DK is a year old female who was born after a normal pregnancy and delivery.  At 17 months of age DK showed signs of speech delay, increased lethargy and vomiting up to four times per day.  She had a history of protein avoidance and her vomiting was more pronounced after protein consumption.  

Lab Data:

DK’s values Normal

Serum ammonia 312 µmol/L 22-48 µmol/L

Plasma glutamine 1700 µmol 123-600 µmol/L

Urinary orotic acid 40 mmol/mol 0.1-2.3 mmol/mol

Diagnosis:

Based on DK’s symptoms and lab findings, a partial ornithine transcarbamylase deficiency (OTCD), a urea cycle disorder, was diagnosed.

Questions:1. Describe the role of ornithine transcarbamylase (OTC).

Answer: 

1. Ornithine transcarbamoylase is an enzyme that catalyzes the reaction between carbamoyl phosphateand ornithine to form citrulline and phosphate. 

2. In plants and microbes, the Ornithine transcarbamoylase enzyme catalyze the bio synthesis of  arginine. In mammals it is placed in the mitochondria and act is part of the urea cycle. 

2. Explain why DK’s serum ammonia, plasma glutamine, and urinary orotic acid are elevated in OTCD: (10 points)

Answer: 

1. Ornithine Transcarbamylase deficiency is one of the genetic urea cycle disorders.

2. It affects the body’s natural mechanism of removing toxins like ammonia from the bloodstream. 

3. The first step in the urea cycle is the production of carbamyl phosphate from ammonium and bicarbonate. 

4. In liver, the urea cycle involves a series of biochemical reactions, where nitrogen (a component of protein) is removed from the blood and converted to urea. This condition is referred as hyperammonemia.

5. Then, Ornithine Transcarbamylase leads to the bio synthesis of citrulline from ornithine and carbamyl phosphate. 

6. In case of Ornithine Transcarbamylase deficiency, ammonia and glutamine start accumulation in liver and amount of citrulline is reduced. 

7. Nitrogen converted into ammonia which is more toxic than urea. 

8. Ammonia, then in turn reaches the brain via blood and cause irreversible damage to brain cells. 

9. One major symptoms of  Ornithine Transcarbamylase deficiency is accumulation of orotic acid in the blood. 

10. This is because, accumulating carbamyl phosphate enters the pyrimidine synthetic pathway, which results in elevation in levels of orotic acid. 

3. Describe in detail the metabolic consequences of high ammonia levels in the brain. (8 points)

Answer: 

1. Ammonia is a byproduct of metabolic processes that convert food to usable energy for cells. 

2. Ornithine Transcarbamylase deficiency affects the mechanism of removal  ammonia from the bloodstream in the body. 

3. As ammonia accumulates in the liver and bloodstream, it leads to a severe medical condition known as hyperammonemia. 

4. In healthy livers, ornithine transcarbamylase enzymes help to break down ammonia to a less toxic form called urea. 

5. It is then excreted from the body in urine. 

6. But due to Ornithine Transcarbamylase deficiency, the production of urea is inhibited and level of ammonia is elevated. 

7. The ammonia then  travel via blood stream and reaches brain cells eventually causes brain edema and result in cognitive damage or death of cells. 

8. Ammonia is specially damages the nervous system, so ornithine transcarbamylase deficiency causes neurological problems.

Ornithine Transcarbamylase deficiency is due to a genetic mutations on the X chromosome. 

4 a. What were three “knowledge gaps” you had related to this case that you needed to address before starting this case study?  (NOTE: There are no wrong answers, I am interested in what you needed to know to answer the questions).  For example, someone without a nutrition background may need to look up what the urea cycle is before answering the questions.  (6 points)

Answer:  

The major knowledge gaps needs to be covered are metioned below:

1. Study of metabolic pathways involved in urea cycles.

2. Synptoms and reason for Ornithine Transcarbamylase deficiency.

3. Metabolic consequences of high ammonia levels on the  brain cells. 

4. Activity and participation of ornithine transcarbamylase enzymes.

5. Genetic mutations linked with the Ornithine Transcarbamylase deficiency.

6. Effect of  Ornithine Transcarbamylase deficiency on serum ammonia, plasma glutamine, and urinary orotic acid.

4b.  Select one of your ‘knowledge gaps’ and describe specifically what you  did to learn more about this issue (i.e., did you look up the information in the textbook, go to the library, search the internet, etc.)  (6 points)

Answer: 

The knowledge gap selected for further analysis is: Metabolic consequences of high ammonia levels on the  brain cells.

1. Ornithine Transcarbamylase deficiency is a genetic disorders.

2. The first step is  ammonium and bicarbonate combine to form carbamyl phosphate.

3. In liver, nitrogen is converted to urea. 

4. Ornithine Transcarbamylase then  leads to the ynthesis of citrulline from ornithine and carbamyl phosphate. 

5.  In Ornithine Transcarbamylase deficiency, ammonia and glutamine start accumulating in liver 

6. Ammonia reaches the brain via blood and cause irreversible damage to brain cells

4c.  Identify in detail what you learned by researching your three ‘knowledge gap.’ (NOTE: This can be related to the topic or something else you discovered, such as a helpful web site).  (6 points)

Answer: 

      After extenstive studies, I learned  that:

1. Ornithine Transcarbamylase deficiency is a genetic disorders 

2. It is  one of the rare disorder that affects approximately one in every 80,000 babies born. 

3. It affects the urea cycle due to a mutation of the Ornithine Transcarbamylase enzyme

4. The symptoms  vary from one individual to another. 

5. The common symptoms of the condition include lethargy, feeding difficulties, lack of appetite, poorly-controlled breathing, and fluctuations in body temperature.

6. In severe cases, babies may experience seizures, developmental delays and mental retardation. Liver damage, dry and brittle hair, and skin lesions may also be signs of this disorder.

7. Till now, there is no cure for Ornithine Transcarbamylase deficiency. The only treatment is a low-protein diet. 

8. Medications of sodium phenylbutyrate and sodium benzoate may prove useful in some cases. 

References:

1. Albrecht J, Zielinska M, Norenberg MD:Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal. Biochem Pharmacol. 80:1303–8, 2010. 

2. Brusilow SW. Urea cycle disorders: clinical paradigm of hyperammonemic encephalopathy: Prog Liver Dis. 13:293–309, 1995. 

3. Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders: N Engl J Med.356:2282–92, 2007.

4. Gropman A. Brain imaging in urea cycle disorders: Mol Genet Metab. 100 Suppl 1:S20–30, 2010.