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Disorders of Amino Acid Metabolism

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Disorders of Amino Acid Metabolism Disorders of amino acid metabolism http://plantandsoil.unl.edu/croptechnology2005/UserFiles/Image/siteImages/AminoAcidLG.gif General comments on AA metabolis Urea cycle disorders Disorders of aromatic AA metabolism Disorders of branched chain AA metabolism Disorders of sulfur metabolism Other disorders of AA metabolism ~ 400 g http://uk.geocities.com/[email protected]/images/proteinoverview.png Energy stores amount energy Energy store tissue (g) (kj) (kcal) Glycogen liver 70 1176 280 Glycogen muscle 120 2016 480 Glucose blood 20 336 80 Triacylglycerols fat 15 000 567 000 135 000 Proteins muscle 6000 100 800 24 000 http://www.studentconsult.com/content/default.cfm?ISBN=9780323053716 http://www.mmi.mcgill.ca/mmimediasampler2002/images/Cianflone-60no5.gif http://www.natuurlijkerwijs.com/english/b5e55bf0.gif Protein requirements Protein intake https://astrobiology.nasa.gov/media/medialibrary/2014/03/iGen3_06-01_Figure- Lsmc.jpg Aminoacidopathies-most common mechanisms Accumulation of AA Ammonia accumulation Carbon skeleton accumulations- organic acids Product deficiency http://www.si.mahidol.ac.th/department/Biochemistry/home/md/images/Aa%20met%201.jpg http://www.ucl.ac.uk/~ucbcdab/urea/images/deamination.png Urea cycle disorders https://astrobiology.nasa.gov/media/medialibrary/2014/03/iGen3_06-01_Figure- Lsmc.jpg Ammonia amonnia cationt normal level 50-70 µmol/l somnolence above cca 150 µmol/l coma above 300-400 µmol/l Hyperammonemia is medical emergency Urinary nitrogen excretion Metabolite g 24 h* % total Urea 30 86 Ammonia ion 0.7 2.8 Creatinine 1.0-1.8 4-5 Uric acid 0.5-1.0 2-3 http://www.studentconsult.com/content/default.cfm?ISBN=9780323053716 UCD- frequency OTC-clinical variability Scylla and Charibda http://images.rxlist.com/images/rxlist/ammonul2.gif https://astrobiology.nasa.gov/media/medialibrary/2014/03/iGen3_06-01_Figure- Lsmc.jpg Disturbances of carbon skeleton catabolism https://astrobiology.nasa.gov/media/medialibrary/2014/03/iGen3_06-01_Figure- Lsmc.jpg Organic acidurias Several dozens of small molecule disorders Common feature: increased excretion of carboxylic acids in urine Origin of OA: usually degradation of AA carbon moieties Usually acute manifestation, intoxication type of manifestation Intermittent course frequent Typically metabolic acidosis (and hyperamonemia) Disorders of aromatic amino acid metabolism PAH http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif PAH Phenylketonuria http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif Untreated HPA/PKU CZ 1:6,500, Turkey 1:3,000, very rare Finland, N Europe 1:15,000 1-2% HPA secondary due to primary pterine defectsl 30% patients BH4 sensitive newborn screening untreated HPA- mental retardation, typical mouse odour, light complexions, eczema, epilepsy maternal HPA-VCC, microcephaly a PMR http://www.dshs.state.tx.us/newborn/images/PKU_untreated.jpg Classical dietary treatment of PKU Prof.Horst Bickel http://www.pkux.co.uk/wp-content/uploads/2009/05/horst-bickel-pku-diet.jpg http://www.milupa-metabolics.com/produkte.php?sourceId=162&sysId=139 Dyfsunkce enzymu při nedostatku kofaktoru Těžké mutace PAH Lehké mutace PAH Deficit BH4 zátěžový test s BH4 http://www.rxlist.com/kuvan-drug/clinical-pharmacology.htm PKU- 3rd d PKU- 12the mo http://www.pahdb.mcgill.ca/images/pku.gif&imgrefurl PAH Tyrosinemia 2 http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif Tyrosine http://meded.ucsd.edu/isp/1994/im-quiz/images/tyrosine.jpg http://minimalpotential.files.wordpress.com/2007/11/730px-l-tyrosine-skeletal.png Tyrosinemia type 2 hyperkeratossi herpetiformic keratitis http://www.ijo.in/articles/2007/55/1/images/IndianJOphthalmol_2007_55_1_57_29497_2.jpg http://208.96.47.3/images/community/dermatlas/Tyrosinemia_type_2_2_041213.png Tyrosinemia type 2 very rare herpetiformic keratitis palmoplantar hyperkeratoses with ulcers PMR, growth retardation dietary tretament PAH Alkaptonuria http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif </< td> Coxarthrosis Valvular involvement Urolithiasis Harwa, 1500 př.n.l. http://bjo.bmj.com/content/vol83/issue6/images/large/98532.f1.jpeg http://www.scielo.br/img/revistas/rbr/v46n5/a14fig02.jpg http://www.mja.com.au/public/issues/184_12_190606/sha20286_fm-1b.jpg Alkaptonuria treatment-artifical block above the enzyme block nitison (NTBC) ? what are the possible therapy complications? http://www.natuurlijkerwijs.com/english/b4f4ca00.gif PAH Tyrosinemia 1 http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif Tyrosinemia type I Fumarylacetoacetase deficiency Acute manifestation in infancy Hepatorenal involvement with acute hepatic dysfunction and Fanconi