Amino Acid Metabolism and Its Disorders

7/21/2019 Amino Acid Metabolism and Its Disorders

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Amino Acid Metabolism and its

Disorders


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Protein anabolism

Carried out in ribosomes of almost every cell in the

body 10 essential amino acids in the human

Must be present in the diet because they cannot

be synthesized Complete protein contains sufficient amounts

of all essential amino acids beef, fish, poultry,

eggs

ncomplete protein does not leafy greenvegetables, legumes, grains

10 other nonessential amino acids can be

synthesized by body cells using transamination


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Protein Metabolism

Proteins are converted into substances then can

enter the !reb"s cycle by

deamination # loss of $%&'( from aminogroup

decarbo)ylation # loss of C*' molecule

dehydrogenation # loss of hydrogen atom

Protein synthesis involves transcription and

translation


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Copyright 2009, John Wiley & Sons,Inc+

Protein metabolism

Amino acids are either o)idized to produce APor used to synthesize ne- proteins

.)cess dietary amino acids are not e)creted butconverted into glucose $gluconeogenesis( or

triglycerides $lipogenesis( Protein catabolism

Proteins from -orn out cells bro/en do-n into aminoacids

efore entering !rebs cycle amino group must beremoved deamination

Produces ammonia, liver cells convert to urea, e)creted inurine


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Protein Metabolism

Amino acids may bedeaminated and the resulting

carbon s/eletons2 of

-hatever composition, can be

entered into the glycolytic or!rebs cycle path-ays to

yield an energy harvest of

AP3+ he amino groups

-ill be 4oined -ith C*'

molecules to form the

nitrogenous -aste urea+


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5arious points at -hich amino acids enter the !rebs cycle for o)idation


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Phenyl/etonuria $P!6(


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P&.%78A8A%%.

P!6 is characterized by

the inability of the body

to utilize the essentialamino acid

phenylalanine+


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.ssential and %on .ssential AAs

Amino acids are thebuilding bloc/s for

body proteins+

.ssential amino acids

can only be obtained

from the food -e eat as

our body does notnormally produce them+


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Phe to yr Conversion


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PHENYLALANINE

HYDROXYLASEPHENYLALANINE

Dietary

sources

*D7

P9*.%3

9.A!D*:%

(b)

(a)

he normal metabolism of phenylalanine

$path-ays aand b(

79*3%.


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&7D9*;7P&.%78AC.C

ACD

P&.%78AC.C

ACD*

(c)

(c)

he abnormal metabolism in phenyl/etonuric sub4ects

$path-ay c(


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deamination via transaminase( accumulate in blood = urine+

Mental retardation results unless treatment beginsimmediately after birth+ Treatmentconsists of limiting

phenylalanine intaketo levels barely ade>uate to support

gro-th+ Tyrosine, an essential nutrient for individuals -ith

phenyl/etonuria, must be supplied in the diet+

?enetic deficiencyof Phenylalanine

&ydro)ylase leads

to the disease

phenylketonuria+

Phenylalanine =

phenylpyruvate$the product of

phenylalanine

Transaminase

Phenylalanine Phenylpyruvate (Phenylketone) Phenylalanine Deficient in

Hydroxylase Phenylketonuria

Tyrosine Melanins

Multiple Reactions

Fumarate + cetoacetate


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Tyrosineis a precursor for synthesis of melanins and of

epinephrine and norepinephrine+&igh @phenylalanine inhibits yrosine &ydro)ylase, on the

path-ay for synthesis of the pigment melaninfrom

tyrosine+ ndividuals -ith phenyl/etonuria have light s/in

= hair color+

Transaminase

Phenylalanine Phenylpyruvate (Phenylketone) Phenylalanine Deficient in

Hydroxylase Phenylketonuria

Tyrosine Melanins

Multiple Reactions

Fumarate + cetoacetate


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:hat is P!6

P!6 $phenyl/etonuria(, in its BclassicB form,

is a rare, inherited metabolic disease that

results in mental retardation and other

neurological problems -hen treatment is not

started -ithin the first fe- -ee/s of life+


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ncidence of P!6

P!6 affects about one out of every 10,000 to

'0,000 Caucasian or oriental births+ he

incidence in African Americans is far less+

he P!6 disorder is as fre>uent in men as it is

in -omen+


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.nzymatic Activity

n cases of P!6, the enzyme that brea/s do-n phenylalanine,

phenylalanine hydro)ylase, is completely or nearly completely

deficient+

his enzyme normally converts phenylalanine to another amino

acid, tyrosine, -hich is utilized by the body+

:hen this enzyme, phenylalanine hydro)ylase, is absent ordeficient, phenylalanine and its brea/do-n chemicals from

other enzyme routes, accumulate in the blood and body tissues+


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8evels of lood Phenylalanine

A normal blood phenylalanine level is

about 1mgdl+

n cases of P!6, levels may range from

#E0mgdl, but are usually greater than

F0mgdl+


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:hat happens -hen there is too much blood

phenylalanine

Chronically, high levels of phenylalanine

and some of its brea/do-n products can

cause significant brain problems+ here are

other disorders of hyperphenylalaninemia,

but classic P!6 is the most common cause

of high levels of phenylalanine in the blood+


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t is important to remember that some

phenylalanine is needed to maintain normalbody function+

nsufficient phenylalanine inta/e may cause

mental and physical sluggishness, loss of

appetite, anemia, rashes, and diarrhea+


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:&* D*.3 P!6 .GG.CH

P!6 is inherited as an autosomal recessive

trait+

-o people -ho conceive a child must both be

the carriers of the defective gene in order for

their child to have the disorder+

he carrier2 for P!6 does not have the

symptoms+


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:omen -ith P!6

t is recommended that -omen -ith P!6 -ho

are of child bearing age, closely adhere to the

lo-#phenlyalanine levels before conception

and throughout pregnancy+ he ris/ of

miscarriage, mental retardation, microcephaly,

and congenital heart disease in the child is

high if the mother"s blood phenylalanine ispoorly controlled+


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:hat are the symptoms of P!6About I0J of untreated infants have the follo-ing early symptom

