- Rare, 1/8000 live births - Death in childhood - Store material in lysosome due to defects in substrate degradation

L3 - Lysosomal Storage Disease Flashcards by Michael Bradley

Features of LSD?

Rare, 1/8000 live births
Death in childhood
Store material in lysosome due to defects in substrate degradation

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Features of the lysosome

70 hydrolytic enzymes
low pH (4)
Enzymes trafficked to it via M6P receptor pathway
Material trafficked by endocytosis or autophagy

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What problem does the neuron create for endocytosis?

Trafficking problem in that lysosomes not present at synapse

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What is M6P?

Mannose-6-phosphate group added to hydrolases destined for lysosome

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What are the steps in the M6P pathway?

Added to hydrolases through Golgi
Recognised by M6PRs and deliver to late endosome
Low pH causes dissociation

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What are the general cellular phenotypes of LSD?

Swollen
Accumulation of ageing pigment
Defects in autophagy
Appearance of meganeurites
Excessjve synaptogenesis

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What are the features of mucopolysaccharides?

High rigidity
Lubricator
Component of cell membranes
Mutation causes defective metabolism and accumulation of GAGs

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What does MPS stand for and what is it?

Mucopolysaccharidoses

Accumulation of secondary storage substrates

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Features of Sanfilippo Syndrome (MPS III)

Cannot break down Heparan sulphate

Most common MPS

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What are the symptoms of Sanfilippo Syndrome?

Hyperactivity
Speech delay
Mental retardation
Bone defects

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How can you screen for Sanfilippo Syndrome?

GAGs in urine

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What is mucolipidosis-II also known as?

I-Cell disease or Psuedo-Hurler

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What are the symptoms and occurrence of I-Cell disease?

Developmental delay, death early

1/640000 live births

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What is the genetic defect of I-Cell disease?

N-acetylglucosaminyl-1-phosphotransferase

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What are the internal symptoms of I-Cell disease?

I = Inclusion so stored material is mucolipds, MPS and schingolipids

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What are the internal symptoms of Mucolipidosis-IV

Stored material = mucolipids, MPS, sphingolipids

What is the occurance and symptoms of Mucolipidosis-IV

Occurrence - Jewish 1/90

Symptoms - physchomotor retardation, corneal opacity, retinal degeration, iron definiency, improper stomach pH

What is the genetic defect of Mucolipidosis-IV?

Mucolipin1 and a TRP channel involved in iron efflux from lysosomes

What is important about spingolipids?

A major component of neural tissue and binds cholesterol

What is the usual path of sphingolipids in a cell?

Patches on membrane endocytosed then recycled by TGN

Small amount leak out and are degraded

What is the path of sphingolipids in LSD?

Schingolipids and cholesterol routed mainly to lysosome, swamping them

What are the Symptoms and occurrence of Tay-Sachs disease?

Early death, neurological deterioration (ataxia, atrophy, spasticity)
1/27 in Ashkenazim Jews, Cajuns

What is the genetic defect causing Tay-Sachs disease?

Hexosaminidase A (HEXA)

What are the internal symptoms of Tay-Sachs disease?

GM2 gangliosides, globosides and glycolipid build up

What are the symptoms and occurrence of Niemann-Pick disease?

Enlarged liver, and lymph nodes, darkening of skin, neurologic impairment, cherry red spot Occurrence 1/1000 Ashkenazim Jews

What is the genetic defect for Niemann-Pick disease?

Mutant for sphingomyelinase

What are the internal symptoms of Niemann-Pick disease?

Build up of sphingomyelin, cholesterol and sphingolipids | Causes endosomal traffic jam

What are all the features of Batten disease?

Defect - CLN genes 1-8 Occurrence - 1/8000 Symptoms - visual defects, seizures, loss of sight speech and motor skills, dementia Storage material - lipofuscin

What are some possible treatments of LSD?

Enzyme replacement Gene therapy Substrate reduction Neuronal stem cells

What is spinster?

A gene identified for synaptic growth in drosophila (synapses overgrown in mutant) 12 transmembrane transporter

Where does spinster localise?

To a low pH late-endosomal compartment with lysomal associated membrane protein (LAMP)

What does spinster cause intracellularly?

Expanded endosome and multi-lamellar inclusions

Whats a good way of detecting sphingolipids?

Filipin is a fluorescent antibiotic that binds cholesterol

What does spinster do and how can it be rescued?

Bears an oxidative stress burden. | Reducing oxidative stress rescues synaptic overgrowth

What is activated in spinster and what does blocking this do?

AP-1 cascade (oxidative stress) | Blocking inhibits synapse overgrowth in mutant