Protein diseases

Question 1

Alkaptonuria

Answer 1

• Deficiency in homogentisate oxidase,, an enzyme in the pathway of Tyr metabolism
• accumation of homogentisate -> Dark urine and dark deposits on joints -> severe arthritis

Question 2

Maple syrup urine

Answer 2

• Enzyme deficiency in branched chain alpha ketoacid DH (so Ile, leu, and val)
• accumulation of these changes -> n. defects, and urine smells like maple syrup
• Treat with dietary changes

Question 3

Homocystenuria

Answer 3

• deficiency in cystathione b-synthase OR folic acid
• it’s downstream of the methionine-homocysteine degradation pathway, and so both accumulate, causing
• mental retardation
• CVD
• osteoporosis

Question 4

Urea cycle enzyme defects

Answer 4

• defects in all 5 enzymes + NAGS
• most of them have a late onset, especially with compromised hepatic function (alcohol, infection)
• OTC deficiency is X-linked, others are autosomal recessive
• each defective enzyme produces an -emia of its substrate
• Rx
• gene/transplant doesnt work well
• restrict ptn intake
• use Na phenylbutyrate to divert synthesis
• Arg supplement for arginine synthase deficiency

Question 5

Hyperphenylalaninemias

Answer 5

• elevated conc of Phe in tissues, plasma, and urine
• caused by defects in mb of aromatic amino acids (Phe, Tyr, and Try)
• enzymes that synthesize or reduce bioptrin coenzyme
• more severe forms are d.t. mutations affecting dihydropterin cause the -emia as well, but are worse because they block synthesis of DOPA and 5-HT, which reduces synthesis of catecholamines and serotonin, respectively.

Question 6

PKU

Answer 6

• Deficiency in phenylalanine hydroxylase or tetrahydrobiopterin (cofactor)
• Leads to hyperphenylalanemia and decreased Tyr levels
• Increased Phe also inhibits many of the Tyr metabolic enzyme such as those that produce catecholamines and melanin (leads to alanism)
• Developmental delay and failure to thrive if not treated
• Can detect by elevated levels of phenylpyruvate
• Treat with dietary changes of low Phe and high Tyr
• Can also be caused by a deficiency in biopterin, which is used in Try and Trp metabolism as well, so phenotype is worse

Question 7

Lesch-Nyhan

Answer 7

• This disease cray cray
• Deficiency in HGPRT (Hypoxanthine Guanine Phosphoribosyltransferase), an enzyme in the purine salvage pathway
• Deficiency causes increases PRPP levels and increased free purine bases
• Increased free pruine bases leads to increased catabolism → gout
• Increased PRPP activates PRPP synthase leading to activation of de novo pathway
• Sxs include gout (treated with allopurinol) and self mutilation (unknown mechanism)

Question 8

Gout

Answer 8

• purine degradation -> uric acid, which is excreted in urine
• excessive production or poor renal excretion (most likely one) of uric acid -> gout
• excessive production occurs with unregulated PRPP synthase generating unregulated enzyme
• Lesch Nyhan -> loss of HGRPT activity
• impaird kidney excretion of compromised kidney function
• Rx
• xanthine oxidase block by allpurinol, which also leads to increased nucleotides and de novo pathway activation

Question 9

Adenosine deaminase deficiency

Answer 9

• Deficiency in the enzyme adenosine deaminase, involved in catabolism of dATP
• Increased dATP levels inhibit ribonucleotide reductase because this enzyme tries to keep all dNTP levels the same
• Leads to SCID (immunodeficiency in T and B cells)
• Rx
• bone marrow transplants
• enzyme replacement
• gene transfection of T-cell population

Question 10

pynco-dyso-stosis

Answer 10

• rare lysosomal storage disease that causes cathepsin K deficiency
• dysfunctional osteoclasts -> bone development retardation -> short stature, stubby fingers

Question 11

SERPIN deficiency

Answer 11

• > problems d.t excessive destruction
• symptoms may be dormant until stress or damage occurs, e.g., smoking or drinking
• alpha 1 antitryspin deficiency -> liver aggregates
• C1 INH deficiency -> massive C activation -> angioedema
• antithrombin deficiency -> blood clots, worse with pregnancy