Dr Jaya Krishna

Synonyms:
 Anderson-Fabry disease
 Angiokeratoma corporis diffusum
 Alpha –galactosidase A deficiency
 Lysosomal storage disease
 Incidence :1 in 40,000 to 1 in 1,20,000 live births
 seen in all ethnic and racial groups
 Inherited in an X-linked manner (Xq21.3-q22)
 Males- affected earlier, Females- carriers
 X-linked
(Xq21.3-q22)

Deletion

Frame shift

Non sense

Missense

Splice site
 Deficiency of α-galactosidase A

Prevent degradation of sphingolipids (globotriaosylceramide,Gb3)

Gb3 accumulates in lysosome of tissue & fluids

kidneys; cardiac myocytes; autonomic system; cornea; endothelial,

perithelial , & smooth muscle cells of blood vessels; & histiocytic &
reticular cells of connective tissue
 Angiokeratoma

 Pseudoacromegalic facies

 Lower limb edema and lymphedema

 Raynaud like phenomenon

 Sweating abnormalities
ANGIOKERATOMA CORPORIS DIFFUSUM
 Cutaneous hallmark fabry disease

 Appear between ages 5-12y ( males) 8-25 y ( females)

 Pinpoint to 4mm - dark red to blue-black - macular and/or papular
lesions (do not blanch on pressure).
 Males- Bathing trunk area distribution, palms and soles, vermillion
border of lips,
 Females- sparsely distributed (trunk and proximal limbs)
 Variable overlying hyperkeratosis - genitalia and umbilicus
 1/3rd males and 2/3rd females – not have angiokeratomas

other presentations:

 Early angiokeratomas or macular hemangiomas

 Cherry angiomas

 Telangectasia
 Angiomatous lesions vermilion border lip

Angiomatous lesionsmucosa of lower lip

 Angiokeratomas and telangiectatic
vessels ( angiokeratoma corporis
diffusum.)

Dermatoscopicangiokeratomas and
upper dermal vessel tortuosity.
H&E section

Epidermis:

• Epidermal thining
• Orthohyperkeratosis
• Acanthosis at the
periphery

Dermis:

• Dilated capillaries
in papillary dermis
PSEUDOACROMEGALIC
FACIES
• Supraorbital ridges
• Periorbital fullness
• Large bitemporal width
• Busty eyebrows
• Broad nasal base
• Full lips
• Prominent chin
Lower limb edema and
lymphedema

REASON:
• Glycosphingolipid accumulation
• Recurrent edema
• Primary abnormality of lymphatics
• Higher serum levels VEGF-A
 Reduced sweating
Autonomic neuropathy
Substrate accumulation in sweat glands
 Heat intolerance
 Hyperhidrosis
Common in females
Localized to palms and soles
 Cold intolerance
 Abnormal vasoreactivity of digital vessels
- Autonomic dysfunction
- Abnormalities of NO synthetase
- Increased Oxidative stress in vascular
endothelium and smooth muscle
 Development of extremities pain in cold environments
 Fluoroscopic NFC –more bushy capillaries and clusters
EM-Multiple electron-dense inclusions in
a cutaneous vascular endothelial cell
(×9000 magnification)
EM-At highest power (×223,000 magnification) light and
dark bands with a periodicity of 4 to 6 nm are identified.
  Early manifestation- Seen in first decade

 Fabry Pain-proximally radiating pin prick, shooting, burning sensation in hands and
feet

 Triggers- stress, exercise and changes in body temperatures

 Pain declines over time

 PATHOGENESIS

Glycolipid accumulation In Dorsal root ganglia and peripheral nerves

Loss of small myelinated and non myelinated fibres

Loss of dermal unmyelinated fibres

BUT, preservation of large myelinated fibres

 Cornea verticillata
(whorled streaks)
 Does not affect vision
 R/o Amiodarone/chloroquine
usage
 Lenticular changes
 Posterior opacity (fabry
cataract)
 Vascular lesions
 Conjunctiva
 Retina

