Download Disorders of phenylalanine and tyrosine metabolism

Aminoacidandpeptidemetabolism
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Disorders of phenylalanine and tyrosine metabolism
Biochemistry
Phenylketones
Phenylalanine
Phenylalanine and tyrosine metabolism
PAH
takes place in the cytosol.A deficiency
4-OH-phenylTyrosine
oftheenzymephenylalanine hydroxylase
compounds
Aminotransferase
(PAH)orthecofactortetrahydrobiopterin
(BH4)causestheaccumulationofphenyl4-OH-Phenylpyruvate
4-OH-phenylalaninewhichistransaminatedtophenylcompounds
Dioxygenase
pyruvate. The cleavage of the phenolic
ringisonlypossiblebydioxygenationof
BenzoquinoneHomogentisate
homogentisate.
acetate
Dioxygenase
AdeficiencyoftheenzymefumarylacetoacetasecausesaccumulationoffumarylSuccinylMaleylacetoacetate
acetoacetateandsuccinylacetoacetateand
acetoacetate,
Succinylacetone
-acetone. These highly toxic substances
Fumarylacetoacetate
inhibit several enzymes incl. 4-OHFumarylacetoacetase
phenylpyruvatedioxygenaseandaminolaevulinatedehydrataseandarecarcinoFumarate Acetoacetate
genic(alkylationofDNA).
Phenylketonuria (PKU)
PKUwasoneofthefirstneurogeneticdisordersidentified(Følling1934),thefirstsuccessfully
treatedinbornerrorofmetabolism(diet:Bickel1953)andthedisorderthatwasinstrumentalfor
theintroductionofneonatalpopulationscreening(driedbloodspots:Guthrie1963).
Clinical: Untreated:severebraindamagewithintellectualdisability,seizures,spasticity
Variants: PKU:requiresdiet(differencesindiseaseseverity/Phetolerance:severePKU=homozygousnullmutation,mildPKU=atleastonehypomorphic/residualfunctionmutation)
MHP:mildhyperphenylalaninaemia,doesnotrequirediettherapy(Phe<600 µmol/l
inGermany,<400 µmol/lintheUK,<420 µmol/lintheUSA)
“BH4-sensitive PKU”:reductionofPhelevelsafterBH4supplementationinmanypatientswithmildPKU(stabilisation/activationofmutantprotein)
Enzyme: Phenylalaninehydroxylase;PAHgene
Genetics: >600mutationsinthePAHgene,varyingresidualactivities(seePAHmutationdatabase:www.pahdb.mcgill.ca)
Incidence: InEuropeupto1:4,400(Ireland),average~1:8,000
Diagn.: Newbornscreening(filterpapercard),AA(plasma):↑ Phe,n–↓ Tyr;mutationanalysismayallowpredictionofseverityandBH4sensitivity
DD:
BH4cofactordeficiency(seepage 153)
Therapy: Phe-restricteddiet,supplementationofessentialaminoacids+traceelements(exact
recommendationsdifferbetweencountries;seebelowfortheGermanrecommendations);BH4supplementationinmildPKU(notallpatients)
Progn.: Normaldevelopmentandintelligencewithimmediateandefficienttreatment
Maternal PKU
FetopathyinpregnantmotherswithPKU(Phe>360 µmol/l);strictdiettreatmentmustbestartedbeforeconceptionandmaintainedthroughoutpregnancy!
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Metabolicpathwaysandtheirdisorders
German recommendations for PKU treatment
Phevalues40–240 µmol/l(0.7–4mg/dl)
Goal:
1st–10thyr:
Phevalues40–900 µmol/l(0.7–15mg/dl)
11th–16thyr:
Phevalues<1,200 µmol/l(<20mg/dl)
After16yrs:
Phevalues120–360 µmol/l(2–6mg/dl)
Duringpregnancy:
Follow-up: 1styr:
Labevery1–2wks,clinicalevery3mths
Labevery2–4wks,clinicalevery3–6mths
2nd–10thyr:
Labevery4wks,clinicalevery6mths
11th–16thyr:
Labevery2–3mths,clinicalevery6–12mths
After16yrs:
Tyrosinaemia type I
Clinical: Acute (neonate/infant):severeliverfailure,vomiting,bleeding,septicaemia,hypoglycaemia,renaltubulopathy(Fanconisyndrome)
Chronic:hepatomegaly,cirrhosis,growthretardation,rickets,haematoma,tubulopathy,neuropathy,neurologicalcrises(duetoporphyrins)
Enzyme: Fumarylacetoacetase;FAHgene
Diagn.: OA(urine):(n–) ↑ Succinylacetone(diagnostic),↑ 4-OH-phenylderivatives;AA(plasma):(n–)↑ Tyr,↑ Met(!);(n–)↑ a-fetoprotein(serum);porphyrins(urine):↑ d-aminolaevulinicacid;aminolaevulinatedehydrataseactivity(possibleinDBS)
DD:
Liverdisorders,inparticular“neonatalhepatitis”,respiratorychaindefects,galactosaemia,fructoseintolerance,bileacidsynthesisdisorders
Therapy: Nitisinone(NTBC)1(–2)mg/kgin2doses(inhibitorof4-OH-phenylpyruvatedioxygenase,blockstheaccumulationoftoxicmetabolites;bewareof↑Tyr);Phe-+Tyrrestricteddiet;livertransplantationprobablynotlongerneededinmostpatients
Progn.: Withnitisinonegood(long-termprognosisstillunclear)
Compl.s: Hepatocellularcarcinoma(watchAFP),renalfailure
