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STROKE AND CHRONIC KIDNEY DISEASE IN

FABRY DISEASE

Daisy Tapia, MS, LCGC

Genetic Counselor, Clinical Instructor

Department of Pediatrics, Division of Genetic & Genomic Medicine

University of California, Irvine

MAY 8, 2020

DISCLOSURES

• No conflicts of interest to disclose

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OUTLINE

• Pathophysiology and natural history of Fabry Disease (FD)

• Updated phenotypic impact of FD based on genotype, gender,

severity, and symptom onset

• With emphasis on renal and central nervous system involvement

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CASE STUDY

• 33-year-old male presents to the emergency department with nausea, vomiting, and abdominal pain.

• Laboratory test results:• Creatinine of 19 [0.7-1.3 mg/dL]• BUN of 133 [7-25mg/dL]

• Dialysis was begun.

• ESRD presumed to be due to chronic use of naproxen sodium to treat chronic pain, and due to recreational cocaine use.

• Renal biopsy recommended.

BUN= Blood Urea Nitrogen, ESRD= End Stage Renal Disease

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CASE STUDY Kidney Pathology Suggests A Different Cause

“Zebra bodies” of glycolipid storage in podocytes and epithelial cells.

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CASE STUDYTargeted Medical History

• Anhidrosis

• Chronic, daily neuropathic pain and tingling in hands and feet since childhood that worsens into full body pain crisis with exertion, illness, or extreme temperatures

• Frequent severe abdominal pain and vomiting

• Diffuse scattered reddish-purple rash on lower abdomen

• Chronic depression

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CASE STUDYEvaluations

• Angiokeratoma in umbilicus and genitals

• Corneal verticillata on slit lamp examination

• An ECHO showed moderate left ventricular hypertrophy and diastolic dysfunction

• An ECG revealed bradycardia and nonspecific T-wave abnormalities

ECHO= echocardiogram, ECG= electrocardiogram

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CASE STUDYGenetic Testing

• Biochemical testing to measure levels of alpha-galactosidase A in leukocytes finds 0 nmols/mL/hr(with normal control measurement of beta-galactosidase)

• Reflex to GLA gene sequencing finds a known pathogenic variant

• Diagnosis: Classic Fabry Disease (FD)

• Family testing identified an additional 10 family members affected by FD

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CASE STUDYFamily history

N

N

2

I

II

III

IV

VFabry Disease

Legend:

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Cer = ceramide; Gal = galactose; Glu = glucose. Mehta; Orteu. Fabry disease. In: Goldsmith, Katz, Gilchrest , et al, eds. Fitzpatrick's Dermatology in General Medicine. New York: McGraw-Hill Education; 2012.

• Gene: GLA

• Enzyme: alpha-galactosidase A (α-Gal A)

• Substrate: globotriaosylceramide (GL-3)

• Incidence:1/40,000 in classical males

FABRY DISEASE (FD)

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BLOOD VESSELS

• Buildup of GL-3, primarily in endothelial cells

• Storage narrows blood vessels as the endothelial cells lining the walls store glycolipids such as GL-3

• The Storage of GL-3 initiates a downstream cascade of events including inflammation that results in end organ damage.

Rozenfeld, Feriozzi. Mol Genet Metab. 2017;122:19-27.

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GLA GENE: Genetic Root Cause

Ortiz et al. Mol Genet Metab. 2018;123:416-427

• Location: Xq22.1

• Over 900 pathogenic variants in the GLA gene have been reported

• There are many pathogenic family-specific variants

• Genotype-phenotype classification:• “Classic”• “Non-classic”• Through categorization system using type of mutation, symptoms,

biomarkers, and biochemical analysis

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DISEASE SPECTRUM

Classic FD Non‐classic FD 

AGA enzyme <5% of normal mean in males (N/A females)

>1 key symptom: Neuropathic pain, Corneal verticillata, angiokeratoma

Increased severity in symptoms, predictable multiorgan impact, and earlier onset

Low AGA enzyme in males (N/A females)

Doesn’t meet criteria for classic FD

Still life-limiting, but may onset in adulthood with reduced penetrance in organs

AGA = alpha galactosidase AArends et al. J Am Soc Nephrol. 2017; 28:1631-1641.

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Adapted from DiscoverFABRY. Available at: https://www.discoverfabry.com/. Accessed June 2019.Wang et al. Genet Med. 2007;9:34-45; Ortiz, et al. Mol Genet Metab. 2018;123:416-427. Laney et al. J Genet Couns. 2008;17:79-83.

INHERITANCE: X-linked Condition

100% affected daughters, 0% affected sons 50% affected children

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WOMEN NOT JUST CARRIERS

Wang et al. Genet Med. 2007;9:34-45; Ortiz et al. Mol Genet Metab. 2018;123:416-427.

