Inborn Errors: Glycolipid Disorders

Question 1

Key things to focus on from Dr. Taylor’s lecture

Answer 1

1. Recognition
2. Key diseases – specific features/comps and which enzymes are involved so that you can determine which tests to order and what the Rx is

Question 2

Lysosomal storage diseases

Answer 2

Can’t get rid of it, end up storing it…

A little bit like a garbage strike or recycling strike within the cells. Over the course of years, the disease progress

Question 3

Treatment strategies for lysosomal storage diseases

Answer 3

1. Substrate inhibition
2. Enzyme replacement therapy
3. Chaperones (help stabilize the native enzyme)

Question 4

Glycolipids

Answer 4

• molecules that contain both carbohydrate and lipid components
• roles in cell signaling, cell membranes, and an energy source

Question 5

Storage diseases pathophysiology

Answer 5

• Substrates normally degraded end up accumulating
• Typically due to a missing/malfunctioning enzyme
• Not acutely toxic, usually gradual accumulation –> cellular dysfunction and death

Lysosomal storage diseases represent important examples of storage diseases

Question 6

Organic acidemias

Answer 6

Fairly acute problem (House on fire)

vs. Mitochondrial disease (House without power)
vs. Storage disease (House w/o garbage or recycling service)

Question 7

LSD mode of inheritance

Answer 7

• Most are autosomal recessive with the exception of: Fabry XLD, Hunter XLR, Danon disease XLD)

Men like to Hunt (XLR)

Question 8

Pathophys of LSD

Answer 8

swollen lysosome –> swollen cell –> cell dysfunction –> organ dysfunction

All cells are probably affected, but the cells producing or supposedly degrading the problem protein are the most affected.

Usually normal delivery but failed breakdown

Question 9

LSD incidence

Answer 9

• Rare individually but overall incidence is (1:5000)
• Populations:
  
  • Gaucher: 1:855 in Ashkenazi Jews (also elevated risk of Tay Sachs)
  • Aspartylglucosaminuria: 1:18,500 (Finnish)

These are due to founder effects!

Question 10

Unique phenotypes

Answer 10

• Cherry red spot (Tay Sachs)

- Acroparethesias, angiokeratomas (Fabry) (burning palms)

Question 11

Complications

Answer 11

• blindness, will die (Tay Sachs)

- renal failure (fabry)

Question 12

Treatment available

Answer 12

• Gaucher, Fabry, Pompe, Hunter (MPSII), Maroteaux-Lamy (MPS VI)

Question 13

What does storage look like?

Answer 13

• Skin: Coarse skin
• Skull: Macrocephaly, cognitive regression
• Eyes: Corneal clouding, cherry red spot
• ENT: Macroglossia, sleep apnea
• Liver: hepatosplenomegaly
• Kidneys: proteinuria (fabry)
• Skeletal: dystosis multiplex, joint stiffness, short stature

Question 14

Classic Gaucher cell in bone marrow

Answer 14

“tissue paper” appearance of cytoplasm caused by enlarged, elongated lysosomes filled with glucocerebroside

Question 15

Cell with alpha-mannosidosis

Answer 15

Lysosomal swelling

Question 16

Cell with Pompe

Answer 16

Intralysosomal storage

Question 17

Dystosis multiplex

Answer 17

1. Vertebral “beaking”

2. Broad bases of metacarpals and phalanges

Question 18

Erlenmeyer flask deformity

Answer 18

Marrow infiltration from Gaucher cells displaces normal marrow, causes femur to look like an erlenmeyer flask.

Found in Gaucher Disease Type I

PROBABLY ON THE EXAM!

Question 19

Cherry red spot

Answer 19

1. Tay Sachs Disease
2. White pallor surrounding a central red, stuff is accumulating in the nearby ganglion cells

This is an early finding. The white milky fluid will disperse and you can no longer see it as the disease progresses