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Morbus Fabry Arndt Rolfs, M.D. Email: arndt.rolfs@med.uni-rostock.de
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Disclosure The speaker disclocures the following financial support from industry in the last years: Unrestricted, educational grants from Shire HGT, Genzyme, Actelion, Biomarin, Amicus Travelling support and honorarium for this talk Scientific grants from Centogene AG/Germany SWITCH study was financially supported by Shire for the first 12 months; since then the study is exclusively paid by a scientific grants from the University of Rostock
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Lysosomal disease Nearly 60 different types of lysosomal disease
Most characterized by prominent lysosomal storage (but primary storage substrates vary) Two-thirds affect brain Disease cascades poorly understood, and few treatments available Lysosomal enzyme defects Pompe disease (glycogenosis) Tay-Sachs, Sandhoff diseases Niemann-Pick A/B disease GM1 gangliosidosis Gaucher disease Fabry disease All MPS diseases Infantile and Late Infantile Batten diseases (CLN1 and CLN2) -Mannosidosis Fucosidosis Defects in other proteins Niemann-Pick type C disease Mucolipidosis II/III Sialidosis and Galactosialidosis Mucolipidosis IV Juvenile Batten disease (CLN3) Cystinosis Sialic Acid Storage disease Salla disease Danon disease
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QUIZ How common are lysosomal diseases? a. 1 in 5000 live births
b. 1 in 50,000 live births c. 1 in 100,000 live births Answer: a.
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QUIZ With what frequency are children born world-wide with a lysosomal disease? a. Every 30 minutes b. Every 2 hours c. Once a day Answer: a.
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Enzyme deficiency leads to accumulation of globotriaosylceramide (Gb3)
Fabry disease Fabry disease Fabry disease is an X-linked lysosomal storage disorder- caused by deficiency of -galactosidase A Enzyme deficiency leads to accumulation of globotriaosylceramide (Gb3) Frequency is estimated in the general population for 1 : and 1: 12,000 0.5 to 1.0% of all young stroke patients are suffering from Fabry disease Brady RO et al. N Engl J Med 1967; 276: 11637. Meikle PJ et al. JAMA 1999; 281: 24954 Lappa et al. , JAMA 2006 Rolfs et al, LANCET, 2005
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Fabry pathology Fabry pathology Accumulation of Gb3 damages Epithelial cells (e.g. renal epithelium, airway epithelium) Myocardial cells Dorsal root ganglia Neuronal cells Cells of the autonomic nervous system Endothelial, perithelial and smooth muscle cells of the vascular system Brady RO et al. N Engl J Med 1967; 276: 11637. deVeber GA et al. Ann Neurol 1992; 31: 40915. Kahn P. J Neurol Neurosurg Psychiatry 1973; 36: 105362. Kaye EM et al. Ann Neurol 1988; 23: 5059 Courtesy of Dr. Jansen/Essen
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Fabry disease, X-linked genetic, multi-organ disorder
Globotriaosylceramide (Gb-3) Lactosylceramide + Galactose -galactosidase A Eyes Brain Skin Kidney Heart Peripheral nervous system Cellular Gb-3 storage TIME
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Screening results in risk populations
Patient number Male Fabry Female Fabry Unclear females sum stroke < 55 yrs 14,267 57 (0.4%) 91 (0,6%) 34 (0,2%) 1,2%*** proteinuria 4,637 11 (0.2%) 15 (0,3%) 6 (0,1%) 0,6% dialysis 4,838 7 (0,1%) 11 (0,2%) 18 (0,3%) cardiomyopathy 1,326 3 (0,2%) 4 (0,3%) 0,7% ***p< 0.01; all patients have been sequenced for the coding GLA stretch and the exon-intron boundaries; samples with mutations/VUS have been tested for enzyme activity and lysio-Gb3
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Prevalence of Fabry in Stroke Populations
Rolfs et al Lancet (Germany); Stroke 2013 prevalence in cryptogenic stroke in 721 (males and females; yrs age) 4.9% of males (mean age 38.4 yrs) 2.4% of females (mean age 40.3 yrs) increased dolichoectasia, periventricular white matter lesions Fabry symptoms: sensory neuropathic pain, proteinuria, corneal whorls Brouns et al Stroke 2010 (Belgium) screened consecutive 1000 (18-60 yrs age; 54.7% males) with stroke, TIA, intracranial hemorrhage unexplained white matter lesions vertebrobasilar dolichoectasia 1% confirmed by enzyme/molecular analysis Baptista et al Stroke 2010 (Portugal) (one year experience) first stroke (18-55 yrs age) n=493 (61% males) 12 (2.4%) with GLA mutations 5 with cardiac source, 4 ischemic, 2 hemorrhagic, 1 thrombosis