5omiting

rritability

.czema#li/e rash

6nusual odor to urine

%ervous 3ystem Problems $increased muscle tone, more active muscle

tendon refle)es(

Microcephaly

Decreased body gro-th Prominent chee/ and 4a- bones -idely spaced teeth

Poor development of tooth enamel+


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:hat happens if P!6 untreated

f P!6 goes untreated or undetected, severe

brain problems occur such as seizures and

mental retardation+

his can occur as early as the second month of

life, if not detected and treated+


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&o- can P!6 treated

.very state no- screens the blood

phenylalanine level of all ne-borns at about F

days of age+

his test is one of several ne-born screening

tests performed before or soon after discharge

from the hospital+


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6sually a fe- drops of blood are obtained by a

small pric/ on the heel, placed on a card and

then sent for measurement+

f the screening test is abnormal, other tests are

needed to confirm or e)clude P!6+

%e-born screening allo-s early identification

and early implementation of treatment+


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:hat type of diet appropriate for some one

-ith P!6

he goal of P!6 treatment is to maintain the blood levels of

pheylalanine bet-een ' and 10mgdl+

reatment for P!6 consists of a diet lo- in phenylalanine,

-hich is maintained infants -ith special formulas and in

individuals by eliminating meat and using lo- protein grain

products+ Measured amounts of cereals, starches, fruit, andvegetables, along -ith a mil/ substitute are recommended

instead+


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*ther foods to stay a-ay from

ndividuals -ith P!6 must be alert for food

s-eetened -ith aspartame+

%utra3-eet in particular, should be avoided

because it is a derivative of phenylalanine+


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9.AM.% P9*C.33

5ital importance of early identification

%e-born 3creenings done to all ne-borns inthe 6nited 3tates K Prevention

:ithin a fe- days after birth

9epeated -ithin the ne)t t-o -ee/s after birth


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9.AM.% P9*C.33

Phenylalanine restricted diet

Phenylalanine#free medical formulas

9estrictions of high phenylalanine foods such as

proteins, dairy products, nuts, and beans

Measured amounts of fruits, vegetables, bread,

pasta, cereals

May eat special lo- protein breads and pastas


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%69*% CA9. P9*C.33L

A33.33M.%

aseline data must be collected

#Age# 3e)

#?eneral &ealth# &eight

#Activity# :eight

#Assessment of nutritional status

All play a significant role in determining theamount of phenylalanine needed in the diet


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%69*% CA9. P9*C.33L DA?%*33

.arly dentification

%e-born 3creening estL

All babies in the 6nited 3tates are tested -ithin a

fe- days after birth

A blood sample is ta/en from the baby"s heeltoe

he blood samples are then measured to see if they

have the enzyme phenylalanine hydro)ylase, forthe ability to brea/ do-n Phe in the diet

f this enzyme is lac/ing, it is diagnosed that the

ne-born has Phenyl/etonuria


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%69*% CA9. P9*C.33L

%.95.%*%

Parent .ducationL informing the parents about -hatthe disease is and ho- it is treated

Monthly lood estsL help people -ith P!6 tracttheir progress -ith the diet

9egular 5isits to the P!6 Clinic

Good 9ecordsL helps to identify problem areas andfoods

P! "iet #alculations


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:&.9. 3 P&.%78A8A%%. G*6%D

&igh Protein Goods

Mil/

Dairy Products

Meat

%uts

Fish

Chicken

Eggs

Beans


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3AMP8. P9*8.M G*9 P!6 D.

CA8C68A*%3

aseline Data Age F+I months

3e) Male

:eight $/g+( + :eight on 0 N score

&eight $cm+( +E

&eight on 0 N score

&ead Circumference $cm+( OF+F

?eneral &ealth ?ood

Activity 5ery active


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3.P 1

Calculate the child"s re>uirement for

phenylalanine, protein and /ilocalories

using able ' Phenylalanine + /g body -eight ) 0 mg Phe/gday K O' mg Pheday

Protein

+ /g body -eight ) F+F gm protein/gday K 'I+O gm proteinday

!ilocalories + /g body -eight ) 11I /cal/gday K EEI /calday


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A8. '# 9.C*MM.%D.D DA87 %A!.3 *G %69.%3 G*9

C&8D9.% :& P!6

Age Phe (mg/kg) Protein (gm/kg) Energy (cal/kg)

0-3 mo 40-70 2.5-3.5 120

4-6 mo 30-50 2.5-3.2 110

7-12 mo 30-40 2.5-3.0 105

1-3 yr 20-40 2.0-2.5 100

4-6 yr 15-35 1.5-2.0 90

7-10 yr 10-25 1.0-1.5 70

11-15yr 10-25 1.0-1.5 7011-15 yr 10-25 1.0-1.5 45-55

15-18 yr 5-15 1.0-1.3 40-45

Adult 5-10 1.0-1.3 40


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3.P '

Determine the amount of 8ofenalac re>uired per day+ his

information is determined from the infant"s or child"s protein

re>uirement+

25.4 gmproteindayx 90% of protein from 8ofenalac

K 22.9 gmprotein 1.5 gmproteinpac/ed tsp 8ofenalac

K 15pac/ed tbsp, -hich is e>ual to 150 gm of 8ofenalac per

day


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3.P F

Determine the amount of evaporated mil/ to be

included in the diet+ ' or ' Q oz+ *f

evaporated mil/ is recommended for an infant

F to months of age

3.P O


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3.P O

Determine the amount of -ater to mi) -ith the

8ofenalac+ he fluid consistency of theformula varies according to the infant"s age

and fluid re>uirements+ Gor an infant

consuming a formula of '0 /caloz, 1 level E#

oz measuring cup of 8ofenalac is mi)ed -ith 1

>t of -ater

o prepare formula for the infant described in

the case study, mi) 1I pac/ed tbsp $1I0 gm( of8ofenalac and ' Q oz of evaporated mil/ -ith

