HUNTINGTON DISEASE

Introduction

Huntington's disease is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. Symptoms commonly become noticeable between the ages of 35 and 44 years, but they can begin at any age from infancy to old age. In the early stages, there are changes in personality, cognition, and physical skills. The physical symptoms are usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at the earlier stages.

            We will focus on the genetics aspects of the Huntington’s disease, and then, on its cellular mechanism.

Genetics Aspects

            Our organism has two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (Htt), on the chromosome 4p13.3. A part of this gene is a repeated section called a trinucleotide repeat. If the number of repetition is too high in a healthy gene, a dynamic mutation may result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces another form of the protein, called mutant Huntingtin protein (mHtt).

HTT contains a sequence of three DNA bases : Cytosine-Adenine-Guanine (CAG), repeated multiple times (CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the codon for the amino acid glutamine, so a serie of them results in the production of a chain of glutamine, known as a polyglutamine tract (PolyQ tract), and the repeated part of the gene, the PolyQ region.

In a normal situation, the codon CAG is repeated 26 times tops. A sequence of 27 or more glutamines results another form of protein which has different characteristics. This is the mutant Huntingtin protein. From 27 to 35 repetitions, it’s an intermediate form of the disease, appearing after 80 years old, people are not affected. From 36 to 39 repetitions, it’s a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that the symptoms are never noticed. With more than 39 repeats, Huntington disease has full penetrance and can occur under the age of 20. We talk about juvenile Huntington disease. (See the array below)

                                                     Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats

The disease mutation is genetically dominant.  It is not inherited according to sex, but the length of the repeated section of the gene can be influenced by the sex of the affected parent. In fact, if the affected parent is a male, the section will be longer for the offspring, than if it’s a female. That’s why we talk about autosomal dominant inheritance. It means that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. The probability of each offspring inheriting an affected gene is 50%. In rare situations, where both parents have an expanded Huntington’s disease gene, the risk increases by 75%. When either parent has two expanded copies, the risk is 100% (all children will be affected).

The Huntingtin protein interacts with over 100 other proteins, and appears to have multiple biological functions. The behavior of the mutated protein is toxic to certain cell types, particularly in the brain. We will explain you the cellular mechanism