Grand RoundsGrand Rounds

CYSTINOSISCYSTINOSIS

Denis Jusufbegovic, M.D.Denis Jusufbegovic, M.D.

University of LouisvilleUniversity of Louisville

Department of Ophthalmology and Visual SciencesDepartment of Ophthalmology and Visual Sciences

10/05/1210/05/12

SubjectiveSubjectiveCC:CC: “bilateral ocular opacities x yrs ” “bilateral ocular opacities x yrs ”

HPIHPI: 11 yo WF referred to pediatric ophthalmology : 11 yo WF referred to pediatric ophthalmology clinic by her nephrologist for re-evaluation of clinic by her nephrologist for re-evaluation of bilateral ocular opacities. These opacities were bilateral ocular opacities. These opacities were initially noted at 2 yrs of age, but have been initially noted at 2 yrs of age, but have been getting worse over last 2-3 yrs. Pt. has no visual getting worse over last 2-3 yrs. Pt. has no visual complaints, ocular pain, redness or photophobia. complaints, ocular pain, redness or photophobia.

POHPOH: Mild hyperopic astigmatism : Mild hyperopic astigmatism

PMHPMH: Fanconi syndrome, stage IV CKD, HTN, h/o : Fanconi syndrome, stage IV CKD, HTN, h/o Rickets, Rickets, hypothyroidism hypothyroidism

Subjective Subjective FHFH: non-contributory : non-contributory

MEDS: Enalapril, Amiloride, Calcitriol, Enalapril, Amiloride, Calcitriol, Levocarnitine, Levocarnitine, Cystagon, Synthroid Cystagon, Synthroid

All:All: NKDA NKDA

ROS:ROS: Negative Negative

ObjectiveObjective

20/25

20/20 P

4 2

4 2O RAPD, brisk

OU

T14

16

VAsc

EOM: Full OU, ortho

ObjectiveObjective

SLE:SLE: ODOD OSOS

ExtExt WNL OU WNL OU

C/SC/S clear OU clear OU

KK diffuse iridescent diffuse iridescent crystals OUcrystals OU

ACAC no C/F OUno C/F OU

I/LI/L wnl, clear OUwnl, clear OU

Anterior segment photoAnterior segment photo

Anterior segment photo of the right eye shows iridescent corneal crystals. Left eye had similar findings.

Corneal photoCorneal photo

This photo shows numerous iridescent corneal crystals involving entire cornea

Corneal photoCorneal photo

This corneal photo shows iridescent corneal crystals

Corneal photoCorneal photo

Slit-lamp beam showing corneal crystals in all corneal layers

Color fundus photosColor fundus photos

Color fundus photos of both eyes demonstrate mild optic disc drusen, otherwise it is unremarkable

Assessment Assessment

11 yo WF with bilateral corneal 11 yo WF with bilateral corneal iridescent crystals, end-stage kidney iridescent crystals, end-stage kidney disease, hypothyroidism and h/o disease, hypothyroidism and h/o rickets. rickets.

Diagnosis: Diagnosis:

Infantile Cystinosis Infantile Cystinosis

TreatmentTreatment

Observation Observation

Topical cysteamine drops discussed Topical cysteamine drops discussed as a therapeutic optionas a therapeutic option

Cystinosis Cystinosis

Metabolic disease characterized by an Metabolic disease characterized by an accumulation of cystine in different organs and accumulation of cystine in different organs and tissuestissues

Three forms exist: infantile (nephropathic), Three forms exist: infantile (nephropathic), intermediate (adolescent), adult (benign) intermediate (adolescent), adult (benign)

Rare disorder affecting 1:100,000-200,000 Rare disorder affecting 1:100,000-200,000 children with incidence of 6 per 100,000 in children with incidence of 6 per 100,000 in Newfoundland, Canada Newfoundland, Canada

Pathogenesis Pathogenesis

Transmitted as an autosomal Transmitted as an autosomal recessive trait recessive trait

Caused by mutation in CTNS gene Caused by mutation in CTNS gene on Chr 17p13 which codes for on Chr 17p13 which codes for lysosomal membrane protein lysosomal membrane protein named cystinosin named cystinosin

Pathogenesis Pathogenesis

Cystine is derived from protein Cystine is derived from protein degradation within the lysosomesdegradation within the lysosomes

It is normally transported through the It is normally transported through the lysosomal membrane to the cytosol lysosomal membrane to the cytosol

