Di d f i id t b liDisorders 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 metabolism Disorders of branched chain AA metabolism Disorders of sulfur metabolism Disorders of propionate, B12 and biotinDisorders of propionate, B12 and biotin

metabolismUrea cycle disordersUrea cycle disordersOther disorders of AA metabolism

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

Energy stores

Energy store tissueamount

(g)energy

(kj) (kcal)Energy store tissue (g) (kj) (kcal)Glycogen liver 70 1176 280

Glycogen muscle 120 2016 480Glycogen muscle 120 2016 480

Glucose blood 20 336 80

Triacylglycerols fat 15 000 567 000 135 000acy g yce o s at 5 000 56 000 35 000

Proteins muscle 6000 100 800 24 000

http://www.studentconsult.com/content/default.cfm?ISBN=9780323053716

~ 400 g

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

Protein requirements

Protein intakeProtein intake

H T A hi A P iti Nit B l A d Wh Y CHow 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

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

Patients with disorders of AA metabolismPatients with disorders of AA metabolism

sacharidy12%beta-oxidace a

OAU14%

puriny/pyrimidiny3%

AMK bez HPA

mitochondriální20%

%

AMK bez HPA18%

peroxisomální4%

HPA a PKU13%

lysosomální16%

ČR, 2005, n=127

incidence of aminoaciopathies for ČR ~ 1:300020 pacients with HPA/PKU~ 20 pacients with HPA/PKU

~ 30 pacients with other AA/OAU

Diseases of small molecules

usually dependent on exogenous supplymanifestation: (repeated) acute toxicity usuallymanifestation: (repeated) acute toxicity, usually with encephalopathy/comahepatopathy commonhepatopathy commoncommon disturbances in routine labs-ammonia, Astrup, ketone bodies, glycemia, uric acid...p, , g y ,symptoms develop due to specific type of food, fasting, catabolismchronic course possible (if toxicity low)usually good therapeutic response to diet and/or it ivitamins

Food and IEMs (small molecules)

(sub)acute toxicitymilk (lactose)-hepatopathysaccharose/fructose/sorbitol- hepatopathy and hypoglycemiahypoglycemia

excess protein- vomiting, lethargy, ( l di d icoma (urea cycle disorders, organic

acidurias))MCT oils- may be dangerous in MCAD deficiency

Patophysiology IEM

substrate

vedl.produkt<1500 Da

vedl.produkt

product

1 32

Aminoacidopathies-most commonAminoacidopathies most common mechanisms

Accumulation of AAAccumulation of AA

Ammonia accumulation

Carbon skeleton accumulations-organic acidsg

Product deficiency

Organic acidurias

several dozens of diseases

common feature: excretion of carboxylic acids (test-organic acids in urine)

orginin usually from carbon skeleton degradation of AAs (or saccharides or lipids)( p )

usually acute presentation- „intoxication type“

metabolic acidosis common (combination withmetabolic acidosis common (combination with hyperammonemia frequent)

Disorders of aromatic amino acid metabolism

PAH

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

PAH PhenylketonuriaPhenylketonuria

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

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/PKU

CZ 1:6,500, Turkey 1:3,000, very rare Finland, N Europe y , p1:15,0001-2% HPA secondary due to primary pterine defectslprimary pterine defectsl30% patients BH4 sensitivenewborn screeningguntreated HPA- mental retardation, typical mouse odour, light complexions eczemalight complexions, eczema, epilepsymaternal HPA-VCC, microcephaly a PMRmicrocephaly a PMR

http://www.dshs.state.tx.us/newborn/images/PKU_untreated.jpg

Cl i l di t t t t f PKUClassical dietary treatment of PKU

Prof.Horst Bickel

http://www.milupa-metabolics.com/produkte.php?sourceId=162&sysId=139

http://www.pkux.co.uk/wp-content/uploads/2009/05/horst-bickel-pku-diet.jpg

Sapropterinu (Kuvan)

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

LNAA in PKU treatment

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

PKU- 3rd d PKU- 12the mo

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

PKU 3rd d PKU 12the mo

PAH Tyrosinemia 2y

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

T iTyrosine

http://meded.ucsd.edu/isp/1994/im-quiz/images/tyrosine.jpghttp://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://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

Tyrosinemia type 2

very rareherpetiformicherpetiformic keratitispalmoplantarpalmoplantarhyperkeratoses with ulcersPMR, growth retardationdi t t t tdietary tretament

PAH Alkaptonuriap

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

</< td>

CoxarthrosisCoxarthrosisValvular involvementUrolithiasis

Harwa, 1500 př.n.l.

http://www.mja.com.au/public/issues/184_12_190606/sha20286_fm-1b.jpghttp://www.scielo.br/img/revistas/rbr/v46n5/a14fig02.jpghttp://bjo.bmj.com/content/vol83/issue6/images/large/98532.f1.jpeg

Alkaptonuria treatment artificalAlkaptonuria treatment-artifical block above the enzyme block

nitison (NTBC)

y

? what are the possible therapy complications?