O oz of -ater to prevent lumps from forming+

han add -ater to ma/e a total of F' oz+ *f


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3.P I

Determine the amounts of phenylalanine,

proteinand /ilocalories in the 8ofenalac and

evaporated mil/

Phenylalanine Protein !cal

8ofenalac, 1I pac/ed tbsp 1'0 ''+I E1

.vaporated mil/, '+I oz 'I I+I R

otal FEI 'E+0 E

+


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3.P

Determine the amount of phenylalanine,

protein and /ilocalories to be obtained from

foods other than the formula+

otal phenylalanine K O' mgday

Phenylalanine in formula K FEI mgday

Phenylalanine from other foods K mgday


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3.P C*%S

otal protein 'I+O gmday

Protein in formula 'E+0 gmday

Protein from other foods 1+0#'+0 mgday

otal /calories EEI /calday

!calories in formula E /calday!calories from other foods 10 /calday


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3.P

Determine the amount of foods other than formula to be included in the

dietary plan+

Phenylalanine Protein !cal

aby rice cereal 1E 0+O 1E

Applesauce, bsp E 0+' '?reen beans, strained

strained 1E 0+O E

anana, mashed, I0gm '' 0+ OO

Carrots, strained, F bsp R 0+F 1'

otal I 1+R 1IO


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A5.9A?. 5A86. *G P&., P9*.%,

A%D !CA8 P.9 C&8D 3.95%? 3N.

Phenylalanine $mg( Protein $gm( !cal

5egetables 1I 0+I 10

Gruit 10 0+O II

reads and Cereals 1E 0+O 1I

Gats O 0+1 R0

Gree Goods # tr+ #1'F


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%69*% CA9. P9*C.33L

M*%*9%?

Patients should have their laboratory studies

evaluated periodically for nutritional indices

such as Albumin otal Protein

Complete blood count

ransthyretin

.ssential fatty acids

Calcium

Magnesium

Ninc


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%69*% CA9. P9*C.33L

M*%*9%?

!eep regular appointments -ith the clinic

?et regular blood testing

Ma/ing sure goals are being met

Gocusing on trouble areas

Possible food diary

Ai f h lth f d h i


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Aim for healthy food choices


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yrosinemia


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What is Tyrosinemia?

&ereditary tyrosinemia is a genetic inborn error of

metabolism associated -ith severe liver disease in

infancy+ he disease is inherited in an autosomal

recessive fashion -hich means that in order to have

the disease, a child must inherit t-o defective genes,one from each parent+ n families -here both parents

are carriers of the gene for the disease, there is a one

in four ris/ that a child -ill have tyrosinemia+

About one person in 100 000 is affected -ithtyrosinemia globally


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yrosinemia is an error of metabolism, usually

inborn, in -hich the body cannot effectively

brea/ do-n tyrosine+ 3ymptoms include liverand /idney disturbances and mental

retardation+ 6ntreated, tyrosinemia can be

fatal+ Most inborn forms of tyrosinemia produce

hypertyrosinemia $high levels of tyrosine(


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here are three types of tyrosinemia, each -ith

distinctive symptoms and caused by the

deficiency of a different enzyme+

ype tyrosinemia

ype tyrosinemia

ype tyrosinemia


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.levated blood tyrosine levels are associated

-ith several clinical entities+ he term

tyrosinemia -as first given to a clinical entity

based on observations $eg, elevated blood

tyrosine levels( that have proven to be

common to various disorders, includingtransient tyrosinemia of the ne-born $%(,

hereditary infantile tyrosinemia $tyrosinemia

(, 9ichner#&anhart syndrome $tyrosinemia (,and tyrosinemia +


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ransient tyrosinemia is believed to result

from delayed enzyme maturation in the

tyrosine catabolic path-ay+ his condition is

essentially benign and spontaneouslydisappears -ith no se>uelae+ ransient

tyrosinemia is not categorized as an inborn

error of metabolism because it is not caused bya genetic mutation+


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&ereditary infantile tyrosinemia, or

tyrosinemia , is a completely different disease+

Patients have a peculiar $cabbageli/e( odor,

renal tubular dysfunction $Ganconi syndrome(,and survival of less than 1' months of life if

untreated+ .)plode onset of liver failure occurs

in the first fe- months of life+ 3ome patientshave a later onset, usually before age months,

-ith a some-hat prolonged course+


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Gor many years, the diagnosis -as based on the

observation that plasma tyrosine andmethionine levels -ere significantly elevated+Postmortem e)amination revealed that both theliver and the /idney had a highly unusual

pattern of nodular cirrhosis, the histopathologichallmar/ of the disease+ n the early 1R0s,researchers discovered that most severe liverdiseases caused such findings regardless of

etiology, and, in the late 1R0s, the biochemicaland enzymatic causes of the disease -erereported+


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yrosinemia is a disease -ith a clinicalpresentation distinctly different from thatdescribed above+ his presentation includes

herpetiform corneal ulcers and hyper/eratoticlesions of the digits, palms, and soles, as -ellas mental retardation+ he biochemical andenzymatic basis for the disease bears no

relationship to that of tyrosinemia


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yrosinemia is an e)tremely rare cause ofintermittent ata)ia, -ithout hepatorenalinvolvement or s/in lesions