Vision loss ( secondary to

retinal artery occlusion)
 Isosthenuria ( inability to concentrate urine)
 Microalbuminuria
 Proteinuria Renal disease leading cause of death in
men with Untreated fabry disease
 Renal insufficiency
 Renal failure (ESRD)
 Hypertension and other complications
Kidney biopsy (light microscopy): the purple stain is on the
podocytes where there is the most prominent collection of Gb3 in the
kidney. Courtesy Pr Laura BARISONI, New-York University, New
York, USA
Kidney biopsy (electron
microscopy): glycosphingolipid inclusions
of various size and shape are seen in the cells
of distal tubules of the kidney in Fabry disease.
 LVH in a fabry patient

 Left ventricular hypertrophy

 Arrhythmias
 Myocardial infarction
 Chest pain
 ECG changes mimic MI
 Mitral regurgitation
 Aortic Root dilatation Heart disease is currently the major cause
of death for men and women
 Congestive heart failure Most frequent complication in women
with fabry disease
 Early stroke Stroke and other neurological complications
severely decrease ability to function
may be lethal
 Vertigo/dizziness
 Small vessel ischemia - key feature
 Ischemic or hemorrhagic strokes- early in life
 TIA
 Strokes affecting posterior circulation
Increased prevalence of Factor V leiden
Stroke in a patient affected with
Fabry disease: axial brain MRI
section showing stroke of the left
cerebellar hemisphere that revealed
Fabry disease in an otherwise
asymptomatic 27-year-old male
patient.
Dolichoectasia of the vertebro-basilar circulation:
time of flight magnetic resonance angiographies showing ectatic
vessels in four patients affected with Fabry disease.
• Cornea verticillata
• Conjunctival vessel Chronic Renal Failure
aneurysms
• Retinal vessels
tortuosity
• Fabry cataract
• Hypertension
NON • Left ventricular
CUTANEOUS hypertrophy
FINDINGS • Valvular regurgittions
• Postprandial flank
pain • Coronary vascular
• Diarrhea disease
• Constipation • Arrhythmias
• Malabsorption

Others- Acroparesthesiaa
• High frequency SNHL Cerebrovascular disease
• Tinnitus
• Depression
 Because manifestations are non specific
 Wrong diagnosis is often made initially
Present history
 Detailed History – Past history

Family history

General
 Examination-
Local
 Skin- thorough examination, biopsy

 Eye- slit lamp and fundus exam

 Heart- Echo, MRI, ECG, biopsy

 Renal- urine analysis, GFR, Creatinine clearance

Biopsy

 Brain- MRI

 Annual follow up is necessary

 For Boys
 Enzyme activity level
Electron microscopy- electron
 Molecular study for mutation dense lamellated
 Kidney biopsy ,heart biopsy intracytoplasmic vacuolar
with typical inclusions inclusions ( zebra bodies)
For girls
 Enzyme activity is not reliable
 Polarizing microscopy
 Molecular testing for mutations

 Kidney or heart biopsy

of urine – Birefringent
lipid globules
“maltese crosses”

X-inactivation ( Lyonisation)
All mutated turned off- no symptoms
All mutated turned on- severe like males
Random turned off- variable presentation
 Currently
- helps with testing other family members
- helps predict severity

 Future
- may have different treatments based on
specific mutation
ERT vs Chaperon vs Substrate inhibition
 Established Family history and classic phenotype
Enzyme assay
( leucocytes or plasma or cultured skin
fibroblasts)

 Diagnosis in females or males with atypical presentaion

Molecular analysis ( Gene study )

Any male or female with :
 Intermittent episodes of neuropathic pain

 Angiokeratomas at bathing trunk area

 Corneal verticillata

 Hypohydrosis

 LVH, STROKE & CKD of unknown etiology in young adulthood

 Family history

 Abnormal tissue biopsy with storage

  NON SPECIFIC
 SPECIFIC
- Symptoms management
-Enzyme Replacement (Multidisciplinary approach)
therapy
-substrate inhibition
-chaperon based therapy
-Migalastat ( for patients
with amenable mutations)
-Genetic counselling
 Enzyme Replacement Therapy as soon as diagnosis made
 First treatment for fabry disease was approved by FDA on April
24,2003
 Helps but does not cure
 Better impact if started early
- microscopic level clearance
- prevent or slow progression
 Still has benefit when started late
- study on advanced disease
 Daily oral medication
 Blocks GL3 synthesis ( you can’t store what you don’t have)
 Currently in clinical trials
 Is not mutation specific
When Enzyme Replacement Therapy ?

