Block 1- Lysosomal Storage Diseases

Question 1

Answer 1

Heparan Sulfate

Question 2

Answer 2

Dermatan Sulfate

Question 3

Hurler Disease:

1. Mechanistic Defect
2. Symptoms
3. Diagnosis
4. Method of Inheritance
5. ERT

Answer 3

1. defect in alpha-iduronidase enzyme which breaks the glycosidic bond connecting iduronate sulfate and NAc-glucossamine sulfate in dermatan sulfate and heparan sulfate. (impaired GAG = mucopolysaccharide degredation; GAG accumulation)
2. GAG accumulation in joints, bone, CNS; coarse face, coroneal clouding, bony changes of spine including atlas bone (not associated w metabolic crisis; instead, progressive)
3. blood smear: vaculoes in WBCs that contain accumulated GAGs or granules (Alder Reilly granulation); urine test (add dimethylmethyline blue to bind to GAGs): GAG test showing increased heparan/dermatan sulfate; bone xray: dystosis multiplex (flattening of vertebral bodies); enzyme assay: reduced alpha-iduronidase activity below 1%. ; DNA testing: iduronidase w402x/w402x)
4. Autosomal Recessive

Question 4

Hunter Disease

1. Mechanistic Error
2. Symptoms
3. Diagnosis
4. MOI
5. Treatment

Answer 4

1. defect in iduronate sulfatase enzyme which breaks the O-S bond in iduronate sulfate in dermatan sulfate and heparan sulfate, leading to GAG buildup.
2. coarse face (frontal bossing, prominent supraorbital ridges, thickening of nasal tip,full lower face, no coroneal clouding, hearing problems; progressive (not associated w acute metabolic derangements/acute metabolic crisis)
3. blood smear: vaculoes in WBCs that contain accumulated GAGs or granules (Alder Reilly granulation); urine test (add dimethylmethyline blue to bind to GAGs): GAG test showing increased heparan/dermatan sulfate; bone xray: dystosis multiplex (flattening of vertebral bodies); enzyme assay: reduced alpha-iduronidase activity below 1%. ; DNA testing: iduronidase w402x/w402x)
4. X-Linked Recessive
5. ERT

Question 5

Tay Sachs disease:

1. Mechanistic Defect
2. H/P

Answer 5

1. defect in hexosaminidase A, which remove GalNAc from GM2 (a sphingolipid). Sandhoff’s is a defect in hexosaminidase A or B, which reomves GalNAc from globoside (a sphingolipid); leads to GM2 accumulation in CNS neurons. “Tay SaX lacks heXosaminidase”
2. loose milestones of development (initally learns, later regression), hypersensitive to sound (hyperacusis), blindess, seizures.

Irregular vasculature in retina; “cherry red spot” with accumulation of white gangliosides around the fovea of the retina.

3. Autosomal Recessive

Question 6

Fabry Disease (GL-3)

1. Mechanistic Defect
2. H/P
3. MOI
4. Treatment

Answer 6

1. defect in alpha-galactosidase A, which removes galactose from ganglioside GL-3 (globotriaosylceramide); results in GL-3 accumulation; lysosomes swell and take over cell; GL-3 can also bind LDL to accumulate in brain and kidney.
2. ganglioside accumulation in blood vessels; lumen of blood vessels narrows and 2ndary ischemic disease occurs (ie: low blood flow to the organs). This causes burning pain in hands and feet b/c vasa-vasorum/vasa-nervorum of nerves are limited by accumulation of GL-3.

stroke, ischemic heart and kidney disease, skin w angiokeratomas (knotting of small blood vessels in skin)

3. X-linked but females can have b/c of Barr Body inactivation (inactive X chromosome in a female)
4. ERT!!!

Question 7

Gaucher Disease (GL-1):

1. Mechanism
2. H/P
3. Types
4. MOI
5. Treatment

Answer 7

1. Defect in beta glucocerebrosidase enzyme, final step of removal of glucose from ceramide.; GL-1 accumulation, macrophages affected
2. limited symptoms, can be adults: anemia, low platelets, huge hepatosplenomegaly, bone diseases
3. Type 1: Hepatosplenomegaly (enlargement of liver and spleen)

Type II: Severe neurological disease

Type III: chronic neurological disease

4. MOI
5. ERT?

Most common LSD!

Question 8

Pompe Disease (Glycogen Storage Disease II)

1. Mechanistic Defect
2. Physical Exam
3. Treatment Principles
4. MOI

Answer 8

1. defect in alpha 1,4 glucosidase, a lysosomal exnzyme that degrades glycogen (particularly active in muscle tissues); glycogen accumulates in cardiac and skeletal muscle.
2. Low muscle tone “hypotonia,” cardiomyopathy (enlargement of heart w abnormal sounds ie: gallop), large tongue (macroglossia)
3. enzyme replacement: missing enzyme +mannose sugars; substrate deprivation therapy: block enzymes that allow ceramide to make glucoceramide (miglustat: Gaucher’s disease drug); enzyme enhancement therapy: help fold prot that are abnormally folded; stem cell transplants: provide wild type bone marrow cells that have the capacity to excrete defective enzyme. Does not work for Tay Sachs, a CNS disorder.
4. Autosomal Recessive

Question 9

____ see clearly (no coronea clouding) and aim for the X.

Answer 9

Hunters

Question 10

Fab Gal:

Answer 10

Fabry’s: alpha-galactosidase deficiency

Question 11

____ disease affects the PUMP of the body (cardiomegaly/cardiomyopathy)

Answer 11

Pompe’s