Evaluation and Management of Fabry Disease - PowerPoint Presentation

1. Evaluation and Management of Fabry DiseaseSupported by Sanofi Genzyme

2. AgendaPathogenesis of Fabry DiseaseEvaluation of Fabry DiseaseFabry Disease Management

3. Learning ObjectivesDiscuss the pathophysiology of Fabry disease and its impact on kidney function to increase awarenessDescribe appropriate clinical diagnosis in Fabry disease, and explain the role of nephrologists in the early identification of patientsDescribe high risk patients as target of screening, including hereditary aspect of Fabry diseaseDiscuss methods of testing for Fabry disease and those currently availableDiscuss treatment strategies in kidney disease patients with Fabry disease, including symptom management and addressing the underlying pathology, to improve patient outcomes 

4. Pathogenesis of Fabry Disease

5. Fabry DiseaseAn X-linked lipid storage disorderDeficient or absent lysosomal α-galactosidase A (α-gal A) activity  systemic deposition of glycosphingolipids [mainly globotriaosylceramide (Gb3 or GL3)]Affects the heart, kidney, and neurologic systems, but can impact all organsIs considered a genetic risk factor for kidney disease, cardiomyopathy, stroke, and early death

6. EpidemiologyFabry disease is pan-ethnic, but due to its rarity, determining an accurate disease frequency is difficult Reported incidence: 1/47,600 to 1/117,000 in the general population, but the true prevalence is probably much higher Newborn screening: 1/~3,100 newborns in Italy1/~1,500 newborns in Taiwan (86% with cardiac variant)

7. Etiologya-Galactosidase A deficiencyAccumulation of GL3 in cells starts in-utero

8. EtiologyCurrently 790 GLA mutations are recorded (HGMD), ~70% of which are missense/nonsense mutations. The rest are splicing mutations, regulatory mutations, small deletions or insertions, large deletions or insertions, or complex mutationsThe majority of these mutations make the enzyme completely or partially non-functionalNon pathological single nucleotide polymorphisms and other sequence variations (VNTR) have been describedHuman Gene Mutation Database (HGMD). http://www.hgmd.cf.ac.uk/ac/index.php

9. Genotype/Phenotype CorrelationsHigh degree of clinical variability both among patients from the same family and among those from unrelated families with the same mutationMany of the clinical features of Fabry disease are frequently observed in the general population, such as neuropathic and abdominal pain, headache, tinnitus, hearing loss, diarrhea and cardiovascular disease (Fabry disease as a risk factor for commonly encountered pathology)1Genetic and environmental modifiers of the phenotypeX-chromosome inactivation impacts the phenotype and natural history of Fabry Disease in females2Germain D. Fabry disease. Orphanet J Rare Dis. 2010;5:30Echevarria L, et al. Clin Genet. 2016: 89:44-54.

10. InheritanceLyonization and Mosaicism

11. Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry RegistryWilcox et al. Molecular Genetics and Metabolism. 2008;93:112-128.Fabry disease is X-linked, NOT X-linked “recessive”

12. NeurologicalAbdominal pain DiarrheaNauseaGastrointestinalAcroparesthesiaSmall nerve fiber degeneration, neuron degeneration in dorsal root gangliaPain Crisis and FeverAversion to exerciseHypohydrosis, anhydrosis, heat intoleranceSmall vessel vasculopathy, peripheral neuropathyProduction of tears and saliva reduced in 40%Strokes, Transient Ischemic AttacksThrombosis of small arteriesHypertension secondary to kidney disease Complications of Fabry DiseasePsychologicalAnxietyDepressionSuicide

13. Cardiac Complications of Fabry DiseaseLeft Ventricular Hypertrophy/cardiac fibrosis Usually in patients older than 30 yrs, can lead to CHF and death In females often fibrosis (MRI) W/O hypertrophy by USEKG AbnormalitiesShort P-R intervals, AV blockRepolarization abnormalities, ST-T changesArrhythmiasAortic root dilatation, valvular diseaseCardiac Variant of Fabry DiseaseResidual AGA activityPresents later in life, no other manifestationUnder-recognized: 3% of 230 men with LVH had low AGA activityComplications of Fabry Disease