Defect in the transport system leads to Defect in the transport system leads to the cellular accumulation of poorly the cellular accumulation of poorly soluble cystine crystals soluble cystine crystals

Pathogenesis Pathogenesis

Clinical Manifestations Clinical Manifestations Infantile cystinosisInfantile cystinosis:: Clinical signs appear between 3-6 mo of ageClinical signs appear between 3-6 mo of age Renal disease (Fanconi syndrome) and extrarenal Renal disease (Fanconi syndrome) and extrarenal

involvement of eyes, liver, pancreas, thyroid, brain, involvement of eyes, liver, pancreas, thyroid, brain, etcetc

Intermediate cystinosis Intermediate cystinosis – similar to infantile similar to infantile but starts after 8 yrs of age and milder involvementbut starts after 8 yrs of age and milder involvement

Adult Adult – generally asymptomatic but may have photophobia

Ocular manifestation Ocular manifestation

Affects multiple ocular tissuesAffects multiple ocular tissues

Corneal crystals are the pathognomonic Corneal crystals are the pathognomonic ophthalmic manifestation of cystinosis and ophthalmic manifestation of cystinosis and are found in the epithelium, stroma, and are found in the epithelium, stroma, and endotheliumendothelium

Accumulation of crystals in the cornea Accumulation of crystals in the cornea starts in infancy and usually leads to starts in infancy and usually leads to photophobia and blepharospasms, but they photophobia and blepharospasms, but they don’t affect visual acuitydon’t affect visual acuity

A childhood nephropathic cystinosis patient displays typical fair features and photophobia.

Krachmer: Cornea, 3rd ed. - 2010 - Mosby, An Imprint of Elsevier

Anterior segment SD-OCT of a patient with ocular cystinosis shows hyperreflective deposits in the stroma and endothelium likely representing cystine crystals

Guignier, B etc. Archives of Ophthalmology, August 2012, p 1018

Ocular manifestation Ocular manifestation

Crystals are also found in the conjunctiva, iris Crystals are also found in the conjunctiva, iris and ciliary body, choroid, fundus, and optic and ciliary body, choroid, fundus, and optic nervenerve

Risk of glaucoma increases with age due to Risk of glaucoma increases with age due to crystal accumulation in the ciliary body ( CB ) crystal accumulation in the ciliary body ( CB ) and trabecular meshwork ( TM ) and trabecular meshwork ( TM )

Angle closure glaucoma can occur from Angle closure glaucoma can occur from plateau iris-like syndrome due to crystal plateau iris-like syndrome due to crystal deposition in the ( CB )deposition in the ( CB )

Ocular manifestation Ocular manifestation Retinal involvement is most commonly manifested Retinal involvement is most commonly manifested

by patches of depigmentation with pigmentary by patches of depigmentation with pigmentary mottlingmottling

Pigmentary abnormality is confined to the Pigmentary abnormality is confined to the periphery in the early stagesperiphery in the early stages

Fluorescein angiography shows window defects Fluorescein angiography shows window defects corresponding to the patches of depigmentationcorresponding to the patches of depigmentation

Posterior progression of pigmentary abnormalities Posterior progression of pigmentary abnormalities can lead to vision loss in 15% of casescan lead to vision loss in 15% of cases

Ophthalmic manifestations of infantile nephropathiccystinosis: corneal crystals (A), iris crystals (B),retinal crystals (C ), peripheral retinal pigmentary changes (D)

Tsilou E, Zhou M, Gahl W, Sieving PC, Chan CC.Ophthalmic manifestations and histopathology of infantile nephropathic cystinosis: report of a case and review of the literature. Surv Ophthalmol. 2007 Jan-Feb;52(1):97-105.

DiagnosisDiagnosis

Confirmed by determining the cystine Confirmed by determining the cystine content of peripheral blood leukocyte content of peripheral blood leukocyte or fibroblastsor fibroblasts

5 to 15 nmol/mg protein in the 5 to 15 nmol/mg protein in the infantile forminfantile form

3 to 6 in the intermediate 3 to 6 in the intermediate less than 1 in heterozygous carriersless than 1 in heterozygous carriers less than 0.2 in normal individuals less than 0.2 in normal individuals

Treatment of Corneal Treatment of Corneal InvolvementInvolvement

Cysteamine hydrochloride 0.55% (50 mM) solution Cysteamine hydrochloride 0.55% (50 mM) solution with benzalkonium chloride 0.01%with benzalkonium chloride 0.01%

