NeuroLearn NeuroHelp Metabolic @ Lysosomal storage disorders, classification
Background Histopathology & Immunohistochemistry
BACKGROUND AND CLINICAL INFORMATION:
Head
Summary:
Fabry’s disease is an X-linked lysosomal storage
disease due to a-galactosidase A deficiency that leads to the
accumulation of ceramide trihexoside and ceramide dihexoside. Major clinical
manifestations include telangiectases, burning pain int eh lims and abdomen,
unexplained fever and autonomic dysfunction. Pathologically, it is essentially a
vasculopathy with ballooning of endothelial cells accompanied by deposit of
lipid in endothelial cells, a process that lead to thromboses. As a result,
hypertension, myocardial infarction, and strokes are common among these
patients. Death is often due to renal involvement.
Genetics:
X-linked inheritance with the gene on chromosome
Xq22.1. Female carriers usually display late and milder symptoms. Female
carriers may have mild manifestations.
Biochemistry:
Fabry’s disease is a lysosomal storage disese due
to a-galactosidase A deficiency leading to the
accumulation of ceramide trihexoside and ceramide dihexoside.
Clinical:
Clinical
course: Fabry’s disease is a progressive disease
characterized by visceral and cerebral vascular diseases often associated
with hypertension or myocardial infarction. Proteinuria is often found early
in the disease. Renal failure often occurs in the 3rd and 4th
decade and death is most often secondary to renal involvement.
Manifestations usually begin in childhood with
clusters of punctate red black telangiectases in the bathing trunk area,
genetalia, and umbilicus and mucous membranes (angiokeratoma corporis
diffusum).
Patients also have episodes of deep and extreme
burning pain in the limbs and the abdomen, often associated with unexplained
fever.
Autonomic dysfunction, with diminished sweating,
reduced tear and saliva formation and disordered intestinal motility, is
well recognized.
Multiple episodes of early onset cerebral vascular
diseases lead to seizures, hemiplegia and dementia.
Cornea verticillata is seen by slit lamp examinatin
and is often present in heterozygotes.
HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:
Head
Skin: Dilated blood vessels in the upper dermis with
flattening of the overlying basal keratinocytes. Thrombosed vessels may be seen.
Endothelial cells may bulge into the lumen in smaller vessels. Deposits in
endothelial cells can be demonstrated by PAS on frozen section and these
deposits are mostly Sudan black (+) and birefringence. Deposits are also seen in
the smooth muscle cells and pericytes around blood vessels; they appear as small
dark rounded bodies in endothelial cells.
Renal
biopsy: There is marked ballooning and vacuolation of
glomerular epithelium. Foamy interstitial cells and vacuolated cells in the loop
of Henle and distal tubular epithelium are present. Deposits similar to those in
the endothelial cells are present.
Muscle:
Cardiac muscle fibers also contain the deposited lipid.
Skeletal muscle: Muscle fibers and wall of intramuscular vessels contain punctate acid phosphate-positive activity. Lamellar material with a periodicity of 5.5 nm are seen under electron microscope.
Nervous
system:
Storage
in CNS: Certain neurons, particularly those in the amygdala,
hypothalamus, brain stem, anterior horn cells and ganglia contain storage
material. The striatum, globus pallidus and thalamus are spared. Astrocytes
may show marked storages. Storage material may also be present in the
leptomeninges. Storage material are usually removed in routine paraffin
sections but can be demonstrated in frozen sections.
Damage
of the CNS is predominantly due to vascular changes and
characterized by small infarcts.
PNS is only slightly involved. Prominent acid
phosphatase activity can be seen in the perineurium in nerve twigs that are
often included in muscle biopsies.
EM: Collections of inclusions measuring 0.1-10 mm which are composed of tightly packed lipid
lamellae with a periodicity of 4-10 nm depending on the site, the age of the
patient and/or the processing protocol.
NeuroLearn NeuroHelp Metabolic For Comment: KarMing-Fung@ouhsc.edu