disorders of amino acid metabolism - univerzita karlovache1.lf1.cuni.cz/html/4 pbch disorders of aa...
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Disorders of amino acid metabolism
http://plantandsoil.unl.edu/croptechnology2005/UserFiles/Image/siteImages/AminoAcidLG.gif
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General comments on AA metabolisDisorders of aromatic AA metabolismDisorders of aromatic AA metabolismDisorders of branched chain AA metabolismDisorders of sulfur metabolismDisorders of propionate, B12 and biotin
metabolismUrea cycle disordersOther disorders of AA metabolism
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http://www.natuurlijkerwijs.com/english/b5e55bf0.gif
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Energy stores
24 000100 8006000muscleProteins135 000567 00015 000fatTriacylglycerols
8033620bloodGlucose4802016120muscleGlycogen280117670liverGlycogen
(kcal)energy
(kj)amount
(g)tissueEnergy store
http://www.studentconsult.com/content/default.cfm?ISBN=9780323053716
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Protein requirements
Protein intake
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How To Achieve A Positive Nitrogen Balance And Why You CareBy Fitness Atlantic Writer: Mike Westerdal
http://www.fitnessatlantic.com/how_achieve_nitrogen_balance.htm
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http://www.mmi.mcgill.ca/mmimediasampler2002/images/Cianflone-60no5.gif
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Patients with disorders of AA metabolism
peroxisomální4%
sacharidy12%beta-oxidace a
OAU14%
AMK bez HPA18%
HPA a PKU13%
lysosomální16%
mitochondriální20%
puriny/pyrimidiny3%
incidence of aminoaciopathies for ČR ~ 1:3000~ 20 pacients with HPA/PKU~ 30 pacients with other AA/OAU
ČR, 2005, n=127
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Diseases of small molecules
usually dependent on exogenous supplymanifestation: (repeated) acute toxicity, usuallywith encephalopathy/comahepatopathy commoncommon disturbances in routine labs-ammonia, Astrup, ketone bodies, glycemia, uric acid...symptoms develop due to specific type of food, fasting, catabolismchronic course possible (if toxicity low)usually good therapeutic response to diet and/orvitamins
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Food and IEMs (small molecules)
(sub)acute toxicitymilk (lactose)-hepatopathysaccharose/fructose/sorbitol- hepatopathy andhypoglycemia
excess protein- vomiting, lethargy, coma (urea cycle disorders, organicacidurias)MCT oils- may be dangerous in MCAD deficiency
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Patophysiology IEM
product
vedl.produkt
substrate<1500 Da
1 32
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Aminoacidopathies-most commonmechanisms
Accumulation of AA Ammonia accumulationCarbon skeleton accumulations-organic acidsProduct deficiency
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Organic acidurias
several dozens of diseasescommon feature: excretion of carboxylic acids(test-organic acids in urine) orginin usually from carbon skeleton degradationof AAs (or saccharides or lipids)usually acute presentation- „intoxication type“metabolic acidosis common (combination withhyperammonemia frequent)
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Disorders of aromaticamino acid metabolism
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PAH
http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif
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PAH
http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif
Phenylketonuria
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Mutations in PAH gene
zdroj: PAH mutation database
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http://www.elmhurst.edu/~chm/vchembook/images/635pku.gif
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http://www.bh4.org/biodefimages/Fig_bh4biox.gif