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

PAH Tyrosinemia 1y

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

Tyrosinemia type IFumarylacetoacetaseFumarylacetoacetase deficiencyAcute manifestation in i finfancyHepatorenal involvement with acute hepaticwith acute hepatic dysfunction and Fanconi syndromeporfyric crises abdominalporfyric crises-abdominal crampsChronic- ci heatis and ca i i h iin cirhosimDiet, nitisone, liver transplantp

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

By Angie SchumacherBy Angie Schumacher

Amino Acids (BCAA's)Amino Acids (BCAA s) and your Workouts

http://www.wellsphere.com/vitamins-supplements-article/amino-acids-bcaa-s-and-your-workouts/9828

http://www.sportyshealth.com.au/images/T/87e9202fdfa362030ecb8bc0d5fd41bf.jpg

Leucinosis/maple syrup urine disease

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

MSUDPeracute presentation in newborns, intermittent variantsintermittent variantsComa, dystonia-boxing cyclingboxing, cyclingmaple syrup odour

i i iacute crisis prevention and managementl t t t tlong term treatment-diet

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

Psychomotor development-MSUD

Isovaleric acidemia

htt //i l /i ?i l htt // i t /i /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 deficiency P t /i t itt tPeracute/intermittent courseComa with acidosis/ketonuria,

t f t dsweaty feet odourAcute crisis-eliminationLong term-diet, karnitine, glycineNewborn screening

http://www.arxmanstyle.com/wp-content/uploads/2009/01/sweaty-feet.jpg

Disorders of sulfur amino acid metabolism

Homocysteine

Homocysteine metabolism

CH3

methioninemethionine

CH3

cystathionineotherS compounds(C GSH T S)

3

(Cys,GSH, Tau, anorg. S)

Methionine cycle

THFMethionine

DMG

y

Gly

Ser

S-AdoMet

S Ad H

DMG

Methylene-THF

MGGly

S-AdoHcy

Homocysteine

Betaine

Methyl-THF

Cystathionine

Cysteine L-gamma-glutamylcysteineH2S

CysteinesulfinateGlutathione

Hypotaurine

Taurine

CysGlySO32- SO4

2-

Remethylation

THFMethionine

DMG

y

Gly

Ser

S-AdoMet

S Ad H

DMG

Methylene-THF

MGGly

S-AdoHcy

Homocysteine

Betaine

Methyl-THF

Cystathionine

Cysteine L-gamma-glutamylcysteineH2S

CysteinesulfinateGlutathione

Hypotaurine

Taurine

CysGlySO32- SO4

2-

Transsulfuration

THFMethionine

DMGGly

Ser

S-AdoMet

S Ad H

DMG

Methylene-THF

MGGly

S-AdoHcy

Homocysteine

Betaine

Methyl-THF

Cystathionine

Cysteine L-gamma-glutamylcysteineH2S

CysteinesulfinateGlutathione

Hypotaurine

Taurine

CysGlySO32- SO4

2-

Vitamins and Hcy metabolism

THFMethionine

DMG

y

Gly

Ser

S-AdoMet

S Ad H

DMG

Methylene-THF

MGGly

S-AdoHcy

Homocysteine

Betaine

Methyl-THF

Cystathionine

Cysteine L-gamma-glutamylcysteineH2SFolates

CysteinesulfinateGlutathione

B12

B2Hypotaurine

Taurine

CysGlySO32- SO4

2-

B2

B6

Two types of homocystinuriaTwo types of homocystinuria

CBS ÚDMP/KDDL: 16 patients

Remethylation

ÚDMP/KDDL:ÚDMP/KDDL: 4 patientsMTHFR, cblE

Cystine

1810 W ll t bl dd t1810 Wollaston- bladder stone (Greek cystos)- „cystic oxid“

1817 Marcet- the same compound also found in kidney stones, family y yoccurence (2 sibpairs)

http://www.acvs.org/AnimalOwners/HealthConditions/SmallAnimalTopics/Urolithiasis(UrinaryStones)/http://content.revolutionhealth.com/contentimages/images-image_popup-ww5rm52.jpg

Cystine

cystinuriacystinuria

History of cystinuria

1908 Garrod- one of 5 IEMs

incidence cca 1: 10 000

1994 SLCA1 gene 1999 SLC7A91994 SLCA1 gene, 1999 SLC7A9

hundreds of mutations

treatment: fluid intake, penicillamine, thioproninethiopronine

ticystine

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

Aim of treatment= increased solubility

merkaptopropionylglycine(thiopronine)

Cys-Cys

(thiopronine)

4-5 L fluids/dayalkalinizationalkalinization

Cystine

cystinosiscystinosis

Adult cystinosis

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

Cystinosisdefect of lysosomal transporter cystinosintransporter cystinosininfantile form: Fanconiho

dsyndrome-severe tubulopathyFTTFTTadultní forms: ocular involvement myopathymyopathy, hypothyreosisRx- cysteamine l ll d

Chemiosmotic coupling between cystinosin and the lysosomal H+-ATPase

locally and systematically

ATPase.