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Pathophysiology

he biochemical basis for

tyrosinemia remained

un/no-able until the late 1R0s,

-hen researchers described acompound called

succinylacetone found in the

urine of infants -ith the

condition++


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3uccinylacetone -as ultimately determined to be the

decarbo)ylation product of succinyl acetoacetate, a

compound derived from the tyrosine catabolic

intermediate fumarylacetoacetate+ nvestigators

inferred that the enzymatic defect might reside in

deficiency of fumarylacetoacetase, -hich mediates

production of fumaric acid and acetoacetate+ his

inference -as later proven correctT succinyl

acetoacetate accumulated because of this defect+

Decarbo)ylation produced succinylacetone, -hich-as then e)creted in the urine+

#atabolic path$ay %or phenylalanine an& tyrosine


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Defect herecauses Type ITyrosinemia

Defect here

causesalkaptonuria

Homogentisatedioxygenase

Fumarylacetoacetatehydrolase

Phenylalanine


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Nitisinone

Tyrosine

Phenylalaninehydroxylase

4-ydro!yphenylpyru"ic acid

omo#entisic acid

$aleylacetoacetate

%umarylacetoacetate

%umaric acid & acetoacetic acid

Tyrosine

aminotransferase

4-hydroxyphenylpyruvicacid dioxygenase

Homogentisate1,2-dioxygenase

Fumarylacetoacetatehydrolase

'uccinylacetoacetate

'uccinylacetone

Alkaptonuria

Tyrosinemia I

Tyrosinemia III

Tyrosinemia II


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Pathology

6nable to metabolize tyrosine

9esults in abnormally high levels of tyrosine

$hypertyrosinemia(

hree different enzymes can cause three

different pathological states


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ype 1 yrosinemia

Most severe case

3hortage of enzyme fumaryloacetate hydrolase

3ymptoms

Gailure to gro- at normal rate leeding

Diarrhea

5omiting Uaundice

Can lead to liver and /idney failure


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ype ' yrosinemia

3hortage of tyrosine aminotransferase

3ymptoms

earing

Photophobia

3/in lesions


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ype F yrosinemia

Most rare case

3hortage of O#hydro)yphenylpyruvate

dio)ygenase

3ymptoms

Mild mental retardation

3eizures

Ata)ia


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reatment

8o- protein diet

8iver transplant $type 1(

%itisinone $type 1(


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Medical Care

Most patients -ith tyrosinemia are so ill at the time of

presentation that inpatient treatment is mandatory+

Direct medical therapy is aimed at the acute hepatic

decompensation and coagulopathy from the outset+9eplenishment of depleted coagulation factors may

be essential to prevent blood loss+

%utritional treatment should be designed to minimize

the phenylalanine#tyrosine load to only essentialre>uirements+


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Diet

All children should be prescribed a lo-#

phenylalanine lo-#tyrosine diet designed to

meet their needs for gro-th -ithout providing

e)cesses of these amino acids+ *nly a highly e)perienced nutritionist -or/ing

-ith a biochemical geneticist can properly

oversee the nutritional regimen+


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Medication

n addition to dietary treatment, some advise

the use of '#$'#nitro#Otrifluoromethylbenzoyl(#

1,F#cyclohe)anedione $%C(, a highly

potent inhibitor of the enzymehydro)yphenylpyruvate dio)ygenase+


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Tyrosine "egra&ation Inhibitor

%C prevents the formation offumarylacetoacetate from tyrosine+ 9esults

from an international study initiated in 1RR'

resulted in the 63 Good and Drug

Administration $GDA( approving the drug in

Uanuary '00'+


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%itisinone $*rfadin(

Ad4unct to dietary restrictions to treathereditary tyrosinemia type#1+ &ighly potentreversible inhibitor of O#

hydro)yphenylpyruvate dio)ygenase+ Preventsformation of catabolic intermediates fromtyrosine $ie, maleylacetoacetate,fumarylacetoacetate( that are converted to

to)ic metabolites $ie, succinylacetone, succinylacetoacetate( and that are responsible forobserved liver and /idney to)icity+


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Maple 3yrup 6rine Disease $M36D(


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Maple syrup urine disease $M36D( results

from a deficient enzyme $branched#chain

alpha#/eto acid dehydrogenase,

C!D( necessary for the brea/do-n of the

amino acids leucine, isoleucine, and valine+

:ithout the C!D enzyme, these amino acids

build up to to)ic levels in the body


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M36D derives its name from the s-eet burnt sugar or


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M36D derives its name from the s-eet, burnt sugar, or

maple syrup smell of the urine+ he disorder affects the

-ay the body metabolizes $processes( certain components

of protein+ hese components are the three branched#chain

amino acids leucine, isoleucine, and valine+ hese amino

acids accumulate in the blood causing a to)ic effect that

interferes -ith brain functions+ f left untreated, this leads

to

brain damage and progressive nervous system

degeneration


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3ymptoms

Maple syrup urine disease is an inherited disorder in

-hich the body is unable to process certain protein

building bloc/s $amino

acids( properly+ eginning in early infancy, this condition

is characterized by poor feeding, vomiting, lac/ of energy

$lethargy(, seizures, and developmental delay+

here are several types of maple syrup urine disease he most


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here are several types of maple syrup urine disease+ he most

common $classic( form typically -ill produce symptoms in

ne-born infants aged O# days+ hese symptoms may includeL

Poor feeding

5omiting

Poor -eight gain

ncreasing lethargy $difficult to -a/e up(

Characteristic burned sugar smell to urine

Changes in muscle tone, muscle spasms, and seizures

:ithin days they lose their suc/ing refle) and gro- listless,

&ave a high#pitched cry, and become limp -ith episodes of

rigidity+ :ithout diagnosis and treatment, symptoms progress

rapidly to seizures, coma, and death+ n some variant types,

failure to thrive may be the first sign+ f left untreated, these

infants -ill die -ith the first months of life


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:hen the C!AD acts

normally it produces

energy and supports gro-th+

:hen the

C!AD is mutated

to)ins build up in thebody as -ell as no energy is

produced+ Also -hen the

gene is mutated the gro-th

of the body ishindered+

d f h i


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Mode of nheritance

M36D is traveled through genes ransferred through chromosome 1R

on the gene C!&DA

t is inherited in an autosomal

recessive pattern

t is so rare that only 1 in 1E0,000

babies are born -ith M36D+

P tt '