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Untreated HPA/PKUCZ 1:6,500, Turkey 1:3,000, very rare Finland, N Europe1:15,0001-2% HPA secondary due to primary pterine defectsl30% patients BH4 sensitivenewborn screeninguntreated HPA- mentalretardation, typical mouse odour, light complexions, eczema, epilepsymaternal HPA-VCC, microcephaly a PMR
http://www.dshs.state.tx.us/newborn/images/PKU_untreated.jpg
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Prof.Horst Bickel
http://www.milupa-metabolics.com/produkte.php?sourceId=162&sysId=139
Classical dietary treatment of PKU
http://www.pkux.co.uk/wp-content/uploads/2009/05/horst-bickel-pku-diet.jpg
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http://www.mims.com/spldata/20080617_AF38711E-8873-4790-A92D-4D583E23FB89/kuvan-figure-02.jpg
Sapropterinu (Kuvan)
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http://www.funpecrp.com.br/gmr/year2006/vol1-5/gmr0182_full_text.htm
LNAA in PKU treatment
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http://www.pahdb.mcgill.ca/images/pku.gif&imgrefurl
PKU- 3rd d PKU- 12the mo
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PAH
http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif
Tyrosinemia 2
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Tyrosine
http://meded.ucsd.edu/isp/1994/im-quiz/images/tyrosine.jpg
http://minimalpotential.files.wordpress.com/2007/11/730px-l-tyrosine-skeletal.png
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Tyrosinemia type 2
http://208.96.47.3/images/community/dermatlas/Tyrosinemia_type_2_2_041213.png
http://www.ijo.in/articles/2007/55/1/images/IndianJOphthalmol_2007_55_1_57_29497_2.jpg
hyperkeratossi herpetiformic keratitis
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Tyrosinemia type 2
very rareherpetiformickeratitispalmoplantarhyperkeratoses withulcersPMR, growthretardationdietary tretament
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PAH
http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif
Alkaptonuria
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http://www.mja.com.au/public/issues/184_12_190606/sha20286_fm-1b.jpghttp://www.scielo.br/img/revistas/rbr/v46n5/a14fig02.jpg
</< td>
http://bjo.bmj.com/content/vol83/issue6/images/large/98532.f1.jpeg
CoxarthrosisValvularinvolvementUrolithiasis
Harwa, 1500 př.n.l.
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http://www.natuurlijkerwijs.com/english/b4f4ca00.gif
nitison (NTBC)
Alkaptonuria treatment-artificalblock above the enzyme block
? what are the possible therapy complications?
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PAH
http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif
Tyrosinemia 1
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Tyrosinemia type IFumarylacetoacetasedeficiencyAcute manifestation in infancyHepatorenal involvementwith acute hepaticdysfunction and Fanconisyndromeporfyric crises-abdominalcrampsChronic- ci heatis and ca in cirhosimDiet, nitisone, livertransplant
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Tyrosinemia type I
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http://www.natuurlijkerwijs.com/english/b4f4ca00.gif
nitison (NTBC)
Alkaptonuria a tyrosinemia 1 treatment
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Disorders of branchedchain amino acids
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BCAA
http://www.agron.iastate.edu/courses/Agron317/Images/Branched_chain_aa.jpg
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http://www.sportyshealth.com.au/images/T/87e9202fdfa362030ecb8bc0d5fd41bf.jpg
By Angie Schumacher
Amino Acids (BCAA's) and your Workouts
http://www.wellsphere.com/vitamins-supplements-article/amino-acids-bcaa-s-and-your-workouts/9828
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http://www.childrenshospital.org/newenglandconsortium/NBS/MSUD/MSUD1.jpg
Leucinosis/maple syrup urine disease