14. Pathology of Fabry Disease ComplicationsHeartFrustaci et al. Circulation 2014GL3 accumulation in cardiac myocytes; left ventricular hypertrophyGL3 accumulation in vascular endothelial and smooth muscle cells; ischemic heart diseaseArrhythmias, valvular heart disease

15. Fabry CardiomyopathyRight side: Echocardiographic image of the LV in apical 4-chamber viewEchocardiography with LVH and prominent papillary musclesEchocardiographic image of the left-ventricular short-axis of a 50 year old Fabry patientArrows: Prominent papillary muscleBar: Hypertrophic Septum (14mm)LVH, Left ventricular hypertrophyWeidemann F, et al. Curr Pharm Des. 2015;21:473-478.

16. Pathology of Fabry Disease ComplicationsNervous SystemPeripheralCentralGL3 accumulation in Schwann cells and dorsal root gangliaLoss of intra-epidermal innervationPredominantly involves small myelinated (Aδ) and unmyelinated (C) fibers.The main CNS involvement is due to vasculopathyGL3 accumulation in neuronsScott et al. Neurology. 1999;52:1249–54Schiffmann R et al. Neurological manifestations of Fabry disease. Oxford: Oxford PharmaGenesis; 2006.

17. Pathology of Fabry Disease ComplicationsKidneyAlroy J, Sabnis S, Kopp J. JASN. 2002;13(suppl 2):S134-S138. Electron Microscopy: Enlarged Secondary Lysosomes (Myeloid or Zebra bodies)Light Microscopy

18. Kidney Injury in Fabry DiseaseNajafian et al. Kidney International. 2011;79,663-670.

19. 19Evaluation of Fabry Disease

20. Clinical Manifestations of Fabry DiseaseSkin lesions (angiokeratomas)Pain and burning in the hands and feet (acroparaesthesia)Fatigue, impaired sweatingGastrointestinal problems (e.g., diarrhea, constipation, nausea, and vomiting)Corneal opacities that progress to a characteristic “whorled” pattern

21. Dark red/purple lesions, not blanchableButtocks, groin, umbilicus, and upper thighsAdolescence or young adulthoodAll ‘classic male’ hemizygotes; 30% of heterozygous females Biopsy shows dilated capillaries and parakeratosis (dry scaly skin) and endothelial inclusionsAngiokeratomasKashtan CE. “Alport’s and other familial glomerular syndromes,” in Comprehensive Clinical Nephrology. Feehally J, Floege J, Johnson RJ, eds, pp. 543-548, Mosby Elsevier. Philadelphia, PA, USA, 3rd edition, 2007.

22. Whorled” or “spoke-like” pattern: cornea verticillataAlmost all hemizygotes males and 70% of heterozygous females. Present very early in life Do not impair visionTypical Conjunctival InvolvementCorneal Opacities Germain D. Fabry disease. Orphanet J Rare Dis. 2010;5:30.

23. Dysmorphic Facies in Fabry disease23Prominent ear lobulesPeriorbital fullnessBushy eyebrowsRecessed foreheadPronounced nasal angleGenerous nose Bulbous nasal tipProminent supraorbital ridgesShallow midfaceFull lipsProminent nasal bridgeBroad alar baseCoarse featuresPosteriorly rotated earsPrognathismReis M et al. Genet Med 2006:8:96-101.

