Etty Widayanti, SSi. MBiotech.

Biologi - Anatomi

Fakultas Kedokteran Univ. YARSI

Just as abnormalities arise from changes in chromosomal structure and number, so also changes in the structure of the genes cause several defects in metabolism. Due to breakage in the chromosome and their irregular reconstitution, absence of certain genes causes such defects.

During the gene disorders, the DNA changes. These disorders are hereditary. Such disorders are seen due to alternation in the nitrogen base composition type, number, linear order and base pairing in the DNA is altered.

Due to such changes, the information (code) is wrongly copied on to the mRNA and abnormal mRNA is produced. As a result, the specific type of protein which is to be synthesized in the cell, is not correctly produced (leading to an error) in the cell. These proteins may be structural or functional.

Consequently, the organism may develop phenotypic or functional disorders. The cause for induction of such disorders may be physical or chemical. For examples, ionizing radiation such as X-rays and several chemicals may also cause disorders.

Products of genes  - usually protiens. Enzymes are proteins 1  gene = 1 protein

genes mutate thus creating abnormal proteins (mutations occur in both directions,  in other words not all mutations are bad, some can be good and most are meaningless)

Mutational changes of genes can be related to losses of specific enzymes. This concept was widely known as "one gene one enzyme hypothesis." This hypothesis can be understood well by knowing the phenomenon of metabolic block.

Block of a normal pathway results in: 1) Accumulation of products preceding block 2) Succeeding reactions are inhibited 3) Deficiency of protein (the final product)

The most frequent defects in amino acid metabolism involve the amino acids phenylalanine and tyrosine. Numerous enzymes are required to convert phenylalanine into a variety of biochemical products.

Change in the metabolism of amino acids result in disorders such as phenylketonuria, tyrosinosis, alkaptonuria, albinism and cretinism.

Inborn errors of metabolism (IEM) comprise a group of disorders in which a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product. All IEMs are all genetically transmitted typically in an autosomal recessive or X-linked recessive fashion.

The metabolism of the aromatic amino acids-phenylalanine and tyrosine in man provides a best example of a gene-controlled, enzyme catalyzed biochemical reaction.

In man, phenylalanine is an essential amino acid which must be supplied in the dietary proteins. Once in the body, phenylalanine may follow any of three paths. It may be (1) incorporated into cellular proteins, (2) converted to phenylpyruvic acid, or (3) converted to tyrosine.

The conversion of phenylalanine into tyrosine takes place in the presence of phenylalanine hydroxylase enzyme, in the liver cells.

Tyrosine is converted in turn to 3-4-dihydroxy phenylalanine (nick-named DOPA) by another enzyme and DOPA serves as a precursor for the hormones adrenaline and noradrenaline and for the black pigment, melanin.

Tyrosine itself serves as a precursor of the hormones thyroxine and triiodothyronine.

Excess tyrosine is degraded to carbon dioxide and water by a series of steps which involves the formation of p-hydroxyphenyl pyruvate, 2-5 dihydroxy phenyl pyruvate, homogentisic acid, maleylacetoacetic acid, fumaryl acetoacetic acid and fumaric and acetoacetic acid.

Excess phenylalanine is degraded by a series of steps to compounds which include phenylpyruvic acid and phenyl lactic acid.

The amino acid phenyl alanine is generally found in normal diet. This phenyl alanine is converted to the amino acid tyrosine with the help of phenyl alanine hydroxylase.

In this disorder Phenyl Ketonuria (PKU), the enzyme phenyl alanine hydroxylase is not produced due to the alteration of a homozygus recessive gene. This gene is termed pk gene. As a result this disorder arises and phenyl alanine is not converted to tyrosine. On the other hand phenyl alanine is converted to phenyl pyruvic acid.

Under normal circumstances, phenyl pyruvic acid is released as an excretory product. Abnormal increase in concentration of phenyl pyruvic acid in blood has an adverse effect on the nervous system and reduces the intelligence. Therefore individuals with this disorder should be given a diet which is low in phenyl alanine content.

The recessive gene, t in its homozygous condition, blocks the conversion of p-hydroxyphenylpyruvate into 2, S-dihydroxyphenyl pyruvate. This leads to the accumulation of tyrosine, excesses of which are excreted via the urine. This condition is called tyrosinosis.

Accumulation of p-hydroxyphenylpyruvic acid usually leads to an enlargement of the liver and spleen. Death results from liver failure between 4 months and 5 years of age. Diet control may help in reducing the symptoms of tyrosinosis.

Tyrosinosis

Alkaptonuria results from the absence of an enzyme homogentisic acid dehydrogenase. An autosomal recessive gene is associated with the absence of this enzyme. The urine turns black because of the presence of homogentisic acid in it.

Alkaptonuria is a rare condition in which a person's urine turns a dark brownish-black color when exposed to air.

Causes:A defect in the HGD gene causes

alkaptonuria. The gene defect makes the body unable to properly break down certain amino acids (tyrosine and phenylalanine). As a result, a substance called homogentisic acid builds up in the skin and other body tissues. The acid leaves the body through the urine. The urine turns brownish-black when it mixes with air.

Alkaptonuria is inherited, which means it is passed down from parents to their children. To get this disease, each of your parents must pass you a copy of the faulty HGD gene.

Symptoms:Urine in an infant's diaper may darken and can

turn almost black after several hours. However, many persons with this condition may not know they have it until mid-adulthood (around age 40), when joint and other problems occur.

Symptoms may include:- Arthritis (especially of the spine) that gets worse

over time- Darkening of the ear- Dark spots on the white of the eye (sclera) and

cornea

Possible ComplicationsPeople with this condition also can get

arthritis in adulthood. The build-up of homogentisic acid in the cartilage causes arthritis in about 50% of older adults with alkaptonuria.- Homogentisic acid also can build up on the heart valves, especially the mitral valve. This can sometimes lead to the need for valve replacement.- Coronary artery disease may develop earlier in people with alkaptonuria.- Kidney stones and prostate stones may be more common in people with alkaptonuria.

Exams and Tests:A urine test (urinalysis) is done to

test for alkaptonuria. If ferric chloride is added to the urine, it will turn the urine a black color in patients with this condition.

TreatmentSome patients benefit from high-dose

vitamin C. This has been shown to decrease the build-up of brown pigment in the cartilage and may slow the development of arthritis.

Alkaptonuria

Albinism is a group of genetic conditions that causes a lack of pigment. It can effect only the eyes or both the eyes and skin. Most types of albinism are inherited when an individual receives the albinism gene from both parents. The exception is one type of ocular albinism, which is passed on from mothers to their sons.

Albinism results from the deficiency of enzyme Tyrosinase. This enzyme is required for conversion of tyrosine to melanin. Because of this disorder tyrosine is not converted to melanin.

The persons with recessive aa genotype lack in the tyrosinase enzyme system which is required for the conversion of 3, 4-dihydroxyphenyl alanine (DOPA) into melanin pigment inside the melanocytes.

In an albino patient melanocytes are present in normal numbers in their skin, hairs, iris, etc., but lack in melanin pigment. The skin and hair remain white and pigmentless. These individuals have a very white skin, fine white hair, pink or light blue irises of the eyes, and a variety of other eye disturbances. Various types of localized albinism are characterized by the absence of pigment in specific parts of the body.

Individuals with this disorder are extremely sensitive and cannot withstand much light.

Black albinism

Balthazar Telez coined the term "albino“, meaning white Negro, when he saw white African tribe members along the coast of West Africa. He and the other explorers thought they were seeing two different races of people

The persons with cc genotype fail to produce the enzyme which is required for the conversion of tyrosine into thyroxine and triiodothyronine hormones in their thyroid glands.

Cretinism (infantile hypothyroidism) - shows stunted growth, thickened facial features, abnormal bone development and mental retardation

SymptomsMost affected infants have few or no

symptoms, because they only have a mild decrease in thyroid hormone production. However, infants with severe hypothyroidism often have a distinctive appearance. Symptoms may include: - Puffy-appearing face- Dull look- Thick, protruding tongue

Cretinism

TreatmentEarly diagnosis is very important. Most of the

effects of hypothyroidism are easily reversible. Replacement therapy with thyroxine is the standard treatment of hypothyroidism. Once medication starts, thyroid blood tests are regularly done to make sure levels are within a normal range.

Very early diagnosis generally results in a good outcome. Newborns diagnosed and treated in the first month or so generally develop normal intelligence.

ReferencesSuryo. 2001. Genetika manusia. Gadjah Mada

University Press.