Fabry Disease X-linked genetic, multi-organ disorder. Fabry disease screening program in Hypertrophic p Cardiomyopathy: preliminary results.

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1 Fabry Disease X-linked genetic, multi-organ disorder Fabry disease screening program in Hypertrophic p Cardiomyopathy: y preliminary results. Globotriaosylceramide, GL3 Brain -galactosidase A Eyes Lactosylceramide + Galactose Paelinck Bernard, Cardiology, UZA Eyskens François, Metabolic Diseases, UZA Skin Heart Kidney Peripheral nervous system Cellular GL-3 storage TIME Figure 1 Left ventricular mass (LVM) index according to age in 140 untreated female patients with Fabry disease enrolled in FOS. Left ventricular hypertrophy 600 male LVM Mass (gm) female Deegan, P B et al. J Med Genet 2006;43: Age (yrs) Copyright 2006 BMJ Publishing Group Ltd. 1

2 Epidemiology of Cardiac Involvement What is the prevalence of left ventricular hypertrophy? In the Fabry Outcome Survey, LVH was observed in 46% of males and 28% of females. The age at onset of LVH in males and females was 38 and 55 years, respectively. Arguably the most common cause of death in Fabry patients? Left ventricular hypertrophy and Fabry disease: 6% of males (late-onset) 5 % of females (late-onset) Spectrum of Cardiac Involvement Valve disease: lipid deposition and fibrosis leads to regurgitant lesions, prolapse. Severe disease requiring surgical repair is rare. Vascular disease. Anginal pain is common, though macrovascular disease is not suggesting microvascular disease. Aortic root dilation Conduction system disease: tachy- and bradyarrhythmias, heart block, ventricular ectopy LVH typically concentric. This may be a progression from mild diastolic dysfunction to LVH with normal systolic function, to systolic dysfunction. Rarely restrictive disease. Mehta A et al: Eur J Clin Invest: 2004;34(3):236 Linhart A et al: Eur Heart J 2007; 28: 1228 Cardiac Pathology Vacuolization and hypertrophy of myocytes without myofibrillar disarray. Vacuolization of endothelial cells and smooth muscle Endocardium and subendocardial space are thickened with GSL deposits Results in a glycolipid-rich inner myocardial layer EM of lysosomal glycolipid deposits within a cardiomyocyte On electron microscopy the vacuoles show concentric lamellar figures (myelin bodies), consistent with glycosphingolipid accumulation. Pieroni M, et. al. JACC Linhart A, Elliott PM. Heart