24. When to Consider Fabry Disease as a DiagnosisTest ANY patient who has:A family history of Fabry disease ORCorneal verticillata (“whorls”) on slit lamp examLaney DA, Bennett RL, Clarke V, et al. J Genet Counsel. 2013;22:555-564

25. In the absence of these two factors, test patients with at least two of the following features:Decreased sweating (anhidrosis or hypohidrosis)Reddish-purple skin rash in the bathing trunk area (angiokeratomas)Personal and/or family history of kidney failurePersonal or family history of “burning” or “hot” pain in the hands and feet, particularly during fevers (acroparesthesias)Personal or family history of exercise, heat, or cold intolerancePatients with sporadic or non-autosomal dominant (no male-to-male) transmission of unexplained cardiac hypertrophyWhen to Consider Fabry Disease as a DiagnosisLaney DA, Bennett RL, Clarke V, et al. J Genet Counsel. 2013;22:555-564

26. Fabry Testing RoadmapDoes the patient have clinical features, medical history, laboratory evidence, or family history suggestive of Fabry Disease?Male PatientFemale PatientOrder α-galactosidase A enzyme assay of patient ‘s leukocytesDoes the patient have a known family history of Fabry Disease with identified GLA mutation?YesThe patient has α-gal A activity within normal rangeThe patient has deficient α-gal A activity The patient is unaffected by Fabry diseaseThe patient is affected by Fabry diseaseOrder GLA gene sequencing with reflex testing to GLA duplication/ deletion testing Targeted sequencing for family mutationWas a disease causing mutation identified?YesNo*No*Standard sequencing of GLA will not detect large deletions, large duplications, some intronic mutations, and mutations in the promoter or other regulatory regions. Results must be interpreted in the context of an individual's clinical and/or biochemical profile.Laney DA, Bennett RL, Clarke V, et al. J Genet Counsel. 2013;22:555-564

27. DiagnosisMales WBC a-gal activity < 5% normalFemales mosaics: a-gal low/normal; DNA Family Hx; new mutations 5%Biopsy kidney, heartIncr Gb3 plasma, urine (enzyme substrate)Incr lysoGb3* plasma, urine (metabolite)Rombach SM, et al. Biochim Biophys Acta. 2010;1802:741-748.*deacylated form of Gb3

28. Newborn Screening Earlier diagnosis promotes timely interventions and the potential to slow the progression of complications such as kidney failureNewborn screening is detecting a large number of milder mutations, many of unknown clinical significance

29. Nephrology and Early Identification of PatientsNephrologists rarely make the diagnosis of Fabry disease other than through surprise findings on kidney biopsyUndiagnosed Fabry disease patients are typically referred to nephrologists for evaluation of proteinuria and/or decreased GFRNephrologists can play a role in early detection, which can present the opportunity to initiate appropriate and timely interventions

30. Natural History of Fabry Renal DiseaseProteinuria is usually the first manifestation. Its earliest appearance is ~14 years of age. Its peak onset is in the 40sAge of chronic renal insufficiency: 42 (19-54)Kidney failure develops in most males, usually ~10 years after the onset of proteinuria, and 4±3 years from onset of CKD 3Kidney failure can occur as early as 21 years of age, and with the peak incidence in the 50sMore recent registry data found males and females with preserved renal function into their late sixties Branton et al. Medicine 81:122-38, 2002Schiffmann: J Inherit Metab Dis 24 (Suppl 2):15-17, 2001Ortiz et al, NDT 23:1600-7, 2008

31. Once Kidney Dysfunction is Detectable, it Tends to be ProgressiveBranton et al. Medicine. 2002;81:122-138.

32. Effect of Proteinuria on eGFR in Untreated Adults Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 monthsWanner, et al. Clin J Am Soc Nephrol. 2010;5:2220-2228.

