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24 Cards in this Set

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Theoretically speaking, what are some categorical ways you could tx metabolic dz? (3)
metabolite level (restrict substrate and replace deficient product)

Dysfunctional protein level

Enzyme replacement
PKU is caused by what?
- successful tx requires intervention by when?
either a deficiency of the enzyme phenylalanine hydroxylase; or more rarely a deficiency of the cofactor tetrahydrobiopterin.
- 3wks of age
What is classical galactosemia?
- how does it usually present?
- even if you get them on galactose/lactose restricted diet, can you prevent all disabilities?
due to the deficiency of the enzyme galactose-1-phosphate uridyltransferase.
- within the first two weeks of life with jaundice (conjugated hyperbilirubinemia), lethargy, cataracts, hepatomegaly, failure to thrive, E. coli sepsis and rapidly proceeds to death if untreated.
- no, short stature, ovarian failure, viz/perceptual, speech, and other learning disabilities are common.
Decreased mental awareness, vomiting, combativeness, slurred speech, unstable gait, and unconsciousness --> cerebral edema --> brain damage/death...

This progression of sx is seen in what class of metabolite disorders?

Possible Tx?
urea cycle dz, on account of hyperammonemia.

Decrease protein intake, remove ammonia via hemodialysis, increase waste nitrogen excretion w/ arginine/citrulline, sodium benzoate, sodium phenylacetate/phenybutyrate
abscission
n. removal by cutting off, as in surgery; seperation.

Gangrene spreads so swiftly and is so potentially deadly that doctors advise absicission of the gangrenous tissue.

When a flower of leaf separates naturally from the parent plant, this process is called abscission or leaf fall.
What is the goal of substrate reduction tx (SRT)?
- are big or small compounds typically used?
- can they typically cross the BBB?
to decrease the synth of the accumulating compounds to reduce the influx into the catabolically comprised lysosome.
- small
- yes.
What type of dz is Gaucher's disease?
- features?
- tx with N-butyldeoxynorjirimycin is what type of tx?
+ is this preferred over Enzyme replacement tx?
lysosomal storage dz

deficiency of the enzyme glucocerebrosidase, resulting in the accumulation of glycolipids primary in macrophages and the CNS.

Clinical features included progressive enlargement of spleen and liver, anemia, thrombocytopenia, skeletal involvement with osteoporosis and bone infarcts and neurological disease in the severe forms.

