Download Diseases/Disorders

Diseases/Disorders
Lipase Disorders
Familial lipoprotein lipase deficiency: observe elevated chylos, normal VLDL (expect to be
elevated), and low LDL and HDL levels; pancreatitis and abdominal pain; no risk
of atherosclerotic disease; analysis of postheparin serum (heparin stimulates LPL
release) in presence of apoC-II = no /low LPL activity
Apolipoprotein C-II deficiency: symptoms of LPL deficiency; diagnose with immunoblot (low
apoC-II) or analysis of postheparin serum—low LPL activity but increases with
addition of exogenous apoC-II; autosomal recessive
Hepatic lipase deficiency: observe hypertriglyceridemia, increased chylos remnant particle, and
triglyceride rich LDL and HDL (via CETP action); increases risk of
atherosclerotic disease
Excess hepatic lipase problems: observe accumulation of small dense LDL and decreased
cholesterol content of HDL (fewer cholesterol esters in HDL core)—smaller HDL3 particles have lower lipid to protein ration and is atherogenic rather than antiatherogenic
More Lipid Diseases
Homozygous apoE-2 isoform (dysbetalipoproteinemia): observe increases chylos remnant
particles and elevated serum levels of TGs and CEs; chylos remnants and IDL
taken up less effectively by liver and accumulate in plasma; increased early
atherosclerotic disease; deposits of cholesterol in palm of hand (palmar
xamthomas)
Familial LCAT deficiency: observe low levels of mature HDL, elevated phospholipids levels
(due to PLTP action), and low plasma LDL-cholesterol (macrophages?); no
increased risk of atherosclerosis (surprisingly)
Tangier disease (familial analphalipoproteinemias): observe reduced or immature HDL
(absence of HDL-cholesterol) and increased cellular cholesterol esters (especially
in macs of tonsils: orange tonsils; increased atherosclerotic disease; result of
defect in ABC-1 gene
Disorders involving B apolipoproteins
Abetalipoproteinemia: observe absence of chylos, VLDL, and IDL; mutation in MTP
(microsomal TG transfer protein) interferes with packaging or secretion of apoB
containing lipoproteins; accumulation of TG in enterocytes and malabsorption of
fats leads to increased FFA in stool; autosomal recessive
Familial ligand-defective apoB-100: observe increased serum cholesterol and LDL; increased
risk of atherosclerotic disease; prescribe inhibitors of HMG-CoA reductase (rate
limiting step in cholesterol biosynthetic pathway; autosomal recessive
Familial hypercholesterolemia: same symptoms as ligand-defective apoB-100 (increased serum
cholesterol and LDL) but due to lack of functional LDL receptors; atherogenic;
common (1/500); autosomal dominant with heterozygous advantage
Congenital Adrenal Hyperplasias (CAH)
3-β-hydroxysteroid dehydrogenase deficiency: no glucocorticoids (cortisol), mineralcorticoids
(aldosterone), androgens (testosterone) or estragens (estradiol); marked salt
excretion in urine; early death
17-α-hydroxylase deficiency: no sex hormones or cortisol; increased production of
mineralocorticoids causes sodium and fluid retention leading to hypertension;
patient is phenotypically female but unable to mature
21-α-hydroxylase deficiency: usually a partial deficiency with reduced aldosterone,
corticosterone and cortisol; ACTH levels elevated causing an increased flux to sex
hormones and, therefore, masculinization; most common form of CAH
11-β-hydroxylase deficiency: decrease in serum cortisol, aldosterone, and corticosterone;
