Medical Genetics > Complex Molecule Disorders > Flashcards

Complex Molecule Disorders Flashcards

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1
Q

Describe the basic premise of lysosomal storage disorders

A
  • so in metabolic conditions, we can see a buildup of upstream products bc enzyme dysfunction
  • lysosome is likel recycling bin of the cell, and when there is a progressive accumulation of dif partially degraded substances, we have issues
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2
Q

Describe the basic premise of enzyme replacement therapy

A
  • Admin via IV
  • replaces missing enzyme so that body can degrade what it needs to degrade
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3
Q

Describe the basic premise of bone marrow transplant

A
  • the donor cells are able to produce the enzyme that is missing (not curative though, and this can be a really tough process)
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4
Q

What is the main job of the peroxisome?

A
  • recycling center
  • breaks down long chain fatty acids (VLCFA)
  • about 30 PEX genes are involved in making peroxisome
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5
Q

Describe Zellweger spectrum

A
  • peroxisome disorder in which one cannot produce peroxisomes
  • Results in neuro abnormal, cognitive dysfunc, liver dysfunc, and skeletal changes
  • one thing to remember = chondrodysplasia punctata = stipling of the bones
  • distinctive facial features
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6
Q

How can we test and treat Zellweger spectrum?

A

Test: VLCFA - looking for elevations
Therapy: sadly none, just based on symptoms

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7
Q

Describe cause of X-ALD (adrenoleukodystrophy)

A
  • peroxisome disorder bc disrupts transported of VLC into peroxisome –> so they cannot breakdown and accumulate
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8
Q

Describe two forms of X-ALD (adrenoleukodystrophy)

A

childhood cerebral (1/3 boys)
- 4-8y onset
- neurological regression (eventually lose all purposeful movements + interaction; can see on brain MRI)

Adrenomyeloneuropathy (AMN) (2/3 boys + some females)
- 20-40y onset
- progressive leg stiffness
- bowel/bladder dysfunction

BOTH
- adrenal insufficiency (body cannot produce enough cortisol & cannot resp to illness or keep electrolytes in balance)

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9
Q

How can we test and treat X-ALD?

A
  • testing: VLCFA (like other X-linked disorders, blood test can be falsely normal w females)
  • treatment: stem cell transplant –> do this as soon as you see effects on MRI (usu see this before cog decline) & can prevent that decline
    ^ this = why it is on NBS
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10
Q

How do sphingolipids play a major role?

A

job = break down complex lipids

major role in cell membrane, protein lipid complexes, spec in nervous tissue

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11
Q

Describe what causes Gaucher

A
  • sphingolipidoses
  • Gene: GBA
  • What happens: there is a slow buildup of glucosal ceramide in the liver and spleen and bones
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12
Q

Describe main findings in Gaucher

A
  • sphingolipidoses (GBA gene)
  • bone pain (27%) –> can lead to bone crisis, fractures, etc
  • hepatomegaly (87%)
  • splenomegaly (95%)
  • anemia (40%)
  • thrombocytopenia (50%)
  • bone marrow infiltration (38%)

the thing is though that they were talking about how a lot of these cases do not present this severe and are found incidentally ex: car accident and get x-ray

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13
Q

What testing and treatment are available for Gaucher?

A

Testing:
-biomarker lyso-Gb1 +
- enzyme testing (ABG deficiency = pretty diagnostic)

Treatment:
- enzyme replacement therapy
- Substrate reduction (pills)

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14
Q

Describe what causes Fabry

A

GLA
x-linked

sphingolipidoses

deficient activity of the enzyme alpha-galactosidase A

(AYYY it is FabRAY where we don’t have any Alpha-galac-A)

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15
Q

Describe main findings with Fabry

A

sphingolipidoses
GLA
x-linked

GI
- cramps, constipation, diarrhea
Neuropathic pain
- hands and feet
- tingling and prickling
- burning
Angiokeratomas
- lower abdomen
- bathing trunk
dec sweating

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16
Q

What can happen when Fabry does untreated?

