De novo mutation in a male patient with Fabry disease: a case report

BMC Research Notes

Giovanni Duro²  Caterina Bartolotta³  Simone Scalia³  Paolo Colomba²  Carmela Zizzo²  Giuseppe Albeggiani²  Federica Pizzo²  Francesco Iemolo¹ 

[1] Department of Neurology, “R. Guzzardi” Hospital, Via Papa Giovanni XXIII, Vittoria, Ragusa, Italy;CNR-IBIM: Institute of Biomedicine and Molecular Immunology “A. Monroy”, Via Ugo la Malfa n.153, Palermo, Italy;Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Via del Vespro 141, Palermo, Italy

关键词: De novo mutation;    D165H mutation;    GLA gene;    α-galactosidase A;    Fabry disease;   

Others  :  1134946
DOI  :  10.1186/1756-0500-7-11

 received in 2013-03-29, accepted in 2013-12-17,  发布年份 2014

【 摘 要 】

Background

Fabry disease is an X-linked inherited metabolic condition where the deficit of the α-galactosidase A enzyme, encoded by the GLA gene, leads to glycosphingolipid storage, mainly globotriaosylceramide. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD, including missense and nonsense mutations, small and large deletions. Such mutations are usually inherited, and cases of de novo onset occur rarely.

Case presentation

In this article we report an interesting case of a 44-year-old male patient suffering from a severe form of Fabry disease, with negative family history. The patient showed signs such as cornea verticillata, angiokeratomas, cardiac and neurological manifestations, an end-stage renal disease and he had low α-galactosidase A activity. We detected, in this subject, the mutation c.493 G > C in the third exon of the GLA gene which causes the amino acid substitution D165H in the protein. This mutation affects the amino acid - belonging to the group of buried residues - involved, probably, in the preservation of the protein folding. Moreover, studies of multiple sequence alignment indicate that this amino acid is highly conserved, thus strengthening the hypothesis that it is a key amino acid to the enzyme functionality.

The study of the relatives of the patient showed that, surprisingly, none of the members of his family of origin had this genetic alteration, suggesting a de novo mutation. Only his 11-year-old daughter - showing acroparaesthesias and heat intolerance with reduced enzymatic activity - had the same mutation.

Conclusions

We suggest that a non-inherited mutation of the α-galactosidase A gene is responsible for Fabry disease in the patient who had reduced enzyme activity and classical clinical manifestations of the disease. In a family, it is rare to find only one Fabry disease affected subject with a de novo mutation. These findings emphasize the importance of early diagnosis, genetic counselling, studying the genealogical tree of the patients and starting enzyme replacement therapy to prevent irreversible vital organ damage that occurs during the course of the disease.

【 授权许可】

   
2014 Iemolo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Germain DP: Fabry disease. Orphanet J Rare Dis 2010., 5(30)
• [2]Desnick RJ, Ioannou YA: α-galactosidase a deficiency: fabry disease. In The Metabolic and Molecular Basis of Inherited Disease. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D, Kinzler KE, Vogelstein B. New York: McGraw-Hill; 2001:3733-3774.
• [3]Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ: High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet 2006, 79(1):31-40.
• [4]Mehta A, Beck M, Sunder-Plassmann G: Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis Ltd; 2006.
• [5]Brokalaki EI, Hentschke M, Grabbe S, Jansen T: Fabry disease in a female patient due to a de novo point mutation at position 691 of exon 5. Eur J Med Res 2006, 11(7):306-308.
• [6]Colomba P, Nucera A, Zizzo C, Albeggiani G, Francofonte D, Iemolo F, Tuttolomondo A, Pinto A, Duro G: Identification of a novel mutation in the alpha-galactosidase A gene in patients with Fabry disease. Clin Biochem 2012, 45(10–11):839-841.
• [7]Tuttolomondo A, Duro G, Miceli S, et al.: Novel alpha-galactosidase A mutation in a female with recurrent strokes. Clin Biochem 2012, 45(16–17):1525-1530.
• [8]Cybulla M, Kurschat C, West M, Nicholls K, Torras J, Sunder-Plassmann G, Feriozzi S: Kidney transplantation and enzyme replacement therapy in patients with Fabry disease. J Nephrol 2012. doi: 10.5301/jn.5000214
• [9]Schiffmann R: Fabry disease. Pharmacol Ther 2009, 122:65-77.
• [10]Alfadhel M, Sirrs S: Enzyme replacement therapy for Fabry disease: some answers but more questions. Ther Clin Risk Manag 2011, 7:69-82.
• [11]Raas-Rothschild A: Pediatrics: implementing the promise of early intervention for Fabry disease. Clin Ther 2007, 29(Suppl 1):S6.
• [12]Ries M, Gupta S, Moore DF, et al.: Pediatric Fabry disease. Pediatrics 2005, 115:344-355.
• [13]Bono C, Nuzzo D, Albeggiani G, Zizzo C, Francofonte D, Iemolo F, Sanzaro E, Duro G: Genetic screening of Fabry patients with EcoTILLING and HRM technology. BMC Res Notes 2011, 4(323):1-7.
• [14]Erdros M, Németh K, Tóth B, et al.: Novel sequence variants of the α-galactosidase A gene in patients with Fabry disease. Mol Genet Metab 2008, 95:224-228.
• [15]Chamoles NA, Blanco M, Gaggioli D: Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta 2001, 308(1–2):195-196.
• [16]Garman SC, Garboczi DN: The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J Mol Biol 2004, 337(2):319-335.
• [17]Davies J, Christomanou H, Winchester B, Malcolm S: Detection of 8 new mutations in the α-galactosidase A gene in Fabry disease. Hum Mol Genet 1994, 3(4):667-669.
• [18]Eng CM, Ashley GA, Burgert TS, Enriquez AL, D’Souza M, Desnick RJ: Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. Mol Med 1997, 3(3):174-182.
• [19]Shabbeer J, Yasuda M, Benson SD, Desnick RJ: Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genomics 2006, 2(5):297-309. BioMed Central Full Text
• [20]Okumiya T, Ishii S, Kase R, Kamei S, Sakuraba H, Suzuki Y: Alpha-galactosidase gene mutations in Fabry disease: heterogeneous expressions of mutant enzyme proteins. Hum Genet 1995, 95(5):557-561.
• [21]Mehta A, Hughes DA: Fabry disease. In GeneReviews. Edited by Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP. Seattle (WA): University of Washington, Seattle; 2011.