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

8/28/2014 Disclosure  Speakers bureau: Genzyme Pi Pinakin Davey OD, PhD, FAAO ki D OD PhD FAAO Professor Western University of Health Sciences College of Optometry Fabry Disease Overview Contents Silently progressive Disease overview Cellular substrate (globotriaosylceramide, or GL ‐ 3) progressively accumulates, beginning at birth or before, regardless of overt Pathophysiology symptoms I h Inheritance i Increasingly debilitating l d b l Signs and symptoms Without intervention, GL ‐ 3 build ‐ up can result in irreversible life ‐ threatening organ damage Diagnosis Often life ‐ threatening Disease management Resources Impacts quality of life and affects key organ function CONFIDENTIAL CONFIDENTIAL FOR INTERNAL USE ONLY FOR INTERNAL USE ONLY Pathophysiology of Fabry Disease Light microscopy of the renal capillary endothelium. Disease overview Deficiency of the lysosomal enzyme alpha ‐ galactosidase A Pathophysiology ( α‐ GAL)  Inheritance Signs and symptoms Leads to progressive substrate accumulation of globotriaosylceramide (GL ‐ 3) Diagnosis  GL ‐ 3 accumulates in the renal capillary Disease management endothelium (see arrows), among other cells. Results in organ dysfunction Resources Over time, the build ‐ up can cause irreversible organ damage and death. 1

8/28/2014 Pathophysiology of Fabry Disease Disease overview Inability to • In tissues lower GL ‐ 3 throughout the body Pathophysiology Inheritance Multisystemic l • Begins in B i i Signs and symptoms signs & childhood or symptoms adolescence Diagnosis Disease management Life ‐ • Renal failure • Heart disease threatening Resources • Stroke complications Fabry Disease Inheritance Fabry Disease Inheritance X ‐ linked (dominant) disease α‐ GAL gene located AFFECTED FATHER | HEMIZYGOTES on the X chromosome No male ‐ to ‐ male transmission Males with the defective gene are always affected Will pass defective gene to all daughters, but no sons Females with the defective gene are affected to varying degrees, possibly due to skewed X inactivation Fabry Disease Inheritance Fabry Mutations and Enzyme Activity  -Galactosidase A Levels In Various  More than 420 mutations Populations 1 documented 2 AFFECTED MOTHER | HETEROZYGOTES TYPE % of NORMAL PLASMA  -GAL*  Most mutations result in <1% 50% risk of passing defective Hemizygotes Usually less than 1% gene to both sons and residual enzyme activity in (males) daughters hemizygotes; 0 to 100% yg ; Heterozygotes 0-100% (females) residual enzyme activity in Atypical Variant <5-35% heterozygotes Sons who inherit gene will have (patients with Fabry disease symptoms limited to  Females may have higher one organ system) •  -GAL levels can vary considerably levels of enzyme since they depending on the tissue or cell type assayed have a second (non ‐ Daughters will have disease defective) α‐ GAL gene manifestations to varying 1. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A degrees 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. 2

8/28/2014 Early Signs and Symptoms Disease overview Pathophysiology Inheritance Lysosomal Signs and symptoms storage of GL ‐ 3 Diagnosis begins early in life Disease management Resources Early Signs and Symptoms Later Signs and Symptoms Without the GL ‐ 3 ability to lower accumulation GL ‐ 3, causes life ‐ threatening increasingly complications damaging develop manifestations Fabry Disease in Children & Multisystemic Manifestations Adolescents Clinical Presentation to a Range of Specialists Neuropathic pain (often in the extremities) Pain crises Pediatricians Neurologists Angiokeratomas (skin lesions) Nephrologists Corneal whorling/corneal verticillata (pattern visible with slit lamp ophthalmoscopy) (pattern visible with slit lamp ophthalmoscopy) Cardiologists Heat/cold or exercise intolerance Primary Care Physicians Hypohidrosis or anhidrosis Ophthalmologists and Optometrists Dermatologists Postprandial pain, diarrhea, nausea, or vomiting Gastroenterologists Mild proteinuria (important to treat) Pain Specialists While symptoms primarily affect quality of life in childhood, they progress to Psychologists/psychiatrists life-threatening manifestations by adulthood 3

