ࡱ> cebE@ ebjbj (f'2222222F%%%%T&<F7J&J&J&J&J&J&J&J&6666666$8R:62&J&J&&&622J&J&7333& 2J&2J&63&63,3=35226J&>& ɍ%0567075,s;2Ls;6FF2222s;26|J&^&3l& x&SJ&J&J&66FFJd3 FFJDiseases/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 serumlow 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--hydroxysteroid dehydrogenase deficiency: no glucocorticoids (cortisol), mineralcorticoids (aldosterone), androgens (testosterone) or estragens (estradiol); marked salt excretion in urine; early death 17--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--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--hydroxylase deficiency: decrease in serum cortisol, aldosterone, and corticosterone; increased production of deoxycorticosterone causes fluid retention and hypertension; masculinazaion **differential diagnosis** Is cortisol reduced? Yes CAH Is aldosterone reduced? No: 17--hydroxylase deficiency Yes go to #3 Are sex hormones reduced? Yes: 3--hydroxysteroid dehydrogenase deficiency No go to #4 Is desoxycorticosterone/deoxycortisol reduced? Yes: 21--hydroxylase deficiency No: 11--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 Hartnups disease: defect in transporter for neutral amino acids (ile, leu, phe, thr, trp, val); lack of tryptophan is problemif 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 urineturns 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 -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 -aminolevulinic acid dehydratase causing buildup of - 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--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%LNVrZ [ { } 8 9 T V ^   ! j  , . B E G O   U V ɱɩɱɩɱwp h@/hcWh@/h@/5h@/h@/6h@/h5B*phhgH5B*phhcW5B*phh@/h5 hhcWh5B*ph h:hcWhh@/h6h@/h:6h:h%c5B*phhcW5B*ph hcW>* hcW5+%[ \ 9 : P  i V W ,-<=c^gd^gd@/^gdeV W p r z +,=?]`b;<=cxzF\쿵ޥޡ|umeumehk Yhk Y5hk Yhk Y6 hk Yh bhk Y5B* phh b5B* ph h b>* h b5 h@/hcWhk Yh@/h@/5hMMh@/6h b5B*phhgH5B*phhhcW6 h6h@/h@/6h@/h@/5B*phhcW5B*phhcW5B*ph'c,r|~*TV^gd\gd\ ^`gd {8^gd {8^gdk Y,j<z|$F`RT8"xzҶŮܝܝ}uujhhB* phh\B* phh\h\B* ph h\h\h\h\56B* phh\5B* ph h\h bh\h\6h\ h {8h bh {8 h\6h {8h {86h {85B* phh b5B* phh b h b>*h b5B* ph hk Yh b)TBhi`a! " x !!!*!! ^`gdD^gd^gd^gd & Fgd\z @BLgh{}U_`a ! 8 : w x Вzrngrb h6 hhgHhDhh6hh56B*phh5B*phhgH5B*phhhh6 hhgHhh6h5B*phfhgH5B*phf h b>* hgH>*h\5B* ph hh hh\hhB* phh\h&x !!!!)!*!+!:!* h>* hgH>* hhgHhhh6/!!!d"i%j%%&&&'''@(((()**n*++gdH^^gdH^ ^`gdogdo^gdD^gd+t ^`gd&&&''''(((((((<)@)**&*F*I*J*M*O*m*n** +++;+=+k+l+p++H,I,q,s,,ÿ蟮葍~y~rhhnM15B* ph hH^hgH hnM16hnM1hH^6 hohH^hgHhH^ho5B* ph hohgHhoB* phhgH5B* ph hnM1hgHhnM1 hgH>* hohohoho6ho5B* ph hDhgHhohD5B* phhgH5B* ph(+l+I,J,,,,&-B-C-----B.D./t/v/ L"LLLLMM ^`gd| ^`gdnM1^gdnM1,,,, -#-A-B-V-W-n---------".*.