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Molecular Basis of Disease > Lysosomal storage disorders > Flashcards

Lysosomal storage disorders Flashcards

1
Q

Who discovered LSDs?

A

Christian de Duve

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2
Q

How many genes control LSDs?

A

One gene

Monogenic disease

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3
Q

What type of diseases are LSDs?

A

Metabolic diseases

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4
Q

Why do biological materials build up in LSDs?

A

Enzyme or membrane protein of lysosome is defective

Causes build up of proteins or substrate

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5
Q

What two proteins can be defective in LSDs?

A

Lysosomal membrane proteins

Enzymes

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6
Q

What is the incidence of LSDs?

A

Singularly rare

Many types of the disease

Combined frequency is very high

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7
Q

How many diseases do LSDs encompass?

A

More than 60 diseases

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8
Q

What type of mutation causes LSDs?

A

Many different mutations in the same or different gene causes the disease

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9
Q

How do the mutations influence the gravity of the symptoms in LSDs?

A

Mutation influences

  • severity of symptoms
  • onset of symptoms
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10
Q

Genetic analysis not enough to rule out diagnosis in patients presenting symptoms of LSD

TRUE or FALSE

A

TRUE

Not always a direct genotype-phenotype correlation

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11
Q

What two factors are used to classify LSDs?

A

Substrate that builds up

Gene that is mutated

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12
Q

Different gene mutations have similar phenotypic characteristics

TRUE or FALSE

A

TRUE

Same metabolic pathway is affected in the different subtypes of LSD

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13
Q

What are the four main roles of the lysosomes?

A

Endocytosis/autophagy

Apoptosis

Unfolded protein response

Mitochondrial/Ca2+ balance

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14
Q

What role do lysosomes play in endocytosis?

A

Internalisation of extracellular material through

  • invagination
  • formation of vesicles

Release of material into the intracellular lysosomal compartment

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15
Q

What is autophagy?

A

Normal physiological process in the body that deals with destruction of cells in the body

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16
Q

How does autophagy maintain homeostasis?

A

Protein degradation

Turnover of the destroyed cell organelles for new cell formation

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17
Q

What triggers autophagy?

A

Cell starvation

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18
Q

What is apoptosis?

A

Programmed cell death

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19
Q

What is the role of lysosomes in apoptosis?

A

Membrane of the lysosome becomes more permeable

Release proteases into the cytosol

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20
Q

Examples of proteases released from the lysosome into the cell during apoptosis

A

Cysteine

Cathepsin

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21
Q

What is UPR?

A

Unfolded protein response

Unfolded proteins must be removed from the cell environment to maintain cell homeostasis

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22
Q

Which two mechanisms deal with unfolded proteins in the cell environment?

A

Proteasomes

Chaperones

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23
Q

How do chaperones deal with unfolded proteins?

A

Break the misfolded proteins down into their primary structure

Try to fold them into the correct shape

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24
Q

What happens to the misfolded proteins if the aren’t folded into their correct shape by the molecular chaperones?

A

They are discarded in the lysosome

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25
Q

What happens to the misfolded proteins if they are folded into the correct shape by molecular chaperones?

A

Released systematically

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26
Q

How do mitochondria and lysosomes maintain dynamic homeostasis?

A

Degrade dysfuntional mitochondria

Maintain lysosomal function by acidification

Lysosomal calcium regulates mitochondrial catabolism

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27
Q

In which processes is calcium signalling useful for between mitochondria and lysosomes?

A

Autophagy

Membrane fusion

Apoptosis

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28
Q

What is the size of lysosomes?

A

1-2 micrometers

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29
Q

How many acid hydrolases and membrane proteins are found in lysosomes?

A

> 50

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30
Q

How is the pH maintained in lysosomes?

A

Actively concentrate H+ by a proton pump ATPase

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31
Q

In what way is the cell adapted to withstand lysosomal damage?