A

sphingolipidoses
GLA
x-linked

  • kidney disease
  • abnormal heart rhythms
  • heart enlargement
  • increased stroke risk
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17
Q

What treatment is available for Fabry?

A

sphingolipidoses
GLA
x-linked

  • enzyme replacement therapy
    (this is more so for the GI symptoms while the organ damage may persist)
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18
Q

What is the cause of Pompe?

A

GAA
sphingolipidoses

there is little to no alpha-glucosidase

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19
Q

What are the main findings of Pompe?

A

Infantile-form:
- onset in 1st months
- hypertrophic cardiomyopathy
- skeletal muscle weakness (esp diaphragm + breathing) –> can be profoundly weak

Late-onset form:
- onset any age
- proximal limb muscle weakness
- progressive diaphragm weakness
- NO heart involvement

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20
Q

What testing and treatment are available for Pompe?

A
  • test urine for Hex4 (tetrasaccharide)
  • treat w enzyme replacement therapy
    –> improves muscle weakness + allows for walking + some breathing abilities
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21
Q

What is the cause of Niemann Pick C?

A

NPC1, NPC2
sphingolipidoses

lipid storage disorder that results from the deficiency of acid sphingomyelinase

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22
Q

What are the main findings in Niemann Pick C?

A

NPC1, NPC2
sphingolipidoses

  1. Early infantile onset
    - delay in dev motor milestones
    - dev regression
  2. Infantile + Childhood onset
    - slurred speech
    - learning difficulties
    - unsteady gait
    - seizures or cataplexy
  3. Teenage + Adult onset
    - psychiatric symptoms (cataplexia)
    - progressive cognitive impairment

also can see enlargement of spleen and liver

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23
Q

What are the testing and treatment options in Niemann Pick C?

A

NPC1, NPC2
sphingolipidoses

Testing: blood test - oxysterols - looking for elevated level

Therapy: therapy w Miglustat = oral drug that slows disease but does not stop it

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24
Q

Gene for Krabbe?

