Question

There are several examples of human genetic disorders that affect amino acid catabolism. Three examples include, phenylketonuria, Argininemia, carbamoyl phosphate synthetase I deficiency. For each indicate the process that is defective in the disease condition, name the defective enzyme and list a few symptoms/effects.

Answer 1

The basic unit of heridity is the genes. They are inherited from parents to offsprings. They hold our genetic materials. They are highly protected, but in some cases these genes may get mutated or missing from their normal organisation. In such cases, these abnormal genes can cause human genetic disorders. Some of these human genetic disorders can even affect the amino acid metabolism. Some of them are: Phenylketonuria, Argininemia, carbamoyl phosphate synthetase I deficiency, tyrosinemia, maple syrup urine disease, etc.

Phenylketonuria -  This is an innate metabolic disorder due to an autosomal recessive mutation. This results in the decreased metabolism of the amino acid phenylalanine. Thus the amount of phenylalanine increases in the blood. If this progresses, it can lead to severe mental retardation and other health problems.

Defective enzyme: Phenylalanine hydroxylase.

Process: This mutation causes the non-production of the liver enzyme phenylalanine hydroxylase. This enzyme converts phenyl alanine to tyrosine. So, if this enzyme is absent, the amount of phenylalanine and its derivatives in blood increases and they excrete through the urine. In normal cases, phenylalanine is converted to tyrosine by phenylalanine hydroxylase. The production of this enzyme is controlled by an autosomal dominant gene. But, in patients with phenylketonuria, this gene undergoes recessive biochemical mutation. As a result, the enzyme will not produce in the body of the patient. This leads to the blocking of the conversion of phenylalanine to tyrosine. This block in the metabolic pathway will cause the excessive accumulation of phenylalanine, resulting in phenylketonuria.  

Symptoms: The symptoms may vary from mild to severe. This disorder results in severe mental retardation and idiocy. Some of such children will never be able to talk or walk. Reduced hair, poor skin pigmentation, irritability, tremors, convulsions, etc are other symptoms.

Argininemia - Argininemia is a type of urea cycle disorder. This is an autosomal recessive disorder which causes mutation in the ARG1 gene. This mutation leads to the non-production of the enzyme arginase. As a result, the amino acid arginine and ammonia accumulates in the blood. Ammonia is highly toxic to our body especially to the brain.

Defective enzyme: Arginase

Process: The ARG1 gene controls the production of the enzyme arginase. When proteins are used by the body, excess nitrogen is produced as a byproduct. This excess nitrogen is processed and converted to urea for the excretion through kidney is done by the urea cycle. The final step of the urea cycle is controlled by the enzyme arginase. In this step, urea is produced by removing nitrogen from arginine. But, in patients with Argininemia, due to the absence of the enzyme arginase, the conversion of arginine to urea will not take place. As a result, the amount arginine and nitrogen (in the form of ammonia) increases in the blood.

Symptoms: The common symptoms of argininemia are dehydration, lethargy, stunted growth, seizures, microcephaly, hypotonia (reduced muscle strength), intellectual diability, tremors, etc.

Carbamoyl phosphate synthetase I deficiency - This is an autosomal recessive metabolic disorder. This is also a urea cycle disorder. Here, the enzyme carbamoyl phosphate synthetase I is not produced. As a result, the amount of ammonia in blood increases. Ammonia is highly toxic to our body. In severe cases, the accumulation of ammonia will affects the functioning of the brain.

Defective enzyme: Carbamoyl phosphate synthetase I.

Process: The production of the enzyme carbamoyl phosphate synthetase I is controlled by CPS1 gene. This enzyme plays a major role in the urea cycle which occurs in liver cells. Through the urea cycle, the excess nitrogen produced in the body as a result of the protein breakdown is converted to urea and is then excreted by the kidney. The enzyme carbamoyl phosphate synthetase I controls the first step of the urea cycle. In this step excess nitrogen compounds are added to the cycle which is then processed. So, the absence of this enzyme leads to an abnormal urea cycle. This results in the accumulation of nitrogen compounds in the form of ammonia in the blood.

Symptoms: In infants, this disorder leads to lethargy. They will have breathing problems and poorly or unregulated body temperature. Some other common symptoms are seizures, abnormal body movements, mental retardation, developmental problems and in some cases it can lead to coma.