detective’ Identifies the ‘Rogue’ Hidden in the GLA Gene
A 59-year-old man with a history of hypertrophic cardiomyopathy, kidney transplantation, and unusual multifocal ischemic lesions in the cerebral white matter visited our hospital for resuscitated cardiac arrest. Electrocardiogram and 2D-echocardiography demonstrated concentric hypertrophy (left ventricular wall thickness 23–24mm) and left ventricular systolic dysfunction (ejection fraction 44%) (Figure 1 and Supplementary Videos 1, 2, 3). Endomyocardial biopsy showed enlarged, irregular-shaped, lipid-laden cardiomyocytes (Figure 2).1)
Fabry disease (FD) is a rare X-linked inherited disease due to decreased lysosomal α-galactosidase A (GLA) activity. Considering the late-onset of clinical events, we strongly suspected a variant form of FD and measured the patient's plasma GLA level and the enzyme activity. The plasma GLA level was 4.4 nmol/hr/mg protein (reference range=35–100 nmol/hr/mg protein) and the enzyme activity was 68.3% (reference range=85–95%). Both next-generation and Sanger sequencing of the GLA gene identified a novel mutation (c.775C>T [p.Pro259Ser]) at exon 5 (Figure 3A). The pedigree did not provide any more diagnostic clues (Figure 3B).
The mutation was not found in known public database of control subjects,2) and a different mutation at the same amino acid residue had been reported before.3) The genetic variation was located in a functionally critical domain and we found multiple computational evidences supporting the deleterious effect of the genetic variation (Supplementary Table 1). Combining these findings to pathogenicity criteria by the American College of Medical Genetics and Genomics,4) the novel mutation c.775C>T (p.Pro259Ser) was considered to be likely pathogenic and we concluded the patient had a variant form of FD.

Figures and Tables

Figure 1

Transthoracic echocardiography of the patient. There was marked concentric hypertrophy and systolic dysfunction. (A) Parasternal long axis view. (B) Parasternal short axis view at the level of papillary muscles. (C) Apical four chamber view. (D) 12-lead electrocardiogram consistent with left ventricular hypertrophy.

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Figure 2

Histologic examination of the endomyocardial biopsy specimen. (A) Hematoxylin-and-eosin staining. (B) Masson's trichrome staining for myocardial fibrosis. (C) PAS staining for glycogen storage. The pathologic examination demonstrated perinucleolar vacuolization and hypertrophy of the cardiomyocyte with some interstitial fibrosis. The PAS staining revealed glycolipid storages accumulated within cardiomyocytes.

PAS = Periodic acid-Schiff.
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Figure 3

Confirmation of the patient's GLA gene variation by Sanger sequencing and a pedigree. (A) The variant c.775C>T was identified at the exon 5 of the GLA gene of the patient. (B) Pedigree of the patient. The father had sudden cardiac death without a known cause. The mother of the patient had no significant medical history but refused genotyping. Among the siblings, only the 1st daughter agreed to the genetic test and was demonstrated to have the same mutation. However, her echocardiography was normal. In this case, Fabry disease may be not manifested because of the normal GLA produced by the other X chromosome.

ICH = intracranial hemorrhage; SCD = sudden cardiac death.
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Notes

Conflict of Interest The authors have no financial conflicts of interest.

Author Contributions

  • Conceptualization: Kwon S, Lee SP, Kim HK, Cho HJ, Sohn DW.

  • Data curation: Kwon S, Lee SP, Park SS, Kim HK, Cho HJ, Seong MW, Sohn DW.

  • Formal analysis: Kwon S, Lee SP, Kim BJ.

  • Investigation: Kwon S, Lee SP, Park SS, Kim BJ, Cho HJ.

  • Methodology: Kwon S, Lee SP, Park SS, Kim HK.

  • Project administration: Lee SP.

  • Supervision: Sohn DW.

  • Visualization: Lee SP, Park SS.

  • Writing - original draft: Kwon S.

  • Writing - review & editing: Kwon S, Lee SP.

References

1. Thurberg BL, Fallon JT, Mitchell R, Aretz T, Gordon RE, O'Callaghan MW. Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy. Circulation. 2009; 119:2561–2567.
2. Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016; 536:285–291.
3. Lukas J, Scalia S, Eichler S, et al. Functional and clinical consequences of novel α-galactosidase A mutations in Fabry disease. Hum Mutat. 2016; 37:43–51.
crossref
4. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17:405–424.
crossref

SUPPLEMENTARY MATERIALS

Supplementary Video 1

The parasternal long axis view of transthoracic echocardiography of the patient.

Supplementary Video 2

The parasternal short axis view at the level of papillary muscles of transthoracic echocardiography of the patient.

Supplementary Video 3

The apical four chamber view of transthoracic echocardiography of the patient.

Supplementary Table 1

The evaluation of evidence of pathogenicity of the patient's GLA gene mutation using the ACMG criteria4)
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ORCID iDs

Soonil Kwon
https://orcid.org/0000-0002-4791-6855

Seung-Pyo Lee
https://orcid.org/0000-0002-5502-3977

Seung Shin Park
https://orcid.org/0000-0001-5719-1539

Beom Joon Kim
https://orcid.org/0000-0002-2719-3012

Hyung-Kwan Kim
https://orcid.org/0000-0001-7950-2131

Hyun-Jai Cho
https://orcid.org/0000-0002-2779-4037

Moon-Woo Seong
https://orcid.org/0000-0003-2954-3677

Dae-Won Sohn
https://orcid.org/0000-0001-7950-2131

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