increased production of deoxycorticosterone causes fluid retention and
hypertension; masculinazaion
**differential diagnosis**
1. Is cortisol reduced?
Yes—CAH
2. Is aldosterone reduced? No: 17-α-hydroxylase deficiency
Yes—go to #3
3. Are sex hormones reduced?
Yes: 3-β-hydroxysteroid dehydrogenase deficiency
No—go to #4
4. Is desoxycorticosterone/deoxycortisol reduced? Yes: 21-α-hydroxylase deficiency
No: 11-β-hydroxylase deficiency
Diseases Associated with Amino Acid Transport
Cystinuria: defect in transport of cystine, lysine, arginine and ornithine into intestinal epithelial
and renal tubular cells (basic aa and cystine); cystine accumulates in kidneys
forming renal calculi (stones), but no aa deficiencies develop
Hartnup’s disease: defect in transporter for neutral amino acids (ile, leu, phe, thr, trp, val); lack
of tryptophan is problem—if niacin is low, there are problems making NAD;
pellagra-like symptoms; treat by administering tryptophan and niacin
Defects Associated with Phenylalanine Metabolism
Alcaptonuria: buildup of homogentistic acid in urine—turns black when oxidized, causing black
urine; buildup in joints may lead to arthritis
Phenylketonuria (PKA): missing phenylalanine hydroxylase or have inability to make/
regenerate tetrahydrobiopterin (problem in biopterin synthesis); buildup of
phenylpyruvate leads to neuronal damage and mental retardation
Other Amino Acid Associated Diseases
Cystathionuria: cystathionine in urine; common in premature infants; caused by deficiency of
cystathionase or from deficiency of vitamin B6 (pyridoxal phosphate); benign
Homocysteinemia/urea: elevated levels of homocysteine and methionine in blood and urine
caused by: cystathionine β-synthase deficiency, defective B12 transport or
coenzyme sythesis, defective methionine synthase, or 5,10-methylene THF
reductase deficiency and thermolabile variant (if hereditary); also caused by various
drugs, diseases, and vitamin deficiencies (B6, B12, folic acid); treat with vitamin
supplementation; risk factor for cardiovascular disease because homocystein
inhibits endothelial cell growth and promotes smooth muscle proliferation
(atherosclerosis); also blocks action of an inhibitor of coagulation cascade
(thrombotic problems)
Maple syrup urine disease: deficiency in branched chain aa (L,I,V) dehydrogenase leads to
ketoacidosis and mental retardation; treat with dietary restriction of branched chain
aa, but all essential so not very effective
Heme Biosynthesis Disorders
Porphyrias: lack of heme causes anemia and sensitivity to sun; secondary skin infections
common
Lead poisoning: lead inhibits γ-aminolevulinic acid dehydratase causing buildup of γaminolevulinic acid and heme reduction
Urea Cycle Disorders—arg becomes an essential aa
Defect in N-acetylglutamate synthase: cannot make N-acetylglutamate and cannot activate
CPS-I; elevated ammonia in blood and urine; death in only reported case
Defect in carbamoyl phosphate synthetase (CPS)-I: no accumulation of urea cycle
intermediates; elevated ammonia in blood and urine; treat with agents that reduce
ammonia levels (remove glycine and glutamine from system); less than 50 cases
Defect in ornithine transcarbamoylase (OTC): hyperammonemia with elevated levels of orotic
acid; orotic aciduria caused by buildup of carbamoyl-phosphate in mitochondria,
which diffuses into cytoplasm and stimulates pyrimidine biosynthesis, resulting in
high levels of orotic acid; most common urea cycle defect
Defect in argininosuccinate synthetase: hyperammonemia, slight orotic aciduria, and
hypercitrullinemia (citrulline buildup)
Defect in argininosuccinate lyase: moderate hyperammonemia with argininosuccinate buildup;
second most common disorder
Defect in arginase: elevated blood arginine with only slight ammonia elevation
Sphingolipidoses
Generalized gangliosidosis: defect in GM1-β-galactosidase; GM1 accumulates
Tay Sachs disease: defect in hexosaminidase A; GM2 accumulates; cherry-red spot in retina of
eye, muscular weakness, seizures, and mental retardation
Sandhoff’s disease: defect in hexosaminidases A and B; globoside and GM2 accumulate
Fabry’s disease: defect in α-galactosidase; globotriaosylceramide accumulates; X-linked
recessive
Lactosyl ceramidosis: defect in ceramide lactosidase/ β-galactosidase; lactosyl-ceramide
accumulates
Gaucher’s disease: defect in β-glucosidase; glucocerebroside accumulates; liver and spleen
enlarge, long bones and pelvis erode, and infantile mental retardation
Metachromatic leukodystrophy: defect in arylsulfatase A; 3-sulfogalactosylceramide
accumulates
Krabbe’s disease: defect in β-galactosidase; galactosylceramide accumulates
Niemann-Pick disease: defect in sphingomyelinase; sphingomyelin accumulates
Farber’s disease: defect in ceramidase; ceramide accumulates
Other Phospholipid Disorders
Zellweger syndrome: membranes of liver and brain mitochondria are depleted of plasmalogens
(phosphoglyceride w/ 1st FA attached by vinyl-ether linkage), preventing transport
of peroxisomal enzymes into peroxisomes; fatal
Sandhoff’s activator disease: symptoms like Tay Sachs, but HexA and HexB enzymes are
normal; lack of HexA activator causes disease
Mucopolysaccharidoses: diseases caused by loss of a lysosomal enzyme that degrades
glycosaminoglycans; partially degraded glycosaminoglycans accumulate in
lysosomes of almost all tissues
Purine Synthesis Diseases
Adenosine deaminase deficiency: T-cell and B-cell dysfunction; large buildups of dATP inhibit
ribonucleotide reductase (inhibiting DNA synthesis); die of infection
Purine nucleoside phosphorylase deficiency: T-cell impairment; decrease in uric acid
formation; increased purine nucleoside levels; dGTP accumulates and inhibits CDP
reductase (may be toxic agent in T-cell development)
Lesch-Nyhan Syndrome: hypoxanthine-guanine phosphoribosyl transferase deficiency leads to
excessive production of uric acid and neurological problems (self-mutilation,
involuntary movements, mental retardation); increased PRPP and decreased IMP
and GMP leading to increased de novo purine synthesis
Gout: overproduction of uric acid or reduction in fractional renal urate clearance causes
hyperuricemia; possible enzyme defects are glucose 6-phosphatase deficiency,
hypoxanthine-guanine phosphoribosyltransferase deficiency and PRPP synthetase
variants; arthritis typically responsive to colchicine
Pyrimidine Synthesis Disorder
Hereditary orotic aciduria: reduced activities of orotate phosphoribosyl transferase and
orotidine 5’-phosphate decarboxylase lead to retarded growth and development,
hypochromic anemia, and excessive excretion of orotic acid