biochem madd

7/24/2019 Biochem MADD

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Myoadenylate Deaminase

DeficiencyGroup 9: Ghising, Orquia, Reyes, Sangalang, Salvador


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Myoadenylate Deaminase Deficiency

A metaolic muscle disease that interferes !ith the

muscle cell"s processing of adenosine triphosphate$A%&'

Autosomal recessive genetic metaolic disorder

Mutations in the AM&D( gene cause AM& deaminase

deficiency)


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%hree types:

Inherited typemutation in oth copies of the AM&D( gene in each cell

Acquired type

decreased levels of AM& deaminase due to the

presence of a muscle or *oint condition

Coincidental inherited type

mutation in oth copies of the AM&D( gene and have a

separate *oint or muscle disorder


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Signs andSymptoms


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+atigueithout myoadenlyate deaminase

-eavy activity causes adenosine to e released into

cells or perfused into the surrounding tissues

Signals muscle fiers to feel +A%.G/0


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Muscle &ain

Due to the high levels of lactate)

Increased in adenosine temporarily decreased

pain, allo!ing over e1ertion !ithout a!areness)

Over e1ertion causes rhadomyolysis !hich is

painful)


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Muscle 2ramping

Related to elevated 3actate)

.ncreased calcium signaling across the SR caused

memrane instaility from decreased levels of

A%&)


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Muscle ea4ness

&rogressive effects of chronic muscle damage

from rhadomyolysis causes weakness

3ong term metaolic effects may result to NERVE

DAMAGE.


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&athophysiology56iochemical

&ath!aysaffected


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&urine 7ucleotide

2ataolism


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Salvage &ath!ay of

&urine 7ucleotides


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&urine 7ucleotide 2ycle


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.ncreases in muscle

activity create a demand

for an increase in the %2A

cycle, in order to generatemore 7AD- for A%&

production)

Muscle replenishes %2A8

cycle intermediates in theform of fumarate

generated y the purine

nucleotide cycle)


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%he generation of fumarate provides s4eletal

muscles !ith its" only source of anapleurotic

sustrate for the %2A cycle)

.n order for continued operation of the cycle

during e1ercise, muscle protein must e

utilied to supply the amino nitrogen for the

generation of aspartate, !hich occurs y the

standard transamination reactions thatinterconvert amino acids !ith 84etoglutarate

to form glutamate and glutamate !ith

o1aloacetate to form aspartate)


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Myodenylate Deaminasee1ists in a unique isoenymatic form in s4eletal

muscle and appears to provide the rate limitingstep for entry in the purine nucleotide cycle

necessary for regeneration of inosine

monophosphate $.M&' and ultimate repletion of

adenosine triphosphate $A%&'plays a role in the overall e1traction of energystored in the adenine nucleotide pool and to

prevent accumulation of AM& and its attendant

influence on other metaolic path!ays


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removal of AMP formed during exercise, in order to favor

the formation of ATP from ADP by myokinase (adenylatekinase)

release of !" and #MP, both stimulators of glycolysis

and hence of energy $roduction$roduction of fumarate, an intermediate of the %itric Acid

%ycle, &hich also yields energy' #t has therefore been$ro$osed that the muscle dysfunction observed in $rimary

AMDA deficiency is caused by im$airment of energy

$roduction for muscle contraction'

Metaolic effects of AM& deaminase


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Eects o ailure to dea!inate

the AM" !olecules

() Significant amounts of AM& are lost from the cell

and the ody

) Ammonia is not freed !hen the cell does !or4

;) %he level of .M& in the cell is not maintained


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Diagnosis Screening for the defect can e performed y an

e#ercise test ) A several8fold ele$ation o $enous

plas!a a!!onia, seen in normal su*ects, is

asent in AM&8DA deficiency)

+inal diagnosis is estalished y histochemical or

iochemical assay in a !uscle %iopsy)

.n the primary defect, the activity of AM&8DA is elo! < of normal,and little or no immunoprecipitale enyme is found)

.n the secondary defect, the activity is =(>< of normal, and usually

appreciale immunoreactivity is present )

.n several large series of muscle iopsies for diagnostic purposes,

lo! enyme activities !ere found in aout < of patients)


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Management


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Management

D&ri%ose

serves as an additional source of energy for muscle, and is

only efficient as long as it is present in lood $short half8

life'

Creatine !onohydrate

provides an alternative source of energy for anaeroic muscle

tissue y increasing the formation of adenosine triphosphate $A%&'


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