FABRY DISEASERoshan Gunathilake MDJohn Hunter HospitalNewcastle, Australia

Case report44 year-old-manR/weakness, gait ataxia and

nausea x 4 hoursRecurrent posterior circulation

ischemic stroke /TIAsRenal Transplant 2 yrs agoTreated HTN

BackgroundCKD 2ry to FSGS 6 yrs agoHD x 4 yrsCadaveric renal transplant 2 yrs agoOn MMF, Tacrolimus & prednisoloneStable renal function, No Hx graft

rejectionNo Hx opportunistic infections /

malignancyHTN (irbesartan) x 8yrs, no other

vascular risk factors

HistoryRecurrent transient vertigo 4

months ago, but no signs of brain stem dysfunction

Transient gait ataxia, andR/occipital infarction 3 months

agoNormal work up incl. metabolic

panel, Holter, TTE, Carotid duplex, MRA and thrombophilia screen

Started on clopidogrel + statin

Sudden onset L/ hemiparesis, ataxia, dysarthria and nausea

No diplopia, facial weakness, vertigo, dysphagia or sensory loss

Symptoms started improving after 6-8 hrs, resolving after 24-48 hrs

No cardiac HxNo Hx of acroparesthesiaNo family Hx of stroke,

premature vascular disease or kidney disease

No Hx of alcohol, tobacco or drug abuse

Physical ExamResidual L/visual field defect,

otherwise normal CR N examL/ pronator drift, Grade 4

weaknessNo sensory deficitsNo cerebellar signsGait?

Physical ExamNormal skin + corneaHR 84/min SRPeriph pulses+BP 138/84S1S2, no murmur/ carotid bruitLungs clearAbdo transplant kidney

ImagingCT Brain: old

R/occipital strokeMRI brain : new

lesion of high intensity in the right pons on T2-weighted images

Differential diagnosis of recurrent stroke/ TIAsCardioembolismPremature atherosclerotic disease ±

atheroembolismDissectionCerebral vasculitisInfectionAtrial Septal abnormalitiesSubstance abuseThrombophiliaRare: Fabry disease, MELAS, CADASIL

InvestigationsESR 13Hb 145 WBC 5.4PLT 235Cr 112LFTs normalLipid profile

normalFBSL 4.9CXR - NAD

Vasculitic screen –ve

Syphilis serology –ve

S.homocysteine normal

CSF exam – normal protein, glucose, cells & microscopy; no oligoclonal bands

-ve VZV PCR

Cardiac InvestigationsECG - SR, LVH24 h telemetry -

NADTTE – LVH,

“binary apperance”

TOE – No septal defect/ PFO, No intracardiac source of thrombi

InvestigationsPlasma α-galactosidase A activity

very low (on 2 occasions)Pedigree analysis : no other

affected family members

Referred to Statewide Fabry disease service for consideration for counseling, genetic testing and ?ERT

Fabry DiseaseX-linked inborn error of

metabolismDeficient -Galactosidase A

enzyme activityProgressive

globotriaosylceramide (GL-3) accumulation

Severe endothelialGL-3 accumulation

The classical phenotype

Early (adolescence)◦Acroparesthesia, ◦Angiokeratomas, anhydrosis◦Corneal opacities

Late (4th- 5th decade)◦Renal failure◦Recurrent stroke◦Cardiomyopathy

Fabry Disease Progression

0

Acroparesthesia

Renal Disease

CNS Disease

Cardiac Disease

[Age] 40+

Diagnosis (average)

The later-onset phenotype

Residual α-galactosidase A activity due to missense and splicing mutations

Lack the early manifestations Typically present with cardiac,

renal or cerebrovascular manifestations

Diagnosis of Fabry Disease

Presumptive diagnosis – observation of symptoms and laboratory

findings– family history/medical pedigree

Definitive diagnosis – enzyme assay in plasma, leukocytes, or

biopsied tissue– gene mutation analysis or linkage

analysis

Fabrazyme® Shown in randomized, double-blind,

placebo-controlled trials to be safe and effective at 1 mg/kg every 2 weeks

Clear the vascular endothelial glycolipid deposits and reverse, stabilize or markedly improve symptoms

Early intervention is essential to avoid the irreversible renal, cardiac and cerebro-vascular complications

Cost USD 200,000/ patient per annum