Disorders of propionate, cobalamin and biotin metabolism

Vitamin B12•complicated synthesis•exogenous intake needed•implied in only 2 reactionsp y•nutritional or endogenous deficiency is common

•pregnancy and lactationpregnancy and lactation•advanced age•GIT disorders

•long latent course•long latent course•anemia•demyelinizationpsychiatric manifestation•psychiatric manifestation

•treatment efficient and cheap

http://www.health-spy.com/hydroxob12.png

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 ofnewborn variant: episodes of ketoacidosis/hyperammonemia, coma, pancytopeniap y pmilder froms-repeated encefalopathic crises,FTTchronic problems: FTT, infections, variable CNS involvementinvolvementtherapy: IMTV restriction, gut sterilization, biotin in some patients, aggresive treatment of crises, gastrostomy,liver transplanttransplant

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 crisis with ketoacidosis, hyperammonemia and comaypmilder forms-repeated encephalopatic episodeschronic problems:chronic problems: nephropathy progressing in renal failure, variable CNS i l t ( i i tinvolvement (pacin picture partially deaf and mute), infections Candida sp.treatment: IMTV restriction, gut sterilization, in some pateints B12, aggresivní p , ggtreatment 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 BTDVarious degree of BTD deficiencyimpaired breakdown of pbiocytin and thus biotin incorporation

lti l b lmultiple carboxylase deficiencyeczema seizureseczema, seizures, PMRmiraculous responsemiraculous response to biotin administration

http://www.rug.nl/umcg/faculteit/disciplinegroepen/kindergeneeskunde/liverdigestivemetabolicdiseases/enzyme/images/biotinidase-grafiek.jpg

Urea cycle disorders

Ammoniaamonnia cationt

normal level 50-70 µmol/lµmol/l

somnolence above cca 150 µmol/l150 µmol/l

coma above 300-400 l/lµmol/l

Hyperammonemia is medical emergency

Vigility test

Why do patients with organic acidurias exhibit frequently elevated ammonia blood levels?

rinaryy

nitro

Urinary nitrogen excretion ogen

eMetabolite g 24 h* % total

xcreti

Urea 30 86

Ammonia ion 0.7 2.8ion.Creatinine 1.0-1.8 4-5

U i id 0 5 1 0 2 3Uric acid 0.5-1.0 2-3

http://www.studentconsult.com/content/default.cfm?ISBN=9780323053716

UCD- frequencyUCD frequency

OTC-clinical variability

Lethality of OTC

Scylla and Charibda

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

Monitoring of substrateMonitoring of substrate restriction

Tolerance

Dietaryrecords Analyte(s)

Within range

Analyte low/low intake

Analyte high/ high intake

Analyte high/low intakerange low intake high intakelow intake

Other disorders of amino acid metabolism

Glutaric aciduria type 1Glutaric aciduria type 1

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

GlutarylCoA DHGlutarylCoA DH deficiency—glutarate, 3-OH-glutarate

l tiaccumulationneurotoxicity, basal ganglia involvementganglia involvement, dystonia, PMRíeasy intracranial ybleedingdown-the-staircase coursecoursediet (Lys, Trp), aggresive prevention of catabolismprevention of catabolismnewborn screening

www.medscape.com/viewarticle/501097_2

Prolidase deficiencyabnormal recycling of Pro into collagen-urinary loss of yiminodipeptides secondary immune defectsdefectsulcers and typical facial appearancePMR, splenomegaly, bone changes, mikrocytic anemiaytherapy local, systemic proline administrationadministration

http://dermatology.cdlib.org/127/case_presentations/prolidase/2.jpg

Hyperornithinemia

OAT deficiencyl t t 3 d 4thlate onset 3rd-4th decade-night blindnessblindnessgyrate atrophy of retinaretinatreatment with pyridoxine and dietarypyridoxine and dietary restriction of Orn

http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/gnd/OAT.gif

Nonketotic hyperglycinemiaglycine cleaveage system deficiencyl t d f d bl delevated csf and blood

glycinesometimes prenatalsometimes prenatal manifestation, typical onset early after birthsevere axial hypotoniasevere axial hypotonia and peripheral hypertonusi t t bl iintractable seizures, hypsarytmietherapy inefficient: pyNMDA receptor block

A i id thi h iAminoacidopathies-mechanisms

Amino acid accumulationAmino acid accumulation

Ammonia accumulation

Carbon skeleton accumulation- organic acids

Product deficiency

Summary aminoacidopathiesSummary aminoacidopathies

G f b t 50 di dGroup of about 50 disorders

Mechanisms: varying toxicity and metabolite concentration

subgroup organic acidurias

subgroup hyperammonemias

Clinical presentation highly variable

Diagnossis by special assays

Treatment usually available and efficientTreatment usually available and efficient

Prenatal diagnosis usually possible