biochem

Auto R. No nucleotide excision repair -- of thymidine dimers. Dry skin w/melanoma & other cancers.

Can't do adenosine --> inosine for purine breakdown, so adenosine goes back up to AMP --> nucleic acids: inhibits de novo nucleic acid synthesis. Most severe cause of SCID.

DNA ligase. The 5' end of incoming nucleotide bears the triphosphate.

Disorder of purine metabolism: mad because you can't "climb up the ladder." Absent HGPRT, so can't do hypoxanthine --> IMP or guanine --> GMP. Excess uric acid --> gout, aggression, retardation.

• Can't do homocysteine --> cystathionine (via cystathionine synthase), which eventually gives you cysteine.
• Tall, hunchback man w/osteoporosis (but it's auto recessive inheritance) with lens subluxation, mental retardation, atherosclerosis.

• Defective renal tubular transporters, so lots of cysteine excreted in urine (plus ornithine, lysine, & arginine).
• Cysteine kidney stones; treat by alkalinizing urine.

Deficient Alpha-ketoacid dehydrogenase, so no breakdown of branched-chain AA's (Isoleucine, Leucine, Valine = I Love Vermont maple syrup).

Maple syrup-smelling urine, feeding problems/vomit, mental retardation, CNS deficits, death.

• Black urine, CT, & pigmented sclerae; also, arthralgias. Usually asymptomatic until ~age 40!
• Defective tyrosine breakdown, via homogentisic acid oxidase... so more tyrosine --> dopa --> melanin.

• Defective phenylalanine --> tyrosine (done by phenylalanine hydroxylase). Eczema, fair skin, mental & growth retardation, musty body odor, seizures. Not observable right away at birth, but they do testing.
• Tx: dec'd phenylalanine (in NutraSweet).

Can't do carbamoyl P + ornithine --> citrulline. X-linked recessive. Hyperammonemia sx (slurred speech, blurred vision, tremor, somnolence), plus excess carbamoyl P --> orotic acid in blood & urine.

Tyrosine --> dopa --> melanin, so albinism = defective tyrosine transporter or tyrosinase. Can be due to lack of neural crest cell migration. Variable inheritance patterns, but ocular albinism = X-linked recessive.

Ordinarily, careless crappers are also frivolous about urination. (Aspartate = the first A)

• Megaloblastic anemia. Causes of excess carbamoyl P:
• 1) Urea cycle: ornithine transcarbamoylase deficiency: can't do carbamoyl P + ornithine --> citrulline, so excess carbamoyl P --> converted to orotic acid.
• 2.) De novo pyrimidine synthesis: you're supposed to have carbamoyl P --> orotic acid, but then it's supposed to go orotic acid --> OMP --> UMP. Deficiency in orotic acid phosphoribosyltransferase or orotidine 5'-P decarboxylase.

Difference between the 2: only #1 has hyperammonemia.

• Hexosaminidase A deficiency --> accumulation of GM2 ganglioside in lysosomes.
• Confusion, blind/deaf (cherry-red spots on macula), developmental delay, death by age 4-5. Lysosomes have onion-skinning.

Blind/deaf (cherry-red spots on macula), hepatosplenomegaly (unlike Tay-Sachs). Sphingomyelinase deficiency in lysosomes, so sphingomyelinase accumulates. Foam cells w/zebra bodies, progressive neurodegeneration.

Fabry's & Hunter's (both X-linked recessive)

Lots of organ systems: cardiovascular, renal, GI, peripheral neuropathy, eyes (angiokeratomas, corneal dystrophy). Deficient alpha-galactosidase A (think "alpha-males"); ceramide trihexoside accumulates. X-linked recessive inheritance.

• The most common lysosomal storage disease. Bones: aseptic necrosis of femur, bone crises, Gaucher's cells (macrophages look like crumpled tissue paper = get gifts when you break bones). Hepatosplenomegaly, too. Almost all present in adulthood.
• Deficient B- glucocerebrosidase. Accumulate glucocerebroside.

Crabbiness = cerebral, so galactocerebrosidase deficiency (accumulate galactocerebroside). Peripheral neuropathy, optic atrophy, developmental delay, globoid cells.

• Demyelination -- both central & peripheral. Ataxia, dementia, death age 5-10.
• Deficient arylsulfatase A, accumulate cerebroside sulfate.

Both glucose --> sorbitol and galactose --> galctitol... both cause eye probs.

PITT: Phe, Isoleucine, Tryptophan, Threonine

Leucine, Lysine

Deficient in maple syrup urine disease (can't break down branched-chain AA's: ILV -- isoleucine, leucine, valine)

Airway obstruction, corneal clouding, gargoylism, developmental delay, hepatosplenomegaly. Enzyme deficient: alpha-L-iduronidase. Accumulated substrate: heparan & dermatan sulfate

Mild Hurler's + aggressive behavior & no corneal clouding. Deficiency of iduronate sulfatase. Accumulated heparan & dermatan sulfate.

• Helps to detach RNA polymerase from RNA after transcription ends.
• RNA polymerase 1 = rRNA, 2 = mRNA, 3 = tRNA