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