Download Disorders of phenylalanine and tyrosine metabolism

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts

Biochemistry wikipedia, lookup

Point mutation wikipedia, lookup

Amino acid synthesis wikipedia, lookup

Artificial gene synthesis wikipedia, lookup

Clinical neurochemistry wikipedia, lookup

Metabolism wikipedia, lookup

Biosynthesis wikipedia, lookup

Enzyme wikipedia, lookup

Ketosis wikipedia, lookup

Catalytic triad wikipedia, lookup

Gene therapy wikipedia, lookup

Gene therapy of the human retina wikipedia, lookup

Transcript
Aminoacidandpeptidemetabolism
67
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!
68
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
69
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.
70
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