Fabry Disease: A complex multisystem disorder

Dr. Bertram Henderson

Division of Clinical Genetics, UFS/FPA

| 1

| 2

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.

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Metachromatic

Leukodystophy

8%

Sanfilippo A

7%

Hunter Severe

5%

Krabbe

6%

Sandhoff

2%GM 1

Gangliosidosis

2%

Mucolipidosis type II / III

2%

Niemann-Pick A2%

Niemann-Pick C

4%

Tay-Sachs

4%

Sanfilippo B

4%

Gaucher type 2 & 3

1%

Niemann-Pick B

2%

Maroteaux-Lamy

3%

Cystinosis

4%

Morquio

5%

Pompe

5%

Hurler/Scheie (MPS I)

4%

Gaucher type I

13% Scheie (MPS I)

1%

Hurler (MPS I)

4%

Hunter Mild

1%

Fabry

7%

Adapted from Meikle P et al. JAMA. 1999;281:249-254.

Other

2%

a-Mannosidosis

Sanfilippo D

1%

1%

●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

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) 416–427.

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) 416–427.

1. Desnick et al. Online Metabolic and Molecular Bases of Inherited Disease, http://ommbid.mhmedical.com/content.aspx?bookid=971&sectionid=62644837&jumpsectionID=62644922; 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.

Epidemiology

● The estimated incidence of Fabry disease is 1 in 40,000 men and 1 in 20,000 women1,2

● However, accurate estimates are difficult to make as Fabry disease is likely under-

recognized due to the3:

- 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 groups3

● It affects multiple generations in the family (of an affected individual) emphasizing the

importance of family screening2

- On average 5 affected family members per index case2

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 4th to 7th decade,

usually renal only or more commonly cardiac only

phenotype

| 9

● 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 studies1,2

Classic Fabry disease is only the tip of the iceberg

Classic Fabry disease

Late-onset/monosymptomatic/oligosymptomatic

Fabry disease

10

The Problem: Insufficient α-galactosidase A

NH3

O

Globotriaosylceramide (GL-3)α-galactosidase A

● Without this step GL-3 is not metabolized further and accumulates

in the lysosomes of numerous cell types

Vascular Endothelium

From R.J. Desnick, PhD, MD

●Vascular

endothelium in Fabry

disease

Note electron-

dense

lysosomes

containing

undegraded

glycosphingolipid

Pathophysiology

Defect in the gene encoding α-Gal A1

Deficient/undetectable α-Gal A activity:

FABRY DISEASE

(often <1% residual enzyme activity in males)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;99:99-108.

Progressive lysosomal accumulation of GL-3 and

other α-Gal A substrates starting in the fetal stage

of development1,2

GL-3 accumulates in plasma and cell types

throughout the body, including capillary endothelial

cells, and renal, cardiac and nerve cells1

GL-3 accumulation induces cell injury and tissue responses (e.g. inflammation, hypertrophy,

apoptosis, fibrosis) and a wide variety of clinical complications1,3

Pathogenic hypothesis of tissue damage in Fabry disease

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.

Figure from Rozenfeld P & Feriozzi S.1

Disease Progression

GL-3 Accumulation

Infant

As GL-3 accumulates and organ systems are affected, early symptoms of Fabry disease progress to life-threatening complications1-3

Bu

rden

of

Dis

ease

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.

Child Adult Adolescent

Symptoms in boys and girls with classic disease

Cornea verticillata

Hypohidrosis

• dry skin

• heat & exercise intolerance

GI problems

• pain & bloating

• diarrhoea & nausea

Renal

• microalbuminuria / proteinuria

• impaired filtration & function

Peripheral neuropathy

• chronic burning pain

• episodic pain crises

Angiokeratoma

Growth retardation

Hearing loss, tinnitus

Psychological issuesFatigue

Eng et al 2006; Genet Med; 8: 539-48

Cardiac

• arrhythmias

autonomic neuropathy may contribute to GI, CVS &

sweating

Multi-organ involvement Adult Males and Females

Cornea verticillata

Hypohidrosis

GI dysmotility

Renal complications

• decline in GFR

• overt proteinuria

•end-stage renal disease

Peripheral neuropathy

Angiokeratoma

Hearing loss, tinnitus

Fatigue Early stroke, TIAs

Cardiac complications

• arrhythmias

• conduction abnormalities

• valvular dysfunction

• LVH

• myocardial infarction

• heart failure

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 respectively1,2

1. MacDermot et al. J Med Genet 2001;38:750-60; 2. MacDermot et al. J Med Genet 2001;38:769-75. Figures adapted from these references.

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

Renal ManifestationsProgression of renal disease over time

GL-3 accumulation in renal cells

• End-stage renal disease

in 3rd-5th decade of life

• Premature death

Bu

rden

of

Ren

al

Dis

ease

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;5:2220-8.

