Lysomal storage diseases

Question 1

Lysosomes break down:

Answer 1

GAGs, sphingolipids, glycogen by removing 1 sugar or whatever unit at a time

Question 2

Hurler Syndrome

Answer 2

MPS I H (mucopolysaccharidoses)
Deficient Enzyme: (α-L-)Iduronidase (autosomal recessive)
Fxn: cleave IdUA off of dermatan sulfate and heparan sulfate
Treatments: bone marrow or cord blood transplant (before 18 months ideally), ERT
Tests: Urine positive for GAGs, fibroblast assay shows enzyme deficiency
Symptoms: Corneal Clouding, mental retardation, dwarfing, coarse (dysmorphic) facial features, upper airway obstruction, hearing loss, hepatosplenomegaly
Metabolites that accumulate: Heparan sulfate and Dermatan sulfate
Notes: More sever than hunter

Question 3

Hunter Syndrome

Answer 3

MPS II (mucopolysaccharidoses)
Deficient Enzyme: Iduronate Sulfatase (X-linked recessive)
Fxn: Cleave sulfate from IdUA
Metabolites accumulating: Heparan and Dermatan sulfates
Symptoms: Wide range of severity, physical deformity (coarse facial features) and mental retardation are mild to severe. Hepatosplenomegaly. No corneal clouding
Tests: Uring + for GAGs and fibroblast assay
Treatments: ERT
Notes: Less severe than hurler

Question 4

Common features of lysosomal storage disorders

Answer 4

Autosomal recessive (some are X-linked);
affect infants and young children;
hepatosplenomegaly (caused by storage of insoluble intermediates in mononuclear phagocyte system);
frequent CNS involvment (developmental delay) (not amenable to ERT as enzymes cannot cross blood brain barrier)
Cellular dysfuction (storage of undigested material, macrophage activation adn relase of cytokines)
Diagnoses by assay of enzyme in fibroblasts (or WBCs)

Question 5

Tay-Sachs

Answer 5

Deficient Enzyme: β-Hexosaminidase A (autosomal recessive)
Class: (glyco)Shingolipidoses
Fxn: Cleave GalNAc from ganglioside GM2
Metabolites accumulating: GM2
Symptoms: Minimal hepatosplenomegaly. Progressive neurodegeration after age of 3-6 months (developmental milestone delay), blindness (gangliosides accumulate around macula leavinga white region and a cherry red spot in the middle), Onion-shell inclusions in lysosomes, usually fatal by 2-6
Tests: enzyme assay, cherry red macula
Treatments:
Notes: Especially common in Ashkenazi Jews

Question 6

Ceramide

Answer 6

Sphingosine + Fatty acid

Question 7

Glycosphingolipids

Answer 7

Carbohydrate moiety + ceramide

Question 8

Shingophospholipids

Answer 8

Phospoorylcholine + ceramide

Question 9

Gaucher Disease

Answer 9

Deficient Enzyme: β-Glucosidase
Class: (glyco)Shingolipidoses
Fxn: cleave glucose from …
Metabolites accumulating: Glucosyl ceramide (glucocerebroside)
Symptoms: macrophages engorged with glucocerebrosides (crumpled tissue paper appearance), no neruological damage (adult, most common form), hepatosplenomegaly, osteoporosis of long bone
Tests:
Treatments: ERT
Notes: Most comon lysosomal storage disorder

Question 10

Fabry Disease

Answer 10

Deficient Enzyme: α-Galatosidase (X-linked)
Class: (glyco)Shingolipidoses
Fxn: cleave terminal galactos from…
Metabolites accumulating: Globoside (ceramide triheoside)
Symptoms: peripheral neuropathy (globoside accumulating in nerves); kidney damage, heart attack and stroke (in children) caused by accumulation in blood vessles of kidney and heart. Also accumulates in blood vessels of skin and nerves. Skin rash with ‘bathing-trunk’ distribution
Tests:
Treatments: ERT (doesn’t fix neuropathy)
Notes:

Question 11

Niemann-Pick Disease

Answer 11

Deficient Enzyme: Sphingomyelinase
Class: (phospho)Sphingolipidoses*
Fxn: Cleave phosphoryl choline from …
Metabolites accumulating: sphyingomyelin (sphingophospholipid)
Symptoms: foamy cell appearance (lipid droplet accumulation)
Type A-infantile, more severe, primarily neurological, accumulation of sphingomyelin in neuronal tissues, cherry-red spot in macula (∴blindness), fatal in 2-3 years (similar to Tay-Sach’s)
Type B-juvenile, less severe, hepatosplenomegaly, similar to Gaucher’s
Tests:
Treatments: ERT (type B)
Notes: only disease we’re studying with phospholipid accumulation

Question 12

Metachromatic Leukodystrophy

Answer 12

Deficient Enzyme: Aryl Sulfatase A (autosomal recessive)
Class: (gluco)Shingolipidoses
Fxn: Cleave sulfate Sulfatide–>galactosyl ceramide
Metabolites accumulating: Sulfatide
Symptoms: Progressive paralysis and demyelination
Tests:
Treatments:
Notes:

Question 13

Pompe

Answer 13

Deficient Enzyme: Lysosomal acid maltase (1–>4 glucosidase)
Class: Glycogen Storage Disease (type II)
Fxn: Break down glycogen (break α 1, 4 bonds)
Metabolites accumulating: Glycogen
Symptoms: generalized accumulation of glycogen in heart, muscle, kidney and liver. cardiomegaly, cardiomyopathy, myopathy of skeletal muscles, hepatocellular damage
Tests:
Treatments: ERT
Notes:

Question 14

I-cell Disease

Answer 14

Deficient Enzyme: GlcNAc Phosphotransferase (wikipedia)
Class: mucolipidosis II (wikipedia)
Fxn: Add phosphate to mannose residues
Metabolites accumulating: GAGs and sphingolipids–>lysosomal enzymes improperly tagged (no mannose-6-Pi) and are transported out of the cell instead of to lysosomes
Symptoms: intracytoplasmic inclusions in fibroblasts (Inclusion cells/I-cells), generally resmebles Hurler disease, hepatosplenomegaly, Corneal Clouding, mental retardation, dwarfing, coarse (dysmorphic) facial features, upper airway obstruction, hearing loss
Tests: high concentration of lysosomal enzymes in blood
Treatments: none really, just treat symptoms (wikipedia)
Notes: