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