퇴행성 뇌질환 - 3. HD(Huntington’s Disease)’s Pathogenesis

▣ HD(Huntington’s Disease)’s Pathogenesis

Huntington's disease results from genetically programmed degeneration of nerve cells, called neurons, in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. Huntington's disease results from a genetic mutation on the fourth chromosome. This abnormality causes the death of vital nerve cells in a region of the brain known as the 'basal ganglia'.

Specifically affected are cells of the basal ganglia, structures deep within the brain that have many important functions, including coordinating movement. Within the basal ganglia, HD especially targets neurons of the striatum, particularly those in the caudate nuclei and the pallidum. Also affected is the brain's outer surface, or cortex, which controls thought, perception, and memory.

Huntington's disease is found in every country of the world. It is a familial disease, passed from parent to child through a mutation or misspelling in the normal gene. HD is an autosomal dominant disorder, which means that each child of a parent with the disease has a 50 percent risk of inheriting the illness. The huntington gene (IT15 gene which is located on the short arm of chromosome 4 - 4p16.3) is considered virtually 100 percent 'penetrant', meaning that anyone who inherits the faulty gene will inevitably develop the disease. All 'carriers' eventually become 'patients'.   

A single abnormal gene, the basic biological unit of heredity, produces HD. Genes are composed of deoxyribonucleic acid (DNA), a molecule shaped like a spiral ladder. Each rung of this ladder is composed of two paired chemicals called bases.

There are four types of bases - adenine, thymine, cytosine, and guanine - each abbreviated by the first letter of its name: A, T, C, and G. Certain bases always 'pair' together, and different combinations of base pairs join to form coded messages.

A gene is a long string of this DNA in various combinations of A, T, C, and G. These unique combinations determine the gene's function, much like letters join together to form words.

Each person has about 30,000 genes - a billion base pairs of DNA or bits of information repeated in the nuclei of human cells - which determine individual characteristics or traits.

Genes are arranged in precise locations along 23 rod-like pairs of chromosomes. One chromosome from each pair comes from an individual's mother, the other from the father.

Each half of a chromosome pair is similar to the other, except for one pair, which determines the sex of the individual. This pair has two X chromosomes in females and one X and one Y chromosome in males.

The gene that produces HD lies on chromosome 4, one of the 22 non-sex-linked, or ‘autosomal’, pairs of chromosomes, placing men and women at equal risk of acquiring the disease.

The impact of a gene depends partly on whether it is dominant or recessive. If a gene is dominant, then only one of the paired chromosomes is required to produce its called-for effect. If the gene is recessive, both parents must provide chromosomal copies for the trait to be present. HD is called an 'autosomal dominant disorder' because only one copy of the defective gene, inherited from one parent, is necessary to produce the disease.

The genetic defect responsible for HD is a small sequence of DNA on chromosome 4 in which several base pairs are repeated many, many times. The normal gene has three DNA bases, composed of the sequence CAG. In people with HD, the sequence abnormally repeats itself dozens of times. Over time - and with each successive generation - the number of CAG repeats may expand further.

Each parent has two copies of every chromosome but gives only one copy to each child. Each child of an HD parent has a 50-50 chance of inheriting the HD gene. If a child does not inherit the HD gene, he or she will not develop the disease and cannot pass it to subsequent generations. A person who inherits the HD gene, and survives long enough, will sooner or later develop the disease. In some families, all the children may inherit the HD gene; in others, none do. Whether one child inherits the gene has no bearing on whether others will or will not share the same fate.

A small number of cases of HD are sporadic, that is, they occur even though there is no family history of the disorder. These cases are thought to be caused by a new genetic mutation-an alteration in the gene that occurs during sperm development and that brings the number of CAG repeats into the range that causes disease.

HD is a genetic disorder, inherited in an autosomal dominant pattern, which means that each child of an affected parent has a 50% chance of inheriting the disease-causing gene. Individuals who inherit the HD gene almost always develop the symptoms of HD, usually at the same age as their affected parent or earlier.