Huntington’s disease (HD) is a progressive neurological disorder that gradually affects a person’s physical abilities, cognitive functions, and emotional well-being. It is a condition that worsens over time, leading to a decline in movement control, thinking, and behavior.
The Affected Chromosome
Huntington’s disease is directly linked to a specific genetic defect located on chromosome 4. Chromosomes are thread-like structures found within the nucleus of our cells, carrying our genetic information in the form of DNA. In humans, there are 23 pairs of chromosomes, and chromosome 4 holds the particular gene responsible for HD. This specific location, identified as 4p16.3, signifies the short arm (p) of chromosome 4.
The Gene and Its Specific Mutation
Within chromosome 4, the gene implicated in Huntington’s disease is known as the huntingtin gene, often abbreviated as HTT. A gene serves as a unit of heredity, carrying instructions for building and maintaining an organism. The problem in Huntington’s disease arises from a specific alteration within this HTT gene.
This alteration is a “CAG repeat expansion,” where a sequence of three DNA building blocks—cytosine (C), adenine (A), and guanine (G)—is repeated too many times. While a normal HTT gene has 10 to 26 CAG repeats, an individual with 36 or more repeats will typically develop Huntington’s disease. The presence of 40 or more CAG repeats usually ensures the disease will manifest during a person’s lifetime.
How the Mutation Leads to Disease
The expanded CAG repeats within the HTT gene lead to the production of an abnormally long and altered huntingtin protein. This mutated protein, often referred to as mutant huntingtin (mHtt), has a section with an excessive number of glutamine units, known as a polyglutamine tract. The abnormal length of this polyglutamine tract causes the protein to misfold and clump together.
These protein clumps are toxic to nerve cells, or neurons, particularly in specific brain regions like the basal ganglia and cerebral cortex. The basal ganglia are crucial for regulating movement, while the cerebral cortex is involved in thinking and memory. The progressive damage and eventual death of these neurons lead to the characteristic symptoms of Huntington’s disease, including uncontrolled, dance-like movements (chorea), cognitive decline, and psychiatric disturbances.
Inheritance and Genetic Testing
Huntington’s disease follows an autosomal dominant inheritance pattern. This means that a person needs to inherit only one copy of the mutated HTT gene from either parent to develop the condition. Consequently, each child of a parent with Huntington’s disease has a 50% chance of inheriting the altered gene and, therefore, the disease.
Genetic testing can accurately identify the CAG repeat expansion on chromosome 4. This blood test determines the number of CAG repeats in an individual’s HTT gene. Such testing can confirm a diagnosis in symptomatic individuals or predict the presence of the disease in those at risk.