Fabry Disease: A complex multisystem disorder

Transcription

1 Fabry Disease: A complex multisystem disorder Dr. Bertram Henderson Division of Clinical Genetics, UFS/FPA 1

2 2

3 Speaker Disclosure The speaker has received sponsorship from Sanofi Genzyme to attend workshops, congresses. The speaker has received payment from Sanofi Genzyme for CPD and advisory activities. The speaker has received sponsorship from Shire to attend workshops/congresses. 3

4 Krabbe 6% Niemann-Pick A 2% Niemann-Pick C 4% Sanfilippo B 4% Tay-Sachs 4% Mucolipidosis type II / III Sandhoff GM 1 2% Gangliosidosis 2% 2% Other 2% Gaucher type I 13% Scheie (MPS I) 1% Hurler/Scheie (MPS I) 4% Fabry 7% Hunter Mild 1% Pompe 5% Hunter Severe 5% Sanfilippo A 7% Metachromatic Leukodystophy 8% Adapted from Meikle P et al. JAMA. 1999;281: Hurler (MPS I) 4% 1% a-mannosidosis Maroteaux-Lamy 1% Niemann-Pick B 2% 3% Gaucher type 2 & 3 1% Sanfilippo D Morquio 5% Cystinosis 4%

5 Fabry as a LSD: Is genetic (inherited enzyme deficiency) Affects numerous systems and organs Is progressive It is also variable Between families Within families Between genders 5

6 Genetics α-gal A is a homodimeric glycoprotein encoded by the GLA gene which is located on the long arm of the X chromosome. Alberto Ortiz, Dominique P. Germain, Robert J. Desnick, et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Molecular Genetics and Metabolism 123 (2018)

7 Genetics Numerous GLA mutations are currently reported in gene mutation databases Missense, nonsense, consensus splice site, cryptic splicing, and frameshift mutations (small and large deletions and insertions) cause Fabry disease. Mutations Alberto Ortiz, Dominique P. Germain, Robert J. Desnick, et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Molecular Genetics and Metabolism 123 (2018)

8 Epidemiology The estimated incidence of Fabry disease is 1 in 40,000 men and 1 in 20,000 women 1,2 However, accurate estimates are difficult to make as Fabry disease is likely underrecognized due to the 3 : - Non-specific nature of early symptoms - Heterogeneous phenotypes and genotypes - Lack of disease awareness among clinicians - Late diagnosis and mis-diagnosis common Fabry disease is seen across all ethnic and racial groups 3 It affects multiple generations in the family (of an affected individual) emphasizing the importance of family screening 2 - On average 5 affected family members per index case 2 1. Desnick et al. Online Metabolic and Molecular Bases of Inherited Disease, accessed on Nov. 9, 2015; 2. Laney et al. J Genet Couns 2008;17:79-83; 3. Germain. Orphanet J Rare Dis 2010;5:30.

9 Epidemiology Classic Fabry in males: early onset and multisystem involvement Classic Fabry in females: variable clinical expression and age of onset Late onset (type 2): presents in 4 th to 7 th decade, usually renal only or more commonly cardiac only phenotype 9

10 Classic Fabry disease is only the tip of the iceberg Classic Fabry disease Late-onset/ monosymptomatic/ oligosymptomatic Fabry disease According to recent newborn screening, classic Fabry disease accounts for only approximately 2 14% of all cases of the disease A much higher incidence of Fabry disease associated with late-onset mutations has been revealed in these epidemiological studies 1,2 10

11 The Problem: Insufficient α- galactosidase A Globotriaosylceramide (GL-3) O α-galactosidase A NH 3 Without this step GL-3 is not metabolized further and accumulates in the lysosomes of numerous cell types

12 Vascular Endothelium Vascular endothelium in Fabry disease From R.J. Desnick, PhD, MD Note electrondense lysosomes containing undegraded glycosphingolipid

