INBORN ERRORS OF UREA SYNTHESIS

Group 8 SAMARASINGHE, Ruwanthi SAMARAWEERA, Udari SANGLAY, Aurea Mae Ceferine SEBIAL, Geneda Camille SHARMA, Prayga SINGH KUSHWAHA, Rabindra SYGUAN, Michelle TANEDO, Giann Carlo

UREA CYCLE
The urea cycle consists of 4 reactions. The first reaction occurs in the matrix of the mitochondria. The subsequent reactions occur in the cytosol.

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)

 The first reaction occurs in the matrix of the mitochondria. The subsequent reactions occur in the cytosol. This is a pathway that spans two cellular compartments. The first reaction is catalyzed by ornithine transcarbamoylase which transfers a carbamoyl group from carbamoyl phosphate to ornithine to form citrulline.

 The second reaction is catalyzed by argininosuccinate synthetase. This enzyme uses ATP to activate citrulline by forming a citrullyl-AMP intermediate. This intermediate is attacked by the amino group of an aspartate residue to form argininosuccinate.

 The third step is catalyzed by argininosuccinate lyase which cleaves argininosuccinate into fumarate and arginine.

 The last step is catalyzed by arginase which cleaves arginine to produce urea and ornithine completing the cycle.

Carbamoylphosphate synthetase I deficiency (CPSI deficiency).

Along with OTC deficiency, deficiency of CPSI is the most severe of the urea cycle disorders. Patients with complete CPSI deficiency rapidly develop hyperammonemia in the newborn period. Patients who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia.

Ornithine transcarbamylase deficiency (OTC deficiency).

Absence of its activity in males is as severe as CPSI deficiency. Approximately 15% of carrier females develop hyperammonemia during their lifetime and many require chronic medical management [Brusilow 1995 ].

Citrullinemia (ASS deficiency).

The hyperammonemia in this disorder is quite severe. These patients are able to incorporate some waste nitrogen into urea cycle intermediates, which makes treatment slightly easier.

Argininosuccinic aciduria (ASL deficiency).

This disorder also presents with rapid-onset hyperammonemia in the newborn period. This enzyme defect is past the point in the metabolic pathway at which all the waste nitrogen has been incorporated into the cycle. Treatment of these patients often only requires supplementation of arginine. Marked by chronic hepatic enlargement and elevation of transaminases. 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 of fragile hair. Patients who have never had prolonged coma, but nevertheless have significant developmental disabilities.

Argininemia (ARG deficiency).

This disorder is not typically characterized by rapidonset hyperammonemia. These patients develop progressive spasticity. They can also develop tremor, ataxia, and choreoathetosis. Growth is also affected [Cederbaum et al 1977, Cederbaum et al 1982].

NAGS deficiency.
Deficiency of this enzyme has been described in a number of patients. Symptoms mimic those of CPSI deficiency, since CPSI is rendered inactive in the absence of NAG. Mutation in the gene NAGS encoding the protein N-acetyl glutamate synthetase are causative [Caldovic et al 2003].

SIMILARITIES
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

Infants with a urea cycle disorder often initially appear normal but rapidly 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

DIFFERENTIAL DIAGNOSIS

DIFFERENTIAL DIAGNOSIS

MANIFESTATIONS

a) Hyperammonemia
excess of ammonia in the blood TYPES: 1) Primary hyperammonemia

2)

reduced activity of any of the enzymes in the urea cycle reduced activity in enzymes that are not part of the urea cycle or dysfunction of cells that make major contributions to metabolism

Secondary hyperammonemia

 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

b) Orotic Aciduria
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 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

Treatment

c) Hyperglutaminemia
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.

d) Arginine Deficiency (Low levels of citrulline)

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

e) Altered levels of consciousness

Level Conscious

Summary (Kruse) Normal Disoriented; impaired thinking and responses Disoriented; restlessness, hallucinations, sometimes delusions Sleepy

Description People who are able promptly and spontaneously to state their name, location, and the date or time are said to be oriented to self, place, and time, or "oriented X3". People who do not respond quickly with information about their name, location, and the time are considered "obtuse" or "confused". Some scales have "delirious" below this level, in which a person may be restless or agitated and exhibit a marked deficit in attention. A somnolent person shows excessive drowsiness and responds to stimuli only with incoherent mumbles or disorganized movements. In obtundation, a person has a decreased interest in their surroundings, slowed responses, and sleepiness. 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,

Confused

Delirious

Somnolent

Obtunded

Decreased alertness; slowed psychomotor responses

Sleep-like state (not unconscious); little/no spontaneous activity

Stuporous

 Signs and Symptoms

Impaired consciousness Reduced alertness Reduced awareness of surroundings

Treatment
Treatment depends on the degree of decrease in consciousness and its underlying cause. Initial treatment often involves the administration of dextrose if the blood sugar is low as well as the administration of naloxone and thiamine.

TREATMENT
Dialysis reversal of catabolic state by administration of : fluids, dextrose, fat emulsion, arginine and Nitrogen scavenging drugs pharmacologic treatment such as : benzoate and phenyl acetate