• Women with FD are NOT just carriers

• Women are complicated:• Skewed X-inactivation/lionization• Lack of cellular cross correction

• Females are at high risk for major organ involvement (about 2/3 lifetime risk).

• They need monitoring and treatment

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Left Ventricular Hypertrophy,

Arrhythmias, Chest Pain, Valvular Diagnosis

Early Ischemic Stroke, TIAs

Angiokeratomas

Proteinuria and Progressive Renal Insufficiency

Corneal and Lenticular Opacities

Hypohidrosis

Neuropathic Pain/Tingling

Chronic Fatigue

Recurrent fever

Heat and Cold Intolerance

Depression/AnxietyHearing loss and Vertigo

GI Pain, Diarrhea, Constipation

Intermittent Pain Crises

Bradycardia

Autonomic Dysfunction

Edema

GI = gastrointestinal; TIA = transient ischemic attackOrtiz et al. Mol Genet Metab. 2018;123:416-427; Hopkin et al. Mol Genet Metab. 2016;117:104-113.

SIGNS AND SYMPTOMS

Low Bone Mineral Density

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CLASSIC FD PROGRESSION

0

Acroparesthesia

Renal Disease

CNS Disease

Cardiac Disease

[Age]40+

ClinicalPresentation

Diagnosis (average)

10 20 30

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PROGRESSION

Eng et al. J Inherit Metab Dis. 2007;30:184-192.

Bur

den

of D

isea

se

Time

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• Event-free survival stratified for sex and phenotype

• Onset of renal, cardiac, or cerebral events

• Classic males had highest event rate, median event free survival of 49.5 years

• Overlap between classic females and non-classic males

Arends et al. J Am Soc Nephrol. 2017;28:1631-1641.

EVENT-FREE SURVIVAL

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FDA APPROVED PRIMARY THERAPIES

(1) Ortiz et al. Mol Genet Metab. 2018;123:416-427; Hopkin et al. Mol Genet Metab. 2016;117:104-113. (2) Banikazemi et al. Ann Intern Med. 2007;146:77-86. (3) Desnick . Expert Opin Biol Ther. 2003;4:1167-1176. (4) Eng et al. N Engl J Med. 2001;345:9-16. (5) Ortolano. J Inborn Errors Metab Screen. 2016;4:1-11.

• Enzyme replacement therapy (ERT)1

• 1mg/kg body weight IV infusion once every two weeks• Effective in reducing plasma and tissue GL-3 levels in the vascular endothelium of

the kidney, skin, and heart as surrogate markers of clinical benefit.2-4

• Chaperone Therapy5

• 123 mg orally every other day • For individuals with amenable GLA variants

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ORGAN INVOLVEMENT

AV = aortic valve; MV= Mitral valve; cMRI= cardiovascular magnetic resonance imaging; LV= Left ventricularImage adapted from Putko et al. Heart Fail Rev. 2015;20:179-191. Seydelmann et al. Best Pract Res Clin Endocrinol Metab. 2015;29:195-204.

CARDIAC INVOLVEMENT• Syncope (related to AV blocks or LV outflow obstruction)

• Diastolic dysfunction

• Valvular disease

• Vasospastic and/or exertional angina pectoris

• Preserved global ejection fraction with heart failure

• Small vessel disease

• Delayed gadolinium enhancement on cMRI

• Concentric left ventricular hypertrophy

• Bradycardia

• Short PR interval

• Non-specific T-wave abnormality

• Paroxysmal atrial fibrillation

• Malignant arrhythmias in 40s+ are the predominant cause for the substantially increased morbidity and reduced life expectancy

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RENAL INVOLVEMENT

• Glycosphingolipid accumulation throughout the nephron

• GL-3 deposits can be found in most renal cell types prior to loss of glomerular filtration rate (GFR)

• Continuous buildup leads to progressive renal failure

• Albuminuria usually starts in the 2nd and 3rd decade of life

• Fibrosis and tubular atrophy usually in the 3rd to 5th decades of life

• Classic Fabry patients typically develop chronic kidney disease (CKD) culminating in end-stage renal disease (ESRD) before the 5th decade

Eikrem et al. Cell Tissue Res. 2017;369:53-62.

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PATHOMECHANISMS IN FABRY

NEPHROPATHY

Eikrem et al. Cell Tissue Res. 2017;369:53-62.

• GL-3 accumulates in glomeruli, especially podocytes

• Foot process effacement precedes pathological albuminuria

• Podocyte GL-3 accumulation correlated with level of proteinuria

• Accentuated by coexisting arterial hypertension

Some of the most important pathomechanisms in Fabry nephropathy

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KIDNEY PATHOLOGYB.A.