Fabry nephropathy

• Proteinuria

• Progressive GFR decline

• Hypertension

Albuminuria

Infant Child Adult Adolescent

Renal Manifestations - Summary

• Progressive GL-3 accumulation occurs in various renal cells1,2 and

may start in the fetal stage of development3

• Leads to kidney damage (e.g. podocyte injury, irreversible fibrosis,

sclerosis) which may be present at pediatric age4

• High proteinuria levels and low eGFR are associated with more rapid

decline in renal function5,6

• Patients are at risk of developing end-stage renal disease between

the 3rd and 5th decade of life7

• Fabry disease should be considered in the differential diagnosis of

patients with renal failure of unknown cause8-10

• 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 disease8-10

1. Thurberg et al. Kidney Int 2002;62:1933-46; 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 SocNephrol 2013;24:137-48; 5. Wanner et al. Clin J Am Soc Nephrol 2010;5:2220-8; 6. Schiffmann et al. NDT 2009;24:2102-11; 7. Ortiz et al. NDT 2008;23:1600-7; 8. Oqvist et al. NDT 2009;24:1736-43; 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;17:79-83.

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

Cardiovascular ManifestationsProgression of cardiac disease over time

GL-3 accumulation in cardiac cells

• Heart failure

• Malignant arrhythmia

• Cardiac death

Bu

rden

of

Card

iac D

isease

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;130:367-73.; Patel et al. J Am Coll Cardiol 2011;57:1093-9; Schiffmann et al. Nephrol Dialysis Transplant 2009;24:2102-11.

• LVH, diastolic dysfunction

• Arrhythmias

• Impaired exercise capacity

• Angina, myocardial

infarction

• Valvular insufficiency

• Lymphedema, thrombosis

Infant Child Adult Adolescent

Cardiovascular ManifestationsLeft ventricular hypertrophy (LVH)

LVH is a key feature in Fabry disease1-3

● 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.

Cardiovascular Manifestations Arrhythmias

By age 45 years, 50% of ERT-naïve males reported to have a rhythm disturbance1

• Bradycardia, atrial flutter/fibrillation, ventricular arrhythmias

• Conduction impairment: short PR interval (early), AV block (later stage)2

• Arrhythmias can occur even before age 10

100

80

70

50

40

30

20

10

0

0 5 201510 25 30 35 40 45 50 55 60 65 70 75 80

60

90

Female (n = 168)

Male (n = 279)

Pa

tie

nts

wit

ho

ut

arr

hyth

mia

(%

)

Age

1. Schiffmann et al. Nephrol Dial Transplant 2009;24:2102-11; 2. Germain. Orphanet J Rare Dis 2010;5:30. Figure adapted from Schiffmann et al. Nephrol Dial

Transplant 2009;24:2102-11.

Time to first cardiac arrhythmia1

• Of untreated patients, 5.8% of males and 3.7% of females in the Fabry Registry had major CV events defined as1

- Myocardial infarction

- Heart failure

- Cardiac-related death

● First CV event at mean age1

- 45 years in males

- 54 years in females

● LVH and hypertension were identified

as risk factors for experiencing life-

threatening CV events at relatively

young age1

Cardiovascular Manifestations Cardiovascular (CV) events

1. Patel et al. J Am Coll Cardiol 2011;57:1093-9.

Age at first CV event in

Fabry Registry patients1

Cardiovascular Manifestations - Summary

• GL-3 accumulates in cardiomyocytes, conduction system cells and

vascular endothelial and smooth muscle cells1

• This causes progressive LVH, irreversible fibrosis and cardiac

insufficiency, and potentially life-threatening arrhythmias1-5

• Replacement fibrosis in the posterior-lateral wall is an important

predictor of cardiac outcome5

• LVH and hypertension are predictive of life-threatening

cardiovascular events at relatively young age3

• Cardiovascular disease is the most common cause of death in Fabry

patients6

• 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 disease7-10

1. Linhart et al. Heart 2007;93: 528-35; 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;24:2102-11; 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;17:79-83.

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

Neurologic ManifestationsProgression of neurologic disease over time

GL-3 accumulation in neural cells and vascular endothelium

Bu

rden

of

Neu

rolo

gic

Dis

ease

• Pain (chronic, attacks)

• GI problems

(diarrhea, dysmotility)

• Hypohidrosis

• Sensory loss

• Headaches

• Depression

• Abnormalities of

intracranial vessels

• Stroke, transient

ischemic attacks

• White matter lesions

+

• Premature death

Cable et al. Neurology 1982;32:498-502; 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;30:943-51.

Infant Child Adult Adolescent

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)

Neurologic ManifestationsAutonomic nerve system

Progressive loss of function in both peripheral and central autonomic

nerve cells1

●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;32:498-502.

