Lysosomal Storage Diseases
Symptomology: brusing and anemia, fatigue, enlargement of liver and spleen- skeletal dysplasia, joint swelling, neurological issues, and yellow fatty deposits in the eye
Gaucher Disease
enlargement of spleen, plus liver and bone lesions. Low platelet counts, anemia, bruising, and fatigue are often seen. Some forms affect the brain, causing neurological problems (glucocerebroside accumulation)
Gaucher Disease
glucocerebroside accumulates inside the cells of various organs
Gaucher disease
2 LSD Categories: ______ defects in the delivery system that targets proenzymes to the lysosome, or in the function of the lysosomes themselves. _____ defects in the enzymes that degrade certain macromolecules, or in the transporters that clear specific degradation products from lysosomes.
General, specific
An activated, phosphorylated form of ______ is required for the synthesis of the Mannose 6 Phosphate
GlcNAc
defect in the lysosomal enzymes needed to degrade glycogen, or defects in the removal of carbohydrates from glycoproteins
Glycogen or Glycoprotein Storage Diseases (GSD)
defects in the degradation of glycosaminoglycans (GAGs)
Mucopolysaccaridoses (MPS)
Defect in membrane transporter ______ that removes cholesrterol drom the lysosome is the problem in Niemann-Pick Type C
NPC1or2
Progressive neurological illness, enlargement of spleen and liver, cerebellar ataxia, vertical supranuclear gaze palsy, dystonia, difficulty swallowing, intellectual decline and seizures
Niemann-Pick Type C
progressive neurological illness, with enlargement of the spleen liver(sphingomyelin accumulation, as well as cholesterol)
Niemann-Pick Type C
often fatal in infancy, affects mainly the heart. Progressive shoulder and hip problems, and respiratory muscle failure. glycogen accumulation.
Pompe Disease
causes severe and progressive neurodegenration in infants and both peripheral nerve and psychiatric problem in adolesence and adulthood- ganglioside accumulation
Tay-Sachs Disease
Defective enzyme in Fabry Disease
a-Galactosidase A (GLA)
enzymes destined for the lysosome are synthesized in the ____ ____, post-translationally modified with an ______, and transported, where they are activated by the low ____ environment of the lysosome
rough ER, Manose-6-phosphate, pH
defects in the removal of carbohydrates from the glycolipids containing sphingosine
shingolipidoses (SL)
Two therapy mechanisms for LSDs: reducing biosynthesis of _____ restore ____ activity
substrate, enzyme
in Niemann Pick Type C, fibroblasts stain for _____ _____
unesterified cholesterol
2 types of Recombinant Enzyme therapies for Fabry Disease
-Agalsidase beta -Agalsidase alfa
3 types of recombinant enzyme therapy for Gaucher disease
-Imiglucerase -Velaglucerase alfa -Taliglucerase alfa
2 types of substrate reduction therapy for Gaucher disease
-Miglustat -Eliglustat
on the rough ER's luminal surface, a protein with the sequence _____-____-____ is coupled to N-Acetylglucosamine/Mannose
Asn-X-Ser
An X-Linked disease, but can affect females as well; kidney, heart, skin, and circulatory problems due to sphingolipid accumulation
Fabry Disease
X linked recessive disorderwith severe kidney disease, heart problems, angiokeratoma, and corneal whorls, cerebrovascular disease with stroke or transient ischemic attacks, proteinuria/nephropathy
Fabry Disease
corse facial features, developmental cartilage abnormalities, hepatosplenomegaly, hernias, frequent otitis media, mental retardation and cognitive decline. mucopolysaccharide accumulation.
Hunter and Hurler Syndomres
aka for Mucolipidosis II
I-Cell Disease
symptoms of __-____ ____: -severe radiologic features and peculiar fibroblast inclusions -congenital dislocation of the hip, thoracic deformities, hernia, and hyperplastic gums are evident soon after birth -retarted psychomotor development -death between 5&8 YO
I-Cell Disease
defects in the handling of storage of cholesterol or lipoproteins
Lipidoses or lipid storage diseases (LS)
chaperone therapy for Fabry disease
Migalastat
Substrate reduction therapy for Niemann-Pick Type C
Miglustat
Hunter syndrome has ____ ____ but Hurler doesnt
clouded corneas
defect in the enzyme ______ caused Gaucher DIsease
glucocerebroside (GBA)
LSD pathogenic cascade involved ____ of function mutations
loss
mis-targeting of enzymes to the lysosome diseases
mucolipidoses
a ______ then removes the GlcNAc, leaving behind the mannose-6-phosphate labeled protein
phosphodiesterase
In the Golgi, a ______ attaches the UDP-GlcNAc to mannose residues on the protein
phosphotransferase
Underlying problem of I-Cell Disease: deficiency of a ______ enzyme, leading to accumulations of material as inclusion bodies that progressively damage cells
phosphotransferase