Lysosomal Disorders Flashcards
Lysosome functions
- 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
Lysosomal enzymes breakdown macromolecules in a ___ fashion to create small macromolecules recycled to ____
Stepwise - if one step doesn’t occur, subsequent steps may not occur
the cytoplasm
Abnormal lysosomal storage
MIssing enzymes –> Lysosomal storage in sphingolipidoses (“onion skin” morphology on EM looks big)
Molecules that aren’t broken down accumulate in the cell
All LSDs are ____disorders, except…
All are autosomal recessive except…
Fabry disease and Hunter’s syndrome are X-linked
Clinical generalizations about LSDs
-
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
Classification of LSDs - Mucopolysaccaridoses
GAGs storage
In MPS I-VII
Classification of LSDs - Sphingolipidoses
Sphingolipid storage
Seen in Tay-Sachs, Gaucher, Fabry, and Niemann Pick
Pompe disease
glycogen storage disorder
Glycoproteinoses
Storage of glycoprotein material
Classification of LSDs - Mucolipidoses
Storage of glycoproteins, GAGs, glycolipids in ML-II (I-Cell disease)
Membrane transporter defects are seen in what 2 diseases?
in cystinosis and sialic acid storage disease
Gaucher disease is the most common LSD- what is it and what system is particularly involved?
Autosomal recessive deficiency of glucocerebrosidase –> build up of glucocerebrosides affecting multiple organ systems
Especially involves the reticuloendothelial system (macrophages, monocytes)
Nonneuronopathic Gaucher’s disease Type1
- 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
Neuronopathic Gaucher’s disease Type 2
- Severe neurological regression
- Acute
- Onset in infancy
- Life expectancy: 2-3yrs
Neuronopathic Gaucher’s disease Type 3
- 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
How are membrane transporter defects different from the other LSDs?
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
How is Fabry disease inherited?
X-linked
Clinical manifestations of Gaucher’s disease
- 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
Clinical manifestations of Fabry disease
Painful skin rash (angiokeratoma)
Corneal clouding
Cardiovascular disease
Proteinuria leading to end-stage renal disease
X-linked with milder phenotype in females
Which mucopolysaccharidoses (MPS’s) involve somatic and neurologic features?
MPS I (Hurler)
MPS II (Hunter)
What MPS involve neurologic symptoms (regression of milestones) only?
MPS III (Sanfilippo)
What MPS involves somatic features (storage in liver/spleen, bones, corneal clouding) only?
Pictured: bone dysplasia with no neuropathic sequelae
MPS IV (Morquio)
If you think a patietn has MPS, what do you check for?
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
Gaucher’s disease - the earlier the onset,
the more severe the phenotype
Different genotypes have different onsets
