Lysosomal Disorders Flashcards
Enzymes that are present in the acidic interior of a lysosome
Acidic hydrolases
Only work in an acidic environment…so won’t work in the cytosol if there is a lysosome membrane rupture
Lysosomes play a role in the follwing
Cholesterol regulation
Synthesis and transport of TH
Osteocalst function
In liver cells
LDLs are endocytosed in clathrin coated pits, the endocytic vesciel becomes acidified and becomes a lysosome
In thyroid cell
Cell makes thyroglobulin which is stored in the thyroid follicle
When TH is needed thyroglobulin is endocytosed and processed into T3 and T4 inside a lysomsome, then secreted
Histological feature of diseased lysosome disorder
Lamellar appearance
‘Onion like’
Clinical presentations of LSDs
DO present with normal newborns…progressive chronic symptoms of storage in bone/CT,joints, brain, cardio system, liver/spleen, dysmorphic newborn (unlike other metabolic diseases like IVA, in which a newborn usually presents in metabolic cirisis)
Gaucher disease
Most common LSD
Type of spingolipidoses
AR inheritance
Glucocerebrosidase deficiency
So cannot cleave glucocerebroside (big molecule) into smaller molecules
Symptoms: heptasplenomegaly, palpable spleen, risk for splenic rupture
‘Erlenmeyer flask femur’ = bone marrow is affects, low WBCs, RBCs, platelet counts can be seen…small models of fat in the femur (bright spots ) on the MRI
Type 1 Gaucher
Most common
No neuro
Responds well to enzyme replacement therapy (ERT) if started early
Type 2 Gaucher
Infant acute (similar to Tay-SAchs if severe)
Stiffness
Don’t eat well…not alot of room in abdomen
Pathognomonic (unique to this disease_
Cherry red macula…storage is around the macula of the eye
Therapy is not normally useful
Type 3 Gaucher
Severely affected in first 2 years by somatic symptoms
Neuro problems 3-5 years (ERT cannot cross BBB so cannot help with this)
Abnormal saccades…difficulty with looking side to side…disconjuage movement…one eye lags behind the other…helps distinguish Type 1 and 3 Gaucher
Fabry disease
Non neuropathic
Pain skin rash (painful hands especially)
Proteinuria that eventually progresses to end stage renal disease (ESRD)…storage product clogs the glomeruli
Cardio disease and stroke
Corneal opacity
X-linked inheritance
Mucopolysaccharidoses (MPS)
3 possible presentations
-somatic and neuro (MPS 1 (Hurler), and MPS 2 (Hunter))
-neuro only (MPS 3, Sanfilipo)
Somatic only (MPS 4, morquio)
Testing = look for the storage product
—> heparan sulfate, keratin sulfate, dermastan sulfate…in the urine
Symptoms:
Som mild facial coarsening
Lateral spine film (bullet looking)
Morquio — fragiule cervical spine
Bone marrow transplantation
Traditional approach
Initial approach to replace the enzyme
Can reach the brain and can half neurodegeneration
Not always effective…multuple iatrogenic complications (immunosuppressed for life, graft vs. host disease)
BMT must happen before neuro starts
ERT
High mannose-6-phosphate signal on the enxyme is a signal sequence for the lysosme —> the enzyme in the infusion will target the lysosome
ERTs made in recombinant protein factoreis
Pros: simple IV, highly effective for somatic cell redu ction
Cons: no neuro effect