13 Pathophysiology GL-3 accumulation induces cell injury and tissue responses (e.g. inflammation, hypertrophy, apoptosis, fibrosis) and a wide variety of clinical complications 1,3 GL-3 accumulates in plasma and cell types throughout the body, including capillary endothelial cells, and renal, cardiac and nerve cells 1 Progressive lysosomal accumulation of GL-3 and other α-gal A substrates starting in the fetal stage of development 1,2 Deficient/undetectable α-gal A activity: FABRY DISEASE (often <1% residual enzyme activity in males) 1 Defect in the gene encoding α-gal A 1 1. Germain. Orphanet J Rare Dis 2010;5:30; 2. Tsutsumi et al. Asia Oceania J Obstet Gynaecol 1985;11:39-45; 3. Rombach et al. Mol Genet Metab 2010;99:

14 Pathogenic hypothesis of tissue damage in Fabry disease Figure from Rozenfeld P & Feriozzi S. 1 Gb3, globotriaosylceramide; inkt, invariant natural killer T; lyso-gb3, globotriaosylsphingosine; NF-κB, nuclear factor kappa B; TGF-β, transforming growth factor beta; TLR, toll-like receptor 1. Rozenfeld P & Feriozzi S. Mol Genet Metab. 2017;122:19 27.

15 Burden of Disease Disease Progression As GL-3 accumulates and organ systems are affected, early symptoms of Fabry disease progress to life-threatening complications 1-3 GL-3 Accumulation Infant Child Adolescent Adult 1. Eng et al. Genet Med 2006;8:539-48; 2. Germain. Orphanet J Rare Dis 2010;5:30; 3. Wanner. Clin Ther 2007;29, Suppl A:S2-5. Figure adapted from Wanner. Clin Ther 2007;29, Suppl A:S2-5.

16 Symptoms in boys and girls with classic disease Cornea verticillata Hypohidrosis dry skin heat & exercise intolerance Cardiac arrhythmias Fatigue Psychological issues Growth retardation Hearing loss, tinnitus Renal microalbuminuria / proteinuria impaired filtration & function GI problems pain & bloating diarrhoea & nausea Angiokeratoma Peripheral neuropathy chronic burning pain episodic pain crises autonomic neuropathy may contribute to GI, CVS & sweating Eng et al 2006; Genet Med; 8:

17 Multi-organ involvement Adult Males and Females Cornea verticillata Hypohidrosis Fatigue Early stroke, TIAs Hearing loss, tinnitus Cardiac complications arrhythmias conduction abnormalities valvular dysfunction LVH myocardial infarction heart failure Peripheral neuropathy Renal complications decline in GFR overt proteinuria end-stage renal disease GI dysmotility Angiokeratoma

18 Reduced Life-Expectancy Survival in Fabry males (left figure) and females (right) is 50 and 70 years, respectively (medians) 1,2 - Figure represents a 20-year and 15-year reduction in life span in males and females respectively 1,2 1. MacDermot et al. J Med Genet 2001;38:750-60; 2. MacDermot et al. J Med Genet 2001;38: Figures adapted from these references.

19 Clinical Presentation to Nephrologist Abnormal urinalysis Proteinuria Hematuria Lipiduria Elevated serum creatinine Tubular dysfunction (polyuria, polydipsia) Early renal failure Progressive renal insufficiency of unknown etiology Family history of renal problems

20 Burden of Renal Disease Renal Manifestations Progression of renal disease over time Albuminuria Fabry nephropathy Proteinuria Progressive GFR decline Hypertension End-stage renal disease in 3 rd -5 th decade of life Premature death GL-3 accumulation in renal cells Infant Child Adolescent Adult Tøndel et al. J Am Soc Nephrol 2013;24:137-48; Tøndel et al. Am J Kidney Dis 2008;51:767-76; Ramaswami et al. Clin J Am Soc Nephrol 2010;5:365-70; Ortiz et al. Nephrol Dial Transplant 2008;23:1600-7; Wanner et al. Clin J Am Soc Nephrol 2010;5:

21 1. Thurberg et al. Kidney Int 2002;62: ; 2. Sessa et al. JIMD 2001;24:66-70; 3. Tsutsumi et al. Asia Oceania J Obstet Gynaecol 1985;11:39-45; 4. Tøndel et al. J Am Soc Nephrol 2013;24:137-48; 5. Wanner et al. Clin J Am Soc Nephrol 2010;5:2220-8; 6. Schiffmann et al. NDT 2009;24: ; 7. Ortiz et al. NDT 2008;23:1600-7; 8. Oqvist et al. NDT 2009;24: ; 9. van der Tol et al. J Med Genet 2014;51:1-9; 10. Terryn et al. Nephrol Dial Transplant 2013;28:505-17; 11. Laney et al. J Genet Couns 2008;17: Renal Manifestations - Summary Progressive GL-3 accumulation occurs in various renal cells 1,2 and may start in the fetal stage of development 3 Leads to kidney damage (e.g. podocyte injury, irreversible fibrosis, sclerosis) which may be present at pediatric age 4 High proteinuria levels and low egfr are associated with more rapid decline in renal function 5,6 Patients are at risk of developing end-stage renal disease between the 3 rd and 5 th decade of life 7 Fabry disease should be considered in the differential diagnosis of patients with renal failure of unknown cause 8-10 Screening in high-risk populations may identify yet undiagnosed patients, and subsequent family screening may identify affected relatives at a relatively early stage of the disease 8-10

22 Clinical Presentation to Cardiologist Patients may present with: Left ventricular hypertrophy Mitral valve prolapse and/or regurgitation Premature coronary artery disease Angina Myocardial infarction Arrhythmia

23 Burden of Cardiac Disease Cardiovascular Manifestations Progression of cardiac disease over time LVH, diastolic dysfunction Arrhythmias Impaired exercise capacity Angina, myocardial infarction Valvular insufficiency Lymphedema, thrombosis Heart failure Malignant arrhythmia Cardiac death GL-3 accumulation in cardiac cells Infant Child Adolescent Adult Waldek et al. Genet Med 2009;11:790-6; Shah et al. Am J Cardiol 2005;96:842-6; Linhart et al. Acta Paediatr Suppl 2002;91:15-20; Kampmann et al. Int J Cardiol 2008;130: ; Patel et al. J Am Coll Cardiol 2011;57:1093-9; Schiffmann et al. Nephrol Dialysis Transplant 2009;24:

24 Cardiovascular Manifestations Left ventricular hypertrophy (LVH) LVH is a key feature in Fabry disease 1-3 Reported in up to 50% of male and one-third of female patients May be the only involvement with late onset variants May be observed as early as in childhood or adolescence Progressive and mostly concentric Left ventricular contractility and diastolic function deteriorate Reduced ejection fraction and congestive heart failure in advanced stages 1. Kampmann et al. Int J Cardiol 2008;130:367-73; 2. Havranek et al. JIMD Rep 2013;11:53-64; 3. Linhart et al. Acta Paediatr Suppl 2002;91:15-20.

25 Cardiovascular Manifestations Arrhythmias Patients without arrhythmia (%) By age 45 years, 50% of ERT-naïve males reported to have a rhythm disturbance 1 Bradycardia, atrial flutter/fibrillation, ventricular arrhythmias Conduction impairment: short PR interval (early), AV block (later stage) 2 Arrhythmias can occur even before age Time to first cardiac arrhythmia 1 Female (n = 168) Male (n = 279) Age 1. Schiffmann et al. Nephrol Dial Transplant 2009;24: ; 2. Germain. Orphanet J Rare Dis 2010;5:30. Figure adapted from Schiffmann et al. Nephrol Dial Transplant 2009;24:

26 Cardiovascular Manifestations Cardiovascular (CV) events Of untreated patients, 5.8% of males and 3.7% of females in the Fabry Registry had major CV events defined as 1 - Myocardial infarction - Heart failure - Cardiac-related death Age at first CV event in Fabry Registry patients 1 First CV event at mean age 1-45 years in males - 54 years in females LVH and hypertension were identified as risk factors for experiencing lifethreatening CV events at relatively young age 1 1. Patel et al. J Am Coll Cardiol 2011;57:

27 1. Linhart et al. Heart 2007;93: ; 2. Kampmann et al. Int J Cardiol 2008;130:367-73; 3. Patel et al. J Am Coll Cardiol 2011;57:1093-9; 4. Schiffmann et al. NDT 2009;24: ; 5. Weidemann et al. Orphanet J Rare Dis 2013;8:116; 6. Waldek et al. Genet Med.2009;11:790-6; 7. Yousef et al. Eur Heart J 2013;34:802-8; 8.Weidemann et al. Int J Cardiol 2010;141:3-10; 9. van der Tol et al. J Med Genet 2014;51:1-9; 10. Laney et al. J Genet Couns 2008;17: Cardiovascular Manifestations - Summary GL-3 accumulates in cardiomyocytes, conduction system cells and vascular endothelial and smooth muscle cells 1 This causes progressive LVH, irreversible fibrosis and cardiac insufficiency, and potentially life-threatening arrhythmias 1-5 Replacement fibrosis in the posterior-lateral wall is an important predictor of cardiac outcome 5 LVH and hypertension are predictive of life-threatening cardiovascular events at relatively young age 3 Cardiovascular disease is the most common cause of death in Fabry patients 6 Screening in high-risk populations may identify yet undiagnosed patients, and subsequent family screening may identify affected relatives at a relatively early stage of the disease 7-10

28 Clinical Presentation to Neurologist Patients may present with: Acroparesthesia Early stroke Transient ischemic attacks Muscle weakness Vertigo/dizziness Tinnitus Hyperacusis/deafness Nystagmus Gait disturbance - hemiataxia/ataxia

29 Burden of Neurologic Disease Neurologic Manifestations Progression of neurologic disease over time Pain (chronic, attacks) GI problems (diarrhea, dysmotility) Hypohidrosis + Abnormalities of intracranial vessels Stroke, transient ischemic attacks Premature death Sensory loss Headaches White matter lesions Depression GL-3 accumulation in neural cells and vascular endothelium Infant Child Adolescent Adult Cable et al. Neurology 1982;32: ; Uçeyler et al. Clin J Pain 2014;30:915-20; Sims et al. Stroke 2009;40:788-94; Fellgiebel et al. Neurology 2009;72:63-8; Moore et al. Brain Res Bull 2003;62:231-40; Cole et al. J Inherit Metab Dis 2007;30:

30 Neurological Manifestations - Pain Acroparesthesias Constant, beginning in the first decade of life, diminishing with age Affects hands and feet Described as burning, tingling, pain and discomfort Triggered by fever, heat, physical exercise, fatigue, stress, and weather changes Unresponsive to narcotic analgesics Caused by small-fiber neuropathy (Brady,Schiffman, 2000)

31 Neurologic Manifestations Autonomic nerve system Progressive loss of function in both peripheral and central autonomic nerve cells 1 Gastrointestinal dysmotility - Postprandial cramping; episodic/chronic diarrhea; recurrent abdominal pain; feeling of fullness; small bowel dilatation Hypohidrosis May also be a result of dysfunction of sweat glands due to GL-3 accumulation Sensory loss Reduced saliva/tear formation Reduced heart rate variability Changes in cerebrovascular circulation 1. Cable et al. Neurology 1982;32:

32 Neurologic Manifestations Depression Clinical depression is common among Fabry patients - Severe depression reported to occur in 36% of male and 22% of female patients 1 Depression often goes undiagnosed 1,2-72% of Fabry patients with severe depression had not received a diagnosis of clinical depression Further classification due to pain 2 - Primary (related to Fabry) - Secondary (response to chronic pain) - or both 1. Cole et al. J Inherit Metab Dis 2007;30:943-51; 2. Bolsover et al. J Inherit Metab Dis 2014;37:

33 Neurologic Manifestations Transient ischemic attacks (TIAs), stroke TIAs and stroke are common in both male and female patients and may occur at an early age 1 Of untreated patients in the Fabry Registry, 6.9% of males and 4.3% of females experienced strokes 1 Majority of first strokes (86.8%) were ischemic 1 Compared to non-stroke patients, those who had strokes were more likely to report 1 - TIAs (36.2% vs. 5.4%) - Arrhythmias (32.6% vs. 12.7%) - Hypertension (52.9% vs. 20.5%) 1. Sims et al. Stroke 2009;40:

34 Neurologic Manifestations Strokes commonly occur during adulthood Percentage Patients with Stroke by Age Category Age at first stroke in Fabry Registry patients 1 35 Males (N=86) 30 N=25 Females (N=52) 25 N=20 N=20 N=12 N=11 N=18 20 N=10 N=10 N= N=1 N=1 10 to < to < to < to < to < 60 >= 60 Age at First Stroke (years) 22% of untreated patients had strokes under the age of 30 years 1 Mean age at first stroke was 39.8 for males and 45.7 years for females 1 Stroke incidence was markedly higher as compared to the general US population for all age groups 1 1. Sims et al. Stroke 2009 ;40: Figure adapted from Sims et al. Stroke 2009;40: N=2

35 Neurologic Manifestations White matter lesions (WMLS) Single, multiple or confluent hyper-intensities in white matter 1 Small vessel infarctions resulting from GL-3-related endothelial damage might play a causative role 1 Progressively increases in number with age 1 WML load similar in male and female patients 2 May be observed in pediatric patients 3 1. Moore et al. Brain Res Bull 2003;62:231-40; 2. Gavazzi et al. Radiology 2006;241: ; 3. Cabrera-Salazar et al. J Pediatr 2005;147:102-5.

36 Neurologic Manifestations White matter lesions Arrows indicate sites of increased signal in periventricular white matter on an MRI of a 11-year-old boy with Fabry disease 1 1. Cabrera-Salazar et al. J Pediatr 2005;147:102-5.

37 Neurologic Manifestations Intracranial vasculopathy Vertebrobasilar vessels tortuosity and basilar dolichoectasia (dilatation + elongation) are common findings in adult patients 1 Etiology is unknown but appears to be related to aberrant vascular remodeling 2 May cause reduction of cerebral blood flow 3 Basilar artery diameter may be an sensitive parameter for separating Fabry patients from controls 1 1. Fellgiebel et al. Neurology 2009;72:63-8; 2. Fellgiebel et al. Lancet Neurol 2006;5:791-5; 3. Mitsias et al. Ann Neurol.1996;40:8-17.

38 Neurologic Manifestations - Summary Progressive GL-3 accumulation and secondary pathology causes early small fiber neuropathy and may lead to potentially lifethreatening complications in adulthood 1-6 Most of the childhood symptoms, incl. pain, GI problems and hypohidrosis, reflect damage to the small fibers of the peripheral and autonomic nervous systems 1,2 Adult patients are at risk of developing complications including ischemic cerebral small vessel disease, vasculopathy of large intracranial vessels, stroke/tias, white matter lesions, and clinical depression due to pain 3-6 TIAs and stroke may occur at an early age as the first clinical event in patients who have not yet been diagnosed 3 1. Cable et al. Neurology 1982;32: ; 2. Uçeyler et al. Clin J Pain 2014;30:915-20; 3. Sims et al. Stroke 2009;40:788-94; 4. Fellgiebel et al. Neurology 2009;72:63-8; 5. Moore et al. Brain Res Bull 2003;62:231-40; 6. Cole et al. J Inherit Metab Dis 2007;30:

39 Gastrointestinal Manifestations Post-prandial abdominal pain/cramps often with debilitating diarrhea Begins in childhood or adolescence Weight loss or lack of weight gain Associated with nausea and vomiting and morphologic changes in large and small intestine radiography Caused by GL-3 accumulation in autonomic ganglia of bowels and in intestinal vessels (Desnick et al., 1995)

40 Dermatologic Manifestations Angiokeratomas Bathing trunk distribution Non-blanching, dark red to blue-black maculopapular lesions Appear in adolescence and worsen in adulthood Hypohidrosis or anhidrosis Results in heat and exercise intolerance Caused by endothelial cells filled with GL-3 (Meroni et al., 1997)

41 Angiokeratoma Reported in 37% of boys and 23% of girls, and in 66% of adult males and 36% of females 1 Proliferation of dilated blood vessels in the upper dermis 2 Red-purple, non-blanching vascular skin lesions 2 Most commonly in area from umbilicus to thigh 2 1. Orteu et al. Br J Dermatol 2007;157: 331-7; 2. Zampetti et al. Br J Dermatol 2012;166: Figure left: Germain. Orphanet J Rare Dis 2010;5:30. Figure right: Zampetti et al. Br J Dermatol 2012;166:

42 Other Key Clinical Features Cornea verticillata Whorl like corneal opacities (Posterior capsule) usually have a cream-like color Can only be seen during slit lamp exam Detected in approx. 70% of boys and girls in a pediatric study 1 Vision not affected Increased conjunctival and retinal vessel tortuosity also reported 2 1. Ries et al. Eur J Pediatr 2003;162: ; 2. Burlina et al. BMC Neurology 2011:11:61; Figure: SpringerImages.com.