SRT
+ no, indicated in those that can't/won't take ERT anymore.
What sx characterizes GSD Type 1 (G6PD)?
- what does this result in?
hypoglycemia occurring 2 to 3 hours after eating, secondary to an inability to release free G from the liver.
- chronic episodic hypoglycemia results in hepatomegaly, poor growth, lactic acidosis, hyperlipidemia, easy bruising and, if severe and untreated, life threatening hypoglycemic seizures
How do you tx G6PD?
- how is raw cornstarch helpful?
frequent feedings w/ G or G polymers
- slowly digested glucose polymer, can act as a time-release source of glucose and can be very helpful in maintaining glucose levels when taken orally every 4 to 6 hrs
2 yr 9 mo old child with history of recurrent metabolic acidosis, failure to thrive, alopecia, periorbital and perioral rash.
- possible metabolic disorder?
- what other sx might this child develop?
- tx?
Biotinidase deficiency
- hypotonia, seizures, ataxia.
- between 5 and 20 mg oral biotin (in the free, unbound form) per day.
Under physiological conditions, what do chaperones do?
aid in the normal folding of proteins.
About 1/3 to 1/2 of patients with homocystinuria, due to a deficiency of cystathionine beta-synthase, can have a significant reduction of their plasma homocystine by treated with large doses of ...
- this is an example of what type of tx?
pyridoxine (50-500 mg/day).
- activation/chemical chaperone tx.
__ different mRNA stop codons are used in mammals.
- if the pt w/ metabolic dz is dysfunctional b/c of a premature stop codon mutation, what can allow the ribosome to "read through" the premature stop signals?
3
- aminoglycoside antibiotics
About 1/3 to 1/2 of patients with homocystinuria, due to a deficiency of cystathionine beta-synthase, can have a significant reduction of their plasma homocystine by treated with large doses of ...
- this is an example of what type of tx?
pyridoxine (50-500 mg/day).
- activation/chemical chaperone tx.
What are mucopolysaccharidoses?
- what type of tx works well?
- this tx improves all sx except...
group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans
- Enyzmatic correction is possible at the cellular level in LSD fibroblasts because if you inject cultured cells they release small amounts of lysosomal enzymes "correction factors" --> uptake --> takes care of the GAG buildup.
- except CNS dz.
__ different mRNA stop codons are used in mammals.
- if the pt w/ metabolic dz is dysfunctional b/c of a premature stop codon mutation, what can allow the ribosome to "read through" the premature stop signals?
3
- aminoglycoside antibiotics
What is the most common lysosomal storage dz?
- defect?
- result?
- tx?
Gaucher's dz
- defective glucocerebrosidase (acid-B-glucosidase)
- accumulation of glucocerebroside, particularly in mononuclear cells.
- mannose-terminal glucocerebrosidase (the mannose makes it easier for the defective cells to take up the enzyme)
What are mucopolysaccharidoses?
- what type of tx works well?
- this tx improves all sx except...
group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans
- Enyzmatic correction is possible at the cellular level in LSD fibroblasts because if you inject cultured cells they release small amounts of lysosomal enzymes "correction factors" --> uptake --> takes care of the GAG buildup.
- except CNS dz.
What is the most common lysosomal storage dz?
- defect?
- result?
- tx?
Gaucher's dz
- defective glucocerebrosidase (acid-B-glucosidase)
- accumulation of glucocerebroside, particularly in mononuclear cells.
- mannose-terminal glucocerebrosidase (the mannose makes it easier for the defective cells to take up the enzyme)
What sx category of Lysosomal storage dz does HSCT (hematopoietic stem cell transplant) not improve?
- who is it recommended for?
- MPS II and III? why?
- MPS VI?
- MLD (metachromatic leukodystrophy) and Krabbe?
skeletal manifestations and ocular manifestations.
- MPS I pts under 2yo w/ MDI>70.
- no; preservation of neurological fx has not been reported.
- somatic benefit; no CNS help?
- No somatic help, but CNS help.
What are some criterion for considering a genetic disorder as a candidate for somatic gene tx?
- what are the two general vector categories that have been used for gene transfer?
- what application are most of the gene tx protocols targeted towards?
Single gene disorder of recessive inheritance
Molecular biology of disorder understood
Genomic DNA or cDNA sequences are available
High morbidity/mortality
Limitations of current therapy to justify experimental approaches
Expression of gene product should be obtained in an accessible tissue and at levels that are beneficial.
- virus vs chemical (~75% are viral)
- cancers
Differentiate between the 1 indirect and 2 direct methods of clinical gene transfer.
Indirect (ex vivo) - Cells are removed from the body, incubated with the vector in culture and the genetically modified cells are returned to the body. Blood cells are a common target tissue for this approach.
Direct (in vivo) - Vector is directly injected into the bloodstream.
Direct (in situ) - Vector is placed directly on or into the affected tissue. Examples are the placement of a vector into the trachea of a patient with CF or injection of a tumor with a vector containing a cytotoxic gene.
What are SCID?
- early presenting features?
- conventional tx?
SEVERE COMBINED IMMUNODEFICIENCY (SCID)
- Heterogenous group of rare genetic disorders characterized by primary failure of T-cell immunity.
- FTT, chronic diarrhea, serious recurrent infections.
- HSCT w/ HLA-matched donor (90% survival rates)
What could be a potential drawback of tx with stem cells modified with a viral vector?
vector has been shown to potentially actv ongogenes --> lymphoproliferative dz.