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Punnett 'uare

f both of

the parents

are carriers,then there is

a 1LO

possibility

that theirchild could

have M36D

G g

G

g

GG Gg

Gg gg


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reatment reatment re>uires dietary restriction of branched#

chain amino acids, a special medical formula $drin/similar to mil/( and intensive dietary monitoring+reatment of children -ith M36D must be started assoon as possible, preferably at birth+ t involves a

comple) approach of maintaining metabolic control+A special, carefully controlled diet is the focus ofdaily treatment+

his re>uires careful monitoring of protein inta/e and

close medical supervision+ he diet centers on asynthetic formula or Bmedical foodB -hich providesnutrients and all the amino acids e)cept leucine,isoleucine and valine


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hese three amino acids are added to the diet -ith

carefully controlled amounts of food to provide the

protein necessary for normal gro-th and development-ithout e)ceeding the level of tolerance+ 5arious tests

are available to monitor the levels of the amino acids

and their /eto acid derivatives in the blood and urine+

llnesses and stress, as -ell as consuming too much

protein, raise these levels+

.ven mild illnesses can become life threatening+

Metabolic imbalance re>uires dietary changes and attimes hospitalization+

Di i i


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Diagnostic esting

n some states, -ithin 'O hours of the

babies birth, all are tested for M36D

Doctors ta/e a blood sample from thebabies heel and the blood is tested for

high leucine levels+

P i


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Prognosis

f M36D is left untreated, because of

protein levels being too high, then it

can lead to constant metabolic shoc/,seizures, and comas, and even death+

T t t


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Treatment

he first thing that can be done to maintain

M36D is a restricted diet, by avoidingL

he amino acids leucine, isoleucine, and

valine+ And high protein foods li/e meat, eggs,and nuts+

Another treatment is a liver transplant

A possible future treatment is to replace themutated gene -ith a ne- one+

:h i i i H


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:hy it is importantH

he branched chain amino acids cannot bemade by the cells in humans so they must beobtained from the diet or by brea/ing do-n

your o-n proteins+ hese amino acids areneeded to ma/e ne- proteins+ f they are notused for ne- protein, they must be bro/endo-n by the cells because there is no storage

form for the amino acids li/e there is forsugars+


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he C!D comple) controls the brea/do-npath-ay for these amino acids+ f this is not-or/ing, the amino acids accumulate in the

cells and they become to)ic+ his causes thecells to die+ f these dying cells are in thebrain, they result in seizures, coma, andpossibly death+

t t


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mportance cont+

3o it is very important that the body controlsthe level of branched chain amino acids it has+&omologues are products of different genes

that loo/ very much li/e the products of thesegenes for C!D+ he homologues ma/e upother enzyme comple)es in the mitochondriathat -or/ in a similar -ay but brea/do-n

molecules other than amino acids+

t f M36D


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ests for M36D esting for this disease is very important in early

years of life because if detected early enough, li/e

diabetes, it -ill not be a fatal disease but rather one

that only needs to be cared for+ he diagnosis can often be suspected from the

obvious odor of the urine+ Also, abnormal levels of

amino acids and /eto acids in blood and urine are

noted+

*th t i l d t b li id i


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*ther symptoms include metabolic acidosis,

and depressed serum alanine levels+ he

enzyme defect may be detected in leu/ocytesand fibroblasts+

A test for elevated leucine on filter paper blood

specimen is an assay -here the presence ofleucine allo-s the gro-th ofB. subtilison an

agar plate+


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&omocystinuria

& ti i l / C t thi i


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&omocystinuria, also /no-n as Cystathionine

beta synthase deficiency $C3( deficiency is

an inherited disorder of the metabolism of the

amino acid methionine, often involving

cystathionine beta synthase+ t is an inherited

autosomal recessive trait, -hich means a child

needs to inherit the defective gene from both

parents to be affected+

3 lf C t i i A i A id


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3ulfur Containing Amino Acids

'AAL M. = C73, M. is converted to C73

through trans#sulfuration path-ay

CystineL dimer of C73

&omocysteineL not a primary AA

3 lf r Containing Amino Acids


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3ulfur Containing Amino Acids

&omocystinuria caused by cystathionine beta


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&omocystinuria caused by cystathionine beta#

synthase deficiency affects at least 1 in

'00,000 to FFI,000 people -orld-ide+ he

disorder appears to be more common in some

countries, such as reland $1 in I,000(,

?ermany $1 in 1,E00(, %or-ay $1 in ,O00(,

and Vatar $1 in F,000(+ *ther forms of

homocystinuria are much rarer, -ith a small

number of cases reported in the scientific

literature+

hi d f t l d t lti t i di d


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his defect leads to a multisystemic disorder

of the connective tissue, muscles, C%3 and

cardiovascular system+ &omocystinuria

represents a group of hereditary metabolic

disorders characterized by an accumulation of

homocysteine in the serum and an increased

e)cretion of homocysteine in the urine+ nfants

appear to be normal and early symptoms, if

any are present, are vague+

P ibl 3i d t


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Possible 3igns and symptoms

A family history of homocystinuria

Glush across the chee/s

Musculos/eletal

all, thin build

8ong limbs

&igh#arched feet!noc/#/nees


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Mental retardation

3eizures

Psychiatric diseas

.ye anomaliesL

?laucoma

*ptic atrophy

5ascular disease


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nborn .rrors of 3ulfur # containing AA Metabolism


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(i) -o of these defects # homocystinuria $type ( = cystathioninuria

involve enzymes of trans#sulfuration path-ay $homo Cys

Cys(

$ii( &omocystinuria $'nd most common genetic AA disease( named

due to homocystine urine $C73 dimer(

homocystine= M. = homoC73 blood -hich spills over into

urine+

Dimer $homocystine( forms spontaneously in tissue

(iii( O types of homoC73 $ see table(


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(iii( O types of homoC73 $see table(