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44 FABRY Facial features

45 Other manifestations of Fabry disease Chronic meningitis 4 Hypothyroidism 5 Leukaemia 3 Raynaud s phenomenon 6 Osteopenia 2 Priapism 7 Azoospermia 1 Rare manifestations of Fabry disease Anaemia 8 1. Papaxanthos-Roche et al. Fertil Steril 2007;88:212.e15 18; 2. Mersebach et al. Genet Med 2007;9:812 18; 3. Cybulla et al. Br J Haematol 2006;135:264 5; 4. Schreiber et al. J. Neurol 2007;254:1447 9; 5. Hauser et al. J Inherited Metab Dis 2005;28:715 22; 6. Deshaves et al. Medicine (Baltimore) 2015;94:e780; 7. Foda et al. Urology 1996;48:949 52; 8. Kleinart et al. Kidney Int 2005;67:

46 Diagnosis Substantial delays from symptom onset to diagnosis Diagnostic delays of approximately 15 years (mean) have been reported for males and females 1 Male patients Female patients Age at first symptoms n Mean, yrs Age at diagnosis n Mean, yrs Time from symptom n onset to diagnosis Mean, yrs Wilcox et al. Mol Genet Metab 2008;93: Table modified from Wilcox et al. Mol Genet Metab 2008;93:

47 Potential Misdiagnoses Feature of AFD Misdiagnosis Angiokeratoma Petechiae of meningococcal meningitis, Hereditary haemorrhagic telangiectasia, SLE, Fordyce disease, Schindler disease, fucidosis, sialidosis, Campbell de Morgan spots Pain Rheumatoid arthritis, rheumatic fever, Raynaud s disease, erythromelalgia, growing pains, Sickle cell disease, malingering Fever Neurological symptoms Stroke Peripheral neuropathy Renal impairment Familial Mediterranean Fever, rheumatic fever Multiple sclerosis, neurosis CADASIL, CARASIL, Sickle cell disease, HERNS HSAN, Allgrove, Tangier disease Glomerulonephritis, pyelonephritis, exposure to silica dust Cardiac involvement Hypertrophic or restrictive cardiomyopathy, congestive cardiac failure, coronary artery disease Gastrointestinal symptoms Irritable bowel syndrome, pancreatic insufficiency, acute appendicitis, renal colic, malingering 47 Cornea verticillata Amiodarone therapy, chloroquine therapy

48 Diagnosis Confirmatory laboratory assays Males Males typically have <1% of normal enzyme activity in plasma and leukocytes Females Females may have normal to low-normal enzyme activity α-gal enzyme assay Plasma, leukocytes, cultured skin fibroblasts, dried blood DNA analysis Fabry GLA gene mutation Low activity Fabry disease diagnosis confirmed DNA analysis Fabry GLA gene mutation 1. Gal et al. J Inherit Metab Dis 2011;34:509-14; 2. Oqvist et al. Nephrol Dial Transplant 2009;24: ; 3. Reuser et al. Mol Genet Metab 2011;104:144-8.

49 Diagnosis Need to diagnose Fabry disease early Progressive GL-3 accumulation starting in fetal stage of development 1,2 Triggering of tissue responses Onset of clinical symptoms in childhood Irreversible fibrotic damage and major organ complications in adulthood End organ damage Early diagnosis provides an opportunity to intervene before irreversible organ damage has developed 1 1. Germain. Orphanet J Rare Dis 2010;5:30; 2. Tsutsumi et al. Asia Oceania J Obstet Gynaecol 1985;11:39-45.

