Complex Molecule Disorders Flashcards
Describe the basic premise of lysosomal storage disorders
- 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
Describe the basic premise of enzyme replacement therapy
- Admin via IV
- replaces missing enzyme so that body can degrade what it needs to degrade
Describe the basic premise of bone marrow transplant
- the donor cells are able to produce the enzyme that is missing (not curative though, and this can be a really tough process)
What is the main job of the peroxisome?
- recycling center
- breaks down long chain fatty acids (VLCFA)
- about 30 PEX genes are involved in making peroxisome
Describe Zellweger spectrum
- 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
How can we test and treat Zellweger spectrum?
Test: VLCFA - looking for elevations
Therapy: sadly none, just based on symptoms
Describe cause of X-ALD (adrenoleukodystrophy)
- peroxisome disorder bc disrupts transported of VLC into peroxisome –> so they cannot breakdown and accumulate
Describe two forms of X-ALD (adrenoleukodystrophy)
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)
How can we test and treat X-ALD?
- 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
How do sphingolipids play a major role?
job = break down complex lipids
major role in cell membrane, protein lipid complexes, spec in nervous tissue
Describe what causes Gaucher
- sphingolipidoses
- Gene: GBA
- What happens: there is a slow buildup of glucosal ceramide in the liver and spleen and bones
Describe main findings in Gaucher
- 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
What testing and treatment are available for Gaucher?
Testing:
-biomarker lyso-Gb1 +
- enzyme testing (ABG deficiency = pretty diagnostic)
Treatment:
- enzyme replacement therapy
- Substrate reduction (pills)
Describe what causes Fabry
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)
Describe main findings with Fabry
sphingolipidoses
GLA
x-linked
GI
- cramps, constipation, diarrhea
Neuropathic pain
- hands and feet
- tingling and prickling
- burning
Angiokeratomas
- lower abdomen
- bathing trunk
dec sweating
What can happen when Fabry does untreated?
sphingolipidoses
GLA
x-linked
- kidney disease
- abnormal heart rhythms
- heart enlargement
- increased stroke risk
What treatment is available for Fabry?
sphingolipidoses
GLA
x-linked
- enzyme replacement therapy
(this is more so for the GI symptoms while the organ damage may persist)
What is the cause of Pompe?
GAA
sphingolipidoses
there is little to no alpha-glucosidase
What are the main findings of Pompe?
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
What testing and treatment are available for Pompe?
- test urine for Hex4 (tetrasaccharide)
- treat w enzyme replacement therapy
–> improves muscle weakness + allows for walking + some breathing abilities
What is the cause of Niemann Pick C?
NPC1, NPC2
sphingolipidoses
lipid storage disorder that results from the deficiency of acid sphingomyelinase
What are the main findings in Niemann Pick C?
NPC1, NPC2
sphingolipidoses
- Early infantile onset
- delay in dev motor milestones
- dev regression - Infantile + Childhood onset
- slurred speech
- learning difficulties
- unsteady gait
- seizures or cataplexy - Teenage + Adult onset
- psychiatric symptoms (cataplexia)
- progressive cognitive impairment
also can see enlargement of spleen and liver
What are the testing and treatment options in Niemann Pick C?
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
Gene for Krabbe?
GALC
sphingolipidoses
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
What does “GM2” represent?
sphingolipidoses
GM2 gangliocyte accumualtes w the dysfunction of enzyme heterodimer (HexA for TaySachs + HexB for Sandhoff)
Gene for Neuronal Ceroid Lipofuscinosis
Sphingolipidoses
CLN1, CLN2, CLN3,…
- presents around 2y
Gene for Metachromatic Leukodystrophy
sphingolidoses
ARSA
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
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
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
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
Describe MPSI
- most common mucopolysaccharidoses
2 types:
- severe Hurler
- attenuated Scheie
both:
- gene: IDUA
- symp: general Mucopolysaccharidoses sympt + corneal clouding
severe Hurler:
- cog impairment
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
Describe MPSIII
Sanfilippo
- gene = SGSH, NAGLU, HGSNAT, GNS
- significant behavioral dif early in life
- severe cog impairment
Describe MPS IV
Morquio
- gene = GALNS, GLB1
- significant skeletal dif
- normal cognition
What testing is available for Mucopolysaccharidoses?
urine glycosaminoglycans (this one will differentiate between the types) + enzyme level
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
What is PMM2-CDG?
congenital disorder of glycosylation
most common CDG
so the process of glycosylation (adding sugars onto proteins) is dysfunctional
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
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
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)
What are treatment options for congenital disorders of glycosylation?
- sadly not many options
- rarely –> can give specific sugars
What causes Smith-Lemli-Opitz?
DHCR7
leads to a defect in cholesterol synthesis
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
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)
What treatment is available for Smith-Lemli-Opitz?
DHCR7
(defective chol synth)
sadly, not much
- really just anecdotal evidence for admin cholesterol
What causes Familial hypercholesterolemia?
LDLR
cells cannot take up LDL and degrade it
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
What testing is available for FH?
- lipid panel (HDL, LDL, tricglycerides)
What treatment is available for FH?
no therapy to target the genes, but can give statins
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
What are the main findings in Lysosomal acid lipase?
(LIPA)
- significant liver damage; scarring leads to cirrhosis
- enlarged spleen too
- astherosclerosis
- heart attacks
- stroke
What testing is available for Lysosomal acid lipase?
Lipid panel (HDL, LDL, triglycerides)
Also enzyme testing
What treatment is available for Lysosomal acid lipase?
enzyme replacement therapy
(the liver will still degrade though - at a slower rate)
What causes Cerebrotendinous xanthomatosis?
CYP27A1
prevents the body from converting cholesterol into bile acids –> then store chol in a related compounds known as cholestanol
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
What testing is available for Cerebrotendinous xanthomatosis?
(CYP27A1)
blood test for cholestanol
What therapy is available for Cerebrotendinous xanthomatosis?
(CYP27A1)
chenodeoxycholic acid (bile acid replacement)
