Disclosure Speakers bureau: Genzyme Pi Pinakin Davey OD, PhD, FAAO - - PDF document

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Pi ki D OD PhD FAAO Pinakin Davey OD, PhD, FAAO Professor Western University of Health Sciences College of Optometry

Disclosure

 Speakers bureau: Genzyme

Contents

Disease overview Pathophysiology I h i Inheritance Signs and symptoms Diagnosis Disease management Resources

Fabry Disease Overview

Silently progressive

Cellular substrate (globotriaosylceramide, or GL‐3) progressively accumulates, beginning at birth or before, regardless of overt symptoms

l d b l Increasingly debilitating

Without intervention, GL‐3 build‐up can result in irreversible life‐threatening organ damage

Often life‐threatening

Impacts quality of life and affects key organ function

CONFIDENTIAL FOR INTERNAL USE ONLY CONFIDENTIAL FOR INTERNAL USE ONLY

Disease overview Pathophysiology Inheritance Signs and symptoms Diagnosis Disease management Resources

Pathophysiology of Fabry Disease

Deficiency of the lysosomal enzyme

alpha‐galactosidase A (α‐GAL)

Light microscopy of the renal capillary endothelium.



Leads to progressive substrate accumulation of

globotriaosylceramide (GL‐3)

Results in

• rgan dysfunction

GL‐3 accumulates in the renal capillary endothelium (see arrows), among other cells. Over time, the build‐up can cause irreversible organ damage and death.



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Pathophysiology of Fabry Disease

Inability to

lowerGL‐3

• In tissues

throughout the body l B i i Multisystemic

signs &

symptoms

• Begins in

childhood

• r

adolescence

Life‐

threatening

complications

• Renal failure
• Heart disease
• Stroke

Disease overview Pathophysiology Inheritance Signs and symptoms Diagnosis Disease management Resources

Fabry Disease Inheritance

X‐linked (dominant) disease α‐GAL gene located

• n the X chromosome

Males with the defective gene are always affected Females with the defective gene are affected to varying degrees, possibly due to skewed X inactivation

Fabry Disease Inheritance

No male‐to‐male transmission

AFFECTED FATHER | HEMIZYGOTES

Will pass defective gene to all daughters, but no sons

Fabry Disease Inheritance

50% risk of passing defective gene to both sons and daughters

AFFECTED MOTHER | HETEROZYGOTES

Sons who inherit gene will have Fabry disease Daughters will have disease manifestations to varying degrees

Fabry Mutations and Enzyme Activity

 More than 420 mutations documented2  Most mutations result in <1% residual enzyme activity in hemizygotes; 0 to 100%

-Galactosidase A Levels In Various Populations1

TYPE % of NORMAL PLASMA -GAL* Hemizygotes (males) Usually less than 1% Heterozygotes 0-100%

yg ; residual enzyme activity in heterozygotes

 Females may have higher

levels of enzyme since they have a second (non‐ defective) α‐GAL gene

(females) Atypical Variant (patients with symptoms limited to

• ne organ system)

<5-35%

• -GAL levels can vary considerably

depending on the tissue or cell type assayed

1. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency:Fabry disease. In: Scriver C, Beaudet A, Sly W, et al., eds. Metabolic andMolecular Bases of Inherited Disease. New York: McGraw Hill, 2001:3733-3774. 2. Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.

