Pharmacogenetics

Question 0

Thiopurine Methyltransferase Deficiency (TPMT)

Answer 0

TPMT metabolizes mercaptopurines (cancer/autoimmune tx).
Symptoms: myelosuppression
Other mechanism for clearing mercaptopurines is xanthine oxidase, which is blocked by allopurinol
Measure red cell thiopurines
AZA toxic for slow methylators, low TPMP

Question 1

Malignant hyperthermia

Answer 1

Autosomal dominant. Reaction to Halothane/general anesthetics.
Symptoms: muscle rigidity, extreme hyperthermia. Due to uncontrolled Ca release in skeletal muscles, uncoupled oxidative phosphorylation.
Tx: dantrolene

Question 2

Acute Intermittent Porphyria (AIP)

Answer 2

Autosomal dominant. Related to inborn errors of metabolism in hydroxymethylbilane (HMB) synthase.
Symptoms: accumulation of porphobilinogen, aminolevulinic acid -> acute abd pain, symp discharge, sensorimotor loss, neuropsychiatric
Triggers: things that induce generation of cytP450 which contains heme

Question 3

UDP-glucuronosyltransferase (UGT) 1A1 Polymorphisms

Answer 3

Reduction in UGT1A1 activity, results in Gilbert’s disease (constitutive unconjugated benign hyperbilirubinemia). Increased SN-28 concentration -> diarrhea, leukopenia.
Prevention: genetic testing