Ornithine transcarbamylase deficiency


Ornithine transcarbamylase deficiency

Description, Causes and Risk Factors:

Abbreviation: OTC deficiency.

Ornithine transcarbamylase (OTC) deficiency is the most common of the urea-cycle disorders. The urea cycle is the body's primary system for removing waste nitrogen produced from the metabolism of protein and other nitrogen-containing molecules. Defects in the urea cycle can lead to life-threatening accumulations of ammonia. Waste nitrogen is converted to ammonia and then transferred to the liver for processing via the urea cycle. OTC is one of the proximal enzymes in the urea cycle and converts carbamylphosphate and ornithine to citrulline. The more distal enzymes in the urea cycle use citrulline as a substrate to produce urea, which is then excreted.

Classic OTC deficiency is characterized by hyperammonemia, cyclical vomiting, seizures, lethargy, coma, and neonatal death if not treated.

Males with OTC deficiency are typically severely affected, with onset of symptoms occurring in the first few days of life. Some males with OTC deficiency may show only mild symptoms with adult onset of disease.

Boys are almost always the most severely affected. Girls can have a wide spectrum of clinical symptoms ranging from mild-to-severe depending on the degree of X-chromosome inactivation in different tissues and especially in the liver.

The gene for Ornithine transcarbamylase (OTC) is located on the short arm of the X chromosome at Xp21.1, and spans approximately 160 kb of sequence.

Over 300 mutations in the OTC gene have been identified in patients, with the majority being single base alterations that alter the amino acid code. Most families have "private" mutations, with recurrent mutations typically found at CpG dinucleotides. CpG dinucleotides tend to be mutation hotspots.

The maximum number of single base polymorphisms using the OTC mRNA sequence to be close to 3195, obtained by summing the possible changes for each codon by only changing one base at a time (3*3*355 codons). Of these, 152 result in a mutation that causes a stop codon (TGA, TAA,TAG), 740 of these changes do not affect the amino acid code (synonymous mutations; ie: CCT, CCC, CCA, CCG all code for proline), and 2303 result in changes that affect the amino acid sequence (nonsynonymous mutations). This analysis does not correctly account for mutations at the splice junctions, or for mutations that may affect cryptic splice sites but provides an approximate estimate of the diversity of mutations.

Symptoms:

The symptoms of OTC can vary from one individual to the next, but common symptoms of the condition include lethargy, feeding difficulties, lack of appetite, poorly-controlled breathing, and fluctuations in body temperature. In severe cases, babies may experience seizures, developmental disabilities and mental retardation. Liver damage, dry and brittle hair, and skin lesions may also be signs of this disorder.

Signs:

    High plasma ammonia level.

  • High plasma glutamine and alanine levels, low plasma citrulline level; low plasma arginine level.

  • Very high urine orotic acid level.

  • Respiratory alkalosis (initially).

Diagnosis:

Tests:

    Assess cardiac, respiratory, neurologic, and hydration status.

  • Identify potential precipitant(s) of metabolic decompensation such as infection (presence of fever) or any other physical stressor (e.g. injury, surgery).

Initial laboratory tests to order:

    Plasma ammonia (1.5 ml blood in sodium-heparin tube sent STAT to lab on ice, run immediately).

  • Plasma amino acid profile.

  • Urine orotic acid.

  • Liver function tests (AST,ALT, alakaline phospatase, bilirubin).

  • Arterial or venous blood gas.

  • Serum electrolytes, bicarbonate, BUN, creatinine.

  • Blood glucose.

  • Blood, urine, and/or CSF cultures (as clinically indicated).

Treatment:

Immediate temporary discontinuation of protein intake in a symptomatic individual with ornithine transcarbamylase (OTC) deficiency is mandatory, with compensatory increases in carbohydrates and lipids in order to offset any catabolic tendency to draw on muscle amino acids for energy.

In a patient who is comatose with extremely high blood ammonia levels (in some cases exceeding 2000 mg/dL), rapid reduction can be achieved with hemodialysis.

Intravenous administration of sodium benzoate, arginine, and sodium phenylacetate is important; however, only administer these drugs in a large medical facility setting with close laboratory monitoring available. Intravenous sodium benzoate and phenylacetate (Ammonul) was approved in the United States in February 2005.

A biochemical geneticist and a highly trained nutritionist should administer long-term outpatient care in a large facility setting with laboratory monitoring available.

NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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