Used 10 -12 times per dayUsed 10 -12 times per day

Reacts with cystine to produce cysteine, which is a Reacts with cystine to produce cysteine, which is a soluble molecule that leaves lysosome soluble molecule that leaves lysosome

Cysteamine is unstable and oxidizes rapidly Cysteamine is unstable and oxidizes rapidly

Should be stored in the frozen state and used within Should be stored in the frozen state and used within one week at room temperatureone week at room temperature

Pharmacies Pharmacies National Institutes of Health (NIH)Eye National Institutes of Health (NIH)Eye

ClinicClinic

Alana Temple, RN Clinical Trials Alana Temple, RN Clinical Trials Coordinator Coordinator Phone: (301) Phone: (301)

402-1369 402-1369 Email: Email: templeal@nei.nih.govtempleal@nei.nih.gov

Leiter's Pharmacy 1700 Park Avenue Leiter's Pharmacy 1700 Park Avenue Suite 30 San Jose CA 95126 Toll free Suite 30 San Jose CA 95126 Toll free (800) 292-6773 or (408) 292-6772 (800) 292-6773 or (408) 292-6772 www.leiterrx.comwww.leiterrx.com

Aurora Pharmacy 3284 W. Main St. Aurora Pharmacy 3284 W. Main St. East Troy, WI 53120 Phone: (262) East Troy, WI 53120 Phone: (262) 642-5800642-5800

Mark Drugs Pharmacy 384 E. Irving Mark Drugs Pharmacy 384 E. Irving Park Road Roselle, IL 60172 Phone: Park Road Roselle, IL 60172 Phone: (630) 529-3400 www.markdrugs.com(630) 529-3400 www.markdrugs.com

Premier Pharmacy Labs Inc. 8269 Premier Pharmacy Labs Inc. 8269 Commercial Way Spring Hill, FL Commercial Way Spring Hill, FL 34639 Phone: (800) 752-7139 Fax: 34639 Phone: (800) 752-7139 Fax: (800) 868-4978 (800) 868-4978 www.rxnations.com Email: vet528@tampabay.rr.com Email: vet528@tampabay.rr.com

Hoosier Prescription Shop 3020 S. 7th Hoosier Prescription Shop 3020 S. 7th St. Terre Haute, IN Phone: (812) 232-St. Terre Haute, IN Phone: (812) 232-96469646

Alberta Children's Hosptial in Calgary Alberta Children's Hosptial in Calgary Phone: (403) 955-7303 Maryanne Phone: (403) 955-7303 Maryanne MacDonald for further information.MacDonald for further information.

© 2012 Cystinosis Research Network

Thank youThank you

ReferencesReferences

1.1.Gahl WA, Thoene JG, Schneider J. Cystinosis. N Engl J Med.2002;347:111–Gahl WA, Thoene JG, Schneider J. Cystinosis. N Engl J Med.2002;347:111–121.121.

2.2.Kaiser-Kupfer MI, Caruso RC, Minkler DS, et al: Long-term ocular Kaiser-Kupfer MI, Caruso RC, Minkler DS, et al: Long-term ocular manifestations in nephropathic cystinosis. Arch Ophthalmol 104:706--11, 1986manifestations in nephropathic cystinosis. Arch Ophthalmol 104:706--11, 1986

3.3.Tsilou E, Zhou M, Gahl W, Sieving PC, Chan CC.Tsilou E, Zhou M, Gahl W, Sieving PC, Chan CC.Ophthalmic manifestations Ophthalmic manifestations and histopathology of infantile nephropathic cystinosis: report of a case and and histopathology of infantile nephropathic cystinosis: report of a case and review of the literature. Surv Ophthalmol. 2007 Jan-Feb;52(1):97-105.review of the literature. Surv Ophthalmol. 2007 Jan-Feb;52(1):97-105.

4.4.Yamamoto GK, et al. Long-term ocular changes in cystinosis: observations in Yamamoto GK, et al. Long-term ocular changes in cystinosis: observations in renal transplant recipients. J Pediatr Ophthalmol.1979;16:16–21.renal transplant recipients. J Pediatr Ophthalmol.1979;16:16–21.

5.5.Zimmerman TJ, Hood I, Gasset AF. ‘Adolescent’ cystinosis: a case report and Zimmerman TJ, Hood I, Gasset AF. ‘Adolescent’ cystinosis: a case report and review of the literature. Arch Ophthalmol. 1974;92:265review of the literature. Arch Ophthalmol. 1974;92:265