 All classically affected males as soon diagnosis is made

 Female carriers and atypically affected males ( with marginal

levels of alpha –Gal A ) if clinical manifestations are present

 Patients who have ESRD – this may reduce cardiovascular and

neurological complications of disease
 0.2mg/kg IVI every 2 weeks

1mg/kg IVI every 2 weeks

  Reduction of
 Reduces Gb3 deposition
neuropathic
pain

Value of ERT
 Clear deposits  Improve GIT
from vascular manifestations
smooth muscle

Clear deposits from Glomerulus

endothelial, mesangial and
interstitial cells

 NO SIGNIFICANT EFFECT
• Podocytes
• Distal tubules
• Arterial smooth muscle
 CKD stage 1-2 :
Significantly reduces rate of deterioration of kidney function

 CKD stage 3-5 and Dialysis patients:

Does not fully clear Gb3 deposits from podocytes
Improves neuronal and cardiac manifestations
 Five and ten year graft survivalsimilar in patients with fabry
disease & other causes of ESRD

 Renal transpalnation with ERT is much more superior than

transplantion only

 Causes of death in transplanted patients – CVS and Neuronal

complications
 Angiokeratoma- Liquid nitrogen,
Surgical excision
Electrocoagulation
Lasers- Pulsed dye 585nm
Nd-YAG 1064nm
Combined
 Lymphedema-manual lymphatic drain massage compression
 Hyperhidrosis- Aluminium chloride hexahydrate
Electrophoresis
Botulinum toxin
 Raynaud phenomenon-
- Avoid smoking, cold, vasoconstrictors
- Avoid drugs like losartan
Diltiazem
Fluoxetine
Sildenafil

 Stroke- anti platelets

anticoagulants

 Hearing – Hearing aids

 Avoid
triggers
 Chronic renal failure  Cardiovascular

 ACE inhibitors  Anti hypertensives

 Hemodialysis  Artificial pacemakers

 Allograft transplant  Anti arrhythmics

 Implantable

defibrillators

 Coronary bypass
 Fabry disease is Rare, but not uncommon disease

 Diagnosis needs high index of suspicion

 Screening of all family members of affected patient is

important

 Start ERT as soon as renal manifestations appear

 Treat female carrier once has manifestations

 Autosomal Dominant
 Tiny red papules to warty
in nature
 Dorsum of the fingers
and toes
 Finger tip ulceration +
 family history of chilblain
/Acrocyanosis
 Commonest

 Small red papules on

scrotum & genital area

 Labia majora-
- Angiokeratoma of vulva

Differential diagnosis:
varicocele
 2nd – 4th decade

 Acquired in response
to trauma

 Solitary warty
papules commonly on leg

Differential diagnosis
Seborrheic keratosis,
melanoma,
Pigmented BCC
 At Birth

 Lower extremities in a U/L

distribution- Keratotic plaques

 Klippel-trenaunay syndrome,
Cavernous hemangiomas,
AV fistulas

 D/D –
Verrucous hemangioma
Lymphangioma circumscriptum
• Fitzpatrick’s Dermatology in General medicine 9th edition; ed Atul
B. Mehta & Catherine H. Orteu;2018;2292p

• Rook’s Textbook of dermatology;9th edition;ed Christopher

G,Jonathan B,Tanya B,Robert C,Daniel C;Wiley
Blackwell;2016;81.7p

• Germain: Fabry disease. Orphanet Journal of Rare Diseases 2010

5:30.

• Fabry's disease-yuri A Zarate, MD Yuri A Zarate

DOI:https://doi.org/10.1016/S0140-6736(08)61589-5