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Rolfs et al., 2005
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The sifap Study – Stroke in Young Fabry Patients
Prospective, multicenter European study 5,024 young stroke patients 15 European countries, 47 study centers Age years Primary aim: Prevalence of Fabry disease in young stroke patients Secondary aim: Description of patterns of stroke in young patients Detailed characterization of clinical, laboratory and radiological data All patients tested for Fabry disease genetically Rolfs et al Lancet 2005; Rolfs et al. Stroke 2013; Fazekas et al. Neurology 2013
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Fabry Disease and Type of CVE
13 Cross-classified table classcve_1 classification of cve Total 1,00 TIA 2,00 primary hemorrhage 3,00 ischemic stroke 4,00 other fabry_diag diagnosis of fabry 1,00 yes Anzahl 4 2 19 25 % 16,0% 8,0% 76,0% 0,0% 100,0% 3,00 no fabry 1062 269 3364 68 4763 22,3% 5,6% 70,6% 1,4% Gesamt 1066 271 3383 4788 5,7% 70,7% p=0.743 for Fishers exact test (not adjusted for centre heterogeneity, which is not possible because of small number of cases) 27 Fabry patients 0.5% of all sifap patients (5005 without Fabry disease) 18 uncertain cases not included in analysis 13
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Fabry Disease and Gender
14 Cross-classified table SEX Sex Total 1 male 2 female fabry_diag diagnosis of fabry 1,00 yes Anzahl 11 16 27 % 40,7% 59,3% 100,0% 3,00 no fabry 2947 2031 4978 59,2% 40,8% Gesamt 2958 2047 5005 59,1% 40,9% p=0.075 (Fisher’s exact test) 14
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Family History of Cardiac Disease
Cross-classified table FAMHIST1 Is there any family history for cardiac diseases Total 0 no 1 yes fabry_diag diagnosis of fabry 1,00 yes Anzahl 18 8 26 % 69,2% 30,8% 100,0% 3,00 no fabry 2771 1932 4703 58,9% 41,1% Gesamt 2789 1940 4729 59,0% 41,0% p=0.323 in fishers exact test p=0.323
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Family History of Renal Disease
16 Cross-classified table FAMHIST2 Is there any family history for renal diseases Total 0 no 1 yes 2 unknown fabry_diag diagnosis of fabry 1,00 yes Anzahl 21 5 1 27 % 77,8% 18,5% 3,7% 100,0% 3,00 no fabry 4100 516 362 4978 82,4% 10,4% 7,3% Gesamt 4121 521 363 5005 82,3% p=0.341
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Cross-classified table
Family History of CVE 17 Cross-classified table FAMHIST3 Is there any family history for CVE diseases Total 0 no 1 yes fabry_diag diagnosis of fabry 1,00 yes Anzahl 18 7 25 % 72,0% 28,0% 100,0% 3,00 no fabry 2969 1748 4717 62,9% 37,1% Gesamt 2987 1755 4742 63,0% 37,0% p=0.411
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Cross-classified table
Prior MIs 18 Cross-classified table MEDHIST5 Prior myocardial infarctions Total 0 no 1 yes fabry_diag diagnosis of fabry 1,00 yes Anzahl 26 1 27 % 96,3% 3,7% 100,0% 3,00 no fabry 4799 153 4952 96,9% 3,1% Gesamt 4825 154 4979 p=0.573
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Age at symptom onset Mean 44.7 41.5 43.5 Median 47.0 45.0 44.0
No Fabry Fabry Uncertain Mean 44.7 41.5 43.5 Median 47.0 45.0 44.0 Std. Deviation 8.2 10.5 8.1 P<0.05 @Beate: kannst du bitte noch die n#s für die jeweiligen gruppen angeben
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Total protein in urine (mg/dl)
No Fabry Fabry Uncertain Mean 38.5 190.3 61.0 Median 6.7 9.0 8.1 Std. Deviation 470.2 928.2 14.5 P<0,05 Beck Depression Inventory – BDI II No Fabry Fabry Uncertain Mean 7.1 8.4 6.5 Median 5.0 7.0 Std. Deviation 7.7 7.9 4.6 P<0,05 Auch bei diesen „neuen“ Variablen zeigen sich höchstwahrscheinlich Probleme mit Fehleinträgen bei Units; es gibt z.B. eine Person mit Maximum mg/dl. Das ist bestimmt nicht sinnvoll, wenn der Median so „niedrig“ ist. Es gab auch negative Werte, die ich durch die Beschränkung der y-Achse im Plot nun einfach abgeschnitten habe. Fraglich, ob man das so (außer Median) schon interpretieren kann. Ug: wie viele extremewerte waren es denn?
