Spinocerebellar ataxia type 3 (SCA3) (Machado-Joseph disease, Spinocerebellar atrophy III; Spinopontin atrophy; Azores neurologic disease; Nigrospinodentatal degeneration) - Gen ATXN3

Spinocerebellar ataxia type 3 (also known as Azorean ataxia or Azores disease) is a disorder characterized by progressive alterations in movement that affect motor coordination and balance. Other signs include impaired speech abilities and swallowing, dystonia (involuntary muscle contractions), spasticity and ophthalmoplegia (inability to voluntarily move the eyeball). Ophthalmoplegia also can lead to nystagmus (involuntary and uncontrolled movement of the eyes), eye swelling and double vision. The affected individuals may also have difficulty processing, learning and remembering information. Over time, individuals with SCA3 may develop peripheral neuropathy, muscle cramps, fasciculations, restless legs syndrome and sleep disturbances (REM sleep behavior disorder). Generally, the signs and symptoms of SCA3 begin in mid-adulthood, but may appear at any time from childhood to late adulthood. The survival of affected individuals ranges from 10 to 20 years after the onset of symptoms.

The affected individuals have mutations in the ATXN3 gene (ataxin 3), located on the long arm of chromosome 14 (14q32.12). This gene contains the information for the synthesis of the enzymatic protein "ataxin-3". This enzyme is found in the cell cytoplasm of cells throughout the body, and is involved in the "ubiquitin-proteosome" system. This system controls the excess of cellular proteins or the existence of damaged proteins. For this, the ubiquitin molecule is fixed to unnecessary proteins (in excess or damaged) and marks them so that they are degraded. "Ataxin-3" is also responsible for removing the ubiquitin molecule just before the labeled protein is degraded, allowing ubiquitin to be reused. In addition, it is believed that ataxin-3 may also be involved in the regulation of the first stage of protein coding (transcription).

Mutations of the ATXN3 gene affect a part of the DNA sequence of chromosome 14 with CAG triplet repeats, located at the 3 'end of the gene. Normally, the sequence with CAG repetitions has 12 to 43 repetitions, with less than 31 repetitions in most people. However, in individuals affected by SCA3 there are more than 50 of these repetitions. Those with 44 to 52 repetitions are in an intermediate situation, and may or may not develop the pathology. On the other hand, those who have 75 or fewer repetitions develop the process in adulthood, while those with 80 repetitions manifest the disease in adolescence. This increase in sequence length with CAG repeats results in an abnormal "ataxin-3" protein, which deploys three-dimensionally erroneously. This abnormal, and therefore non-functional, enzyme is unable to remove ubiquitin from unnecessary cellular proteins, and consequently those proteins along with the attached ubiquitin and abnormal ataxin-3, form aggregates in the cell nucleus. Neurons are the most affected by mutations of the ATXN3 gene among brain cells. For this reason, SCA3 is associated with cell death in the brainstem, cerebellum, and other areas of the brain, and is also related to the death of neurons in the spinal cord. Over time, the loss of cells in the brain and spinal cord produce the characteristic signs and symptoms of SCA3.

The disease has an autosomal dominant inheritance, which implies that a single altered copy of the gene in each cell is sufficient to trigger the disease. Thus, an affected person inherits the altered gene from an affected parent, although some affected individuals do not have a parent with the disease. The length of sequence with repeated CAG triplets usually increases when it is transmitted from one generation to the next, and repetitions are often associated with an earlier onset of signs and symptoms. Moreover, the process is most evident when the altered gene is inherited from the father. In rare cases, individuals with expanded CAG repeats have been reported in both copies of the ATXN3 gene in each cell. These people tend to have more severe signs and symptoms than people with a single mutation, and the characteristics of the condition appear in childhood.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Spinocerebellar ataxia type 3 (SCA3), by means of the complete PCR amplification of the exons of the ATXN3 gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).