A

pH of the cytosol is around neutral

If the lysosome cell membrane breaks down the enzymes are rendered inactive by the high pH of the cytosol

Protective

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32
Q

What processes happen if the intracellular relationships between the lysosome and surrounding organelles is disrupted?

A

Dysfunctional biosynthesis and catabolism of GSLs

Accumulation of substrates

Failed trafficking

Disturbed calcium signalling

Apoptosis

Necroptosis

Macrophage activation

Disturbed autophagy

Disruption of lipid raft - receptor signaling

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33
Q

Why are so many organelles affected if the lysosomes become dysfunctional?

A

A lot of cross-talk between lysosomes and organelles

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34
Q

Complete disruption of the GSL pathway is incompatible with life

TRUE or FALSE

A

TRUE

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35
Q

Why are lysosomes sensitive to enzyme mutations?

A

The enzymes are found in this organelle

Here is where the metabolic pathways take place

When the metabolic pathways are disrupted because of a mutation, the substrate will build up in the lysosome

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36
Q

What are glycosphingolipids?

A

The metabolic pathways of glycosphingoipids are affected in LSDs

The mutated proteins are involved in these metabolic pathways

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37
Q

What are the components of glycosphingolipids?

A

Carbohydrate + ceramide

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38
Q

Examples of specific disorders related to the disruption of the GSL pathway

A

Krabbe

Gaucher

Niemann-Pick disease

Fabry

Sandhoff

Batten

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39
Q

Presentation of LSD varies a lot between patients

TRUE or FALSE

A

TRUE

The same gene can have different mutations

Mutations can affect different organs and cell types

Affected cell population can be widespread or restricted

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40
Q

Why are LSDs so difficult to treat?

A

Same disease may be caused by different mutations

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41
Q

How can different genetic mutations cause the same presentations?

A

Mutations affect the enzymatic pathway along different points

Leads to the same substrate build-up

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42
Q

What is a broad way to classify LSDs?

A

Visceral

Neurological

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43
Q

Clinical features of LSDs

A

Organomegaly

Cardiomyopathy

Respiratory manifestations

Haematological and endocrine symptoms

Bone abnormalities

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44
Q

Main characteristic of neuropathologies related to LSDs

A

Leads to premature death

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45
Q

What are the symptoms of neuropathology in LSD

A

Neurocognitive impairment

Movement disorders

Seizures

Deafness

Parkinson’s

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46
Q

Pathogenesis of LSDs - Krabbe disease

A

Metabolites from GAGs build up

These are recognised by TLRs

Causes secretion of cytokines

Apoptosis of cells

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47
Q

What substrate accumulated in Gaucher disease?

A

Glucocerebroside

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48
Q

What causes the substrate accumulation in Gaucher disease?

A

CBA gene coding for b-glucocerebroside is defective

49
Q

Which cells are particularly affected in Gaucher disease?

A

Macrophages

Gaucher cells

50
Q

What is the main symptom of Gaucher disease?

A

Organ enlargement

As the enlarged cells enter the organs

51
Q

What is the condition where the spleen and liver become enlarged called?

A

Hepatosplenomegaly

52
Q

How many types of Gaucher disease exist?

A

3 types

53
Q

Describe type 1 Gaucher disease

A

Visceral presentation of pathology

Most common type

The b-glucocerebosidase enzyme is less efficient but still functional

54
Q

Describe type 2 Gaucher disease

A

Acute neuropathology

Death < 2 years of age

Enzyme is affected so the active site is disrupted and completely dysfunctional

55
Q

Describe type 3 Gaucher disease

A

Chronic neuropathy

Slow progression

56
Q

What accumulates in cells during Niemann-Pick disease

A

CHolesterol

Sphingolipids

57
Q

What two types of Niemann-Pick disease exist

A

Type A and B

Type C

58
Q

What distinguishes the different types of Niemann-Pick disease

A

Genes that are mutated

59
Q

What gene is mutated in types A and B Niemann-Pick disease?

A

SMPD1

60
Q

What genes are mutated in type C Niemann-Pick disease?

A

NPC1 and NPC2

61
Q

What does SMPD1 code for?