syndrome porfyric crises-abdominal cramps Chronic- ci heatis and ca in cirhosim Diet, nitisone, liver transplant Tyrosinemia type I Alkaptonuria a tyrosinemia 1 treatment nitison (NTBC) http://www.natuurlijkerwijs.com/english/b4f4ca00.gif Disorders of branched chain amino acids BCAA http://www.agron.iastate.edu/courses/Agron317/Images/Branched_chain_aa.jpg How To Achieve A Positive Nitrogen Balance And Why You Care By Fitness Atlantic Writer: Mike Westerdal http://www.fitnessatlantic.com/how_achieve_nitrogen_balance.htm MSUD Peracute presentation in newborns, intermittent variants Coma, dystonia- boxing, cycling maple syrup odour acute crisis prevention and management long term treatment- diet http://losyoruguas.com/archivos/0686.gif Psychomotor development-MSUD Isovaleric aciduria http://images.google.com/imgres?imgurl=http://www.ivasupport.org/images/ Isovaleric aciduria IVA-CoA DH deficiency Peracute/intermittent course Coma with acidosis/ketonuria, sweaty feet odour Acute crisis-elimination Long term-diet, karnitine, glycine Newborn screening http://www.arxmanstyle.com/wp-content/uploads/2009/01/sweaty-feet.jpg http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi Propionic acidemia newborn variant: episodes of ketoacidosis/hyperammonemia, coma, pancytopenia milder froms-repeated encefalopathic crises,FTT chronic problems: FTT, infections, variable CNS involvement therapy: IMTV restriction, gut sterilization, biotin in some patients, aggresive treatment of crises, gastrostomy,liver transplant http://www.uchsc.edu/cbs/images/fig2.JPG http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi Methylmalonic acidemia newborn variant: acute crisis with ketoacidosis, hyperammonemia and coma milder forms-repeated encephalopatic episodes chronic problems: nephropathy progressing in renal failure, variable CNS involvement (pacin picture partially deaf and mute), infections Candida sp. treatment: IMTV restriction, gut sterilization, in some pateints B12, aggresivní treatment of acute episodes http://images.google.com/imgres?imgurl=http://www.toby-churchill.com/files/images/lynn5.jpg Vitamin B12 •complicated synthesis •exogenous intake needed •implied in only 2 reactions •nutritional or endogenous deficiency is common •pregnancy and lactation •advanced age •GIT disorders •long latent course •anemia •demyelinization •psychiatric manifestation •treatment efficient and cheap http://www.health-spy.com/hydroxob12.png Resorpce kobalaminu Metylmalonic and propionic aciduria 1: 50 000 Manoli et Venditti, 2010 Disorders of sulfur amino acid metabolism Methionine cycle Ser Methionine THF Gly DMG S-AdoMet MG Methylene-THF Betaine S-AdoHcy Methyl-THF Homocysteine Cystathionine H2S Cysteine L-gamma-glutamylcysteine Cysteinesulfinate Glutathione Hypotaurine 2- 2- SO 3 SO 4 CysGly Taurine Remethylation Ser Methionine THF Gly DMG S-AdoMet MG Methylene-THF Betaine S-AdoHcy Methyl-THF Homocysteine Cystathionine H2S Cysteine L-gamma-glutamylcysteine Cysteinesulfinate Glutathione Hypotaurine 2- 2- SO 3 SO 4 CysGly Taurine Transsulfuration Ser Methionine THF Gly DMG S-AdoMet MG Methylene-THF Betaine S-AdoHcy Methyl-THF Homocysteine Cystathionine H2S Cysteine L-gamma-glutamylcysteine Cysteinesulfinate Glutathione Hypotaurine 2- 2- SO 3 SO 4 CysGly Taurine Vitamins and Hcy metabolism Ser Methionine THF Gly DMG S-AdoMet MG Methylene-THF Betaine S-AdoHcy Methyl-THF Homocysteine Cystathionine Folates H2S Cysteine L-gamma-glutamylcysteine B12 Cysteinesulfinate Glutathione B2 Hypotaurine 2- 2- B6 SO 3 SO 4 CysGly Taurine CBS deficiency • frequency 1:6.000-1:900.000 • classical and mild forms • clinical triade •Connective tissue: marfanoid features, kyfoskoliosis, osteoporosis, lens luxation •hemokoagulation: thromboses •CNS: cognitive impairment, seizures 16 y-oral contraceptives Headache, thrombosis of sagital sinus tHcy 256 mol/l (<12) P-Met 396 mol/l (15-45) Homocystinuria MAT I/III Methionine Tetrahydrofolate DiMeGly S-adenosyl Met methionine Glycine 5,10-MethyleneTHF Synth GNMT BMT MeCbl Sarcosine MTHFR S-adenosyl homocysteine 5-Methyl-THF Betaine SAHH Homocysteine Adenosine Serine CBS PLP Cystathionine CTH Cysteine Vitamin B12 Sulphate Remethylation homocystinurias About 10 diseases Low Met a low SAM Severely impaired myelinization Neurological sequelae Thrombosis Therapy- betaine, Met, SAM 1810 Wollaston- bladder stone (Greek cystos)- „cystic oxid“ 1817 Marcet- the same compound also found in kidney stones, family occurence (2 sibpairs) http://www.acvs.org/AnimalOwners/HealthConditions/SmallAnimalTopics/Urolithiasis(UrinaryStones)/ http://content.revolutionhealth.com/contentimages/images-image_popup-ww5rm52.jpg cystine http://www.kumc.edu/instruction/medicine/anatomy/histoweb/urinary/large/Ren13.JPG History of
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