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 HDL-3 particles have lower lipid to protein ration and is atherogenic rather than anti-atherogenic

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 γ-

aminolevulinic 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

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