report in inborn errors of urea synthesis

8/13/2019 Report in Inborn Errors of Urea Synthesis

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INBORN ERRORS OF UREA

SYNTHESISGroup 8

SAMARASINGHE, Ruwanthi

SAMARAWEERA, UdariSANGLAY, Aurea Mae Ceferine

SEBIAL, Geneda Camille

SHARMA, Prayga

SINGH KUSHWAHA, Rabindra

SYGUAN, Michelle

TANEDO, Giann Carlo


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The urea cycle consists of 4 reactions.

The first reaction occurs in the matrix of themitochondria. The subsequent reactions occur in thecytosol.

UREA CYCLE


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l 1: Carbamyl phosphate synthase I (CPSI)

l 2: Ornithine transcarbamylase (OTC)

l 3: Argininosuccinic acid synthetase (ASS)

l 4: Argininosuccinic acid lyase (ASL)

l 5: Arginase (ARG) l Co-factor: N-acetyl glutamate synthetase (NAGS)


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The first reaction occurs in the matrix of the

mitochondria. The subsequent reactions occur in thecytosol. This is a pathway that spans two cellularcompartments. The first reaction is catalyzed byornithine transcarbamoylase which transfers a

carbamoyl group from carbamoyl phosphate toornithine to form citrulline.


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The second reaction is catalyzed by argininosuccinate

synthetase. This enzyme uses ATP to activatecitrulline by forming a citrullyl-AMP intermediate. Thisintermediate is attacked by the amino group of anaspartate residue to form argininosuccinate.


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The third step is catalyzed by argininosuccinate lyase

which cleaves argininosuccinate into fumarate andarginine.


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The last step is catalyzed by arginase which cleaves

arginine to produce urea and ornithine completingthe cycle.


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Absence of its activity in males is as severe as CPSI

deficiency. Approximately 15% of carrier femalesdevelop hyperammonemia during their lifetime andmany require chronic medical management

[Brusilow 1995 ].

Ornithine transcarbamylasedeficiency (OTC deficiency).


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The hyperammonemia in this disorder is quite severe.

These patients are able to incorporate some wastenitrogen into urea cycle intermediates,

which makes treatment slightly easier.

Citrullinemia (ASS deficiency).


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This disorder also presents with rapid-onset hyperammonemia inthe newborn period. This enzyme defect is past the point in themetabolic pathway at which all the waste nitrogen has beenincorporated into the cycle. Treatment of these patients oftenonly requires supplementation of arginine.

Marked by chronic hepatic enlargement and elevation oftransaminases. Biopsy of the liver shows enlarged hepatocytes,which may over time progress to fibrosis. These patients can

also develop trichorrhexis nodosa, a node-like appearance offragile hair.

Patients who have never had prolonged coma, but neverthelesshave significant developmental disabilities.

Argininosuccinic aciduria (ASLdeficiency).


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This disorder is not typically characterized by rapid-

onset hyperammonemia. These patients developprogressive spasticity. They can also develop tremor,ataxia, and choreoathetosis. Growth is also affected

[Cederbaum et al 1977, Cederbaum et al 1982].

Argininemia (ARG deficiency).


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VERY elevated NH3 >150mmol/L ( except for

arginase, has a 5-7 fold increase) Normal plasma glucose

Alkalosis

Normal plasma lactate

Normal urine organic acids

SIMILARITIES


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Infants with a urea cycle disorder often initially appear normal butrapidly develop the ff. cerebral edema Lethargy anorexia hyperventilation or hypoventilation; Hypothermia seizures, neurologic posturing, and coma. In milder (or partial) urea cycle enzyme deficiencies, ammonia

accumulation may be triggered by illness or stress

SIMILARITIES


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DIFFERENTIAL DIAGNOSIS


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DIFFERENTIAL DIAGNOSIS


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MANIFESTATIONS


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a) Hyperammonemiaexcess of ammonia in the blood

TYPES:

1) Primary hyperammonemia

reduced activity of any of the enzymes in the urea cycle

2) Secondary hyperammonemia

reduced activity in enzymes that are not part of the ureacycle or dysfunction of cells that make major contributionsto metabolism


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Signs and Symptoms Dehydration Lethargy

Rapid respiration Decreased muscular strength

Management Medications Urea cycle disorder treatment agents (eg, sodium phenylbutyrate, carglumic acid,

sodium phenylacetate, and sodium benzoate)

Antiemetic agents (eg, ondansetron, granisetron, palonosetron, dolasetron) Others: Cessation of protein and/or nitrogen intake Hemodialysis Supportive care with intake of calories


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It refers to an excessive excretion of orotic acid in urine. It causes a characteristic form of anemia and may be associated with mental

and physical retardation. Signs and Symptoms excessive orotic acid in the urine megaloblastic anemia which cannot be cured by administration of vitamin

B12 or folic acid mental and physical retardation

Treatment Administration of cytidine monophosphate and uridine monophosphate reduces

urinary orotic acid and the anemia. Administration of uridine, which is converted to UMP, will bypass the metabolic

block and provide the body with a source of pyrimidine

b) Orotic Aciduria


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Hyperglutaminemia is a consequence involved in

Ornithine transcarbamylase deficiency. It is an X-linked metabolic disorder.

Strong relationship between hyperammonemia,neurologic dysfunction & CSF glutamine

concentration in hepatic encephalopathy.

c) Hyperglutaminemia


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a semi-essential amino acid, a building block of protein.

necessary for the removal of toxic ammonia from the body Signs and Symptoms

Skin rashes and hair loss (increase blood supply to the skin)

poor wound healing

problems with liver functioning

problems with functioning of the blood vessels

d) Arginine Deficiency (Low levels ofcitrulline)


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Level Summary (Kruse) DescriptionConscious Normal People who are able promptly and spontaneously to statetheir name, location, and the date or time are said to be

oriented to self, place, and time, or "oriented X3".

Confused Disoriented; impairedthinking and responses

People who do not respond quickly with information abouttheir name, location, and the time are considered "obtuse" or"confused".

Delirious Disoriented; restlessness,hallucinations, sometimesdelusions

Some scales have "delirious" below this level, in which aperson may be restless or agitated and exhibit a markeddeficit in attention.

Somnolent Sleepy A somnolent person shows excessive drowsiness andresponds to stimuli only with incoherent mumbles ordisorganized movements.

Obtunded Decreased alertness;slowed psychomotorresponses

In obtundation, a person has a decreased interest in theirsurroundings, slowed responses, and sleepiness.

Stuporous Sleep-like state (notunconscious); little/nospontaneous activity

People with an even lower level of consciousness, stupor,only respond by grimacing or drawing away from painful

stimuli.

Comatose people do not even make this response to stimuli,

e) Altered levels of consciousness


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Signs and Symptoms Impaired consciousness

Reduced alertnessReduced awareness of surroundings

Treatment

Treatment depends on the degree of decrease inconsciousness and its underlying cause. Initial treatment ofteninvolves the administration of dextrose if the blood sugar is lowas well as the administration of naloxone and thiamine.


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Dialysis

reversal of catabolic state by administration of :fluids, dextrose, fat emulsion, arginine and Nitrogenscavenging drugs

pharmacologic treatment such as : benzoate and

phenyl acetate

TREATMENT


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report in inborn errors of urea synthesis

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