Lysosomal Storage Diseases

Question 1

LAMP

Answer 1

Lysosome-associated membrane protein

Question 2

3 things that go to lysosome

Answer 2

Endocytosis, autophagy and chaperone mediated degradation

Question 3

Two categories of LSDs

Answer 3

Delivery system defects that target proenzymes from ER to lysosome
Defects in lysosomal enzymes that degrade certain polysaccharides such as glycolipids and glycoproteins

Basically defects in delivery of enzymes or defects in enzymes themselves

Question 4

What targets a lysosomal enzyme to destination?…first part of biogenesis of lysosomal enzymes

Answer 4

Must have a sequence for N-linked glycosylation (Asn-X-Ser or thr)…dolichol acts as lipid anchor that orients it in membrane…then N-acetylglucosamine (GlcNAc) and mannose are attached

Question 5

Biogeneiss of lysosomal enzymes 2

Answer 5

Activated, phosphorylated form of GlcNAc requried for synthesis of the address label for zymogens going to lysosome

Question 6

UDP-GlcNAc pyrophosphorylase rxn and basically what it does

Answer 6

Uridinine triphosphate plus GlcNAc makes UDP-GlcNAc

Activates GlcNAc

Question 7

pyrophosphatase rxn

Answer 7

PPi —-> 2PO43-

Question 8

How is mannose attached?

Answer 8

Via phosphotransferase…UMP GlcNAc converted to UMP

Attachs phosphorylated UDP-GlcNAc to Mannose

Question 9

How is GlcNAc removed?

Answer 9

Phosphodiesterase removes GlcNAc via hydrolysis

Leaves behind the phosphate and generating a mannose 6-phosphate residue

Question 10

Mannose-6-P tag formation summary

Answer 10

Mannose residue transferred to UDP-GlcNAC by phosphotransferase…GlcNAc removed by phosphodiesterase hydrolysis…gives mannose 6-phosphate residue

Question 11

What is enzyme recognized by to leave the ER

Answer 11

M6P receptor…it is a zymogen at this point

Question 12

Inheritance of most LSDs

Answer 12

Auto recessive…some ethnic groups predisposition

Question 13

ERT therapy

Answer 13

Recombinant enzyme introduced…cannot help neurologic

Enzyme degraded so need every 1-2 weeks

Question 14

BMT

Answer 14

macrophages can infiltrate BBB and secrete normal enzymes

Question 15

MIglustat

Answer 15

Example of SRT…used in Gaucher and Niemann-pick type C

Question 16

Mucolipidoses (ML)

Answer 16

Defects in translocation of enzymes to lysosome

Question 17

Glycogen storage disease (GSD)

Answer 17

Defect in enzyme needed to degrade glycogen

Question 18

Sphingolipidoses (SL)

Answer 18

Defects in removal of carbs from glycolipids containing sphingosine

Question 19

Oligosaccharidoses (OS)

Answer 19

Defects in removal of carbs from glycoproteins

Question 20

Mucopolysaccharidoses (MPS)

Answer 20

Defects in degradation of glycosaminoglycans (GAGs)

Progressive damage to multiple organ systems…heart, bones, joints, eyes, resp, CNS…may not have symptoms at birth

Question 21

Fabry dz

Answer 21

X-linked genetic…kidney, heart, pulmonary probs and chronic pain
Sphingolipid accumulation

Question 22

Gaucher dz

Answer 22

Enlargement of spleen, plus liver and bone lesions…some affect brain…glucocerebroside accumulation

Question 23

Niemann-Pick Type C

Answer 23

Progressive neuro illness with enlargement of spleen and liver along with lung dz (Sphingomyelin accumulation)

Question 24

Pompe dz

Answer 24

often Fatal in infancy and affects heart…shoulder and hip probs and resp muscle failure (glycogen accumulation)

Question 25

Tay-Sachs dz

Answer 25

Neurodegeneration, peripheral nerve pain, and psych probs (ganglioside accumulation)

Question 26

ML 1

Answer 26

Cannot attach mannose-rich oligosaccharide

Question 27

ML 2

Answer 27

Cannot modify mannose residues with phosphoryl PO3 groups

Question 28

Sialidosis is example of a

Answer 28

ML

Question 29

Sialidosis type 1 vs. type 2

Answer 29

1 - (20-30 y/o)…difficulty walking and loss of visual activity
2 - (childhood or utero)…mental retardation and coarse facial features

Question 30

Cause of sialidosis

Answer 30

Mutation in neurominidase that precludes attachment of mannose-containing oligosaccharide and blocks delivery of zymogen to lysosome…causes buildup of sialyloligosaccharides in neurons and other tissues and will be present in urine…

Question 31

Lack of neuromoinidase

Answer 31

Causes accumulation of mucopolysaccharides and mucolipids through the body

Normally removes sialyc acid from sialyloligosaccharides

Question 32

Sialic acids are

Answer 32

Nine carbon carbs with carboxylic acid functional group

NANA is example

Attached to non-reducing end of the oligosaccharide

Question 33

I-cell dz example of

Answer 33

ML 2

Question 34

Symtpoms of I-cell dz

Answer 34

Peculiar fibroblast inclusions
Dislocation of hip, thoracic deforms, hernia, hyperplastic gums
Retarded psychomotor development
Death between 5 and 8

Question 35

Problem of I-cell dz

Answer 35

Deficiency of phosphotransferase…leads to accumulations as inclusion bodies (lots of glycosaminoglycans) that progressively damage cells…enzymes secreted into EC space but can;t be moved

Question 36

Mutation in non-coding region

Answer 36

Can result in loss of function because mRNA levels can be lowered

Question 37

Mutation in coding region

Answer 37

Can have loss of function because protein doesn’t get made…OR gain of function

Question 38

Loss of function means

Answer 38

Maybe not made, maybe degraded because of folding errors, maybe not moved to the right place