Tyrosinaemia type II
Clinical: Painfulcorneallesions(lacrimation,photophobia,scars),hyperkeratosis(soles,palms),
mildintellectualdisability
Enzyme: Cytosolictyrosineaminotransferase;TATgene
Diagn.: AA(plasma):↑↑ Tyr,↑ Phe;OA(urine):4-OH-phenylpyruvate,-lactate,-acetate
Therapy: Phe-andTyr-restricteddiet
Alkaptonuria
Clinical:
Enzyme:
Diagn.:
Therapy:
Black/brown/redurinediscolourationatalkalinepH;arthritis,cardiacvalvedisease
Homogentisatedioxygenase;HGDgene
OA(urine):↑↑ homogentisicacid
Low-proteindiet,possiblyNTBC(study)
Other disorders of tyrosine metabolism
• TyrosinaemiatypeIII:4-Hydroxyphenylpyruvatedioxygenasedeficiency,HPDgene;uncertainclinicalrelevance,noskinlesions;aPheandTyr-restricteddietisrecommended
• Hawkinsinuria:unknownenzyme;doubtfulclinicalrelevance;failuretothrive,acidosis
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Aminoacidandpeptidemetabolism
Disorders of the metabolism of sulphur amino acids
Biochemistry (incl. folic acid cycle/cytosolic methyl group transfer)
Folic acid
Serine
Methionine
Tetrahydrofolate
Glycine
S-Adenosylmethionine
5,10 Methylene
tetrahydrofolate
Vitamin B12
MTHFR
5-Methyl
tetrahydrofolate
MS
Methylation
reactions
Betaine
S-Adenosylhomocysteine
Homocysteine
Serine
CBS
Cystathionine
CTH
Homoserine
Cysteine
Sulphite
SO
Sulphate
S-Adenosylmethionine (SAM), is the most important methyl group donor in cellular metabolism.Remethylationofhomocysteinetomethionineiscatalysedmainlybythecobalamin-(vit.B12-)dependentmethioninesynthase(MS)oralternativelybetaine-homocysteine
methyltransferase (methyl group donor betaine). The methyl group is transferred onto
cob(I) alamin(cblI)from5,10-methylenetetrahydrofolatewhichisregeneratedinthefolate
cycle.Thebreakdownofhomocysteinetocysteineiscatalysedbythevit.B6-dependentenzymescystathioninebeta-synthase(CBS)undcystathioninegamma-lyase(CTH).Cysteineis
furthercatabolisedviacysteinesulphinate(precursoroftheaminoacidtaurine,acomponent
ofthebileacids)tosulphitewhichisoxidisedtosulphatebythemolybdenum-containing
enzymesulphiteoxidase(SO)andexcretedintheurine.
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Metabolicpathwaysandtheirdisorders
Methionineandhomocysteineplayacentralroleincytosolicmethylgrouptransferrequiredfor
arangeoffunctionsincl.thesynthesisofcreatine,cholineandadrenalineaswellasDNAmethylation.Disordersofthecytosolicmethylgrouptransfermayalsobeduetoprimarydisordersof
cobalamin(vit.B12)orfolatemetabolism(seepages 156, 157);theyfrequentlycausesevereneurologicaldisorders;symptomsmayalsoberelatedtovascularcomplicationsofelevatedhomocysteine.
Homocysteine(Hcy)andcysteine(Cys)areusuallyfoundasdisulphides(homocystineandcystine)intheextracellularspace.MildelevationsofHcyinplasma(centrifugeimmediately,analysisseepage 33)canonlybedetectedthroughaspecificmethod(e.g.HPLC).Classicalhomocystinuria,however,mayalsoberecognisedbyapositivenitroprussidetest(Brandreaction,see
page 31)intheurine.Cystinosis(page 141)andcystinuria(page 76)arecausedbylysosomaland
renaltransportdefects.
Isolated hypermethioninaemia
Clinical: Oftenasymptomatic,cabbage-likeodour,intellectualdisability,neurologicaldisease,
demyelination
Enzyme: MethionineadenosyltransferaseI/III;MAT1Agene
Diagn.: ↑↑ Met
Therapy: Insymptomaticpatients,Met-restricteddietand/orSAMadministration
DD:
Glycine N-methyltransferase deficiency(GNMTgene):↑↑ Met,SAM;↓ S-adenosylhomcysteine;maybeacoincidentalfinding
S-Adenosylhomocysteine hydrolase deficiency
Clinical: Progressiveintellectualdisability,neurologicaldisease,hypomyelinationandwhite
matteratrophy
Diagn.: ↑ Met;↑↑ SAM; S-adenosylhomcysteine;↑ CK;gene: AHCY
Therapy: Met-restricteddiet
Methionine synthase deficiency (cblG disease)
Clinical: Megaloblasticanaemia,progressiveintellectualdisability,neurologicaldisease,psychiatricdisturbance
Diagn.: ↑ Hcy(>150 µmol/l);AA(plasma):n–↓ Met;OA(urine):↑ methylmalonicacid(cobalamindefects);nitroprussidetestpositive;gene: MTR
Therapy: HO-cobalamin(1mg/day–weeki.m.,dosedependsondefect);considerbetaine(75
mg/kg/day)andfolicacid5–10mg/day
DD:
Methionine synthase reductase deficiency:cblEdisease,MTRRgene;activation/regenerationofcatalyticallyinertcblII(formedevery200–1,000MScatalyticcycles)to
cblI