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K. Sims et al., 2009; Stroke in Fabry patients
Percentages of patients experiencing their first stroke during 6 age categories are shown. Data for males are in dark gray bars and data for females are in light gray bars, with the number of patients in each age category shown above each bar. All data are from patients not treated with ERT at the time of their first stroke.
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Medical history of risk factors in Fabry with stroke
Arrhythmia was more prevalent in male stroke patients. Hypertension was more strongly associated with stroke in female patients. Arrhythmia was more prevalent in male stroke patients. Hypertension was more strongly associated with stroke in female patients. Sims et al 2009 22
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Central Nervous System Pathology
LARGE VESSEL Dolichoectasia brainstem vulnerability SMALL VESSEL Susceptibility to occlusive vascular thrombosis increased endothelial prothrombotic factors Changes in regional CBF [rCBF] cellular metabolic failure Increased ROS metabolic stress Chronic alteration in nitric oxide pathway [NO] altered vascular tone & reactivity WHITE MATTER Perfusion changes, fluid shifts Decreased regional cerebral glucose metabolism GRAY MATTER Decreased NAA – cortical & subcortical neurons Calcification (pulvinar sign)
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Structural lesions in the MRI in Fabry disease
50% of all patients ( n=50, mean age 45 yrs ) demonstrating WML all patients > 54 yrs with microvascular changes No patient < 26 yrs with structural lesions in the MRI About 40 % of patients with lesions suffering from neurological symptoms Crutchfield et al., Neurology 1998 33% of all pts with Fabry with significant WML Fellgiebel et al., Neurology 2005; Fellgiebel et al., Lancet Neurol 2006
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Fabry patients show increased diameter of cerebral vessels
A. Fellgiebel et al, 2011; 2013 95% CI = 95% confidence Interval; post. = posterior cerebral artery; med. = middle cerebral artery; ant. = anterior cerebral artery; carot. = Carotid artery; comp. = Composite z-score (mean z over all arteries)
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Fabry – conjunctival and retinal angiopathy
Normal Ampulla-like conjunctival vessels (98% of all male cases) Dilatation and tortoous retinal vessels (76%) Courtesy of Prof. Dr. R. Guthoff, Rostock
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D313Y – mutation or SNP ? How to classify ?
Multifocal White Matter Lesions Associated with the D313Y Mutation of the a-Galactosidase A Gene (PLOSone, 2013) Malte Lenders1., Thomas Duning2., Michael Schelleckes1, Boris Schmitz1,3, Sonja Stander4, Arndt Rolfs5, Stefan-Martin Brand3, Eva Brand1* Muenster/Rostock, Germany
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Biomarker lyso-Gb3: best but not yet the ideal marker (sensitivity: m 92.4%; f 89.6%)
28 Pathological cut-off: 0.9ng/ml plasma (95% confidence interval) Median lyso-Gb3 values were higher in males. Specificity (0.5) and Sensitivity (1.0) was nearly the same for both genders. "Non-pathological" variants of the GLA gene were restricted to a few genotypes here: S126G (pink dots), A143T (blue dots), D313Y (green dots) J. Lukas, 2013
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Lyso-Gb3 reflects disease severity as an in-vivo parameter
Biomarker Lyso-Gb3 is a reliable indicator for severe mutations in Fabry patients Males females In-vitro enzyme activity < 1%: severe 1-20%: moderate >20%: mild Severe mutations are significantly related to the classic phenotype in FD Lyso-Gb3 reflects disease severity as an in-vivo parameter
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Mild mutations are located on the molecule surface
30 - Mutations D83N, D175N, S102L, R252T, D313Y, T385A, F396Y, E398A display only mild effects on GLA activity. - H-bond disturbances like in the shown mutations are predicted to display only mild effects on enzyme performance S126G I219T R220Q Provided by Prof. A. Markoff, University of Muenster Lukas et al., 2015
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D313Y (Score 5) mutation and Gb3 - Fabry or „Gb3emia“ ?
PATIENT exon mutation sex ALPHAGALACT Gb3 blood µg/ml Gb3 IHC skin Gb3 EM skin total Gb3 Gb3_24 P0037 c937 G>T [D313Y] m 10,2 3,1 91,32 21,18 P0431 f 27 3,9 negative P0558 21 3,0 120,00 24,40 P0607 14 2,2 P0691 3,6 6,4 77,00 16,10 P0649 22 2,7 269,11 58,17 P0839 12,7 5,1 unclear positive 49,00 11,60 P0865 43 130,89 33,15 P1236 17 P1515 15 5,8 228,77 45,59 P3102 19 0,9 P2143 3,4 4,6 317,19 70,63 P4024 11,8 P2704 36 97,76 19,58 P2871 29 P2918 2,4 7,5 67,00 22,30 P3607 48 371,09 79,60 31
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Two patients with D313Y – is that Fabry disease ?