Study These Flashcards
A

GALC
sphingolipidoses

25
What is a similarity between Krabbe and Tay Sachs?
- both begin around 5 months - can have infantile, childhood, and adult onsets - adults presenting may have movement disorder
26
What does "GM2" represent?
sphingolipidoses GM2 gangliocyte accumualtes w the dysfunction of enzyme heterodimer (HexA for TaySachs + HexB for Sandhoff)
27
Gene for Neuronal Ceroid Lipofuscinosis
Sphingolipidoses CLN1, CLN2, CLN3,... - presents around 2y
28
Gene for Metachromatic Leukodystrophy
sphingolidoses ARSA
29
Out of Krabbe, Tay Sachs, NCL, and ML --> which has therapy?
Krabbe + MLD --> stem cell transplant Krabbe - you would need it before the first 2w of life, so sometimes on NBS
30
Out of Krabbe, Tay Sachs, NCL, and ML --> what are all the testing options?
Krabbe - psychosine GM2 - Urine oligosaccharides NCL - DNA testing MLD - urine sulfatides
31
Describe the general idea behind Mucopolysaccharidoses
normal at birth, then slowly develop chronic, progressive symptoms due to lack of enzymes that break down glycoaminoglycans, which then collect in cells, blood, brain and spinal cord, and connective tissues
32
What are the main organ systems affected by Mucopolysaccharidoses?
- skeletal --> abnorm on x-rays & joint contractures - nervous system --> progressive neuro deterioration, carpel tunnel - ears/eyes --> optic atrophy, retinal dystrophy, hearing loss - face/neck --> coarse facieal features, airway narrowing - heart --> thickening valves and dec blood flow - liver and spleen --> enlarged
33
Describe MPSI
- most common mucopolysaccharidoses 2 types: - severe Hurler - attenuated Scheie both: - gene: IDUA - symp: general Mucopolysaccharidoses sympt + corneal clouding severe Hurler: - cog impairment
34
Which MPS is x-linked? Describe it
MPSII Hunter gene: IDS v significant brain involvement w degeneration and behavior issues and outbursts later in life
35
Describe MPSIII
Sanfilippo - gene = SGSH, NAGLU, HGSNAT, GNS - significant behavioral dif early in life - severe cog impairment
36
Describe MPS IV
Morquio - gene = GALNS, GLB1 - significant skeletal dif - normal cognition
37
What testing is available for Mucopolysaccharidoses?
urine glycosaminoglycans (this one will differentiate between the types) + enzyme level
38
What treatment is available for Mucopolysaccharidoses?
Enzym rep therapy for MPSI, II, IV and NOT III - it helps clear the glycoaminoglycans, but still accum in bones and tendons over time also, stem cell transplant ONLY for MPSI
39
What is PMM2-CDG?
congenital disorder of glycosylation most common CDG so the process of glycosylation (adding sugars onto proteins) is dysfunctional
40
Why are most CDG disorders similar?
since you are not ending w a functional product, no matter where you interrupt the glycosylation process will have a similar end result affecting many organ systems
41
What are some common features of PMM2-CDG?
Neuro: - cognitive disability - epilepsy - stroke Organ formation: - distinctive facial features - abnormal fat distribution - renal cysts - brain malformations Organ function: - immune dysfunction - coagulopathy - hormonal imbalance (ex hypothyroid) - livery dysfunction
42
How can we test for PMM2-CDG?
- blood test looking at glycosylated proteins to see if the patterning is normal - N-Glycan - O-Glycan (N or O --> refers to the starting sugar)
43
What are treatment options for congenital disorders of glycosylation?
- sadly not many options - rarely --> can give specific sugars
44
What causes Smith-Lemli-Opitz?
DHCR7 leads to a defect in cholesterol synthesis
45
What are som main features in Smith-Lemli-Opitz?
DHCR7 (defective chol synth) - growth restriction - cognitive disability - distinctive features - 2-3 toe syndactyly - cardiac defects - underdevleoped male genitalia
46
What testing is available for Smith-Lemli-Opitz?
DHCR7 (defective chol synth) 7-dehydrocholesterol (looking for elevated levels bc this is the compound that is made before the process is blocked)
47
What treatment is available for Smith-Lemli-Opitz?
DHCR7 (defective chol synth) sadly, not much - really just anecdotal evidence for admin cholesterol
48
What causes Familial hypercholesterolemia?
LDLR cells cannot take up LDL and degrade it
49
What are the main symptoms for FH?
elevated LDL (>190 mg/dL) leads to astherosclerotic plaque deposition at a young age + risk for cardiovascular disease + heart attack - xanthelasma (around eye) - xanthomas (on tendons like elbows) - corneal arcus
50
What testing is available for FH?
- lipid panel (HDL, LDL, tricglycerides)
51
What treatment is available for FH?
no therapy to target the genes, but can give statins
52
What causes Lysosomal acid lipase?
LIPA this enzyme typically degrades LDL chol, esters, and triglycerides in the lysosomes BUT, when not working, this leads to fat buildup in the muscles --> transported to the liver, which cannot break this down accumulates in the liver and spleen
53
What are the main findings in Lysosomal acid lipase?
(LIPA) - significant liver damage; scarring leads to cirrhosis - enlarged spleen too - astherosclerosis - heart attacks - stroke
54
What testing is available for Lysosomal acid lipase?
Lipid panel (HDL, LDL, triglycerides) Also enzyme testing
55
What treatment is available for Lysosomal acid lipase?
enzyme replacement therapy (the liver will still degrade though - at a slower rate)
56
What causes Cerebrotendinous xanthomatosis?
CYP27A1 prevents the body from converting cholesterol into bile acids --> then store chol in a related compounds known as cholestanol
57
What are the main findings in Cerebrotendinous xanthomatosis?
CYP27A1 infancy: diarrhea childhood: cataracts young adult: xanthomas adult: progressive neurologic dysfunction inc dementia, psych features (hallucinations), difficulty walking
58
What testing is available for Cerebrotendinous xanthomatosis?
(CYP27A1) blood test for cholestanol
59
What therapy is available for Cerebrotendinous xanthomatosis?
(CYP27A1) chenodeoxycholic acid (bile acid replacement)
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