BIOCHEMICAL BASIS OF DISEASE

In biochemical genetics, genes either specify the sequence of amino acids in a protein, or they control the rate or timing of synthesis of a specific protein. The immediate result is a change in the quality and quantity of the specific protein. Over 500 single gene biochemical abnormalities have been studied.

The relationship of genes and enzymes in a concept of " One gene - one polypeptide " has been refined by Beadle and Tatum (1941) to state the following.

1. All biochemical processes are genetically controlled.
2. The different steps in a biochemical pathway are each under the control of a different enzyme.
3. Each enzyme is coded by one or more genes.
4. A single gene mutation produces an abnormal protein which is responsible for an altered biochemical reaction.

DISORDERS OF PROTEINS

Proteins function as enzymes and are involved in metabolism and formation of structures. In each instance, mutations cause specific genetic disorders.

ENZYMES

Enzymes act as catalysts to mediate biochemical reactions and are usually proteins. A few examples of single gene enzyme defects are given below.

1. In Galactosaemia, the most common enzyme deficiency involves the enzyme galactose- 1-phosphate uridyl transferase. Treatment involves elimination of lactose from the diet.
2. In phenylketonuria, an autosomal recessive condition, the enzyme hepatic phenylalanine hydroxylase which converts phenylalanine to tyrosine is deficient and this leads to increased levels of phenylalanine and its metabolites resulting in mental retardation and a pale colouring of affected children. Treatment involvesevere restriction of oral phenylalanine.
3. Mucopolysaccharidosis type I (MPS I) consists of three overlapping clinical phenotypes which are all part of MPS I. The deficient enzyme is alpha - L - iduronidase.
   The three phenotypes are:
1. Hurler's syndrome (MPS IH), the most severe with children having stiff joints, hepatosplenomegaly, corneal clouding and progressive mental retardation. Death results from respiratory infections or cardiac failure.
2. In Scheie syndrome (MPS IS) the features are similar but milder, with no mental retardation.
3. Hurler-Scheie syndrome (MPSIHS) is intermediate in type with slight mental retardation in addition to joint stiffness and corneal clouding. All three conditions are associated with the abnormal excretion of mucopolysaccharides. Mutations of different alleles at the same locus may explain the different clinical entities.

TRANSPORT

Proteins are involved in transport across cell membranes, or within the cell. The clinical manifestations are evident only in homozygotes.

1. In cystic fibrosis, the gene involved is on the short arm of chromosome 7. The normal gene produces a transmembrane conductance regulator protein which assists the transport of chloride ions across membranes of cells in the pancreas, lungs and sweat glands. A defective gene results in chronic obstructive lung disease and pancreatic insufficiency.
2. In Beta thalassemia, mutations at the two beta chain loci produce the clinical features.

CELL STRUCTURE

A particular class of proteins form the structure or framework of extracellular molecules ( eg. collagen), the cell membrane, the cytoskeleton and the intracellular organelles. Defects may manifest in both the homozygote and heterozygote states.

1. Duchenne muscular dystrophy has a defective gene on the short arm of the X chromosome, which is expected to produce dystrophin , which maintains the integrity of the muscle cell membrane. Its deletion leads to decreased or absent dystrophin which is responsible for the clinical features of the condition.
2. Osteogenesis imperfecta are a group with defective production of type I or type II collagen. Affected infants die of severe fractures and bone crumbling.

INTERCELLULAR METABOLISM

Many protein products function as hormones, as receptors for hormones or metabolites or as signal transducers. Red-green colour blindness involves defective specific light receptors. Other more severe examples are Familial hypercholesterolaemia, and the thyroid hormone deficiencies. In thyroid hormogenesis, defects exist as thyroid peroxidase deficiency, abnormal carrier substance or abnormal iodine receptors. The thyroid peroxidase deficiency results in congenital hypothyroidism where the infant has coarse features, delayed growth and eventual mental retardation.

Protein alterations may result from a defect at any of the many stages of synthesis. It may be at transcription and RNA splicing, translation, secondary and tertiary structure formation, formation of the three dimensional structure or even at the stage of association with other proteins.

From a functional point of view, what the clinician observes in a biochemical genetic disorder is the end result, that of failure in the formation of a product, accumulation of precursors, overproduction of a normal product or the results of a transport or receptor disease. Diagnosis of the disorders is based on the identification of accumulated or missing metabolites, the measurement of specific enzyme levels or the identification of protein variants as the case may be.