Which are the causes of Machado-Joseph Disease?

Machado-Joseph Disease (MJD), also known as Spinocerebellar Ataxia Type 3, is a rare genetic disorder that primarily affects the central nervous system. It is characterized by progressive degeneration of certain regions of the brain, leading to a wide range of symptoms including movement abnormalities, muscle weakness, and impaired coordination.

The primary cause of Machado-Joseph Disease is a mutation in the ATXN3 gene. This gene provides instructions for making a protein called ataxin-3, which is involved in the normal functioning of nerve cells. In individuals with MJD, the ATXN3 gene contains an abnormal repetition of the DNA building blocks cytosine, adenine, and guanine (CAG). This abnormal repetition leads to the production of an abnormal form of ataxin-3 protein.

The abnormal ataxin-3 protein accumulates in certain regions of the brain, particularly in the cerebellum and brainstem. Over time, the accumulation of this protein leads to the degeneration and death of nerve cells in these areas, resulting in the characteristic symptoms of MJD.

The number of CAG repeats in the ATXN3 gene is directly related to the age of onset and severity of MJD. Individuals with a larger number of CAG repeats tend to develop symptoms at an earlier age and experience a more severe form of the disease. The normal range of CAG repeats in the ATXN3 gene is between 12 and 44, but in individuals with MJD, the number of repeats is typically expanded to 55 or more.

Machado-Joseph Disease is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the mutated ATXN3 gene from either parent to develop the disease. If one parent has MJD, each child has a 50% chance of inheriting the mutated gene and developing the disorder.

Although the exact mechanism by which the abnormal ataxin-3 protein causes nerve cell degeneration is not fully understood, several theories have been proposed. One theory suggests that the abnormal protein disrupts the normal functioning of cellular structures called proteasomes, which are responsible for breaking down and recycling unwanted proteins. This disruption leads to the accumulation of toxic protein aggregates, ultimately causing cell death. Another theory suggests that the abnormal protein interferes with important cellular processes, such as protein folding and transport, leading to cellular dysfunction and degeneration.

While the genetic mutation is the primary cause of Machado-Joseph Disease, other factors may influence the age of onset and progression of the disease. These factors include the presence of other genetic variations, environmental factors, and lifestyle choices. For example, studies have shown that certain genetic variations in other genes can modify the severity of MJD symptoms. Additionally, environmental factors such as exposure to toxins or certain medications may interact with the abnormal ataxin-3 protein and contribute to disease progression.

Currently, there is no cure for Machado-Joseph Disease. Treatment options focus on managing the symptoms and improving the quality of life for affected individuals. Physical therapy, occupational therapy, and speech therapy can help manage movement difficulties and improve coordination. Medications may be prescribed to alleviate specific symptoms such as muscle stiffness or depression. Ongoing research aims to better understand the underlying mechanisms of MJD and develop targeted therapies to slow down or halt the progression of the disease.