50 Multidisciplinary Care in Fabry Disease Coordinated care by nephrologists, neurologists, cardiologists, geneticists and others o monitor patients, o Introduce ERT at an appropriate time o optimise concomitant medication, o manage co-morbid conditions, o ensure adequate prophylaxis, o promote compliance 1.Wiedemann et al, Am J Med Mehta et al, Goals of therapy in Fabry disease, Gen. Med 2010

51 When should ERT be commenced?

52 ERT for Fabry disease: agalsidase alfa agalsidase alfa produced in a human cell line by gene activation technology 1-3 Extraction Transfection Production R R R R Human cell Human cell R Regulatory DNA sequences function as an on-switch R Gene activation regulatory factor administered at a dose of 0.2 mg/kg body weight EOW by intravenous infusion over 40 minutes 3 EOW, every other week; ERT, enzyme replacement therapy 1. Garman SC & Garboczi DN. J Mol Biol. 2004;337: Bekri S. Importance of glycosylation in enzyme replacement therapy. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry disease: perspectives from 5 years of FOS. Oxford: Oxford PharmaGenesis Ltd; 2006; Chapter 5 3. Replagal, Summary of Product Characteristics. August 2016.

53 ERT for Fabry disease: agalsidase beta Agalsidase beta is produced in a CHO cell line by conventional cloning 1-3 Extraction Transfection Production R R R Human cell CHO cell R Regulatory DNA sequences function as an on-switch Agalsidase beta is administered at a dose of 1.0 mg/kg body weight EOW by intravenous infusion at a rate of 15 mg/hour 3 * *The initial infusion rate should be no more than 15 mg/hour - when patient tolerance is established, the infusion rate may be gradually increased EOW, every other week; ERT, enzyme replacement therapy; CHO, Chinese hamster ovary 1. Garman SC & Garboczi DN. J Mol Biol. 2004;337: Bekri S. Importance of glycosylation in enzyme replacement therapy. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry disease: perspectives from 5 years of FOS. Oxford: Oxford PharmaGenesis Ltd; 2006; Chapter 5 3. Fabrazyme, Summary of Product Characteristics. October 2014.

54 Heart Kidneys Nervous system Positive Effects of ERT in Fabry Disease Symptoms Pain Peripheral neuropathy Increased regional blood circulation in CNS Renal failure Cardiomyopathy Disrupted variability of cardiac frequency Angina pectoris, MI Effect With ERT Pain reduction a,b Improved function of peripheral nerves c Improved function of peripheral nerves d Reversible e Gb3 storage in glomeruli dissolved a Creatinine clearance improved; decrease in number of abnormal glomeruli a Fall in GFR is slowed b,c Creatinine values fall b Regression a,c No progression b Normalisation c Gb3 storage in endothelial cells dissolved a ERT also has positive effects in terms of reducing abdominal pain, normalisation of bowel movements, normalisation of sweating, progression prevention of hearing impairment or loss, regression of disturbances of equilibrium, and improving quality of life a Double-blind RCT. b Cohort study. c Open controlled study. d Open extension study of a double-blind RCT. e Double-blind RCT + open extension study. f Open controlled study; cohort study. CNS: central nervous system; GFR: glomerular filtration rate; RCT: randomised controlled trial. Hoffman B, Mayatepec E. Dtsch Arztebl Int. 2009;106:

55 Time to cardiovascular event by prompt versus delayed agalsidase alfa initiation HR: hazard ratio Giugliani et al Journal of Inborn Errors of Metabolism & screening 2016,(4);1-12.

56 Other medical treatment Genetic Counselling Manage proteinuria, hypertension: ACEI, ARB Prevent stroke: aspirin, clopidrogel Pain management: anticonvulsant such as carbamazepine Hearing loss: hearing aids Skin: laser therapy 56

57 New therapies Chaperones (migalastat - Galafold ) Appear promising for amenable mutations 57

58 CONCLUSIONS Fabry disease is an under-diagnosed inherited complex multisystem disorder It is frequently missed by a range of adult physicians and paediatricians Awareness must be increased Treatment with enzyme replacement therapy is a safe and effective intervention Early initiation of treatment before permanent organ damage

59 59 THANK YOU