A gene mutation is a permanent change in the DNA sequence that makes up a gene.Mutations range in size from a single DNA building block (DNA base) to a largesegment of a chromosome.

  

Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the 

egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person life in virtually every cell in the body.

 

Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder.

 

Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA 

copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation.Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism.

 

 

The understanding of IEM is quite difficult, especially while we still cannot fully visualize the metabolism of the human organism as a whole and the connections that exist among the various metabolic reactions, which are crucial in the maintenance of the basic functions of our body.

Metabolism is basically energy production and consumption, obeying certain priorities. Energy is needed primarily for the basal rate of metabolism, which is the energy spent by an individual at rest and in an absorptive state for the normal corporal functions such as breathing, blood flow and maintenance of muscle integrity. The thermal response to alimentary ingestion may represent 5 to 10% of the total energy expenditure for the body. Finally, physical activity provides largest variation in energy expenditure, with a highly active individuals energy expenditure being up to 100% greater than the basal rate of metabolism.

The largest deposits of energy in the organism are glycogen and the triglycerides and there are two priorities during fasting: (1) the maintenance of plasma glucose levels for cerebral metabolism and other tissues that request glucose and (2) the need to mobilize fatty acids from lipid storage and ketone bodies from the liver so as to liberate energy for all other tissues. In the absence of food, plasma glucose, amino acid and triglyceride levels drop, causing a decline in insulin secretion and an increase in glucagon liberation. The low insulin/glucagon ratio and the low availability of circulating substrates create a catabolic state during the period of nutrient deprivation, characterized by triglyceride, glycogen and protein degradation.

The use of energy by our organism and the metabolism during fasting mentioned above refer to healthy adults. In children in a growth phase and/or during an infection, there is a significant increase in the basal rate of metabolism. When there is an IEM in a child with an infection, we may imagine the profound metabolic alterations that occur and understand the gravity of metabolic decompensation, with its high mortality and great difficulty in treatment.

All metabolic events are driven by enzymes that are catalytic proteins and their main function is to increase the speed of reactions, without being altered during that process. The enzymes possess a highly specific active site that links to one or some specific substrates and catalyzes only one type of chemical reaction. Some enzymes associate with a co-factor (metallic ions or coenzyme) needed for the enzyme activity.

Most IEM are a consequence of enzyme deficiencies. In glycogen storage disease Type I, for example, there is an inability to liberate glucose from the liver, neither as a product of glycogenolysis nor gluconeogenesis. Thus, accentuated hypoglycemia occurs. During fasting, the humoral response to hypoglycemia provokes phosphorylase activation and hepatic glycogenolysis. As there is no glucose liberation, glycolysis continues with production of great amounts of piruvate and consequently lactate. The elevation of glycerol, acetyl-coenzyme A and nicotinamide adenine dinucleotide (NADH) levels generated by the increased flow in the glycolytic pathway contribute to the increase in triglyceride and cholesterol synthesis. The glucagon stimulus mobilizes outlying reserves of fat, elevating the circulating levels of free fatty acid. Therefore, innumerable metabolic alterations occur as a consequence of enzyme deficiency and obviously in the case of a child in a growth phase and with a larger number of viral or bacterial infections, the control of these disturbances is worse.

 

CONCLUSION

IEM are frequently underestimated by the doctor in neonatal and intensive care units of national health clinics or in private clinics. The increase in the rate of identification of these disorders is directly related to clinical judgement and the habit of thinking of those diseases not as rarities but as possibilities, in the light of cases that cannot be explained by more familiar physiopathologies. From this step forward, advances in knowledge and biochemical techniques will really be able to increase the rate of diagnosis.

 Source=http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31801999000600006