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Disease overview Pathophysiology Inheritance Signs and symptoms Diagnosis Disease management Resources

Early Signs and Symptoms

Lysosomal storage of GL‐3 begins early in life

Early Signs and Symptoms

GL‐3 accumulation causes increasingly damaging manifestations

Later Signs and Symptoms

Without the ability to lower GL‐3, life‐threatening complications develop

Multisystemic Manifestations

Pediatricians Neurologists Nephrologists

Clinical Presentation to a Range of Specialists

Cardiologists Primary Care Physicians Ophthalmologists and Optometrists Dermatologists Gastroenterologists Pain Specialists Psychologists/psychiatrists

Fabry Disease in Children & Adolescents

Neuropathic pain (often in the extremities) Pain crises Angiokeratomas (skin lesions) Corneal whorling/corneal verticillata (pattern visible with slit lamp ophthalmoscopy) (pattern visible with slit lamp ophthalmoscopy) Heat/cold or exercise intolerance Hypohidrosis or anhidrosis Postprandial pain, diarrhea, nausea, or vomiting Mild proteinuria (important to treat)

While symptoms primarily affect quality of life in childhood, they progress to life-threatening manifestations by adulthood

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Fabry Disease in Children & Adolescents

Symptoms often mistaken for those of other disorders, including:1 juvenile arthritis growing pains rheumatic fever

1. Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr 2004;144:20-26.

Manifestations: Brain

Intermittent neuropathic pain ‐ Chronic burning, tingling pain ‐ Usually in the extremities Episodic “Fabry crises” of agonizing, incapacitating pain ‐ Can last minutes to days

1. Gibas, A. et al. A survey of the pain experienced by males and females with Fabry disease. Pain Res Manag. 2006 Autumn; 11(3) 185–192. http://www.ncbi.nlm. nih.gov/pmc/articles/ PMC2539000/. Accessed 2-29-12. 2. Hoffman B. et al. Nature and

‐ Can disappear or worsen in adulthood ‐ Experienced by 80%‐90% of patients1,2 Recurrent fever ‐ Accompanying pain Heat/cold or exercise intolerance Hypohidrosis or anhidrosis

Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy-

• a retrospective

analysis from the Fabry Outcome

• Survey. Clin J Pain.

2007 Jul- Aug;23(6):535-42. http://www.ncbi.nlm. nih.gov/pubmed/175 75495 Accessed 2/29/12.

Manifestations: Brain

Early stroke Transient ischemic attacks V ti /di i Vertigo/dizziness Tinnitus Head pain Hemiataxia/ataxia of gait

White matter lesions on MRI, demonstrating evidence of cerebrovascular infarct

Manifestations: Kidney

microalbuminaria proteinuria

GL-3 in kidney cells causes progressive damage

p decrease in glomerular filtration rate (GFR) elevated serum creatinine renal failure

Manifestations: Heart

Left ventricular hypertrophy (LVH) Hypertrophic cardiomyopathy Arrhythmias Impaired diastolic function Conduction abnormalities Valvular disease (especially mitral insufficiency)

GL‐3 accumulation in cardiac vascular endothelial cells (yellow arrow) and cardiomyocytes (green arrow)

Manifestations: Heart

Severe left ventricular hypertrophy in a 50-year-old patient with Fabry disease.

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Manifestations: Gastrointestinal

Diarrhea Pain and bloating after eating Early satiety Can significantly affect quality of life

S i

Nausea and vomiting Weight loss

Some patients report spending hours per day in the bathroom

Manifestations: Dermatologic

“Bathing trunk” distribution Non‐blanching lesions Dark red to blue‐black color

Angiokeratomas

Appear in adolescence Worsen in adulthood

Hypohidrosis or Anhidrosis

Reduced or absence of sweating

Manifestations: Eye

Only visible by slit‐lamp

Corneal and Lenticular Opacities Whorl-like Corneal Rays

Usually does not affect vision Useful diagnostic indicator Found almost universally among males, and in approximately 70% of females with Fabry disease1

With permission of RL Abbott, MD 1. Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr 2004;144:20-26.

Fabry Disease: Ocular Manifestations

Cornea Verticillata in Fabry

 The most common ocular finding  Whorl‐like sub‐epithelial and epithelial deposits  Cream‐colored: white to bronze  C b l 6 th f  Can be seen as early as 6 months of age in hemizygote  Can be seen as early as 3 years of age in heterozygote  Present in almost all males by age 4  Present in most females by age 10

28

Archives Ophthalmol 1979; 97:671-76.