33. Assessment of Kidney FunctionRegular assessments of kidney function in Fabry patients should include estimates of the glomerular filtration rate (eGFR), total protein and albumin excretion, and urinary sodium excretionUrinary protein and urinary albumin excretion, preferably as timed overnight urine collectionsIf serum creatinine is significantly elevated, eGFRs may be adequate. If not, eGFRs are insensitive to early decline and may be better followed by annual or semi-annual measured GFR (e.g,. iohexol clearance)Biopsy studies have shown that glomerular and vascular changes are present before progression to proteinuriaTorra R. Kidney Int Suppl. 2008;111:S29-32.Ortiz A, et al. Nat Clin Pract Nephrol. 2008; 4:327-336.Mehta A, et al. QJM. 2010;103:641-659.Tøndel C, et al. Am J Kidney Dis. 2008;51:767-776.Gaspari F, et al. Kidney Int. 2013;84:164-173.

34. Fabry Disease Management

35. Management: Multi-disciplinary ApproachNephrologistNeurologistCardiologistGeneticistPain managementPediatricianPsychologist/PsychiatristDermatologistOphthalmologist

36. Enzyme Replacement Therapy (ERT)Replacement of the deficient/defective enzyme alpha-galactosidase Two different formulations are available:Agalsidase alpha (Approved in Europe, not FDA approved)Agalsidase beta (FDA approved)

37. Agalsidase Beta Chinese Hamster Ovary cell line1 mg/kg infusion over several hours every two weeksPremedication Infusion center followed by homeLife longMonitor GL3 and antibodies

38. Ten-Year Outcome of Enzyme Replacement Therapy With Agalsidase Beta in Patients With Fabry DiseaseBackground:Analysis of long-term outcomes (median 10 yrs) of patients with classic Fabry disease from the Agalsidase Beta phase 3 clinical trialFirst study to classify patients according to their baseline renal involvement (% glomerulosclerosis, UPCR)Methods:The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluatedDisease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessedGermain D, et al. J Med Genet. 2015;52:353-358.UPCR, urine protein-to creatinine ratio

39. Mean Slopes: eGFREstimated glomerular filtration rate (eGFR) slopes. Blue (Low Renal Involvement [LRI]) and red (High Renal Involvement [HRI]) bold lines represent the mean slopes of regression lines for the groups. Faint lines represent slopes for individual patients in the respective groups.eGFR (Ml/min/1.73m2Years from BaselineGermain D, et al. J Med Genet. 2015;52:353-358.

40. Conclusions and Take Away PointsAfter 10-years of Fabrazyme treatment (1mg/kg/2wks) in classic Fabry disease:94% of the patients were alive81% of the patients remained event-freeLong-term treatment decreased the occurrence of severe clinical eventsEarlier treatment initiation supports most favorable treatment responses:Younger patients Less organ damageGermain D, et al. J Med Genet. 2015;52:353-358.

41. Instituting Enzyme Replacement Therapy (ERT) in Fabry Disease PatientsFabry Population Guideline for Instituting ERTAdult males (>16 y)At time of diagnosis of Fabry diseasePediatric malesAt time of development of significant symptoms, orIf asymptomatic, consider at 10-13 yrFemales (all ages)Monitor; institute if significant symptoms, orevidence of progression of organ involvementEng C, et al. Genet Med. 2006;8:539-548.

42. Fabry Population US Consensus panel recommendationsSymptomatic male or female pediatric patientTreatment with ERT should be considered and is appropriate if Fabry symptoms are present in boys or girls at any ageSigns and symptoms warranting treatment suggest major organ involvement:Neuropathic pain crises/Fabry neuropathyRenal disease (decline in eGFR, pathological albuminuria or pathological proteinuria, creatinine elevation, cellular GL-3 accumulation or evidence of tissue damage such as podocyte effacement on renal biopsy)Cardiac disease (cardiomyopathy or arrhythmia (including sinus bradycardia) attributable to FD)Recurrent abdominal pain and diarrhea (excluding alternative causes)Exercise intolerance and impaired sweatingAsymptomatic male patients with classical (severe) mutationsTiming of ERT depends on individual case (balancing risks and benefits of therapy)Serious discussion regarding the timing of ERT initiation is recommended by age 8–10 years for boys with classical mutationsAsymptomatic female patients and asymptomatic male patients with late-onset mutations or variants of unknown significanceDecision to defer ERT should be based on comprehensive longitudinal monitoring for the development of clinical symptoms and signs of disease, as defined above Family history of the female patients should also be consideredHopkin R, et al. Fabry Pediatric Expert Panel. Mol Genet Metab. 2016;117:104-113.Initiating ERT in Pediatric Patients with Fabry Disease