8/28/2014 Manifestations: Brain Fabry Disease in Children & Adolescents 1. Gibas, A. et al. A Intermittent neuropathic pain survey of the pain experienced by males and females ‐ Chronic burning, tingling pain with Fabry disease. Pain Res Manag. ‐ Usually in the extremities 2006 Autumn; 11(3) 185–192. http://www.ncbi.nlm. Symptoms often mistaken for those of other disorders, including: 1 Episodic “Fabry crises” of agonizing, incapacitating pain nih.gov/pmc/articles/ PMC2539000/. Accessed 2-29-12. ‐ Can last minutes to days 2. Hoffman B. et al. Nature and Nature and ‐ Can disappear or worsen in adulthood prevalence of pain in Fabry disease and its ‐ Experienced by 80% ‐ 90% of patients 1,2 juvenile arthritis growing pains rheumatic fever response to enzyme replacement therapy- -a retrospective analysis from the Recurrent fever Fabry Outcome Survey. Clin J Pain. ‐ Accompanying pain 2007 Jul- Aug;23(6):535-42. http://www.ncbi.nlm. nih.gov/pubmed/175 75495 Accessed Heat/cold or exercise intolerance 2/29/12. Hypohidrosis or anhidrosis 1. Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr 2004;144:20-26. Manifestations: Brain Manifestations: Kidney GL-3 in kidney cells causes progressive damage Early stroke microalbuminaria Transient ischemic attacks p proteinuria V ti Vertigo/dizziness /di i decrease in glomerular filtration rate (GFR) Tinnitus elevated serum creatinine Head pain White matter lesions on MRI, demonstrating evidence of renal failure cerebrovascular infarct Hemiataxia/ataxia of gait Manifestations: Heart Manifestations: Heart Left ventricular Hypertrophic hypertrophy cardiomyopathy (LVH) Impaired Arrhythmias diastolic function Severe left ventricular hypertrophy in a 50-year-old Valvular disease patient with Fabry disease. Conduction GL ‐ 3 accumulation in cardiac vascular (especially mitral abnormalities endothelial cells (yellow arrow) and insufficiency) cardiomyocytes (green arrow) 4

8/28/2014 Manifestations: Gastrointestinal Manifestations: Dermatologic Angiokeratomas Diarrhea “Bathing trunk” distribution Can significantly Pain and bloating after eating Non ‐ blanching lesions affect quality of life Early satiety Dark red to blue ‐ black color S Some patients report i spending hours per day in Nausea and vomiting Appear in adolescence the bathroom Weight loss Worsen in adulthood Hypohidrosis or Anhidrosis Reduced or absence of sweating Fabry Disease: Ocular Manifestations: Eye Manifestations Cornea Verticillata in Fabry Corneal and Lenticular Opacities Whorl-like Corneal Rays  The most common ocular finding  Whorl ‐ like sub ‐ epithelial and Only visible by slit ‐ lamp epithelial deposits  Cream ‐ colored: white to bronze  C  Can be seen as early as 6 months of age b l 6 th f Usually does not affect vision in hemizygote  Can be seen as early as 3 years of age in heterozygote With permission of RL Abbott, MD  Present in almost all males by age 4 Useful diagnostic indicator  Present in most females by age 10 Found almost universally among males, and in approximately 70% of females with Fabry disease 1 Archives Ophthalmol 1979; 97:671-76. 1. Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr 2004;144:20-26. 28 Fabry Disease: Ocular manifestations Corneal Whorling Courtesy of Roscoe Brady, MD Video Courtesy Pinakin Davey OD, PhD 29 5

8/28/2014 Fabry Disease: Ocular Fabry Disease: Ocular Manifestations Manifestations Fabry Cataract 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 (Personal files of Edward M. Kaye, MD) 31 32 Fabry Disease: Ocular Fabry Disease: Ocular Manifestations Manifestations Conjunctival and Retinal Vascular Lesions Conjunctival Vessels in Fabry vey OD, PhD  26 year old hemizygote  Typical Conjunctival Involvement  Note the sausage ‐ like and h l k d Image Courtesy Pinakin Dav markedly dilated vessels  Small vessels of the conjunctive Vascular tortuosity often show aneurysmal dilations, tortuosity and kinking 33 34 Conjunctival aneurysms vey OD, PhD vey OD, PhD Image Courtesy Pinakin Dav Image Courtesy Pinakin Dav 6

8/28/2014 Presumed Fabry cataract vey OD, PhD vey OD, PhD Image Courtesy Pinakin Dav Image Courtesy Pinakin Dav 7

8/28/2014 Vision 20/20 but quality of vision???? Subjects were asked to rate Sample size Results  75 patients with confirmed fabrys disease Question P value  Mean age 32.5 SD 19 years 0.06 Burning / stinging 0 6 0.6 Tearing Tearing  20 healthy subject 0.02* Dryness  Mean age 42.6 SD 14.7 years 0.3 Itching 0.009* * Soreness/ tiredness  Statistical analysis Mann Whitney U test. 8