32 Pts. AW, 28 yrs, male, south Germany: severe cardiomyopathy, hypohidrosis, angiokeratoma, pain in childhood, no Cornea verticillata; a-Gal activity: 5.1* (male Fabry pts. 0 – 6.4 nMol MU/mg protein; normal ); Gb3 blood 5.3 µg/ml (normal < 4.0 µg/ml), lyso-Gb3 2.8 (normal < 1.1 ng/ml) Pts. UK, 41 yrs, male, northern Poland: severe proteinuria, hypohidrosis, stroke and 4 TIAs in last 5 years, mild cardiomyopathy, no angiokeratoma, no Cornea verticillata; a-Gal activity: 7.2** (nMol MU/mg protein); Gb3 blood 4.9 µg/ml (normal < 4.0 µg/ml), lyso-Gb3 1.7 (normal < 1.1 ng/ml) - MLPA was normal in both cases
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Skin: Gb3 immunohistochemistry and electron microscopy
Gb3 immunhohistocehmistry Fabry ctlr. A156V pat AW - D313Y pat UK - D313Y Electron micrsocopy EM: typical inclusions with irregular parallel lamellae, characteristic Zebra bodies (Prof. Jonas, Rostock)
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Lyso-Gb3 of patients on agalsidase alpha (wo back-switch)
males females
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Lyso-Gb3 of patients on agalsidase alpha (wo back-switch)
Males (n= 38, 36, 36, 27 with regard to time points) Females (n=14, 13, 13 , 6 with regard to time points) Males: significant decrease over time in lyso gb 3 levels (p=0.002) (n=137 measures / 38 patients, random intercept models); Females significant decrease over time in lyso gb 3 levels ( p=0.044) (n=14 patients / 46 measures)
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Is time on A. alpha related to lyso-Gb3 values. (only values under A
Is time on A. alpha related to lyso-Gb3 values? (only values under A. alpha) Males Females
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CARDIAC PARAMETERS (agalsidase alfa only)
Switch V1 V2 V3 Filling impairment % (n) 26,3% (15) 26,4% (19) 30,4% (21) 24,2% (8) Valvular lesions % (n) 28,6% (18) 24,3% (18) 29,4% (20) 15,2% (5) Late enhancement % (n) 8,1% (5) 3,7% (2) 3,0% (1) ECG changes % (n) 50% (25) 51,3% (40) 59,4% (41) 43,3% (13) NYHA classification % (n) NYHA I 22,1% (15) 18,8% (16) 19,2% (15) 11,1% (4) NYHA II 11,8% (8) 16,5% (14) 15,4% (12) 13,9% (5) NYHA III 4,4% (3) 5,9% (5) 10,3% (8) NYHA IV Hypertension % (n) 34,7% (25) 30,2% (26) 33,8% (27) 22,2% (8) Pacemaker % (n) 6,5% (5) 11,0% (10) 13,4% (11) NYHA IV raus?
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Creatinine clearance MDRD
P=0.313 (Replagal vs. Fabrazyme)* * adjusted for sex, age, time point and interaction between medication and time point 58 72 73 4 10 22 20 -- 78 66 53 34
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GFR creatinine clearance in ml/min*1.73m2
P=0.183 (Replagal vs. Fabrazyme)* * adjusted for sex, age, time point and interaction between medication and time point 49 68 57 4 8 19 17 -- 61 33 18
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Total protein in urine (mg/dl)
P=0.347 (Replagal vs. Fabrazyme)* * adjusted for sex, age, time point and interaction between medication and time point 49 61 58 4 12 22 17 -- 67 50 36 19
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Total albumin in urine (mg/dl)
P=0.539 (Replagal vs. Fabrazyme)* * adjusted for sex, age, time point and interaction between medication and time point 37 56 54 4 12 21 17 -- 67 40 23
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Mainz Severity Score Index
P=0.080 (Replagal vs. Fabrazyme)* * adjusted for sex, age, time point and interaction between medication and time point 55 68 74 4 13 23 18 -- 86 71 53 35
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Tip of the iceberg model in Fabry
Thx indication Clin Score AOO lysoGb3 +++ ++ + (+) Classical phenotype (10%) Score 10 Oligo-/monosymptomatic phenotype Late-onset, monosymptomatic phenotype Score 1
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