43. CKD ManagementCKD MBDCKD AnemiaAcid Base and ElectrolytesNutritional Vitamin D High Blood Pressure

44. Treatment of ProteinuriaACEI or ARBs in combination with ERT have been shown to decrease the rate of proteinuriaThe overall treatment goal with ACEIs/ARBs, in combination with ERT, is reduction of urinary protein excretion to less than 500 mg/day, and stabilization of the decline of kidney function to –1 ml/min/1.73 m2/year. ERT alone, in the absence of ACEIs/ARBs does not decrease proteinuria in Fabry patientsBased on recent studies, less than half of patients with Fabry are being treated with adequate dose of RAAS inhibitorsWarnock D, et al. J Med Genet. 2015;52:860-866. ACEI, angiotensin-converting-enzyme inhibitor; ARB, Angiotensin II receptor blockers; RAAS, renin-angiotensin-aldosterone system.

45. Renal Replacement TherapyDialysisPoorer survival overallMay still benefit from ERT which can be given with dialysisTransplant Preferred RRT modalityLiving related donorsNo benefit in other organsRecurrenceRRT, renal replacement therapy

46. Schuller Y, et al. BMC Neurol. 2016;16:25Pain ManagementPain is one the most important manifestations of Fabry diseaseIt is mostly because of small fiber dysfunctionDifferent medications have been recommended for pain managementGenerally, studies agree upon starting the medication at low dose, and evaluating tolerability and effectiveness after 2-3 weeksAnalgesics are also an option, but NSAIDs generally are not considered effective, and can negatively impact kidney functionNSAID, nonsteroidal anti-inflammatory drugs

47. Pain ManagementOne study recommended carbamazepine alone or in combination with pregabalin rather than gabapentin as the first line treatmentA recent systemic review concluded that evidence of effectiveness has only been seen with carbamazepine, phenytoin and gabapentinAlthough not supported by data from clinical trials, this study favored gabapentin because of a better safety profileSNRIs like venlafaxine, duloxetine have a black-box warning for use in pediatric age group but are viable options for adult patientsTricyclic anti-depressants have potential concomitant and difficult side-effects in Fabry patientsSchuller Y, et al. BMC Neurol. 2016;16:25.Burlina AP, et al. BMC Neurol. 2011;11:61.

48. Adjunctive Therapy: Chronic PainAgentDoseCardiac restrictions?Renal Restrictions?Clinical EvidenceCarbamazepine250-800 mg/dayMay interfere with activity of other drugs (e.g., warfarin)NoneFilling-Katz et al. 1989GabapentinSlowly titrated from 100 to a max of 2400 mg/dayNoneYes (with precautions in cases of renal insufficiency)Ries et al. 2003 Phenytoin300 mg/dayNoneNoneLockman et al. 1973Pregabalin75-300 mg/dayNoneYes (with precautions in cases of renal insufficiency)Tricyclic antidepressants25-150 mg/dayArrythimasNoneKDIGO Controversies Conference on Fabry Disease | October 15-17, 2015 | Dublin, Ireland

49. Novel TreatmentsSeveral treatments are being looked at for Fabry disease.Chaperones, Substrate Reduction Therapy (SRT), stem cell transplant and gene therapy among othersPharmacological chaperones (PC), also known as small molecule ligands, substrate analog competitive inhibitors, or chemical chaperones, can bind and stabilize some mutant forms of a-Gal A in the endoplasmic reticulum.

50. SummaryDifficult to identify but easy to diagnoseMultisystem progressive diseaseMulti-disciplinary approachSupportive careWhole family needs to be evaluated and treated