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. 2018 Apr 12;6(4):492-503.
doi: 10.1002/mgg3.389. Online ahead of print.

Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study

Dominique P Germain  1 , Eva Brand  2 , Alessandro Burlina  3 , Franco Cecchi  4 , Scott C Garman  5 , Judy Kempf  6 , Dawn A Laney  7 , Aleš Linhart  8 , László Maródi  9 , Kathy Nicholls  10 , Alberto Ortiz  11 , Federico Pieruzzi  12 , Suma P Shankar  7   13 , Stephen Waldek  14 , Christoph Wanner  15 , Ana Jovanovic  16
Affiliations

Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study

Dominique P Germain et al. Mol Genet Genomic Med. .

Abstract

Background: The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease.

Methods: To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events.

Results: In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%).

Conclusion: p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.

Keywords: GLA; Fabry disease; cardiac variant; p.Asn215Ser; p.N215S; phenotype.

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Figures

Figure 1
Figure 1
Interventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT) values at first assessment during natural history follow‐up. IVST values are shown for male (a) and female (b) p.N215S (blue) and classic (red) patients. LVPWT data are shown for male (c) and female (d) p.N215S (blue) and classic (red) patients. Ranges in males: normal, 6–10 mm; mildly abnormal, 11–13 mm; moderately abnormal, 14–16 mm; severely abnormal, >16 mm. Ranges in females: normal, 6–9 mm; mildly abnormal, 10–12 mm; moderately abnormal, 13–15 mm; severely abnormal, >15 mm (Lang et al., 2015). Data are presented as mean and SD
Figure 2
Figure 2
Estimated glomerular filtration rate (eGFR) values at first assessment during natural history follow‐up. eGFR values are shown for male (a) and female (b) p.N215S (blue) and classic (red) patients. Values <60 ml/min/1.73 m2 indicate the presence of chronic kidney disease. Data are presented as mean and SD
Figure 3
Figure 3
Kaplan–Meier curves depicting estimates of time to first severe clinical event. Data are shown for any clinical events, cardiac events, cerebrovascular events and renal events in male p.N215S (solid line) and classic (dashed blue line) patients (a); the same data are presented for female patients (b). Top left panels indicate any clinical events, top right panels cardiac events, bottom left panels cerebrovascular events, and bottom right panels renal events
Figure 4
Figure 4
The overall structure of wild‐type α‐Gal is shown at the top, with a zoom of the N215 carbohydrate region at lower left. At lower right, the p.N215S mutation has been computationally modeled from the wild‐type (wt) structure. The serine at 215 is easily accommodated into the structure, but the resulting loss of the large N‐linked glycan could affect the folding and/or trafficking of the p.N215S mutant α‐Gal enzyme
See this image and copyright information in PMC

References

    1. Arends, M. , Wanner, C. , Hughes, D. , Mehta, A. , Oder, D. , Watkinson, O. T. , … Hollak, C. E. (2017). Characterization of classical and nonclassical Fabry disease: A multicenter study. Journal of the American Society of Nephrology, 28, 1631–1641. 10.1681/ASN.2016090964 - DOI - PMC - PubMed
    1. Desnick, R. J. , Ioannou, Y. A. , & Eng, C. M. (2001). Alpha‐galactosidase A deficiency: Fabry disease In Scriver C. R., Beaudet A. L., Valle D., Sly W. S., Childs B., Kinzler K. W., & Vogelstein B. (Eds.), The metabolic & molecular bases of inherited disease, 8th ed. (pp. 3733–3774). New York, NY: McGraw‐Hill.
    1. den Dunnen, J. T. , Dalgleish, R. , Maglott, D. R. , Hart, R. K. , Greenblatt, M. S. , McGowan‐Jordan, J. , … Taschner, P. E. (2016). HGVS recommendations for the description of sequence variants: 2016 update. Human Mutation, 37, 564–569. 10.1002/humu.22981 - DOI - PubMed
    1. Echevarria, L. , Benistan, K. , Toussaint, A. , Dubourg, O. , Hagege, A. A. , Eladari, D. , … Germain, D. P. (2016). X‐chromosome inactivation in female patients with Fabry disease. Clinical Genetics, 89, 44–54. 10.1111/cge.12613 - DOI - PubMed
    1. Elleder, M. , Bradová, V. , Smíd, F. , Budĕsínský, M. , Harzer, K. , Kustermann‐Kuhn, B. , … Dorazilová, V. (1990). Cardiocyte storage and hypertrophy as a sole manifestation of Fabry's disease. Virchows Archiv. A, Pathological Anatomy and Histopathology, 417, 449–455. 10.1007/BF01606034 - DOI - PubMed

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