Lysosomal storage diseases Flashcards
Lysosomes
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
Lysome interior
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
Lysosome digestion
-Endocytosed vesicles mature early and late into endosomes which fuse with lysosomes and facillitates digestion of endosome contents and release into the cell
Lysosomal storage disorders (LSD)
50 diseases that are characterised by accumulation of waste products in lysosomes
-Occur 1 in 8000 births
LSD caused from
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
E.Protein glycan degradation
-Salidase
-Alpha-mannosidase and aspartylglucosaminidase
Glycan degradation subgroups
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
Glycan
Refers to polysaccharides alone or polysaccharides attached covalently to proteins or lipids
Genetic causes of LSD
Usually autosomal recessive but some are X-linked
Defects in protein glycan degradation
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)
Salidase
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
Defects in glycolipid degradation
-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
Deficiency of A-mannosidase and aspartylglucosaminidase
-Cause accumulation of soluble oligosaccharides
-Symptoms include mild mental retardation, recurrent infections, dysostis multiplex and hearing loss
Glycolipids
Lipids covalently attached to carbohydrates
have roles such as immune recognition and cell-cell interactions and are found on surface of cells
Gangliosides
-Type of glycolipid
-Consist of lipid moiety linked ti oligosaccharide structures differing in glycosidic linkage position, sugar configuration, neutral sugar and sialic acid content
Myelin
Type of ganglioside
It insulates nerve cell axons and increases the efficiency of nerve impulses (action potentials)
Tay Sachs disease
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
identify Tay sachs
-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
Tay sachs demographics
Autosomal recessive
1 in 320,000 live births in USA
found in Ashkenazi Jewish as well as Amish and French-Canadian communities
Pompe disease cause
-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
Tay sachs symptoms
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
Pompe disease
-Type of glycogen breakdown defect
-also known as glycogen storage disease type II
-it creates deposits inside lysosomes within muscle tissue
-Autosomal reccessive disorder
Symptons of Pompe
-symptoms occur before 1 years old
-include hypotonia, cardiomegaly (enlargement of heart), enlarged liver, hearing loss, death from frequent lung infections at early age
treatment for pompe
Enzyme replacement therapy: Intravenous administration of recombinant acid alpha glucosidase prolongs overall survival in patients with infantile-onset Pompe disease
degredation of sphingomyelin
two successive steps:
1) Degraded to ceramide and phosphocholine by sphingomyelinase
2) Degraded to sphingosine and fatty acids
Sphingomyelin
-Lipid derivative found in animal cell membranes and is an NB constituent of myelin
-It consists of phosphocholine or phosphoethanolamine and ceramide
Genotype of Niemann-Pick disease
Autosomal reccesive
caused by defective gene for sphingomyelin phosphodiesterase 1 (SMPD1)
missense mutation
type of lysomal lipid degradation disease
Niemann Pick
NPD type A
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
treatment for NPD
-No cure
-trials for enzyme replacement therapy: Intravenous administration of recombinant acid sphingomyelinase called Olipudase alfa
-reduces symptoms for type B
NPD type B
-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