Type IK defect in cystathionine synthase

$enzyme homoC73C73L first step( Also-ith less homoC73M. therefore

increase homoC73

Type IIL defect in methylene &G reductasedecrease @I methyl &G -hich is necessary to

methylate homoC73

Type IIIL Decrease in 1' Type I'malabsorption of 1'


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ype &omocystinuria


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unresponsive

# enzyme mutation that does not involve cofactor bindingsite

thereforedietary therapy

$i( add betaine:hyH .nhance alternate path-ay

$ii( /eep M. $use plant P li/e soybeanlentil -hich hashalf the M. of animal P(

$iii( C73conditionally essential because M. cannot

be converted to C73

$iv( 3tart therapy early due to serious clinical symptoms

)ystathioninuria


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y

much rarer than ype # due to a defect in cystathion$in(ase $3tep ' C73

synthesis(

# less clinical abnormalities than ype

# accumulation cystathionine in bloodurine $not

detectable normally(

# responds to supplementation in some cases $

Ppal

cofactor to enzyme( -hich also suggests a !mmutant


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Pathophysiology


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he accumulation of homocysteine and its

metabolites is caused by disruption of any of the Finterrelated path-ays of methionine metabolismWdeficiency in the cystathionine #synthase $C3(enzyme, defective methylcobalamin synthesis, or

abnormality in methylene tetrahydrofolate reductase$M&G9( Clinical syndromes resulting from each of these

metabolic abnormalities have been termedhomocystinuria , , and + hree differentcofactorsvitaminsWpyrido)al I#phosphate,methylcobalamin, and folateWare necessary for theF different metabolic paths+

he path-ay, starting at methionine, progressing


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through homocysteine, and on-ards to cysteine,

is termed the transsulfuration path-ay+

Conversion of homocysteine bac/ to methionine,

catalyzed by M&G9 and methylcobalamin, is

termed as the remethylation path-ay+ A minor

amount of remethylation ta/es place via analternate route using betaine as the methyl donor+


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6rea Cycle Disorders

%itrogen#containing components of normal urine


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En& Pro&uct E)crete& *

6rea ED+0

Creatinine O+I

Ammonium '+E

6ric acid 1+M

*ther compounds I+0

H N C

O

NH


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Most terrestrial land animals convert e)cess nitrogen to

urea, prior to e)creting it+

6rea is less to)ic than ammonia+he !rea #ycleoccurs mainly in li+er+

he ' nitrogen atoms of urea enter the 6rea Cycle as NH,

$produced mainly via ?lutamate Dehydrogenase( and asthe aminoN o% aspartate+

he %&Fand &C*F#$carbonyl C( that -ill be part of urea

are incorporated first into carbamoyl phosphate+

H2N C NH2

urea

Carbamoyl Phosphate

3 th $ ( t l

HCO3

ATP


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3ynthase $ype ( catalyzesa F#step reaction, -ith

carbonyl phosphate andcarbamate intermediates+

Ammonia is the % input+

he reaction, -hichinvolves cleavage of ' XP

bonds of AP, is essentially

irreversible+

H2N C OPO32

O

H2N C O

O

HO C

O

OPO32

ATP

NH3

ADP

ATP

Pi

ADP

carbonyl phosphate

carbamate

carbamoyl phosphate

HCO3

ATP


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!lternate "or#s o"

CarbamoylPhosphate'ynthase(Types II III$ initially generatea##onia %y hyrolysis

o" #lutamine'

he type II en)y#eincl*es a lon#

internal tunnelthro*gh +hicha##onia & reactioninter#eiates s*ch as

car%a#ate pass "ro#

H2N C OPO32

O

H2N C O

O

HO C

O

OPO32

ATP

NH3

ADP

ATP

Pi

ADP

carbonyl phosphate

carbamate

carbamoyl phosphate


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#arbamoyl Phosphate -ynthaseis the committe& stepof

the 6rea Cycle, and is sub4ect to regulation+

H2N C OPO32

O

HCO3

+ NH3 + 2ATP

+ 2ADP + Pi

Carbamoyl Phosphate3ynthase

carbamoyl phosphate


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#arbamoyl Phosphate -ynthasehas an absolute

re>uirement for an allostericactivatorN.acetylglutamate+

his derivative of glutamate is synthesized fromacetyl#CoA = glutamate -hen cellular @glutamate is high,

signaling an ecess o% %ree amino aci&sdue to protein

brea/do-n or dietary inta/e+

+rea ycle

En)y#es in

H2N C OPO32

O

CH2

NH3+

CH2

NH

CO NH2

carbamoylh h


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En)y#es inmitochondri

a-.' /rnithine

ranscar%a#ylase

En)y#es incytosol-

2' !rginino S*ccinate

Synthase' !rginino s*ccinase

1' !rginase'

CH2

CH2

HC

COO

NH3+

CH2

CH2

CH2

HC

COO

NH3+ COO

CH2

HC

COO

NH2

CH2

CH2

CH2

HC

COO

NH3+

NH

C NH2+

COO

CH2

HC

COO

HN

AMP + PPi

ATP

CH2

CH2

CH2

HC

COO

NH3+

NH

C

NH2+

H2N

COO

HC

CH

COO

C NH2H2N

O H2O

Pi

ornithine

urea

citrulline

aspartate

arginino#succinate

fumarate

arginine

phosphate

6rea Cycle

1

'

F

O

cytosol

mitochon&rial matri)


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Gor each cycle, citrullinemust leave the mitochondria, andornithinemust enter the mitochondrial matri)+

An ornithine/citrulline transporter in the innermitochondrial membrane facilitates transmembrane flu)es ofcitrulline = ornithine+

carbamoyl phosphate

Piornithine citrulline

ornithine citrulline

urea aspartatearginine argininosuccinate

fumarate

cytosol

mitochon&rial matri)


