Lysosomal storage diseases

Question 1

Lysosomes

Answer 1

Membrane-bound heterogenous organelles found that play a vital role as catabolic sites for the recylcing and degradation of old cell components and waste
-They play an NB role in scavenging metabolic building blocks that sustain biosynthetic reactions during starvation

Question 2

Lysome interior

Answer 2

They contain as many as 40 hydrolytic enzymes such as nucleases, proteases, phosphatases etc
-The enzymes function at low pH and so a proton pump (vaculolar H+ ATPase) in the membrane maintains low pH via hydrolysis of ATP

Question 3

Lysosome digestion

Answer 3

-Endocytosed vesicles mature early and late into endosomes which fuse with lysosomes and facillitates digestion of endosome contents and release into the cell

Question 4

Lysosomal storage disorders (LSD)

Answer 4

50 diseases that are characterised by accumulation of waste products in lysosomes
-Occur 1 in 8000 births

Question 5

LSD caused from

Answer 5

LSD rseults from:
1) A lack of or a defective lysosomal hydroase resulting in the accumulation of a specific substrate (waste product) within the lysosome
2) A defective or absent transporter which prevents transport of substrate into the lysosome
3)Defects in the endosomal/lysosomal system

Question 6

E.Protein glycan degradation

Answer 6

-Salidase
-Alpha-mannosidase and aspartylglucosaminidase

Question 6

Glycan degradation subgroups

Answer 6

Most common form of LSD and causes 30 diseases
Groups are:
-Defects in glycoprotein degradtion
-Defects in glycolipid degradation
-Defects in glycosaminoglycan (negatively charged mucopolysaccharides) degradation
-Defects in glycogen degredation

Question 7

Glycan

Answer 7

Refers to polysaccharides alone or polysaccharides attached covalently to proteins or lipids

Question 8

Genetic causes of LSD

Answer 8

Usually autosomal recessive but some are X-linked

Question 9

Defects in protein glycan degradation

Answer 9

Specific glucosidases in the lysosome cleave protein glycans in a step wise fashion
(different enzymes will cleave different residues and if one doesnt work then it will prevent subsequent enzymes from working)

Question 10

Salidase

Answer 10

Early infantile forms can cause mental retardation, dysostis multiplex (skeletal deformities), hepatosplenomegaly (enlarged liver and spleen) and early death
-Mild forms result in individuals with mild mental retardation and normal lives

Question 11

Defects in glycolipid degradation

Answer 11

-Main gangliosides of CNS belong to ganglio series and are characterised by tetrasaccharide Gal(b1-3), GalNac (b1-4), Gal (b1-4) Glc which have residues of sialic acids linked
-Defects in ganglioside breakdown processes results in accumulation of these glycolipids in CNS which results in severe brain diseases

Question 12

Deficiency of A-mannosidase and aspartylglucosaminidase

Answer 12

-Cause accumulation of soluble oligosaccharides
-Symptoms include mild mental retardation, recurrent infections, dysostis multiplex and hearing loss

Question 13

Glycolipids

Answer 13

Lipids covalently attached to carbohydrates
have roles such as immune recognition and cell-cell interactions and are found on surface of cells

Question 14

Gangliosides

Answer 14

-Type of glycolipid
-Consist of lipid moiety linked ti oligosaccharide structures differing in glycosidic linkage position, sugar configuration, neutral sugar and sialic acid content

Question 15

Myelin

Answer 15

Type of ganglioside
It insulates nerve cell axons and increases the efficiency of nerve impulses (action potentials)

Question 16

Tay Sachs disease

Answer 16

Type of glycolipid degradation disease
-Mutations or deletions occur in HEXA gene that encodes for hexosaminidase and causes it to be non functional (usually present on hexosaminidase A subunit)
-Mutations can be deletions, nonsense and missense
-The enzyme acts on GalNAc residue from GM2 ganglioside and results in cells in nervous system accumulating excess GM2 gangliosides in brain leading to CNS impairment

Question 17

identify Tay sachs

Answer 17

-becomes most apparant in 3-6 months of age and is lethal with children dying from by 3-5 years old
-A cherry red spot in retina is caused by swollen ganglion cells in retina and leads to eye blindness by 30 months in patients

Question 17

Tay sachs demographics

Answer 17

Autosomal recessive
1 in 320,000 live births in USA
found in Ashkenazi Jewish as well as Amish and French-Canadian communities

Question 18

Pompe disease cause

Answer 18

-Caused by mutations in GAA gene on chromosome 17q25.3 which encodes for the lysosomal enzyme acid alfa-glucosidase
-This enzyme degreads alpha-1,4 and alpha-1,6 linkages in glycogen
-Deficiency results in accumulation of glycogen within lysosome and in cytoplasm leading to tissue destruction

Question 18

Tay sachs symptoms

Answer 18

Progressive brain damage leads to:
-A reduction in voluntary movements
-Frequent and large seizures that are often unresponsive to medicine
-Macrocephaly (enlarged head size)
-Unresponsiveness, vegetative state
-Usually, death from respiratory infections

Question 19

Pompe disease

Answer 19

-Type of glycogen breakdown defect
-also known as glycogen storage disease type II
-it creates deposits inside lysosomes within muscle tissue
-Autosomal reccessive disorder

Question 20

Symptons of Pompe

Answer 20

-symptoms occur before 1 years old
-include hypotonia, cardiomegaly (enlargement of heart), enlarged liver, hearing loss, death from frequent lung infections at early age

Question 21

treatment for pompe

Answer 21

Enzyme replacement therapy: Intravenous administration of recombinant acid alpha glucosidase prolongs overall survival in patients with infantile-onset Pompe disease

Question 22

degredation of sphingomyelin

Answer 22

two successive steps:
1) Degraded to ceramide and phosphocholine by sphingomyelinase
2) Degraded to sphingosine and fatty acids

Question 22

Sphingomyelin

Answer 22

-Lipid derivative found in animal cell membranes and is an NB constituent of myelin
-It consists of phosphocholine or phosphoethanolamine and ceramide

Question 23

Genotype of Niemann-Pick disease

Answer 23

Autosomal reccesive
caused by defective gene for sphingomyelin phosphodiesterase 1 (SMPD1)
missense mutation

Question 24

type of lysomal lipid degradation disease

Answer 24

Niemann Pick

Question 25

NPD type A

Answer 25

Niemann-Pick disease type A
-Presents in first few months of life
-Causes enlarged liver, growth retardation and severe neurological symptoms
-Like tay-sachs, patients have cherry red spot on retina
-It is lethal inearly childhood

Question 26

treatment for NPD

Answer 26

-No cure
-trials for enzyme replacement therapy: Intravenous administration of recombinant acid sphingomyelinase called Olipudase alfa
-reduces symptoms for type B

Question 26

NPD type B

Answer 26

-Presents in early childhood and not as severe as type A
-enlarged liver and spleen, interstitial lung disease, poor bone development and thrombocytopenia
-Most patients have little neurological involvement with survival in adulthood
-NPD B pathogenesis is related to defective autophagy