Lysosomal Storage Disorders Flashcards
(57 cards)
How many enzymes does the lysosome contain?
Contains ~50 enzymes
What kind of environment does the lysosome contain?
High acidic environment (low pH) to store hydrolytic enzymes
What cellular processes does the lysosome do?
Breakdown of waste, destruction of foreign material, apoptosis, breakdown of macromolecules into smaller molecules
Types of lysosomes and where they are formed?
Primary: Formed from endolytic vesicles (Golgi)
Secondary: Primary lysosome that has fused with endosome
Movement of lysosomal enzymes (3 steps)
- Enzymes initially generated in ER.
- Enzymes are transported to Golgi where they acquire mannose-6-phosphate (M6P), where is critical for localization to lysosome.
- M6P receptors located on cell membrane to bind with M6P, resulting in localization to the lysosome.
What are lysosomal storage disorders?
Multiple disorders associated with the dysfunction of lysosomal enzymes and the breakdown of macromolecules
Three mechanism of lysosomal storage disorders?
- Failure of gene to produce adequate levels of an active enzyme or enzyme with altered kinetics.
- Failure to incorporate enzyme into lysosome d/t failure of lysosome transport.
- Mutation in primary enzyme, affecting portion of the molecule which identifies it as an enzyme destined for lysosomal uptake.
How do the majority of LSDs arise from?
Defects in sugar hydrolyses responsible for the degradation of complex carbohydrate sequences attached to certain other macromolecules
Glycoprotein disorder
Pompe disease
Glycolipids disorder
Tay Sachs Disease, Gaucher disease, Niemann Pick
Glucosaminoglycans disorders
Mucopolysaccharidosis
What is the inheritance of almost all LSDs
Autosomal recessive
There are two X-linked LSDs, what are they?
Hunter syndrome & Fabry disease
MPS make up about how much of all LSD cases
35%
Most common LSD
Gaucher disease
What are other names for Pompe Disease?
GSDII / Acid Maltase Deficiency / GAA Deficiency
True or false, Pompe is the only GSD which is also an LSD
True
All other GSDs are due to defects in what?
Cytoplasmic enzymes
Pompe is a deficiency in what?
Deficiency of alpha-1,4-glucosidase
What does alpha-1,4-glucosidase do?
Breaks down glycogen into glucose
What does Infantile-onset Pompe disease look like?
Etiology, symptoms, prognosis, treatment, long term complications
- Significantly reduced or absent GAA
- Massive HCM,FTT, rapidly progressing muscle weakness, respiratory failure, aspiration
- Developmental delay
- Death by 1-2 years of age if untreated
- Treated patients may require mechanical ventilation, wheelchair, etc.
- Long-term survivors develop complications (vision/hearing problems, speech issues)
- Overall cognition can be preserved
What does late-onset pompe disease look like?
- Some residual enzyme activity
- Characterized by more slowly progressive muscle weakness and absence of HCM in 1st year
- Proximal muscles (LE>UE) and trunk most affected
- Can have cardiac rhythm disturbances
- Respiratory dysfunction and failure can occur
- Death usually occurs due to respiratory failure but with treatment, lifespan can be close to normal
Pompe Disease Gene affected
GAA
Mechanism of disease in pompe disease
Describe activity in:
* Null alleles
* Missense and other
Mechanism: loss of function
Null: result in 0% enzyma activity
Missense and other may result in some normal activity.