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A complete rebs #yclefunctions only -ithinmitochondria+

ut cytosolic isozymes of some !rebs Cycle enzymes areinvolved in regenerating aspartatefrom %umarate'

carbamoyl phosphate

Pi



urea aspartatearginine argininosuccinate

fumarate

COO

CH2COO

COO

CH2COO


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0umarateis converted to oaloacetatevia !rebs Cycle

enzymes Gumarase = Malate Dehydrogenase+

1aloacetateis converted to aspartateviatransamination $e+g+, from glutamate(+

Aspartate then reenters 6rea Cycle, carrying an aminogroup derived from another amino acid+

aspartate #/etoglutarate o)aloacetate glutamate

Aminotransferase $,ransaminase(

CH2

CH2

C

COO

O

COO

CH2

HC

COO

NH3+

CH2

CH2

HC

COO

NH3+

COO

CH2

C

COO

OY Y

Here&itary &e%iciencyof any of the 6rea Cycle


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enzymes leads to hyperammonemia# elevated

@ammonia in blood+otal lac/ of any 6rea Cycle enzyme is lethal+

.levated ammonia is to)ic, especially to the brain+

f not treated immediately after birth, severe mentalretardation results+

An urea cycle &isor&eror urea cycle &e%ectis a genetic

disorder caused by a deficiency of one of the enzymes in


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disorder caused by a deficiency of one of the enzymes in

the urea cycle -hich is responsible for removing

ammonia from the blood stream+ he urea cycle involves

a series of biochemical steps in -hich nitrogen, a -aste

product of protein metabolism, is removed from the

blood and converted to urea+ %ormally, the urea is

transferred into the urine and removed from the body+ n

urea cycle disorders, the nitrogen accumulates in the

form of ammonia , a highly to)ic substance, and is not

removed from the body+ 6rea cycle disorders are included in the category of

inborn errors of metabolism+ here is no cure+

nborn errors of metabolism are generally consideredto be rare but represent a substantial cause of brain


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to be rare but represent a substantial cause of braindamage and death among ne-borns and infants+

ecause many cases of urea cycle disorders remainundiagnosed andor infants born -ith the disordersdie -ithout a definitive diagnosis, the e)act incidenceof these cases is un/no-n and underestimated+ t is

believed that up to '0J of 3udden nfant Death3yndrome cases may be attributed to an undiagnosedinborn error of metabolism such as urea cycledisorder+ n April '000, research e)perts at the 6rea

Cycle Consensus Conference estimated the incidenceof the disorders at 1 in 10000 births+ his represents asignificant increase in case diagnosis in the last t-oyears

Postulated mechanisms for to)icity of high @ammoniaL


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1+ &igh @%&F -ould drive 2lutamine -ynthaseL

glutamate 3 ATP 3 NH,

glutamine 3 A"P 3 Pihis -ould deplete glutamate a neurotransmitter =

precursor for synthesis of the neurotransmitter ?AA+

'+ Depletion of glutamate = high ammonia level -oulddrive 2lutamate "ehy&rogenasereaction to re+erseL

glutamate 3 NA"(P)3 a.ketoglutarate 3

NA"(P)H 3 NH4

3

he resultingdepletion of a#/etoglutarate, an essential

!rebs Cycle intermediate, could impair energy

metabolism in the brain+

3ymptoms%eonatal


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Children -ith severe urea cycle disorders typically

sho- symptoms after the first 'O hours of life+

he baby may be irritable at first

5omiting

ncreasing lethargy Z3eizures

&ypotonia $poor muscle tone(,

9espiratory distress, and coma may occur+ funtreated, the child -ill die+ hese symptoms are

caused by rising ammonia levels in the blood+

3ymptomsChildhood


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Children -ith mild or moderate urea cycle enzymedeficiencies may not sho- symptoms until early childhood, or

may be diagnosed subse>uent to identification of the disorderin a more severely affected relative or through ne-bornscreening+ .arly symptoms may include

&yperactive behavior, sometimes accompanied by screamingand self#in4urious behavior

9efusal to eat meat or other high#protein foods+

8ater symptoms may include fre>uent episodes of vomiting,especially follo-ing high#protein mealsT

8ethargy and confusion

Ginally, if the condition is undiagnosed and untreated, comaand death+

Children -ith this disorder may be referred to childpsychologists because of their behavior and eating problems+

Sy#pto#s!*lts


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9ecently, the number of adult individuals being

diagnosed -ith urea cycle disorders has increased atan alarming rate+ 9ecent evidence has indicated thatthese individuals have survived undiagnosed toadulthood, probably due to less severe enzymedeficiencies+ hese individuals e)hibitL

3tro/e#li/e symptoms,

.pisodes of lethargy and confusion+

hese adults are li/ely to be referred to neurologist or

psychiatrists because of their psychiatric symptoms+&o-ever, -ithout proper diagnosis and treatment,these individuals are at ris/ for permanent braindamage, coma, and death+

here are si) enzyme disorders of the urea cycle,ll ti l / i b f th i


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collectively /no-n as inborn errors of urea synthesis,or urea cycle enzyme defects+ .ach is referred to by theinitials of the missing enzyme+

