RR - Pathophys of Important Diseases

p. 708-718

Lesch-Nyhan syndrome

Absent HGPRT —> increased de novo purine synthesis —> increased uric acid production

B-thalassemia

mutation at splic site or promoter sequences —> retained intron in mRNA

Lynch syndrome

failure of musmatch repair during the S phase —> microsatellite instability

I-cell disease

N-acetylglucosaminyl-1-phosphotransferase defect —> Golgi mediated mannose residues phosphorylation failure (decreased mannose-6-phosphate) —> increased cellular debris in lysosomesOs

Osteogenesis Imperfecta

type I collagen defect due to inability to form triple helices; mutation in COL1A1 and COL1A2 genesMe

Menkes disease

Defective ATP7A protein —> impaired copper absorption and transport —> decreased lysyl oxidase activity —> decreased collagen cross-linking

Marfan syndrome

FBN1 mutation on chromosome 15 → defective fibrillin (normally forms sheath around elastin)

Prader Willi Syndrome

uniparental disomy or imprinting leading to silencing of maternal gene

• disease expressed when paternal allele deleted or mutated

angelman syndrome

silenced paternal gene leading to mutation, lack of expression, or deletion of UBE3A on maternal chromosome 15

cystic fibrosis

AR deltaF508 deletion in CFTR gene on chromosome 7 → impaired ATP-gated Cl- channel (secretes Cl- in lungs and GI tract and reabsorbs Cl- in sweat gland)

Duchenne muscular dystrophy

dystrophin gene frameshift mutations → loss of anchoring protein to ECM (dystrophin) → myonecrosis

myotonic dystrophy

CTG trinucleotide repeat expansion in DMPK gene → abnormal expression of myotonin protein kinase → myotonia

fragile X syndrome

CGG trinucleotide repeat in FMR1 gene → hypermethylation → decreased expression

blind spots in vitamin A deficiency

decreased differentiation of epithelial cells into specialized tissue → squamous metaplasia

wernicke encephalopathy in alchoholic patient given glucose

thiamine deficiency → impaired glucose breakdown → ATP depletion worsened by glucose infusion

Pellagra in malignant carcinoid syndrome

tryptophan is diverted towards serotonin synthesis by tumor → B3 deficiency (B3 is derived from tryptophan)

Kwashiorkor

protein malformation → decreased oncotic pressure (→ edema), decreased apolipoprotein synthesis (→ liver fatty change)

lactic acidosis, fasting hypoglycemia, hepatic steatosis in alcoholism

increased NADH/NAD+ ratio due to ethanol metabolism

aspirin-induced hyperthermia

increased permeability of mitochondrial membrane → decreased proton [H+] gradient and increased O2 consumption → uncoupling

hereditary fructose intolerance

aldolase B deficiency → fructose-1-phosphate accumulates → decreased available phosphate → inhibition of glycogenolysis and glycogenesis

classic galactosemia

galactose-1-phosphate uridyltransferase deficiency → accumulation of toxic substances (eg galactitol in eyes)