LMP299Y1 Lecture Notes - Lecture 20: Phenylalanine Hydroxylase, Newborn Screening, Phenylalanine
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12 May 2015
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Lecture'20'–'Newborn'screening'
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" Newborn!infants!are!preferably!done!in!the!first!or!second!day!of!life!!
" Take!sample!of!blood!from!heel!and!dot!it!on!filter!paper!(dry!blood!spot)!!
" Fill!out!information!of!infant!along!with!parents!and!physicians!then!sent!to!newborn!screening!program!in!Ottawa!
" Each!province!in!Canada!has!own!newborn!screening!program!–!all!countries!have!their!own!NBS!program!
o Each!state/province!responsible!for!it’s!own!NBS!program!
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Phenylketonuria'(PKU)'(all!of!us!have!been!screened!for!PKU)!
" Distinct!chemical!entity!that!can!be!treated!
" Leads!to!Severe!mental!retardation!if!left!untreated!
" Institutionalized!
" Many!individuals!were!similar!to!each!other!–!could!be!a!common!denominator!to!this!disorder!!!blonde!hair!
(even!if!family!don’t!have!blonde!hair),!fair!skin!
" IQ!was!significantly!low!
" Phe!is!very!high!in!the!blood!!
" Phe!is!the!likely!toxic!chemical!
" Acute!toxicity!if!greater!than!1300!uM!(especially!to!the!brain)!
" Excess!Phe!interferes!with!normal!brain!development!
" If!remain!high!level!for!long!period!of!time!!!inhibits!normal!brain!development!
" Results!in!mental!retardation!
" Phenylketones!in!the!urine!!
" Result!of!the!impairment!of!the!phenylalanine!metabolism!(typically!has!to!be!converted!through!an!enzyme!
phenylalanine!hydroxylase!to!tyrosine!–!if!enzyme!allowing!phenyalanine!hydroxylase!does!not!work!because!
there!is!a!mutation!in!the!gene!that!does!not!allow!enzyme!–!then!phenylalanine!will!not!be!converted!to!tyrosine!
and!level!of!phenylalanine!will!accumulate!in!the!blood)!
" Phe!metabolism!of!phenylalanine!hydroxylase!
" Hyperphenylalaninemia!(high!phenylalanine!in!the!blood)!
" By!virtue!–!phenylketonuria!–!excess!will!be!excreted!in!the!urine!
" High!phenylalanine!in!blood!and!urine!
" We!get!phenylalanine!from!AA!form!proteins!–!we!consume!a!lot!from!our!diet!–!incorporated!in!our!proteins!
which!are!broken!down!in!our!metabolic!pathways!
" Through!phenylalanine!hydroxylase!should!be!metabolized!into!tyrosine!but!in!individuals!with!PKU,!this!does!not!
happen!
" Also!central!to!this!metabolic!pathway!–!individuals!try!to!get!rid!of!excess!phenylalanine!that!they!accumulate!so!it!
mobilizes!alternate!pathways!by!trying!to!convert!phenylalanine!to!phenylketone!!
" Individuals!with!PKU!tend!to!have!high!levels!of!phenylalanine!but!also!phenylketone!which!spill!over!in!urine!
(first!finding!by!physicians!that!first!described!PKU)!
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" Normal!individuals!do!not!have!high!levels!of!phenylketone!in!the!urine!because!they!have!ability!to!convert!
phenylalanine!to!tyrosine!and!move!pathway!to!one!direction!(does!not!have!to!employ!alternate!pathways)!
" At!the!same!time!(classic!paradigm!for!all!inborn!errors!of!metabolism)!tyrosine!will!be!very!low!because!
phenylalanine!isn’t!being!converted!into!tyrosine!
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Metabolism'of'the'Phenylalanine'
" A!mutation,!reduces!enzyme!activity!which!causes!a!block!in!a!metabolic!pathway,!leading!to:!
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PKU'
" Autosomal!recessive!
" Two!mutant!genes!required!to!develop!the!disease!(No!enzyme!activity)!!
" Carriers!have!one!mutant!gene!and!one!normal!gene!
" Incidence!1:10,000!
" 1:50!carrier!
" If!parents!are!carriers!then!25%!chance!child!will!get!PKU!
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PKU@History'
" Folling!1934!
" Penrose!1935!
" Clinical!perspective!–!blonde,!highly!mentally!retarded!individuals!
" Smell!!!distinct!smell!from!phenylketone!–!collected!urine!and!identified!it!through!urine!
" Decreased!pigmentation!!!lack!of!tyrosine!(produces!melanin!so!no!proper!pigmentation)!
" Mental!retardation!
" IQ!of!untreated!is!approximately!35!–!institutionalization!
" Seizures!
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PKU!
" PKU!individuals!are!missing!a!lot!of!neurotransmitters!→!accounts!for!much!of!presentation!of!disease!
" Now,!can!measure!level!of!phenylalanine!in!blood!(easier!than!urine)!
" One!technique!→!high!performance!chromatography!or!ultra!performance!chromatography!
o Take!blood!from!individual!and!separate!all!the!AA!
o Quantify!each!one!
o There!is!a!normal!amount!of!phenylalanine!among!population!
o Anyone!will!high!amount!of!exceed!with!significant!fold!→!assume!has!PKU!
" Don’t!directly!do!genetic!testing!(don’t!look!at!DNA)!but!measure!level!of!phenylalanine!
o Persistent!level!of!phenylalanine!then!assume!have!PKU!
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PKU'treatment!
" Treatment!is!dietary!(at!this!point)!–!limit!amount!of!phenylalanine!in!diet,!lifelong!→!normal!intelligence!
" Must!start!within!10"12!days!of!life!because!short!window!of!opportunity!to!start!treatment!
" If!exposed!to!high!level!of!phenylalanine!then!that!will!affect!development!whether!organs!or!brain!
" Can!have!normal!life!with!exception!of!strict!diet!for!the!rest!of!their!life!
" No!high!protein!foods!→!because!phenylalanine!does!come!from!protein!
" No!meats,!fish,!eggs,!chicken!
" Bread,!potatoes!and!vegetables!restricted!depending!on!tolerance!
" Newborns!and!children!require!frequent!monitoring!!
" Individuals!have!special!formula!and!diets!of!their!own!which!they!can!tolerate!!
" Thought!that!once!brain!is!fully!formed!(16"18YO)!it’s!okay!to!have!less!restriction!
o BUT!if!they!have!high!phenylalanine!–!can!still!affect!brain!even!30YO!or!older!!