INHERITED METABOLIC DISEASES

In 1908 Archibald Garroda,b proposed that cystinuria and several other defects in amino acid and sugar metabolism were “inborn errors of metabolism”, i.e. inherited diseases. Since that time the number of recognized genetic defects of human metabolism has increased at an accelerating rate to ~4000. c–e Hundreds of other genetic problems have also been identified. For over 800 of these the defective gene has been mapped to a specific chromosome. An example is sickle cell anemia in which a defective hemoglobin differs from the normal protein at one position in one of its constituent polypeptide chains. Many other defects involve loss of activity of some important enzyme. Most genetic diseases are rare, affecting about one person in 10,000. However, cysticfibrosis affects one in 2500. There are so many metabolic diseases that over 0.5% of all persons born may develop one. Many die at an early age. A much greater number (>5%) develop such conditions as diabetes and mental illness which are, in part, of genetic origin. Since new mutations are always arising, genetic diseases present a problem of continuing significance. At what rate do new mutations appear? From the haploid DNA content (Table 1-2) we can estimate that the total coding capacity of the DNA in a human cell exceeds two million genes (actually two million pairs of genes in diploid cells). However, only a fraction of the DNA codes for proteins. There are perhaps 50,000 pairs of structural genes in human DNA. The easily detectable rate of mutation in bacteria is about 10–6 per gene, or 10–9 per base per replication. g
As a result of sophisticated “proofreading” and repair systems, it may be as low as 10–10 per base in humans. h Thus, in the replication of the 3 x 109 base pairs in diploid human chromosomes we might anticipate about one mistake per cell division. Only about 1/50 of these would be in structural genes and potentially harmful. Thus, if there are 1016 division
cycles in a normal life spanh each parent may pass on to future generations about 2 mutations in protein sequences. The ~1014 body cells (somatic cells) also undergo mutations which may lead to cancer and to other problems of aging. Most mutations may be harmless or nearly so and a few may be beneficial. However, many are damaging and some are lethal. If a mutation is lethal, a homozygote will not survive and will be lost in an early (and usually undetected) spontaneous abortion. Healthy individuals carry as many as ten lethal recessive mutations as well as at least 3–5 autosomal recessive mutations of a seriously harmful type. Harmful dominant mutations are also frequent in the population. These include an elevated lipoprotein content of the blood and an elevated cholesterol level which are linked to early heart disease. Biochemical disorders are also important because
of the light they shed on metabolic processes. No other species is observed as carefully as Homo sapiens. As a consequence frequent reference will be made to genetic diseases throughout the book. A goal is to find ways to prevent or ameliorate the effects of these disorders. For example, in the treatment of phenylketonuria or of galactosemia, a change in the diet can prevent irreversible damage to the brain, the organ most frequently affected by many of these diseases. Injection of a missing enzyme is giving life to victims of Gaucher’s disease. In many other cases no satisfactory therapy is presently available, but the possibilities of finding some way to supply missing enzymes or to carry out “genetic surgery” are among the most exciting developments of contemporary medical biochemistry.

Photomicrograph of human male metaphase chromosomes. © Photo
Researchers