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http://losyoruguas.com/archivos/0686.gif
MSUDPeracute presentationin newborns, intermittent variantsComa, dystonia-boxing, cyclingmaple syrup odouracute crisis preventionand managementlong term treatment-diet
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Psychomotor development-MSUD
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Isovaleric acidemia
http://images.google.com/imgres?imgurl=http://www.ivasupport.org/images/
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http://img.medscape.com/fullsize/migrated/455/705/smj455705.fig1.gif
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Isovaleric aciduria
IVA-CoA DH deficiencyPeracute/intermittent courseComa with acidosis/ketonuria, sweaty feet odourAcute crisis-eliminationLong term-diet, karnitine, glycineNewborn screening
http://www.arxmanstyle.com/wp-content/uploads/2009/01/sweaty-feet.jpg
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Disorders of sulfuramino acid metabolism
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Homocysteine
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Homocysteine metabolism
methionine
cystathionineotherS compounds(Cys,GSH, Tau, anorg. S)
CH3
CH3
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S-AdoMet
S-AdoHcy
Homocysteine
Cystathionine
Cysteine
THFMethionine
DMG
Betaine
Cysteinesulfinate
Hypotaurine
Taurine
L-gamma-glutamylcysteine
CysGlySO32- SO42-
H2S
Methylene-THF
Methyl-THF
Methionine cycle
Glutathione
MGGly
Ser
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S-AdoMet
S-AdoHcy
Homocysteine
Cystathionine
Cysteine
THFMethionine
DMG
Betaine
Cysteinesulfinate
Hypotaurine
Taurine
L-gamma-glutamylcysteine
CysGlySO32- SO42-
H2S
Methylene-THF
Methyl-THF
Remethylation
Glutathione
MGGly
Ser
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S-AdoMet
S-AdoHcy
Homocysteine
Cystathionine
Cysteine
THFMethionine
DMG
Betaine
Cysteinesulfinate
Hypotaurine
Taurine
L-gamma-glutamylcysteine
CysGlySO32- SO42-
H2S
Methylene-THF
Methyl-THF
Transsulfuration
Glutathione
MGGly
Ser
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S-AdoMet
S-AdoHcy
Homocysteine
Cystathionine
Cysteine
THFMethionine
DMG
Betaine
Cysteinesulfinate
Hypotaurine
Taurine
L-gamma-glutamylcysteine
CysGlySO32- SO42-
H2S
Methylene-THF
Methyl-THF
Vitamins and Hcy metabolism
Glutathione
MGGly
Ser
Folates
B12
B2
B6
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Two types of homocystinuria
CBS
Remethylation
ÚDMP/KDDL: 4 patientsMTHFR, cblE
ÚDMP/KDDL: 16 patients
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Cystine
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http://www.acvs.org/AnimalOwners/HealthConditions/SmallAnimalTopics/Urolithiasis(UrinaryStones)/http://content.revolutionhealth.com/contentimages/images-image_popup-ww5rm52.jpg
1810 Wollaston- bladder stone (Greek cystos)- „cystic oxid“
1817 Marcet- the same compoundalso found in kidney stones, familyoccurence (2 sibpairs)
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Cystine
cystinuria
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History of cystinuria
1908 Garrod- one of 5 IEMsincidence cca 1: 10 0001994 SLCA1 gene, 1999 SLC7A9hundreds of mutationstreatment: fluid intake, penicillamine, thiopronine
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http://www.kumc.edu/instruction/medicine/anatomy/histoweb/urinary/large/Ren13.JPG
cystine
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Cys-Cys
Aim of treatment= increased solubility
merkaptopropionylglycine(thiopronine)
4-5 L fluids/dayalkalinization
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Cystine
cystinosis
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Adult cystinosis
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ctns
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Cystinosis
Chemiosmotic coupling betweencystinosin and the lysosomal H+-ATPase.
defect of lysosomaltransporter cystinosininfantile form: Fanconihosyndrome-severe tubulopathyFTTadultní forms: ocularinvolvementmyopathy, hypothyreosisRx- cysteaminelocally andsystematically
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Disorders of propionate, cobalamin and biotin metabolism
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Vitamin B12
http://www.health-spy.com/hydroxob12.png
•complicated synthesis•exogenous intake needed•implied in only 2 reactions•nutritional or endogenousdeficiency is common
•pregnancy and lactation•advanced age•GIT disorders
•long latent course•anemia•demyelinization•psychiatric manifestation
•treatment efficient and cheap
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http://www.biochem.med.umich.edu/files/2008-student-photos/cracan.figure.jpg
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http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi
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Peritoneal dialysis in PA
http://www.metagene.de/program/d.prg?id_d=18
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Propionic acidemianewborn variant: episodes of ketoacidosis/hyperammonemia, coma, pancytopeniamilder froms-repeatedencefalopathic crises,FTTchronic problems: FTT, infections, variable CNS involvementtherapy: IMTV restriction, gutsterilization, biotin in somepatients, aggresive treatment of crises, gastrostomy,livertransplant
http://www.uchsc.edu/cbs/images/fig2.JPG
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http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi
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Methylmalonic acidemianewborn variant: acute crisiswith ketoacidosis, hyperammonemia and comamilder forms-repeatedencephalopatic episodeschronic problems: nephropathy progressing in renal failure, variable CNS involvement (pacin picturepartially deaf and mute), infections Candida sp.treatment: IMTV restriction, gut sterilization, in somepateints B12, aggresivnítreatment of acute episodes
http://images.google.com/imgres?imgurl=http://www.toby-churchill.com/files/images/lynn5.jpg
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http://www.biochem.med.umich.edu/files/2008-student-photos/cracan.figure.jpg
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Biotinidase deficiency
http://cme.medscape.com/viewarticle/432565_3
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Biotinidase deficiencyVarious degree of BTD deficiencyimpaired breakdown of biocytin and thus biotin incorporationmultiple carboxylasedeficiencyeczema, seizures, PMRmiraculous response to biotin administration
http://www.rug.nl/umcg/faculteit/disciplinegroepen/kindergeneeskunde/liverdigestivemetabolicdiseases/enzyme/images/biotinidase-grafiek.jpg
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Urea cycle disorders
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Ammoniaamonnia cationtnormal level 50-70 µmol/lsomnolence above cca 150 µmol/l coma above 300-400 µmol/l
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Hyperammonemia is medical emergency
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Vigility test
Why do patients with organic aciduriasexhibit frequently elevated ammonia bloodlevels?
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rinary
nitrogen
excretion.
2-30.5-1.0Uric acid
4-51.0-1.8Creatinine
2.80.7Ammonia ion
8630Urea% totalg 24 h*Metabolite
http://www.studentconsult.com/content/default.cfm?ISBN=9780323053716
Urinary nitrogen excretion
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UCD- frequency
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OTC-clinical variability
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Lethality of OTC
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Scylla and Charibda
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http://images.rxlist.com/images/rxlist/ammonul2.gif
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Monitoring of substraterestriction
Tolerance
Dietaryrecords Analyte(s)
Withinrange
Analyte low/low intake
Analyte high/ high intake
Analyte high/low intake
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Other disorders of amino acid metabolism
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Glutaric aciduria type 1
http://images.google.com/imgres?imgurl=http://upload.wikimedia.org/wikipedia/commons/
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GlutarylCoA DH deficiency—glutarate, 3-OH-glutarateaccumulationneurotoxicity, basalganglia involvement, dystonia, PMRíeasy intracranialbleedingdown-the-staircasecoursediet (Lys, Trp), aggresiveprevention of catabolismnewborn screening
www.medscape.com/viewarticle/501097_2
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Prolidase deficiencyabnormal recycling of Pro into collagen-urinary loss of iminodipeptidessecondary immunedefectsulcers and typicalfacial appearancePMR, splenomegaly, bone changes, mikrocytic anemiatherapy local, systemic proline administration
http://dermatology.cdlib.org/127/case_presentations/prolidase/2.jpg
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Hyperornithinemia
OAT deficiencylate onset 3rd-4th decade-nightblindnessgyrate atrophy of retinatreatment withpyridoxine and dietaryrestriction of Orn
http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/gnd/OAT.gif
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Nonketotic hyperglycinemiaglycine cleaveagesystem deficiencyelevated csf and bloodglycinesometimes prenatalmanifestation, typicalonset early after birthsevere axial hypotoniaand peripheralhypertonusintractable seizures, hypsarytmietherapy inefficient: NMDA receptor block
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Aminoacidopathies-mechanisms
Amino acid accumulationAmmonia accumulationCarbon skeleton accumulation- organicacidsProduct deficiency
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Summary aminoacidopathies
Group of about 50 disordersMechanisms: varying toxicity and metabolite concentration
subgroup organic aciduriassubgroup hyperammonemias
Clinical presentation highly variableDiagnossis by special assaysTreatment usually available and efficientPrenatal diagnosis usually possible