3 Mitochondrial Energetics M1I A20P L32P G35R P40S W44X R49L C52R C63S 59del26 125del13 alpha-gal A GENE MUTATIONS V269A S65T G128E R220X Q279E E66Q C142Y C223G M284T M72V P146S N224D W287X S78X A156T W226X M296I E79X A156V D231N N298K G85D W162C I242N R301X E341K 1040ins1 G85N W162X P265R D313Y/G411Y R342Q 1010del19 Y86X D165V D266N V316E R342X 1032del2 A97V L166V 716ins1 G328R E358K 1045del21 R112C 418del1 741ins9 802del4 G361R 1072del3 296del2 IVS3-1g->t 717del2 987del1 Y365X 1080del20 317del1 IVS3-1g->c C202W 718del2 IVS6 +1g->t G411Y 1145del3 337del18 IVS3-1g->a IVS4-2a->t IVS5 +1G->T IVS6-1g->a 1017ins24del41176del F A B R Y G E N E Diagram of the mammalian mitochondrion showing the relationship between energy production, ROS generation, and regulation of apoptosis M1T A31V N34S P40L M42V L45R/H46S H46R R49S M51K C52S C52X C56F C56G C56Y E59K E66Q 25del1 26del1 30del1 35del13 124delAT 82insG renal variant cardiac variant W81X Y86C L89P L89R I91T D92H D92Y D93G C94Y W95S A97V Q99X R100K R100T Q107X R112H* F113L Q119X L120P/A121T 256del1 257del18 304del1 338del18 358del6 IVS2 +1g->a IVS2 +2t->g complex L131P G13A2 R G138E Y134S Y134X D136H G138R T141I C142R C142X A143P A143T G144V S148R S148N Q157X W162R G163V F169S D170V C172F C172Y C172R 485del13 IVS3 +1g->a Complex G183D M187V C202Y W204X P205T 613del9 IVS4 +1g->c IVS4 +2t->c IVS4 +4a->t N215S P259R N272K N320Y Y216D G261D W277X Q321E I219N N263S T282N Q327K N224S D264V W287C G328R* W226R D266D W287G 833ins1 R227Q D266H A288D 892ins1 R227X D266V I298F 893ins1 A230T M267I M296V 903ins1 S235C 639ins37 M296I 954ins5 W236C 656ins1/658del1 S297F 842del3 W236L 773del2 N298H 954del5 D244H 773del3 N298S IVS6-1a->t D244N 774del2 R301P IVS6 +2t->c S247P 777del1 R301Q* Complex Q250X IVS5-2a->g D313Y P259L IVS5 del-2,3 W340R 1033del2 W340X 1057del2 W349X 1074del2 R356W 1076del2 G373D 1077del1 C378Y 1087del1 Q386X 1123del53 E398X 1139del1 W399X 1176del4 T410K 1188del1 1094ins1 1208del3 1188ins1 1212del3 1016del11277del2 1020del1 1284del4 α-gal A replacement therapy: agalsidase alpha and beta Clearance of Gb3 inclusions from vascular endothelial cells but not from the rest of the vessel wall, and from myocytes. What is the clinical significance? Decreased LV mass and improved myocardial function Persistence of coronary microvascular dysfunction? Long-term cardiac benefit is not yet known. M. Piraud, MT. Vanier, Lyon, France. Owens C, et al. Human Path 2006;37:764. Ann Intern Med. 2007;146:77-86.eidemann F, et al. Circulation 2003;108:1299. Mignani R, et al. Kidney Int. 2004;65:1381. Baehner F, et al. J Inherit Metab Dis. 2003;26:617. Eng CM, et al. NEJM Elliott P, et al. Heart. 2006;92:357. 3

4 LVPWD (mm ) Yrs on Rx B Cardiac Hypertrophy ERT response depends on baseline [males] < 11.5 mm 11.5 to 13.5 mm > 13.5 mm B B No Hypertrophy Mean age 34+/-11y n = 10 Mild-Mod Hypertrophy Mean age 43+/-10y n = 16 Severe Hypertrophy Mean age 50+/-10y n = 18 Screening for Fabry disease in Cardiac hypertrophy: 0-12% Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study (Germain et al) 392 patients/278 males 4 male patients with Fabry disease: <40 years: 0% >40 years: 1.8% + AV block No females: 33% can be missed! Strotmann, oral presentation, Salt Lake City, 2007 CardioFabry Study : Methods Patient finding: monocenter study UZA Co-Investigators: Prof. Paelinck/Prof. Eyskens Study Nurse; 2 medical students Septum Hypertrophy/ Left Ventricular Hypertrophy: >18 years of age: male/female Unexplained left ventricular hypertrophy with a minimum left ventricular wall thickness of 13 mm and/or septum 13 mm. >1000 pts to invest α-gal A enzyme activity Bloodspots (Rob Baker, Royal Free Hampsteas NHS Trust, London) In Plasma (Rob Baker, Royal Free Hampsteas NHS Trust, London) (Dr. Ans Groener, AMC, lysosomale stapelingsziekten, Amsterdam) In Leucocytes (Rob Baker, Royal Free Hampsteas NHS Trust, London) Interim Results males 60 females α-gal A gene analysis Marleen Van den Broeck (Instituut Born-Bunge, Laboratory for neurogenetics) (Gb3 and Lyso-Gb3 analysis) 80 males No abnormalities 57 females 2 D313Y 38 Results pending 4

5 p.d313y mutation pseudodeficiency 0,45% of normal X-chromosomes (Hum Mutat 2003) Portugal: 0% in 400 healthy control subjects 1.1 % (453 females; BEFAS I): stroke, TIA, white matter lesions, vertebrobasilar dolichoectasia (Stroke 2010) 1.2% (493; Portystroke: stroke, intracerebral hemorrhage, cerebral venous thrombosis (Stroke 2010) p.d313y mutation The prevalence of this mutation appears to be 1% in patients with cardiovascular disease Predisposes to cerebrovascularcardiovascular disease? Risk factor? 5