Disorders of amino acid metabolism

http://plantandsoil.unl.edu/croptechnology2005/UserFiles/Image/siteImages/AminoAcidLG.gif

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

http://www.natuurlijkerwijs.com/english/b5e55bf0.gif

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

http://uk.geocities.com/david.bender@btinternet.com/images/proteinoverview.png

~ 400 g

Protein requirements

Protein intake

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

http://www.mmi.mcgill.ca/mmimediasampler2002/images/Cianflone-60no5.gif

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

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

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

Patophysiology IEM

product

vedl.produkt

substrate<1500 Da

1 32

Aminoacidopathies-most commonmechanisms

Accumulation of AA Ammonia accumulationCarbon skeleton accumulations-organic acidsProduct deficiency

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)

Disorders of aromaticamino acid metabolism

PAH

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

PAH

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

Phenylketonuria

Mutations in PAH gene

zdroj: PAH mutation database

http://www.elmhurst.edu/~chm/vchembook/images/635pku.gif

http://www.bh4.org/biodefimages/Fig_bh4biox.gif

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

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

http://www.mims.com/spldata/20080617_AF38711E-8873-4790-A92D-4D583E23FB89/kuvan-figure-02.jpg

Sapropterinu (Kuvan)

http://www.funpecrp.com.br/gmr/year2006/vol1-5/gmr0182_full_text.htm

LNAA in PKU treatment

http://www.pahdb.mcgill.ca/images/pku.gif&imgrefurl

PKU- 3rd d PKU- 12the mo

PAH

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

Tyrosinemia 2

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

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

Tyrosinemia type 2

very rareherpetiformickeratitispalmoplantarhyperkeratoses withulcersPMR, growthretardationdietary tretament

PAH

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

Alkaptonuria

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.

http://www.natuurlijkerwijs.com/english/b4f4ca00.gif

nitison (NTBC)

Alkaptonuria treatment-artificalblock above the enzyme block

? what are the possible therapy complications?

PAH

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

Tyrosinemia 1

Tyrosinemia type IFumarylacetoacetasedeficiencyAcute manifestation in infancyHepatorenal involvementwith acute hepaticdysfunction and Fanconisyndromeporfyric crises-abdominalcrampsChronic- ci heatis and ca in cirhosimDiet, nitisone, livertransplant

Tyrosinemia type I

http://www.natuurlijkerwijs.com/english/b4f4ca00.gif

nitison (NTBC)

Alkaptonuria a tyrosinemia 1 treatment

Disorders of branchedchain amino acids

BCAA

http://www.agron.iastate.edu/courses/Agron317/Images/Branched_chain_aa.jpg

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

http://www.childrenshospital.org/newenglandconsortium/NBS/MSUD/MSUD1.jpg

Leucinosis/maple syrup urine disease

http://losyoruguas.com/archivos/0686.gif

MSUDPeracute presentationin newborns, intermittent variantsComa, dystonia-boxing, cyclingmaple syrup odouracute crisis preventionand managementlong term treatment-diet

Psychomotor development-MSUD

Isovaleric acidemia

http://images.google.com/imgres?imgurl=http://www.ivasupport.org/images/

http://img.medscape.com/fullsize/migrated/455/705/smj455705.fig1.gif

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

Disorders of sulfuramino acid metabolism

Homocysteine

Homocysteine metabolism

methionine

cystathionineotherS compounds(Cys,GSH, Tau, anorg. S)

CH3

CH3

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

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

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

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

Two types of homocystinuria

CBS

Remethylation

ÚDMP/KDDL: 4 patientsMTHFR, cblE

ÚDMP/KDDL: 16 patients

Cystine

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)

Cystine

cystinuria

History of cystinuria

1908 Garrod- one of 5 IEMsincidence cca 1: 10 0001994 SLCA1 gene, 1999 SLC7A9hundreds of mutationstreatment: fluid intake, penicillamine, thiopronine

http://www.kumc.edu/instruction/medicine/anatomy/histoweb/urinary/large/Ren13.JPG

cystine

Cys-Cys

Aim of treatment= increased solubility

merkaptopropionylglycine(thiopronine)

4-5 L fluids/dayalkalinization

Cystine

cystinosis

Adult cystinosis

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ctns

Cystinosis

Chemiosmotic coupling betweencystinosin and the lysosomal H+-ATPase.

defect of lysosomaltransporter cystinosininfantile form: Fanconihosyndrome-severe tubulopathyFTTadultní forms: ocularinvolvementmyopathy, hypothyreosisRx- cysteaminelocally andsystematically

Disorders of propionate, cobalamin and biotin metabolism

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

http://www.biochem.med.umich.edu/files/2008-student-photos/cracan.figure.jpg

http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi

Peritoneal dialysis in PA

http://www.metagene.de/program/d.prg?id_d=18

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

http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi

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

http://www.biochem.med.umich.edu/files/2008-student-photos/cracan.figure.jpg

Biotinidase deficiency

http://cme.medscape.com/viewarticle/432565_3

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

Urea cycle disorders

Ammoniaamonnia cationtnormal level 50-70 µmol/lsomnolence above cca 150 µmol/l coma above 300-400 µmol/l

Hyperammonemia is medical emergency

Vigility test

Why do patients with organic aciduriasexhibit frequently elevated ammonia bloodlevels?

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

UCD- frequency

OTC-clinical variability

Lethality of OTC

Scylla and Charibda

http://images.rxlist.com/images/rxlist/ammonul2.gif

Monitoring of substraterestriction

Tolerance

Dietaryrecords Analyte(s)

Withinrange

Analyte low/low intake

Analyte high/ high intake

Analyte high/low intake

Other disorders of amino acid metabolism

Glutaric aciduria type 1

http://images.google.com/imgres?imgurl=http://upload.wikimedia.org/wikipedia/commons/

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

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

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

Nonketotic hyperglycinemiaglycine cleaveagesystem deficiencyelevated csf and bloodglycinesometimes prenatalmanifestation, typicalonset early after birthsevere axial hypotoniaand peripheralhypertonusintractable seizures, hypsarytmietherapy inefficient: NMDA receptor block

Aminoacidopathies-mechanisms

Amino acid accumulationAmmonia accumulationCarbon skeleton accumulation- organicacidsProduct deficiency

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