Neurologic ManifestationsDepression

●Clinical depression is common among Fabry patients

- Severe depression reported to occur in 36% of male and 22% of

female patients1

●Depression often goes undiagnosed1,2

- 72% of Fabry patients with severe depression had not received a

diagnosis of clinical depression

● Further classification due to pain2

- 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;37:177-87.

Neurologic ManifestationsTransient ischemic attacks (TIAs), stroke

1. Sims et al. Stroke 2009;40:788-94.

• TIAs and stroke are common in both male and female patients

and may occur at an early age1

• Of untreated patients in the Fabry Registry, 6.9% of males and

4.3% of females experienced strokes1

• Majority of first strokes (86.8%) were ischemic1

• Compared to non-stroke patients, those who had strokes were

more likely to report1

- TIAs (36.2% vs. 5.4%)

- Arrhythmias (32.6% vs. 12.7%)

- Hypertension (52.9% vs. 20.5%)

1. Sims et al. Stroke 2009 ;40:788-94. Figure adapted from Sims et al. Stroke 2009;40:788-94.

Neurologic ManifestationsStrokes commonly occur during adulthood

0

5

10

15

20

25

30

35

10 to < 20 20 to < 30 30 to < 40 40 to < 50 50 to < 60 >= 60

Age at First Stroke (years)

Pe

rce

nta

ge

Pa

tie

nts

wit

h S

tro

ke

by

Ag

e C

ate

go

ry

Males (N=86)

Females (N=52)

N=1

N=20

N=8

N=25

N=11 N=18

N=12

N=2N=1

N=20

N=10 N=10

• 22% of untreated patients had strokes under the age of 30 years1

• Mean age at first stroke was 39.8 for males and 45.7 years for females1

• Stroke incidence was markedly higher as compared to the general US

population for all age groups1

Age at first stroke in Fabry Registry patients1

● Single, multiple or confluent hyper-intensities in white matter1

● Small vessel infarctions resulting from GL-3-related endothelial

damage might play a causative role1

● Progressively increases in number with age1

●WML load similar in male and female patients2

●May be observed in pediatric patients3

Neurologic ManifestationsWhite matter lesions (WMLS)

1. Moore et al. Brain Res Bull 2003;62:231-40; 2. Gavazzi et al. Radiology 2006;241:492-500; 3. Cabrera-Salazar et al. J Pediatr 2005;147:102-5.

Neurologic ManifestationsWhite matter lesions

Arrows indicate sites of increased signal in periventricular white matter

on an MRI of a 11-year-old boy with Fabry disease1

1. Cabrera-Salazar et al. J Pediatr 2005;147:102-5.

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.

● Vertebrobasilar vessels tortuosity and

basilar dolichoectasia (dilatation +

elongation) are common findings in adult

patients1

● Etiology is unknown but appears to be

related to aberrant vascular remodeling2

●May cause reduction of cerebral blood

flow3

● Basilar artery diameter may be an

sensitive parameter for separating Fabry

patients from controls1

Neurologic ManifestationsIntracranial vasculopathy

Neurologic Manifestations - Summary

• Progressive GL-3 accumulation and secondary pathology causes

early small fiber neuropathy and may lead to potentially life-

threatening complications in adulthood1-6

• Most of the childhood symptoms, incl. pain, GI problems and

hypohidrosis, reflect damage to the small fibers of the peripheral

and autonomic nervous systems1,2

• 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 pain3-6

• TIAs and stroke may occur at an early age as the first clinical

event in patients who have not yet been diagnosed3

1. Cable et al. Neurology 1982;32:498-502; 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;30:943-51.

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)

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)

Angiokeratoma

• Reported in 37% of boys and 23% of girls, and in 66% of adult males and

36% of females1

• Proliferation of dilated blood vessels in the upper dermis2

• Red-purple, non-blanching vascular skin lesions2

• Most commonly in area from umbilicus to thigh2

1. Orteu et al. Br J Dermatol 2007;157: 331-7; 2. Zampetti et al. Br J Dermatol 2012;166:712-20. Figure left: Germain. Orphanet J Rare Dis 2010;5:30.

Figure right: Zampetti et al. Br J Dermatol 2012;166:712-20.

