Genetic Disorders - Lysosomal Storage Dz Flashcards
There is a link between lysosomal storage diseases in that they may cause?
Neurodegenerative diseases
What is primary accumulation?
Substrate catabolism cannot occur in lysosomes
With primary accumulation, lysosomes will?
Enlarge and interfere with normal cell function
What is secondary accumulation?
Impaired autophagy and an accumulation of autophagic substrates
Which type of accumulation is specifically correlated with neurodegenerative diseases?
Secondary accumulation
4 types of lysosomal storage diseases?
Sphingolipidoses
Sulfatidoses
Mucopolysaccharidoses
Glycogenoses
What is an example of a sphinolipidose lysosomal storage disease?
Tay-Sachs Disease
With Tay-Sachs Disease, what is unable to be broken down?
G(M2) Gangliosides
Where is the mutation and what enzyme is deficient with Tay-Sachs Disease?
Alpha subunit on chromosome 15
- Deficient HEXA
With Tay-Sachs Disease, where does G(M2) Gangliosides accumulate?
Retina, neurons, heart
What are the symptoms/stages of Tay-Sachs Disease?
- cherry red spot on macula **
- @ 6 months: motor/mental deterioration, blind, dementia
- @ 1-2 years: Vegetative State
- @ 2-3 years: Death
Which fat stains are positive with Tay-Sachs Disease?
Oil red O
Sudan Black
Lipid vacuole in neuron cytoplasm and whorled lysosomes are seen with what lysosomal storage disease?
Tay-Sachs Disease
What are 2 examples of Sulfatidose lysosomal storage diseases?
Niemann Pick Disease
Gaucher Disease
With Niemann Pick Disease, what is unable to be broken down?
Sphingomyelin
How is Niemann Pick Disease inherited?
Autosomal recessive on Mother’s Chromosome
Which chromosome is the mutation in for Niemann Pick Disease?
11p15.4 on mother’s chromosome
Most severe form of Niemann Pick Disease and symptoms
Type A - complete lack of sphingomyelinase
= Severe infantile form, neuro involvement, wasting, death by age 3
Least severe form of Niemann Pick Disease and symptoms
Type B
= Organomegaly, NO CNS INVOLVEMENT
Intermediate and most common form of Niemann Pick Disease and symptoms
Type C
= Neuro damage, ataxia, supranuclear gaze palsy
What gene is mutated with Niemann Pick Disease Type C and what does it do?
NPC1 - transports free cholesterol from lysosomes to cytoplasm
A majority of the Niemann Pick Disease patients have what enlarged organ and half have what?
Splenomegaly
1/2 have cherry red spot on macula
What do the cells look like with Niemann Pick Disease?
Enlarged, FOAMY CYTOPLASM, Zebra bodies
Foamy cytoplasm cells?
Niemann Pick Disease
How is Gaucher Disease inherited?
Autosomal Recessive
With Gaucher disease, what is not broken down?
Glucocerebroside
With Gaucher disease, Glucocerebroside accumulates in what cells and then what do the cells release?
Phagocytes/macrophages
= Release IL-1, IL-6, TNF
Which lysosomal disease is the most common and is also the greatest genetic risk for parkinson’s?
Gaucher Disease
Type 1 Gaucher Disease symptoms?
NO CNS involvement
= Spleen and bone symptoms
Type 2 Gaucher Disease symptoms?
Infantile cerebral pattern, progressive CNS involvement that leads to death
Type 3 Gaucher Disease symptoms?
Progressive CNS disease that does not begin until adolescence
Type 2 Gaucher Disease does NOT occur in which population?
Jewish
With what disease is the spleen usually heavier than 10kg, with thrombocytopenia?
Gaucher Disease
What do the cells look like with Gaucher disease?
Crumpled tissue cytoplasm, distended phagocytic cells
How are most Mucopolysaccharidoses (MPS) inherited and which one is not inherited that way?
Most are autosomal recessive
- Except for Hunter = X-linked recessive
What enzyme is deficient with Hurler - MPS?
Alpha - L - iduronidase
Symptoms of Hurler - MPS
Hepatosplenomegaly and CARDIOVASCULAR complications!!
- Death by age 6-10
What enzyme is deficient with Hunter - MPS?
Iduronadate - 2- sulfatase
Symptoms of Hunter - MPS
NO corneal clouding, milder clinical course
What symptoms do all types of MPS disease have?
Hepatosplenomegaly, skeletal deformities, brain lesions, coronary A. deposits
Which form of MPS disease does not have corneal clouding?
Hunter
What are Zebra bodies and what 2 diseases are they seen with?
Lysosomes with concentric lamellations
- Seen with Niemann Pick Disease and MPS
Glycogenoses lysosomal storage diseases have trouble synthesizing or degrading _____
Glycogen
What is an example of a hepatic form of a glycogenoses?
Von Gierke
What are the symptoms and deficient enzyme with Von Gierke (hepatic form)?
- Deficient glucose-6-phosphatase
= Increased storage of glycogen in liver and hypoglycemia
What is an example of a myopathic form of a glycogenoses?
McArdle Disease
What 2 enzymes can be possible deficient with McArdle Disease?
Phosphorylase
Phosphofructokinase
What are the symptoms of McArdle Disease (skeletal muscle)?
Increased storage of glycogen in muscle and muscle weakness
= Muscle cramps after exercise
Is there an increase in blood lactate after exercise with McArdle Disease?
NO
If a Glycogenoses has a defect in acid maltase or branching enzyme, when will death occur?
Early in life – glycogen storage in many organs
What is another example of a Glycogenoses?
Pompe Disease
What enzyme is deficient with Pompe Disease?
Acid maltase (acid alpha glucosidase)
What are the symptoms of Pompe Disease?
Cardiomegaly filled with glycogen
