Genetics of Human Metabolic Diseases | Genetics

In this article we will discuss about:- 1. Defects in Amino Acid Metabolism 2. Defects in Lipid Metabolism 3. Defects in Sugar Metabolism 4. Defects in Purine Metabolism 5. Defects in Metabolism of Sulphur-Containing Amino Acids.

1. Defects in Amino Acid Metabolism:

a. Albinism:

The condition is due to lack of melanin pigments caused by the absence of tyrosinase enzyme. There are two types of albinism, one in which only the eye pigment is absent, called ocular albinism. The second where lack of pigmentation occurs in both skin and eyes. This is of two further types namely tyrosinase positive oculocutaneous albinism and tyrosinase negative oculocutaneous albinism.

The enzyme tyrosinase is normally present within structures called melanosomes which occur in melanocytes. In individuals having the autosomal recessive mutant gene for albinism, there is no tyrosinase in the melanosomes and the pathway for production of melanin is blocked (Fig. 21.5).

The tyrosinase negative persons show a more extreme form of albinism, are highly sensitive to sun’s rays and may develop skin cancers. The tyrosinase positive patients show a milder form of albinism and may develop some pigment.

There is a separate gene for each of the tyrosinase positive and negative forms. Because of two distinct loci, a marriage between a tyrosinase positive and a tyrosinase negative individual produces normal children.

b. Alkaptonuria:

This was one of the first metabolic diseases described by Garrod in 1908. It was known to him that this was a recessive disorder occurring more frequently in offsprings of consanguineous matings. It was first noticed that if the diapers of some new-born babies were left exposed to air, the urine turned black.

The affected children were found to excrete a substance called homogentisic acid (alkapton) which becomes oxidized in air to a dark coloration (Fig. 21.6). The enzyme homogentisic acid oxidase was lacking which normally causes breakdown of homogentisic acid.

Children with alkaptonuria appear healthy. The disorder is relatively harmless except that the slow deposition of pigment in the joints sometimes leads to mild arthritis.

c. Phenylketonuria (PKU):

Persons lacking yet another enzyme of the phenylalanine tyrosine pathway called phenylalanine hydroxylase have the condition PKU. This is one of the best understood of the inherited metabolic diseases. The hydroxylase enzyme which is present in the liver normally converts phenylalanine to tyrosine. When this enzyme is absent, there is a high level of phenylalanine in the body fluids like blood, cerebrospinal fluid and sweat.

Besides tyrosine there are a few more breakdown products of phenylalanine such as phenyl-pyruvic acid, also formed. High levels of phenylalanine therefore produce deleterious secondary effects by accumulation of its products. Often fair skin and light hair and eyes are found in PKU patients due to lack of melanin pigment. This is a secondary effect caused by inhibition of enzymes by the abnormal by­products of phenylalanine.

There is progressive deterioration of the central nervous system starting a few months after birth. The affected babies may also show eczema on the skin, defective enamel of teeth and anomalies in bones. PKU patients are severely retarded mentally. The children are hyperactive and have highly increased muscle tone. They can be treated if placed on a diet with low levels of phenylalanine.

PKU also illustrates the phenomenon of pleiotropic (manifold) effects of a gene. A single defect in the gene which controls phenylalanine hydroxylase enzyme results in a primary block. This in turn produces manifold secondary effects.

2. Defects in Lipid Metabolism:

a. Tay Sachs Disease (TSD):

This is an autosomal recessive disease. Homozygous children show degeneration of the central nervous system due to accumulation of a fatty substance (sphingolipid) in nerve cells. This is caused by the enzyme hexosaminidase which in normal individuals exists in two forms A and B. In TSD only the A form is present, the B form is lacking.

The symptoms appear in infants in the first year after birth. They start showing paralysis, mental retardation, and other defects associated with degeneration of the neuromuscular system. After one year’s age the child’s condition deteriorates, there is general paralysis, loss of sight and hearing, and difficulties in feeding. By two years the child becomes immobile.

b. Gaucher’s Disease:

In this condition the breakdown of fatty substances is impaired leading to accumulation of lipid materials in body tissues and blood. It is caused by a recessive gene which inhibits the activity of an enzyme glucocerebrosidase. Consequently there is accumulation of cerebroside (a sphingolipid) in cells of the reticuloendothelial system.

There is enlargement of the spleen and liver, and expansion of some of the limb bones. Of the three clinically distinct forms of this disorder, one called the early infantile form leads to death before two years age. Another form appears after the second year, while the third is present in adults in a chronic form.

c. Mucopolysaccharidoses:

This includes a variety of conditions all related to defective breakdown of mucopolysaccharides in body tissues. A number of intermediate products of the degradative pathway thus accumulate in the lysosomes. A high level of acid mucopolysaccharides such as hyaluronic acid, dermatan sulphate and heparin are excreted in the urine.

Two of the better known examples are Hurler’s syndrome, caused by an autosomal recessive gene, and Hunter’s syndrome, an X-linked recessive disorder. In both there is accumulation of dermatan sulphate and heparin sulphate in the tissues; symptoms include mental retardation and defects in the bone and facial appearance.

3. Defects in Sugar Metabolism:

G6PD:

Here the genetic condition is related to the drugs administered to the individual. The disorder has been studied extensively. It also has a historical background. During World War II some of the U.S. servicemen were found to be sensitive to the antimalarial primaquine and responded with hemolytic anemia. The blood counts became low and the patients became jaundiced. The haemolytic reactions lasted for a few days, then there was spontaneous recovery.

It was found out that the condition was related to low levels of reduced glutathione in the RBCs. The reduced coenzyme NADPH was also deficient in these cells. The appropriate levels of reduced glutathione in red cells are maintained by the enzyme glutathione reductase and its coenzyme NADPH. For adequate supplies of NADPH the enzyme G6PD (glucose 6-phosphate dehydrogenase) is required. Consequently, when activity of G6PD is low it leads to primaquine sensitivity.

There are many different variants of the enzyme G6PD. Some of the variants are normal, while others have low physiological activity so that they are not able to produce enough NADPH. This finally results in lower levels of reduced glutathione in the red cells. Two types of mutations have been recognised for causing haemolytic anaemias. In the African and Black American populations the enzyme G6PD A is synthesized.

In Asian and Mediterranean subjects, the G6PD Mediterranean variant is prevalent. Since G6PD is an X-linked recessive trait, the affected persons are predominantly males. In females, due to inactivation of one of the two X chromosomes in each cell, there are two populations of cells, G6PD deficient and normal.

There is also an indication that persons with an abnormal G6PD allele are less likely to have malaria. It is noteworthy that G6PD deficient persons appear healthy. It is only when they take certain foods or drugs like primaquine or chloroquine, sulpha and some others, that they respond with haemolytic reaction.

4. Defects in Purine Metabolism:

Lesch-Nyhan Syndrome:

This is an X-linked recessive disorder. It is caused by the absence of an enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT) which is required for the utilisation of purines in the synthesis of DNA and RNA. In absence of the enzyme, purines accumulate and are converted into uric acid which passes into the blood stream and urine.

Affected children (usually males) thus show high levels of uric acid in blood and urine and are detected due to the presence of ‘orange sand’ in the diapers of infants. They become mentally retarded and by six months the muscles start becoming weak and flabby. By about one year again the muscles develop excess tone and the children have spasms of arms and legs.

Affected children about 2-3 years old have a tendency for self-mutilation. They start biting their fingers, lips and inside of mouth. They also show aggressive behaviour towards others. Some teen-aged individuals who are affected develop gouty arthritis.

5. Defects in Metabolism of Sulphur-Containing Amino Acids:

a. Homocysteinuria:

This is an autosomal recessive disorder in which homocysteine and serine are not converted into cystathionine due to a defect in the apoenzyme cystathionine synthetase. During methylation of DNA or of RNA, the methionine is derived from S-adenosyl methionine. After giving away methionine, S-adenosyl methionine becomes converted into S-adenosyl homocysteine.

The resulting homocysteine condenses with serine to form cystathionine, catalysed by the enzyme cystathionine synthetase which requires pyridoxal phosphate as the coenzyme. The enzyme action takes place in the liver. Homozygous persons affected with homocysteinuria have a structural change in the apoenzyme, so that it cannot bind to the coenzyme pyridoxal phosphate with the same efficiency as the normal apoenzyme.

The affected individuals have convulsions, mental retardation and abnormalities in the lens of the eye and bones (osteoporosis). The condition can be treated by administering large amounts of vitamin B6 (pyridoxin) in the diet, and by restricting intake of methionine and cystine.

b. Cystathioninuria:

In this rare condition, there is deficiency of the enzyme cystathionase which is required for breaking down cystathionine into homoserine and cysteine. Consequently cystathionine accumulates in the plasma and is excreted. Various external symptoms are associated with this disorder. Treatment with pyridoxin improves the condition.