CP3 # Carbamyl Phosphate 3ynthetase

%A?3#%#Acetylglutamat3ynthetase

*C # *rnithine ranscarbamylase

A3 # Argininosuccinic Acid 3ynthetase $Citrullinemia$

A8A3A # Argininosuccinate8yase $ArgininosuccinicAciduria$

A? # Arginase

Defects of 6rea Cycle
http://www.nucdf.org/medical_information.htm#CPShttp://www.nucdf.org/medical_information.htm#NAGShttp://www.nucdf.org/medical_information.htm#NAGShttp://www.nucdf.org/medical_information.htm#OTChttp://www.nucdf.org/medical_information.htm#OTChttp://www.nucdf.org/medical_information.htm#CIT1http://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#arginasehttp://www.nucdf.org/medical_information.htm#arginasehttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#ASAhttp://www.nucdf.org/medical_information.htm#CIT1http://www.nucdf.org/medical_information.htm#CIT1http://www.nucdf.org/medical_information.htm#CIT1http://www.nucdf.org/medical_information.htm#CIT1http://www.nucdf.org/medical_information.htm#CIT1http://www.nucdf.org/medical_information.htm#CIT1http://www.nucdf.org/medical_information.htm#OTChttp://www.nucdf.org/medical_information.htm#OTChttp://www.nucdf.org/medical_information.htm#NAGShttp://www.nucdf.org/medical_information.htm#NAGShttp://www.nucdf.org/medical_information.htm#NAGShttp://www.nucdf.org/medical_information.htm#NAGShttp://www.nucdf.org/medical_information.htm#CPShttp://www.nucdf.org/medical_information.htm#CPShttp://www.nucdf.org/medical_information.htm#CPShttp://www.nucdf.org/medical_information.htm#CPShttp://www.nucdf.org/medical_information.htm#CPS


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orotic acid

III

IV

V

Treatmentof deficiency of 6rea Cycle enzymes

$d d hi h i d fi i t(


135/143

$depends on -hich enzyme is deficient(L

limiting protein intaketo the amount barelyade>uate to supply amino acids for gro-th, -hile

adding to the diet the a#/eto acid analogs of

essential amino acids+

Li+er transplantationhas also been used, since

liver is the organ that carries out 6rea Cycle+

:hat are the treatment options


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phe treatment of urea cycle disorders consists

of dietary management to limit ammonia

production in con4unction -ith medications

andor supplements -hich provide alternative

path-ays for the removal of ammonia from thebloodstream+ A careful balance of dietary

protein, carbohydrates and fats is necessary to

insure that the body receives ade>uate caloriesfor energy needs, as -ell as ade>uate essential

amino acids $for cell gro-th and development(

Dietary protein must be carefully monitored and

some restriction is necessaryT too much dietary


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some restriction is necessaryT too much dietary

protein causes e)cessive ammonia production+

&o-ever, if protein inta/e is too restrictive orinsufficient calories are provided, the body -ill brea/

do-n lean muscle mass $called catabolism( to obtain

the amino acids or energy it re>uiresT this catabolism

creates e)cessive ammonia+ herefore, the correct

nutritional balance for each individual in each stage

of gro-th is critical in avoiding hyperammonemic

crises+ Gre>uent blood tests $serum ammonia, plasma>uantitative amino acids( are re>uired to monitor the

disorders and are an important tool for optimizing

treatment+

reatment may include supplementation -ith specialamino acid formulas, developed specifically for urea


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, p p ycycle disorders, -hich can be prescribed to provide

appro)imately I0J of the daily dietary proteinallo-ance+ 3ome patients may re>uire individualbranched chain amino acidsupplementation+ Metabolic nutritionists routinely

prescribe calorie modules such as Prophree, Polycoseand ModuCal to be used combination -ith the aminoacid formulas+ Pharmaceutical grade $not over#the#counter( 8#citrulline $for *C and CP3 deficiency(or 8#arginine free base $A3A and citrullinemia( isalso re>uired+ hese are not to be used in ArginaseDeficiency+ Multiple vitamins and calciumsupplements are also recommended+

3odium phenylbutyrate $trade name uphenyl( is the

i di ti b i d t t t l


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primary medication being used to treat urea cycle

disorders+ 3odium benzoate is also used in somepatients, solely or in con4unction -ith uphenylT both

are ammonia scavengers2 ## providing alternative

path-ays for removal of ammonia from the

bloodstream and helping to preventhyperammonemia+ *ne or both of these medications

is administered three to four times per day in order to

insure continual removal of to)ic ammonia from the

bloodstream

Children -ith urea cycle disorders often lac/ appetite

$due to e)cess serotonin in the brain suppressing


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$ pp g

appetite( and some may benefit from receiving

medications and some feedings either via gastrostomytube $a tube surgically implanted in the stomach( or

nasogastric tube $manually inserted through the nose

into the stomach(+ he access these tubes provide

often ma/es a critical difference in metabolic stability

and in prevention hyperammonemic crisesT

medications and formulas can still be administered

-hen children have flu or colds, etc+ 3ome centers

have reported as much as 0J reduction in hospital

admissions after placement of ?#tubes or parents

-ere trained to use %?#tubes+

*ptimal treatment of urea cycle disorders re>uires a

di l t i ti i i ll f


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medical team consisting minimally of a

geneticistmetabolic specialist and nutritionist

specifically e)perienced in successful management of

the disorders+ hese teams are usually found at

university hospitals+ 3pecialty consultation and

second opinions from e)perts in the field of 6CDscan be obtained by families -ho live in areas -here

optimal medical care is not available+

:hen optimal treatment fails, or for neonatal onset

CP3 and *C deficiency liver transplant becomes an


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CP3 and *C deficiency, liver transplant becomes an

option+ 8iver transplants have been done successfully

as a cure for the disorder $although 8#arginine

supplementation is still necessary in

argininosuccinate lyase deficiency posttransplant(+

reatment


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Pyrido)ine, at a dose of 100#I00 mgd, is the drug of choice+

Measuring homocystine levels can be used to monitor the

effectiveness of treatment+ f pyrido)ine alone is not effective,

folic acid and vitamin #1' can be added to the regimen+

f patients are pyrido)ine insensitive, a lo-#methionine diet

initiated at diagnosis, along -ith betaine supplementation, may

help reduce homocysteine levels+

Diet

A methionine#restricted diet is sometimes necessary if

Amino Acid Metabolism and Its Disorders

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Transcript of Amino Acid Metabolism and Its Disorders