A

Enzyme

Sphingomyelinase

62
Q

What do NPC1 and NPC2 code for?

A

Membrane proteins

63
Q

Where are the manifestations of Niemann-Pick disease observed in the body?

A

Type A and B - viscera

Type C - viscera and nervous system

64
Q

Neurodegenerative symptoms in type C Niemann-Pick disease

A

Delay in motor milestones

Ataxia

Psychiatric problems

65
Q

Which gene mutations lead to Batten disease?

A

Neuronal ceroid lipofuscinoses

400 mutations in 13 different CLN genes

66
Q

In Batten disease, depending on the —– affected, the —- of the disease is different

A

Gene

Onset

67
Q

At which developmental stages can Batten disease be observed?

A

Infantile

Late infantile

Juvenile

Adult

68
Q

Symptoms of Batten disease

A

Visual impairment

Seizures

Neurological symptoms

Premature death

Maculopathy and retina atrophy

69
Q

What analysis is needed to diagnose LSD?

A

Biochemical and genetic analysis

70
Q

What are sources of complication when it comes to diagnosing LSDs?

A

Rare disease - no routine prenatal screening

Often misdiagnosed due to the heterogeneity in symptoms

Lack of biomarkers

71
Q

Examples of newborn screening to diagnose LSD

A

Enzymatic activity in blood spots

Detection of urinary oligosaccharides or glycosaminoglycans

Indirect biomarkers

Skin biopsy

72
Q

—- diagnosis is essential for diseases with ——

A

Early

Neurological involvement

73
Q

What are the different approaches of how to treat LSDs

A

Treat

  • the symptoms
  • cell dysfunction and cell death
  • substrate storage
  • enzyme or protein defect
  • gene defect
74
Q

LSD therapies are normally exclusive

TRUE or FALSE

A

FALSE

LSD therapies are normally not exclusive

75
Q

What is the primary care for patients with neuropathologies?

A

Suppotive care for individuals and their families

76
Q

What types of LSDs are particularly hard to treat?

A

LSDs that involve

  • dysfunctional membrane proteins
  • insoluble enzymes
  • the BBB
77
Q

What are the main therapies for LSDs?

A 
Transplantation
Substrate reduction therapy 
Enzyme replacement therapy 
Molecular chaperones 
Gene therapy
78
Q

Procedure of transplantation

A
  1. Multipotent stem cells are obtained from the BM, peripheral blood and umbilical cord
  2. Bone marrow from suitable healthy donor is the therapeutic agent
  3. Healthy haematopoietic cells spread throughout organs
  4. Secrete missing enzyme
79
Q

Why does haematopoietic stem cell therapy help sufferers with neurological presentation?

A

Microglial cells of haematopoietic origin can cross the blood-brain barrier and secrete the therapeutic enzyme in the brain

80
Q

What is the main goal of stem cell therapy?

A

Slow or arrest neurodegeneration

Replace the defective enzyme before significant CNS injury

81
Q

What are the disadvantages of stem cell therapy?

A

Cannot help with diseases where the condition derives from faulty intermembrane proteins

Minimal improvement is seen

No effect on CNS

82
Q

What is the aim of substrate reduction therapy?

A

Reduce the synthesis of the accumulating substrate

83
Q

Two examples of drugs involved in substrate reduction therapy

A

Miglustat

Eliglustat

84
Q

How does Miglustat reduce the substrate concentration?

A

Competitively inhibits the upstream enzyme

Blocks the biosynthesis of the overproduced substrate

85
Q

Diseases that Miglustat targets

A

Gaucher

Fabry

86
Q

Advantage of Miglustat

A

Crosses BBB

87
Q

Disadvantages of Miglustat

A

Causes GI problems

Disrupts metabolic pathway higher up than the overproduced substrate

88
Q

Another example of a substrate reducing therapy

A

Eliglustat

89
Q

Disadvantage of Eliglustat

A

Cannot cross the BBB

Drug transporter causes the compound to be pumped out of the CSF

90
Q

What has been the most successful treatment of LSDs to date?