@.B.h.l...r/t////0LLL LBLFL|LLLLLLLLMMXM h|6h|h|6U h|h:Mh|5B*phf h:Mh%ch|h|5h|h:Mh:M5B*phf hgH>* h%c>* hnM1>*hnM15B* ph hnM1hgHhnM1hgH5B* phhnM1hgH6hnM1hnM161 GM2 accumulate Fabry s disease: defect in -galactosidase; globotriaosylceramide accumulates; X-linked recessive Lactosyl ceramidosis: defect in ceramide lactosidase/ -galactosidase; lactosyl-ceramide accumulates Gaucher s disease: defect in -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 Krabbes disease: defect in -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 Sandhoffs 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 XMZM|MMMMMM NNNNNNNNNNNNN"PFP^P`PPPPPP Q$QPQbQxQzQ|QQQ6RNRPRRRܼƵƱܱܘ{wow{h:Mh:MH*h:MhnM1h%c5B*ph h%c>*h%c5B*phfh+5B*phf h+h:Mh+h+5h+ h2h:Mh25B*phfh2h2h25h|5B*phfh:M5B*phf h|h:Mh|h|5h| h|h|+MM;NNNNNN`PbPPPzQ|QQ8RRRS@SASSST^gd%cgd%c ^`gd+^gd:M ^`gd2RRRRRRS0S?S@SWSTT9T;T`TpTTTTGUWUUUUUUUvVVVVVVV*W7WUWWW}}vl}}h5B*ph hShhShhh6hh%c5B*ph hShh+ hShh%chhSh6hShhSh5B*phh+5B*ph h%c>*h%c h+h%chh+6h+h+5B*phh%c5B*ph hnM1h%chnM1h:M'TTzTTTUUUUUVV*WWWdyde^gd^gdSh ^`gdShgd%cWWWdd9dee hShh%chShh%c5B* ph h%c>*Uh+5B*ph hh+Pyrimidine Synthesis Disorder Hereditary orotic aciduria: reduced activities of orotate phosphoribosyl transferase and orotidine 5-phosphate decarboxylase lead to retarded growth and development, hypochromic anemia, and excessive excretion of orotic acid &1h:pk Y/ =!"#$%@@@ NormalCJ_HaJmH sH tH DA@D Default Paragraph FontRi@R  Table Normal4 l4a (k@(No List' f %[\9:PiVW,-<=c o p d e  > ? * + *r!CDrhi`a!"x*2ijHIe GHynlIJ&BCQ;EF RS  P Q !!!!""i""""L####p$q$r$$%%%&&&H''00p0p0p0p0p0p00p0p0p0p000p0p0p0p00p0p0p000p0p0p0p0p0p0p0p0p0p0p0p0p0p0p0p00p000p0p0p0p0p0 0 0 0 0000000p00p00p0 0 0 0 0 0 0 0 0p0p0p0p0p0p0p00p000p0p0p0p0p00p000p000p00p00p00p00000000p0p0p0p0p0000p0p0p0p0p0000p0p0p000p0p0p0p0p0p0p0p0p0p0p0p0p0 0 0 0 0 0 0 0 0 0 0p0 0 0000%[\9:PiVW,-<=c o p d e  > ? * + *rCDrhi`a!"*ijHIeHyIJ&BCQ;EFR !!!!""i""""L####p$q$r$%%&&&'00000000000000000000000000000000000000000000000000 0 0 0 0000000000000000000000000000:0Q00000000:0W00:0X0:0X0:0X0:0X0:0X0:0X0:0X0:0X0:0X0:0X0:0X0:0X0:0X0000000000000000000000000000V zx &,XMRWe "$,.0c!+MTe!#-/em!''9*urn:schemas-microsoft-com:office:smarttagsplace _e<@\j %.^r~$+-CY_DJKTG^Sbcw{( + , 5 o x # . @ I  ! * , 5  !   [ c e p v -8r| PRirJT"1P[+9<I>KNVT^IMeoz~  .8<]`vx&/:D"#4=Kdjrxy$Tefps MUfn #FNOZgop{S`ao| $ 4 6 C n x z `!k!y!!!!!!!!!!!!"("I"R"i"{""""""""">#B#L#Z#[#d######$$$;$D$r$}$$$$$%%%%% &^&w&&&&&&&&&&' '''('6'7'B'H'Q'_'l''''''P[    x .vxn{lp&,QT;D  !!!!i"{"L#Z###$$% &H'Q''33333333333333333333333333333333333333333##;$;$q$r$$%%&'''Erin Steinbrunner)9W88^8`o(. ^`hH.  L ^ `LhH.   ^ `hH. xx^x`hH. HLH^H`LhH. ^`hH. ^`hH. L^`LhH.)9W̟~        @/nM1 {8gHMMcWk YH^ b+t|:M2D:%co+\Sh@(ڌ  &'@<@"H@&(T@.L@P@@UnknownGz Times New Roman5Symbol3& z Arial"qh4|n8|w!H!H$24d''3QH)?cWDiseases/DisordersErin SteinbrunnerErin Steinbrunner Oh+'0 , H T `lt|Diseases/DisordersiseErin SteinbrunnerrinrinNormaleErin Steinbrunner7inMicrosoft Word 10.0@ c4@CcY@DOƍ!՜.+,0 hp|   sH' Diseases/Disorders Title  !"#$%&'()*+,-./012356789:;<=>?@ABCDEFGHIJKLMNOPQSTUVWXY[\]^_`adRoot Entry Fɍf1Table4;WordDocument(fSummaryInformation(RDocumentSummaryInformation8ZCompObjj  FMicrosoft Word Document MSWordDocWord.Document.89q