Organ manifestations and long-term outcome of Fabry disease in patients with the GLA haplotype D313Y

Daniel Oder, Nurcan Üçeyler, Dan Liu, Kai Hu, Bernhard Petritsch, Claudia Sommer, Georg Ertl, Christoph Wanner, Peter Nordbeck, Daniel Oder, Nurcan Üçeyler, Dan Liu, Kai Hu, Bernhard Petritsch, Claudia Sommer, Georg Ertl, Christoph Wanner, Peter Nordbeck

Abstract

Objectives: The severity of Fabry disease is dependent on the type of mutation in the α-galactosidase A (AgalA) encoding gene (GLA). This study focused on the impact of the GLA haplotype D313Y on long-term organ involvement and function.

Setting and participants: In this monocentric study, all participants presenting with the D313Y haplotype between 2001 and 2015 were comprehensively clinically investigated at baseline and during a 4-year follow-up if available. Five females and one male were included.

Primary and secondary outcome measures: Cardiac, nephrological, neurological, laboratory and quality of life data.

Results: AgalA enzyme activity in leucocytes (0.3±0.9 nmol/min/mg protein (mean±SD)) and serum lyso-Gb3 (0.6±0.3 ng/mL at baseline) were in normal range in all patients. Cardiac morphology and function were normal (left-ventricular (LV) ejection fraction 66±8%; interventricular septum 7.7±1.4 mm; LV posterior wall 7.5±1.4 mm; normalised LV mass in MRI 52±9 g/m(2); LV global longitudinal strain -21.6±1.9%) and there were no signs of myocardial fibrosis in cardiac MRI. Cardiospecific biomarkers were also in normal range. Renal function was not impaired (estimated glomerular filtration rate MDRD 103±15 mL/min; serum-creatinine 0.75±0.07 mg/dL; cystatin-c 0.71±0.12 mg/L). One female patient (also carrying a Factor V Leiden mutation) had a transitory ischaemic attack. One patient showed white matter lesions in brain MRI, but none had Fabry-associated pain attacks, pain crises, evoked pain or permanent pain. Health-related quality of life analysis revealed a reduction in individual well-being. At long-term follow-up after 4 years, no significant change was seen in any parameter.

Conclusions: The results of the current study suggest that the D313Y genotype does not lead to severe organ manifestations as seen in genotypes known to be causal for classical FD.

Keywords: Anderson-Fabry Disease; D313Y genotype; Fabry cardiomyopathy; Fabry nephropathy; Fabry-associated pain; Inherited metabolic disorders.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Cardiac morphology and function of a representative D313Y patient versus a patient with classical Fabry disease and advanced Fabry cardiomyopathy. (A–H) In D313Y patients (participant #3), no signs of cardiac hypertrophy or diastolic dysfunction can be seen. (I–P) Fabry cardiomyopathy in respective genotypes is characterised by advanced hypertrophic thickening of the interventricular septum and the left ventricular posterior wall with left atrial dilation and reduced left ventricular ejection fraction in advanced stages. Moreover, 2D-speckle tracking reveals reduced longitudinal strain (K) with extensive replacement fibrosis visualised by bull's eye in loco typico for Fabry cardiomyopathy (L). Morphologic and LGE cardiac MRI illustrate the difference in cardiac wall thickness between D313Y patients without cardiac involvement (E–H) compared to patients with advanced Fabry cardiomyopathy (M–P).
Figure 2
Figure 2
Family pedigree of a representative female patient (participant #4) with proven D313Y GLA genotype. The index patient was identified due to a history suggestive of a transient ischaemic attack with episodic aphasia and weakness of the left arm. She additionally carries a heterozygous Factor V Leiden thrombophilia mutation as a co-founding risk factor of ischaemic events. In contrast to the findings in patients with ‘classical’ Fabry disease, none of the index patient's family members were willing to investigate their genetic material for the presence of a Fabry disease causing mutation as none of them were reported to suffer from health problems of any kind, suggesting a low penetrance of pathology in D313Y compared to other GLA genotypes.
Figure 3
Figure 3
Brain MRI at baseline (3A) and long-term follow-up after 4 years (3B) in patient #6. In various regions, areas of white matter lesions are apparent, which show no progress in number and extend between baseline and follow-up.

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