Lysosomal Disorders

Question 1

Lysosome functions

Answer 1

• Recycling molecules
• Cholesterol regulation
• Thyroid cell and thyroid hormone synthesis: cleaves thyroglobulin into thyroid hormones
• Osteoclast and bone remodeling: helps break down ground substance of bone

Question 2

Lysosomal enzymes breakdown macromolecules in a ___ fashion to create small macromolecules recycled to ____

Answer 2

Stepwise - if one step doesn’t occur, subsequent steps may not occur

the cytoplasm

Question 3

Abnormal lysosomal storage

Answer 3

MIssing enzymes –> Lysosomal storage in sphingolipidoses (“onion skin” morphology on EM looks big)

Molecules that aren’t broken down accumulate in the cell

Question 4

All LSDs are ____disorders, except…

Answer 4

All are autosomal recessive except…

Fabry disease and Hunter’s syndrome are X-linked

Question 5

Clinical generalizations about LSDs

Answer 5

• Normal newborn
  
  • ​Often takes months or years to show symptoms
• Progressive chronic symptoms of storage in many organs
  
  • Bone/connective tissue, Joints, Brain, Cardiac, Liver/Spleen
• No acute illness/crisis, or acidosis
• Regression: lose cognitive and/or motor abilities or milestones (e.g. forgets how to speak)
• School failure, seizures

Question 6

Classification of LSDs - Mucopolysaccaridoses

Answer 6

GAGs storage

In MPS I-VII

Question 7

Classification of LSDs - Sphingolipidoses

Answer 7

Sphingolipid storage

Seen in Tay-Sachs, Gaucher, Fabry, and Niemann Pick

Question 8

Pompe disease

Answer 8

glycogen storage disorder

Question 9

Glycoproteinoses

Answer 9

Storage of glycoprotein material

Question 10

Classification of LSDs - Mucolipidoses

Answer 10

Storage of glycoproteins, GAGs, glycolipids in ML-II (I-Cell disease)

Question 11

Membrane transporter defects are seen in what 2 diseases?

Answer 11

in cystinosis and sialic acid storage disease

Question 12

Gaucher disease is the most common LSD- what is it and what system is particularly involved?

Answer 12

Autosomal recessive deficiency of glucocerebrosidase –> build up of glucocerebrosides affecting multiple organ systems

Especially involves the reticuloendothelial system (macrophages, monocytes)

Question 13

Nonneuronopathic Gaucher’s disease Type1

Answer 13

• Most common; prevalent in Ashkenazi Jews
• No neurological effects, but chronic
• Onset can occur at any age, but half of pts get it by age 18
• Symptoms
  
  • Hepatosplenomegaly
  • Anemia
  • Thrombocytopenia
  • Bone infarctions

Question 14

Neuronopathic Gaucher’s disease Type 2

Answer 14

• Severe neurological regression
• Acute
• Onset in infancy
• Life expectancy: 2-3yrs

Question 15

Neuronopathic Gaucher’s disease Type 3

Answer 15

• Chronic, juvenile, slow neurologic onset
• Progressive developmental delays
• Onset in childhood (3-10yrs)
• Oculomotor apraxia: really slow, arc-like eye movements
• Anemia / Thrombocytopenia / Massive visceral enlargement / Bone disease

Question 16

How are membrane transporter defects different from the other LSDs?

Answer 16

The problem is due to lack of transporters that move the broken down molecules (cystine, siliac acid, etc) from the lysosome to the cytoplasm.

Whereas, most LSDs have an lysosomal enzyme deficiency

Question 17

How is Fabry disease inherited?

Answer 17

X-linked

Question 18

Clinical manifestations of Gaucher’s disease

Answer 18

• Hepatosplenomegaly
• Anemia/risk for bleeding because bone marrow is replaced with fatty storage material
• Bone issues: Erlenmeyer flask deformity, hemorrhagic infarction, necrosis

Typically diagnosed with a simple blood enzyme assay

Question 19

Clinical manifestations of Fabry disease

Answer 19

Painful skin rash (angiokeratoma)

Corneal clouding

Cardiovascular disease

Proteinuria leading to end-stage renal disease

X-linked with milder phenotype in females

Question 20

Which mucopolysaccharidoses (MPS’s) involve somatic and neurologic features?

Answer 20

MPS I (Hurler)

MPS II (Hunter)

Question 21

What MPS involve neurologic symptoms (regression of milestones) only?

Answer 21

MPS III (Sanfilippo)

Question 22

What MPS involves somatic features (storage in liver/spleen, bones, corneal clouding) only?

Pictured: bone dysplasia with no neuropathic sequelae

Answer 22

MPS IV (Morquio)

Question 23

If you think a patietn has MPS, what do you check for?

Answer 23

Abnormal storage of heparan sulfate (HS), dermatan sulfate (DS), or keratin sulfate (KS) in the urine (indicates enzyme deficiency) –> Then do a leukocyte enzyme assay

Question 24

Gaucher’s disease - the earlier the onset,

Answer 24

the more severe the phenotype

Different genotypes have different onsets

Question 25

The pahtophysiology of LSDs is mediated through

Answer 25

Inappropriate apoptosis with activation of caspases

Seen in cystinosis, tay-sachs

Question 26

Treatment: Bone Marrow Transplant

Answer 26

Ameliorate neurodegeneration by trying to replace enzymes in the brain

• Cons:
  
  • Not always effective
  • Complications;
  • Won’t work if significantneurologic deterioration has already occurred

Question 27

Treatment : Enzyme replacement therapy by IV infusion

Answer 27

Infusionsregularly for somatic cell reduction of lysosomal storage (liver, spleen)

• Cons:
  
  • Not effective for neuronopathic disease because it won’t pass BBB
  • $$, life-long
  • Doesn’t repair damaged bone

Question 28

Treatment: Substrate reduction therapy

Answer 28

Inhibit synthesis of glucocerebroside; minimally invasive

Cons:

• Less effective than ERT
• Side effects from lacking the molecule

Question 29

Chaperone therapy

Answer 29

Use a chaperone to try to make the misfolded lysosomal enzyme partially functional

However, only mildly effective.

Question 31

What kind of disease do you expect?

Answer 31

MPS

Question 32

True/False: lysosomal enzyme deficiencies can be readily detected from newborn screen spots

Answer 32

true