A 6 month old(1) infant began to vomit occasionally(2) and ceased to gain weight(3). At age 8 months he was readmitted to the hospital. Routine examination and laboratory tests were normal, but after one week he became habitually drowsy(4), his temperature rose to 102 F(5), his pulse rate was elevated (6), his liver was enlarged(7).The electrocencephalogram was grossly abnormal(8). Since the infant could not retain milk(9) given by gavage feeding(10), intravenous glucose was administered(11). He improved rapidly and came out of coma in 24 hours(12). Analysis of urine(13) showed abnormal amounts of glutamine(14) ,uracil and orotic acid(15) but decreased levels of urea(16),which suggested a high blood ammonium concentration. This was confirmed by laboratory.
What is your diagnosis of the disease?(17)
- Causes , diagnosis and treatment of disease.
- Steps and regulation of urea cycle.
- Fates of urea.
- Diseases related to hyperammonemia.
Neonates (new born till 1 month of age) commonly present with genetic defects and enzyme deficiency. Infections are also common due to immature immune system.
Vomiting is caused in three conditions related to GIT:
Overdistention, irritation or over excitation of upper GIT.
Other causes of vomiting include stimulation of vomiting centre and metabolic disorders(as in this case).In neonates casues of vomiting can be pyloric stenosis ,Hydrocephalus , benigh intracranial hypertension or emotions etc.In this case accumulation of metabolites like orotic acid stimulate the vomiting centre.
 Inability to gain weight:
Since the child can not retain food in his stomach so he will fail to gain weight.
Due to lack of nutrition caused by vomiting baby will be in hypoglycemic state and therefore would not be able to remain attentive and active.On top of that the hyperammonemia will cause general depression of CNS funtions.
Normal temperature range is 97.5-98.8 F , fever is mostly caused by pyrogens which are released by bacteria or immunological responses of an individual.Some metabolic disorders can also cause rise in temperature. Another cause of high temperature are the lesions of brains and compression of hypothalamus.In hyperammonemia , there is a chance for the developement of cerebral edema which can cause compress the hypothalamus or it can have direct effect on the hypothalamus to increase its set point.
 Increased pulse rate:
High temperature invariably increases the heart rate.
Hepatomegaly almost invariably refers to the some metabolic disorder , which is usually accompanied by the accumulation of the intermediates of the affected the pathway.
Elecetroencephalogram is the recording of the electrical activity of the brain.It varies depending upon the states of brain activity.Its grossly abnormal appearance indicates an underlying the brain dysfuntion.
 Inability to retain milk:
Failure to retain milk is commonly due to lactose intolerance , in this case constant vomiting can not retain milk in the baby.
 Gavage feeding
Gavage is from the french gaver : to force down the throat.It is a method of the feeding through the tube which may be through nasal or GI tract.
 Intravenous glucose
Due to failure to retain milk , the baby can not obtain energy from it, so to relief it glucose is administered to provide energy.
 Improvement in condition
This demonstrates that some of the symptons were due hypoglycemia.
 Urine examination:
Routine urine examination includes physical and chemical examination of the urine.Physical characteristics include appearance,smell,colour pH etc. Chemical examination include tests for glucose , proteins , bile salts and other substances.
Deatils can be found at routine urine examination.
 Glutamine concentration
Glutamine is formed from glutamate when excess ammonia is present, this reaction is catalysed by the enzyme glutamine synthease.Increased levels of this compounds points to hyperammonemia.
 Presence of Uracil and orotic acid
Uracil and orotic acid are the metabolic products of the pyrimidine metabolism.Quantity of these increase most commonly in the deficiency of the enzyme ornithine transcarbamoylase(OTC) of urea cycle.orotic aciduria is diagnostic of OTC deficiency among the urea cycle defects.Orotic aciduria can occur from drugs like allopurinol that compete with orotic acid for UMP synthase enzyme.
 Decreased urea
Decreased level of urea shows the impairment of the conversion of the ammonia into the urea.
The patient is suffering from the OTC deficiency which is the most common type of herediatary hyperammonemia.
Genetic deficiency of OTC of urea cycle.
Urine and blood tests confirm hyperammonemia with orotic aciduria and low levels of urea.
a. Low protein diet,use Na-phenylbutrate and Na-benzoate to remove the excess NH4.
b. Antibiotics to prevent ammonia production from GIT flora (erthromycin).
c. Enzyme replacement therapy.
2.Urea cycle can be found at:
It is allosterically regulated by the N-acetyl glutamate which is formed from Acetyl-CoA and glutamate by synthase enzyme.Arginine activates this process.High level of arginine after meals helps to activates the whole process in liver.
Regulatory step of urea cycle is the synthesis of carbamoyl phosphate by CPS I enzyme.
3. Fates of Urea
Urea has two fates after being formed in the liver:
One is through the kidney to be excreated and another is by conversion into NH3 in interstines by bacterial urease.
4.Disease related to Hyperammonemia:
Hyperammonemia can be herediatary or acquired.Acquired includes liver.
Other metabolic diseases can also cause hyperammonemia like Propionic acidemia, Methylmalonic acidemia
- Nitrogen of urea is derived from asparatate and free NH3.
- C from CO2.
- 3 ATPs are used.
- 4 High energy phosphate bonds are used.
- Synthesis of Cabamoyl Phosphate and conversion of ornithine to citrulline occurs in the mitochodria.
- Rest of steps occur in cytosol.
This article is written to facilitate 34th MBBS especially and other medical students.Writer will not responsible for any untoward result that may arise from this article.