A

Enzyme replacement therapy

91
Q

What is enzyme replacement therapy based on?

A

Replacement of the defective enzyme by systemically administering the recombinant protein

92
Q

It is proven that partial levels of enzymatic activity might be sufficient to help stabilise symptoms of LSD

TRUE or FALSE

A

TRUE

93
Q

How are recombinant enzymes produced?

A

Using recombinant DNA technology

Tagged with a moiety that allows the enzyme to enter the cells and traffic to the lysosomes

Produced in an industrial scale

94
Q

What are the advantages of using recombinant enzymes as therapy for LSD?

A

Safe and well tolerated

Rarely causes an immune reaction

Suitable for cross-correction

95
Q

What is cross-correction?

A

Process by which a recombinant protein can be replicated in the cell and transported to neighbouring cells

96
Q

What moiety are the recombinant proteins bound to?

A

Mannone-6-phosphate

97
Q

What cellular process do pharmacological chaperones take advantage of?

A

Molecular chaperones

98
Q

What do molecular chaperones do?

A

Bind to nascent polypeptides and promote correct folding of them

Traffic mutant proteins that are not able to be folded correctly to be lysed

99
Q

What condition must proteins express in order to be suitable to be corrected by chaperones?

A

Must possess residual enzymatic activity - the mutation cannot affect the active site

100
Q

What are the aims of using molecular chaperones as therapy for LSDs?

A

More enzymatic activity is retained in the lysosome

Small change in enzymatic activity can affect the quality of life

101
Q

What are the names of two molecular chaperones used as therapy for LSDs?

A

Migalastat

Arimoclol

102
Q

Which condition does Migalastat treat?

A

Fabry disease

103
Q

How does Migalastat treat Fabry?

A

Binds to the active site of misfolded a-galactosidase A

104
Q

Which condition does Arimoclomol treat?

A

NPC

105
Q

How does Arimoclol treat NPCs?

A

Co-inducer of the heat-shock response

Activates the natural cellular repair pathways

106
Q

What is gene therapy?

A

Process by which a mutated gene that causes disease is replaced with a therapeutic copy using a viral vectors

107
Q

What are two ways to perform gene therapy?

A

In vivo

Ex vivo

108
Q

What does in vivo gene therapy involve?

A

Inject the vectors directly into the body where the faulty cell’s DNA is affected

109
Q

What does ex vivo gene therapy involve?

A

Take out cells from the body

Inject the vector into the cell

Place them in the incubator

Add the cells to the body

110
Q

What types of vectors can be used in gene therapy?

A

Non-viral

Viral

111
Q

Examples of non-viral vectors

A

Naked DNA

Nanoparticles

Biovesicles

112
Q

Examples of viral vectors

A

Lentivirus

Adenovirus

Adeno-associated virus

113
Q

Advantages of gene therapy

A

Targets the CNS

Cross-correction

Liver is a good target

Long-term therapy

114
Q

What is cross-correction?

A

Translation of beneficial proteins from genetically altered cells enter cells surrounding them

115
Q

Why is the liver a good target for gene therapy?

A

Vectors have a great effect on hepatocytes

Genetically modified cells can produce the advantageous protein

Travel to neighbouring organs in the circulation

116
Q

What are the disadvantages of gene therapy?

A

Gene delivery needs to be targeted to a specific cell population

Difficult to determine the concentration of protein needed and longetivity of effects

Needs to avoid the immune response

Cost

117
Q

Why does the advantageous gene need to be targeted to specific cell populations?

A

Protein produced may be beneficial in some organs and dangerous in other

118
Q

How is the long-term effectiveness of gene therapy sometimes hazardous?

A

If too much protein is made, past the natural concentration, pathological effects may develop

119
Q

Why are AAVs used often as gene delivery vectors?

A

Efficient at delivering gene therapy

High titer

Causes mild immune response

Interacts with a broad number of cells

Very safe

Molecular Basis of Disease (28 decks)

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