Fabry Disease: Ocular manifestations

Corneal Whorling

29

Courtesy of Roscoe Brady, MD

Video Courtesy Pinakin Davey OD, PhD

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Fabry Disease: Ocular Manifestations

Fabry Cataract; posterior lens opacity

 Linear and appear as a whitish translucent deposit on the posterior lens capsule  May be the first ocular manifestation  Best seen by retro‐illumination  Found in 35% of hemizygotes and 15% of heterozygotes

31

(Personal files of Edward M. Kaye, MD)

Fabry Disease: Ocular Manifestations

Fabry Cataract

32

Fabry Disease: Ocular Manifestations

Conjunctival and Retinal Vascular Lesions

 26 year old hemizygote  Typical Conjunctival Involvement h l k d  Note the sausage‐like and markedly dilated vessels  Small vessels of the conjunctive

• ften show aneurysmal dilations,

tortuosity and kinking

33

Conjunctival Vessels in Fabry

Fabry Disease: Ocular Manifestations

vey OD, PhD

34

Vascular tortuosity

Image Courtesy Pinakin Dav

Conjunctival aneurysms

vey OD, PhD Image Courtesy Pinakin Dav vey OD, PhD Image Courtesy Pinakin Dav

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vey OD, PhD Image Courtesy Pinakin Dav vey OD, PhD

Presumed Fabry cataract

Image Courtesy Pinakin Dav

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Vision 20/20 but quality of vision????

Subjects were asked to rate Sample size

 75 patients with confirmed fabrys disease

 Mean age 32.5 SD 19 years

 20 healthy subject

 Mean age 42.6 SD 14.7 years

 Statistical analysis Mann Whitney U test.

Results

Question P value Burning / stinging 0.06 Tearing 0 6 Tearing 0.6 Dryness 0.02* Itching 0.3 Soreness/ tiredness 0.009* *

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Results cont…

Question P value Blurry/ Dim vision 0.02* Feeling of something in your 0 07 Feeling of something in your eyes 0.07 Hard to see in daylight; I need to wear sunglasses 0.15 Hard to see in dark places 0.01* Halos around light 0.01*

Summary of results

 The survey indicates that the patients with Fabry disease may have A ild d

 A mild dry eye  Contrast sensitivity issue particularly in dark  Fatigue  Glare problems

Fabry Disease in Women

Disease severity varies widely in females

(from virtually symptom‐free to more classical male profile of manifestations)

Contradicts older literature that suggests females were strictly carriers Skewed X‐inactivation may play a role in disease variability among females

Fabry Disease in Women

Diminished Life Expectancy

• 1. Waldek S, Patel M,

Banikazemi M, Lemay R, Lee P. Life Expectancy and Cause of Death in Males and Females with Fabry Disease: with Fabry Disease: Findings from the Fabry Registry. Genet

• Med. 2009; 11:790-

796.

N= 1,748

Fabry Disease in Women

Added Challenges

Faced by Women with Fabry Disease

May have been told for years that they were only a “carrier” Often place a greater priority on the health of their family than their own personal health May feel their disease is not as bad as their son’s or their father’s, and may not seek care May be experiencing feelings of guilt

Fabry Disease in Women

18%

• f women with Fabry disease

18%

• f women with Fabry disease

have had at least one serious renal, cardiovascular,

• r stroke event.

N= 1,748 Source: Fabry Registry

Regular follow-up and timely care is as critical in women as it is in men with Fabry disease.

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Disease overview Pathophysiology Inheritance Signs and symptoms Diagnosis Disease management Resources

Recognizing Fabry Disease

Disease usually presents in childhood, yet disease often goes unrecognized until adulthood1,2 (when underlying pathology is advanced) Patients may see a range of specialists before the disease is recognized

1. Shelley ED, Shelley WB, Kurczynski TW. Painful fingers, heat intolerance, and telangiectases of the ear: easily ignored childhood signs of Fabry disease. Pediatr Dermatol 1995; 12:215‐9. 2. Menkes DL, O'Neil TJ, Saenz KK. Fabry's disease presenting as syncope,

Delayed diagnosis may be due to under‐recognition of early signs and symptoms Symptoms of Fabry disease similar to those of other more common disorders

angiokeratomas, and spoke‐like cataracts in a young man: discussion of the differential diagnosis. Mil Med 1997; 162:773‐6.

Potential Misdiagnoses

Misleading symptom Disease Pain in the joints, elevated erythrocyte sedimentation rate Rheumatoid or juvenile arthritis Pain accompanied by fever and elevated erythrocyte sedimentation rate Rheumatic fever erythrocyte sedimentation rate Acute pain in the extremities Erythromelalgia Acute pain with no apparent cause Neurosis Unexplained pain in extremities “Growing pains” Pain and temperature sensitivity in the extremities Raynaud’s syndrome Stroke‐like events in brainstem structures Multiple sclerosis Angiokeratomas Petechiae

Recognizing Fabry Disease

Symptom Onset Diagnosis

Gap between symptom onset and diagnosis1

(N= 890) (N= 1,123)

• 1. Wilcox et al 2008; Mol Genet Metab; 93:112-28

(N= 581) (N= 1,018)

When to Suspect Fabry Disease

Fabry disease should be considered in the differential diagnosis of patients presenting with a constellation of symptoms that may include:

Unexplained episodes of pain unresponsive to conventional analgesics Unexplained pain in the extremities Corneal opacities Unexplained Unexplained conventional analgesics Heat, cold, and exercise intolerance Unexplained GI disturbances Mild proteinuria Proteinuria Unexplained renal dysfunction Positive family history of early kidney disease Unexplained cardiomyopathy, especially left ventricular hypertrophy Valvular abnormalities Positive family history of early stroke

Establishing a Diagnosis

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Disease overview Pathophysiology Inheritance Signs and symptoms Diagnosis Disease management Resources

After Diagnosis: Family Screening

X‐linked pattern makes it easy to determine who is at risk When you identify a Fabry patient, you identify a Fabry family

Comprehensive Disease Management

Supportive Regular, ongoing follow‐up Disease‐specific Optimal Patient Care Supportive therapy Disease‐specific intervention

Regular Follow‐Up

Progressive disease with multisystemic effects Regular assessments recommended Supportive therapies and disease‐specific intervention as indicated

Supportive Therapy

Pain management ACEI/ARBs Dialysis Kidney transplant Cardiac pacing Antidepressants/psychotherapy Hearing aids Disease overview Pathophysiology Inheritance Signs and symptoms Diagnosis Disease management Resources

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Fabry Registry

Goals of the Fabry Registry

Assist with the Enhance the understanding of the variability, progression and natural history of Fabry disease Assist with the development of patient monitoring recommendations and reports to help clinicians optimize care Evaluate the long‐ term safety and effectiveness of enzyme replacement therapy

Online Patient Resources

Fabry Community (Genzyme) www.fabrycommunity.com Fabry Support and Information Group
www.fabry.org National Fabry Disease Foundation (NFDF)
www.thenfdf.org National Kidney Foundation
www.kidney.org

Fabry specific sites in the United States

New England Fabry Support Group
www.negsg.org Genetic Alliance www.geneticalliance.org National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health
www.ninds.nih.gov National Organization for Rare Disorders (NORD)
www.rarediseases.org

Lysosomal storage/genetic/rare disease sites in the United States

Summary

Silently progressive, increasingly debilitating, often life‐threatening disease Inherited (X‐linked), so one diagnosis can lead to many within a family Progressive GL‐3 accumulation leads to debilitating multisystemic symptoms and potentially fatal complications Can be challenging to identify, but is easy to diagnose Early diagnosis may prevent irreversible

• rgan damage