Other Key Clinical FeaturesCornea verticillata

1. Ries et al. Eur J Pediatr 2003;162: 767-72; 2. Burlina et al. BMC Neurology 2011:11:61; Figure: SpringerImages.com.

• 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 study1

• Vision not affected

• Increased conjunctival and

retinal vessel tortuosity

also reported2

43

FABRY Facial features

Other manifestations of Fabry disease

Rare manifestations

of Fabry disease

Azoospermia1

Osteopenia2

Leukaemia3

Chronic meningitis4

Hypo-thyroidism5

Raynaud’s phenomenon6

Priapism7

Anaemia8

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;67:1955−60 45

Diagnosis

Substantial delays from symptom onset to diagnosis

Diagnostic delays of approximately 15 years (mean) have been

reported for males and females1

1. Wilcox et al. Mol Genet Metab 2008;93:112-28. Table modified from Wilcox et al. Mol Genet Metab 2008;93:112-28.

Male patients Female patients

Age at first symptoms n 890 581

Mean, yrs 13.5 19.9

Age at diagnosis n 1123 1018

Mean, yrs 26.3 32.1

Time from symptom n 778 473

onset to diagnosis Mean, yrs 14.2 15.7

Potential Misdiagnoses

47

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 Familial Mediterranean Fever, rheumatic fever

Neurological symptoms Multiple sclerosis, neurosis

Stroke CADASIL, CARASIL, Sickle cell disease, HERNS

Peripheral neuropathy HSAN, Allgrove, Tangier disease

Renal impairment 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

Cornea verticillata Amiodarone therapy, chloroquine therapy

DiagnosisConfirmatory laboratory assays

1. Gal et al. J Inherit Metab Dis 2011;34:509-14; 2. Oqvist et al. Nephrol Dial Transplant 2009;24:1736-43; 3. Reuser et al. Mol Genet Metab 2011;104:144-8.

DNA analysisFabry GLA gene mutation

FemalesFemales may have

normal to low-normal

enzyme activity

MalesMales typically have <1% of

normal enzyme activity in

plasma and leukocytes

α-GAL enzyme assayPlasma, leukocytes, cultured

skin fibroblasts, dried blood

Low activity

Fabry disease

diagnosis confirmed

DNA analysisFabry GLA gene mutation

Diagnosis Need to diagnose Fabry disease early

Progressive GL-3 accumulation starting in fetal stage of development1,2

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 developed1

1. Germain. Orphanet J Rare Dis 2010;5:30; 2. Tsutsumi et al. Asia Oceania J Obstet Gynaecol 1985;11:39-45.

Multidisciplinary Care in Fabry Disease

● Coordinated care by nephrologists, neurologists, cardiologists,

geneticists and others

omonitor patients,

o Introduce ERT at an appropriate time

ooptimise concomitant medication,

omanage co-morbid conditions,

oensure adequate prophylaxis,

opromote compliance

1.Wiedemann et al, Am J Med 2010

2.Mehta et al, Goals of therapy in Fabry disease, Gen. Med 2010

When should ERT be commenced ?

ERT for Fabry disease: agalsidase alfa

● agalsidase alfa produced in a human cell line by gene activation

technology1-3

● administered at a dose of 0.2 mg/kg body weight EOW by

intravenous infusion over 40 minutes3

EOW, every other week; ERT, enzyme replacement therapy

1. Garman SC & Garboczi DN. J Mol Biol. 2004;337:319–335.

2. 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.

Human cell

R

R

RR

Extraction Transfection Production

Human

cell

Regulatory DNA sequences function as an on-switchR R Gene activation regulatory factor

ERT for Fabry disease: agalsidase beta

● Agalsidase beta is produced in a CHO cell line by conventional

cloning1-3

● Agalsidase beta is administered at a dose of 1.0 mg/kg body weight

EOW by intravenous infusion at a rate of 15 mg/hour3*

*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;337:319–335.

2. 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.

Human

cellCHO cell

R RR

Extraction Transfection Production

Regulatory DNA sequences function as an on-switchR

Positive Effects of ERT in Fabry Disease

CNS: central nervous system; GFR: glomerular filtration rate;

RCT: randomised controlled trial.

Hoffman B, Mayatepec E. Dtsch Arztebl Int. 2009;106:440-447.

Symptoms Effect With ERT

Nerv

ou

s

sys

tem

Pain Pain reductiona,b

Peripheral neuropathyImproved function of peripheral nervesc

Improved function of peripheral nervesd

Increased regional blood circulation in CNS Reversiblee

Kid

ne

ys

Renal failure

Gb3 storage in glomeruli dissolveda

Creatinine clearance improved; decrease in

number of abnormal glomerulia

Fall in GFR is slowedb,c

Creatinine values fallb

Hea

rt CardiomyopathyRegressiona,c

No progressionb

Disrupted variability of cardiac frequency Normalisationc

Angina pectoris, MI Gb3 storage in endothelial cells dissolveda

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.

• 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

Time to cardiovascular event by prompt versus delayed agalsidase

alfa initiation

Giugliani et al Journal of Inborn Errors of Metabolism & screening 2016,(4);1-12.

HR: hazard ratio

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

New therapies

●Chaperones (migalastat - Galafold®)

●Appear promising for “amenable” mutations

57

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

THANK YOU

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