Fabry Disease

Question 1

Describe Fabry disease in general.

Answer 1

X-linked AR lysosomal storage disease; GLA gene
deficiency of alpha-galactosidase A (which converts GL3/Gb3 to GL2)
phenotypic spectrum
females affected to some degree

Question 2

Describe Fabry Type 1 classical phenotype.

Answer 2

no (<1%) alpha-Gal-A activity without functional enzyme
prominent vascular endothelial GL3 accumulation
early onset pain, skin lesions, hypohidrosis, eye changes
late onset: renal, cardiac, cerebrovascular disease, early demise

Question 3

What are the major sites of early GL3 accumulations in Type 1 classic phenotype Fabry disease?

Answer 3

microvascular endothelium and smooth muscle (ischemia and occlusion –> acroparesthesias, hypohidrosis, GI pain, angiokeratomas)
cardiomyocytes (early diastolic dysfunction > LVH and mitral insufficiency in adolescence with arrhythmias later)
renal endothelial, podocytes, and tubular cells (microabluminuria > proteinuria; isosthenuria, sediment inclusion)

Question 4

How does Type 1 classic phenotype Fabry disease manifest in children?

Answer 4

skin- angiokeratoma (normally in genital distribution and on mucus mebranes)
peripheral nervous system- acroparesthesias, excrutiating pain (normally presents 4-9 years old), tingling/burning sensations in extrematies lasting about 2 decades before “burning out” or decreasing in frequency/severity
sweat glands- hypohydrosis
intestine- abdominal pain/diarrhea

Question 5

How does Type 1 classic phenotype Fabry disease manifest in adolescents and adults?

Answer 5

skin, peripheral nervous system, sweat glands, and intestines like children
heart- LVH, HCM, arrhythmias
brain- TIA, stroke (likely due to atrial fibrillation/arrhythmias)
kidney- renal failure (due to vascular glycolipid deposition) requiring dialysis by the age of 35 years and transplant for long term management)

Question 6

Describe Fabry Type 2 later onset phenotype.

Answer 6

residual (>1%) alpha-Gal-A activity; CRIM+
NO vascular endothelial GL-3 accumulation
most lack pain, skin lesions, hypohyrosis, and eye changes
two subtypes (renal and cardiac)

Question 7

What symptoms are associated with Fabry Type 2 later onset renal subtype?

Answer 7

variable but late onset renal failure at 50-80s

Question 8

What symptoms are associated with Fabry Type 2 later onset cardiac subtype?

Answer 8

LVH, myopathy, arrhythmias, proteinuria (but normal renal function for age)

Question 9

Describe phenotypic expression of Fabry disease in female heterozygotes.

Answer 9

affectedness affected by how many affected X chromosomes are active in cells (ratio)
about 15% will be highly affected
activation is tissue specific so tissues with the mutant allele expressed will show phenotype while tissues with the normal allele expressed will not

Question 10

What clinical manifestations are common in Type 1 Fabry disease heterozygotes?

Answer 10

corneal dystrophy (prominent in 90%)
isolated/sparse angiokeratomas
h/o acroparesthesias (mostly tingling, no crises, “burned out”)
mild LVH, mitral valve prolapse, GI symptoms
isosthenuria, microalbuminuria, proteinuria (normal serum creatinine for age and GFR)

Question 11

What clinical manifestations are present in symptomatic Type 1 Fabry disease heterozygotes?

Answer 11

cardiac: significant LVH, cardiomegally, miocardial infarction/ischemia, bradycardia, severe arrhythmias
CNS: abnormal brain MRI (>35 years), TIA/strokes
renal: significant isosthenuria, proteinuria, decreased GFR –> renal insufficiency and failure
QOL: frequent acroparesthesias, diarrhea, heat/cold/exercise intolerance, fatigue

Question 12

What biomarkers are available to test for Fabry disease?

Answer 12

lyso-Gb3 can be deacylated making it highly soluble in urine and blood
there will be a constant ration between Lyso-Gb3 and Gb3 in individuals
good for diagnosing and monitoring progression of disease
standard of care (should be done after enzyme and DNA testing)

Question 13

What therapies are available to patients with Fabry disease?

Answer 13

ERT (alpha, beta, and beta-biosimilar available; Fabrezyme)- check titers because neutralizing antibodies can form
pharmacologic chaperone therapy (megalastat)- potent small molecule reversible competitive inhibitor; no known antibody formation; not approved in children
gene therapy/genome editing (none available yet)- would be curative; current research using Tallins, Zinc finger nucleases (two arms of 18 sequences each that are highly specific), and CRISPER/Cas9 (~20 nucleotides total with potential for off-target effects)