A classical phenotype of Anderson-Fabry disease in a female patient with intronic mutations of the GLA gene: a case report

BMC Cardiovascular Disorders

Giovanni Duro³  Francesco Iemolo³  Riccardo Alessandro¹  Paolo Colomba³  Giuseppe Albeggiani³  Carmela Zizzo³  Massimo Imbriaco²  Antonio Pisani⁴ 

[1] Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Sezione di Biologia e Genetica, University of Palermo, Palermo, Italy;Department of Radiology, University of Naples, Federico II, Italy;Institute of Biomedicine and Molecular Immunology “A. Monroy”, National Research Council, Via Ugo La Malfa 153, 90146, Palermo, Italy;Department of Nephrology, University of Naples, Federico II, Italy

关键词: High resolution melting;    Globotriaosylceramide;    GLA;    α-galactosidase A;    Fabry disease;   

Others  :  1084949
DOI  :  10.1186/1471-2261-12-39

 received in 2011-12-20, accepted in 2012-05-21,  发布年份 2012

【 摘 要 】

Background

Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of a lysosomal hydrolase, the enzyme α-galactosidase A (GLA). This inactivation is responsible for the storage of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. The incidence of disease is estimated at 1:40,000 in the general population, although neonatal screening initiatives have found an unexpectedly high prevalence of genetic alterations, up to 1:3,100, in newborns in Italy, and have identified a surprisingly high frequency of newborn males with genetic alterations (about 1:1,500) in Taiwan.

Case presentation

We describe the case of a 40-year-old female patient who presented with transient ischemic attack (TIA), discomfort in her hands, intolerance to cold and heat, severe angina and palpitations, chronic kidney disease. Clinical, biochemical and molecular studies were performed.

Conclusions

Reported symptoms, peculiar findings in a renal biopsy – the evidence of occasional lamellar inclusions in podocytes and mesangial cells – and left ventricular (LV) hypertrophy, which are considered to be specific features of FD, as well as molecular evaluations, suggested the diagnosis of a classical form of FD.

We detected four mutations in the GLA gene of the patient: -10C>T (g.1170C>T), c.370-77_-81del (g.7188-7192del5), c.640-16A>G (g.10115A>G), c.1000-22C>T (g.10956C>T). These mutations, located in promoter and intronic regulatory regions, have been observed in several patients with manifestations of FD. In our patient clinical picture showed a multisystemic involvement with early onset of symptoms, thus suggesting that these intronic mutations can be found even in patients with classical form of FD.

【 授权许可】

   
2012 Pisani et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Garman SC, Garboczi DN: The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J Mol Biol 2004, 337(2):319-335.
• [2]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.
• [3]Hwu WL, Chien YH, Lee NC, Chiang SC, Dobrovolny R, Huang AC, Yeh HY, Chao MC, Lin SJ, Kitagawa T, Desnick RJ, Hsu LW: Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum Mutat 2009, 30(10)):1397-1405.
• [4]Desnick RJ, Ioannou YA, Eng CM: Alpha-Galactosidase A deficiency: Fabry disease. In The metabolic and molecular basis of inherited disease. 8th edition. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. McGraw-Hill, New York; 2001:3733-3774.
• [5]Dobrovolny R, Dvorakova L, Ledvinova J, Magage S, Bultas J, Lubanda JC, Elleder M, Karetova D, Pavlikova M, Hrebicek M: Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population. J Mol Med 2005, 83(8)):647-654.
• [6]Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, Yoshida A, Kuriyama M, Hayashibe H, Sakuraba H, Tanaka H: An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med 1995, 333(5):288-293.
• [7]Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, Kanzaki T, Enriquez AL, Eng CM, Tanaka H, Tei C, Desnick RJ: Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. Kidney Int 2003, 64(3):801-807.
• [8]Sunder-Plassmann G: Renal manifestations of Fabry disease. In Fabry disease: Perspectives from 5 Years of FOS. Section3. Chapter 21. Edited by Mehta A, Beck M, Sunder-Plassmann G. Oxford PharmaGenesis, Oxford; 2006.
• [9]Imbriaco M, Spinelli L, Cuocolo A, Maurea S, Sica G, Quarantelli M, Pisani A, Liuzzi R, Cianciaruso B, Sabbatini M, Salvatore M: MRI characterization of myocardial tissue in patients with Fabry’s disease. AJR Am J Roentgenol 2007, 188(3):850-853.
• [10]Imbriaco M, Pisani A, Spinelli L, Cuocolo A, Messalli G, Capuano E, Marmo M, Liuzzi R, Visciano B, Cianciaruso B, Salvatore M: Effects of enzyme replacement therapy in patients with Anderson-Fabry disease: a prospective long term cardiac magnetic resonance imaging study. Heart 2009, 95(13):1103-1107.
• [11]Higgins CB, Herfkens R, Lipton MJ, Sievers R, Sheldon P, Kaufman L, Crooks LE: Nuclear magnetic resonance imaging of acute myocardial infarction in dogs: alterations in magnetic relaxation times. Am J Cardiol 1983, 52(1):184-188.
• [12]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.
• [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. BioMed Central Full Text
• [14]Oliveira JP, Ferreira S, Reguenga C, Carvalho F, Mansson JE: The g.1170C>T polymorphism of the 5’ untranslated region of the human alpha-galactosidase gene is associated with decreased enzyme expression—Evidence from a family study. J Inherit Metab Dis 2008, 31(Suppl 2):405-413.
• [15]Davies JP, Winchester BG, Malcolm S: Sequence variations in the first exon of α-galactosidase A. Med Genet 1993, 30(8):658-663.
• [16]Shabbeer J, Robinson M, Desnick RJ: Detection of alpha-galactosidase a mutations causing Fabry disease by denaturing high performance liquid chromatography. Hum Mutat 2005, 25(3):299-305.
• [17]Rodríguez-Marí A, Coll MJ, Chabás A: Molecular Analysis in Fabry Disease in Spain: Fifteen Novel GLA Mutations and Identification of a Homozygous Female. Hum Mutat 2003, 22(3):258.
• [18]Tanislav C, Kaps M, Rolfs A, Böttcher T, Lackner K, Paschke E, Mascher H, Laue M, Blaes F: Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: a pilot study. Eur J Neurol 2011, 18(4):631-636.
• [19]Ishii S, Nakao S, Minamikawa-Tachino R, Desnick RJ, Fan JQ: Alternative Splicing in the a-Galactosidase A Gene: Increased Exon Inclusion Results in the Fabry Cardiac Phenotype. Am J Hum Genet 2002, 70(4):994-1002.
• [20]Filoni C, Caciotti A, Carraresi L, Donati MA, Mignani R, Parini R, Filocamo M, Soliani F, Simi L, Guerrini R, Zammarchi E, Morrone A: Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease. Eur J Hum Genet 2008, 16(11):1311-1317.
• [21]Tazi J, Bakkour N, Stamm S: Alternative splicing and disease. Biochim Biophys Acta 2009, 1792(1):14-26.