“Honeycomb” on light microscopy (A.) and “Zebra bodies” on electron microscopy (B.) of glycolipid storage in swollen

podocytes.

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PREVALENCE OF FD IN DIALYSIS PATIENTS

CountryYear

Published Dialysis PopulationPrevalence 

Rate

Western Australia1 2020 526 adult patients 0 (0%)

Argentina2 2019 9,604 male patients 22 (0.23%)

Russia3 2019 5,572 adult patients 20 (0.36%)

United States4 2002 250,352 adult patients  42 (0.0167%)

(1) Jahan et al. Orphanet Journal of Rare Diseases. 2020; 15:10. (2) Frabasil et al. JIMD Rep. 2019; 48: 45-52. (3) Moiseev et al. Nephron. 2019; 141: 249-255. (4) Obrador et al. Journal of the American Society of Nephrology. 2002; 13: S144-S146.

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NERVOUS SYSTEM INVOLVEMENT

• Peripheral nervous system and central nervous system involvement

• Altered cerebrovascular reactivity

• Transient ischemic attack(TIA) and stroke as clinical cerebrovascular events• Majority of strokes are ischemic, less frequently they are hemorrhagic

• White matter hyperintensities and cerebral microbleeds are common

• Length-dependent small fiber neuropathy of the peripheral nervous system leads to chronic neuropathic pain and acute pain crises2

Ortiz et al. Mol Genet Metab. 2018;123:416-427. (2) Biegstraaten et al. Curr Pain Headache Rep. 2013; 17:365.

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• Incidence of stroke in patients with FD• 24-48%

• When compared to the general US population, individuals with FD:• Higher incidence of stroke• Happen at an earlier age

• Can be the first serious FD complication

Koldny et al. Stroke. 2015; 46:302-313.Figure from Sims et al. Stroke. 2009;40:788-794.

STROKE RISKIncidence of stroke in Fabry registry patients

and in the general US population

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CHRONIC WHITE MATTER HYPERINTENSITIES

• Single, multiple or confluent hyperintensities of white matter

• Microvascular injury due to GL-3 related medial arteriolar damage

• May not be related to white matter stroke

• Occur in subcortical, deep, and periventricular white matter

• Usually symmetrical

• Increase in number with age progressively

• May mimic appearance of multiple sclerosis

Koldny et al. Stroke. 2015; 46:302-313. Image from Kolodney et al. (2015)

Brain MRI axial fluid attenuated inversion recovery image showing white matter

hyperintensities present bilaterally29

CEREBRAL INVOLVEMENT

• Dysfunction of cerebral circulation1

• Altered cerebrovascular reactivity to CO21

• Increased signal intensity in the pulvinar3

• Cerebral dolichoestasia, particularly involving the basilar artery4

(1) Moore et al. Journal of Neruo Sci. 2007; 257: 258-263. (2) Phyu et al. Neurology. 2018; 90: 16. (3) Kolodny et al. Stroke. 2015; 46:302-313. (4) Fellgiebel et al. Neurology. 2009; 72:63-68. Image A) from Phyu et al. (2018). Image B) from Moore et al. (2007). Image C) from Kolodny et al. (2015).

A) T1-weighted MRI image showing pulvinar hyperintensity. B) MR angiography showing basilar dolichoestasia

A) Representative Cerebral Blood Flow Maps from a Healthy Control and a Participant with FD

A)

B) C)

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PREVALENCE OF FD IN YOUNG STROKE PATIENTS

• Asia: 0.62%

• Western Countries: 0.88%

Lee et al. European Journal Neurology. 2019; 26: 553-555.

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SUMMARY

• Fabry Disease (FD) leads to an accumulation of glycolipids in

endothelial cells

• FD impacts multiple organ systems, most severely the cardiac, renal

and central nervous system

• Renal involvement can progress to end stage renal disease

• Cerebral involvement leads to an increased risk for stroke

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ACKNOWLEDGMENT

• Thank you to all the patients and researchers who have made this information possible

• Slides adapted from:• Mohamed G. Atta, MD, MPH, FASN – Professor of Medicine at

Johns Hopkins School of Medicine Division of Nephrology Baltimore, Maryland

• Dawn A. Laney, MS, CGC, CCRC – Assistant Professor/Director Emory Genetic Clinical Trials Center Program Leader, Emory Lysosomal Storage Disease Center Department of Human Genetics Emory University Decatur, Georgia

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PLEASE COMPLETE THE EVALUATION FOR THIS PRESENTATION:

www.jhasim.com/Fabry

THANK YOU

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