Spinocerebellar Ataxia (SCA) is a type of rare progressive, neurodegenerative disease. The incidence rate of the disease is varies depends on the subtype of the disease and the region. For instance, SCA3 (also known as Machado-Joseph) is the most common type of SCA, which consists of 20% to 50% of SCA worldwide, and it alone is responsible for 85% of SCA in Brazil. Although SCA is mainly caused by autosomal dominant mutations, it may also be caused by autosomal recessive or x-linked mutations at a rare rate. Mutations can happen in various sites in the genome resulting in altered functions in variety of channels, thus in many subtypes of the disease with slightly different symptoms. There are over twenty subtypes of SCA, each with altered ranges of ages of onsets. The most common cost of SCA is found to be mutations in the CAG sites. Repeats of the CAG sites, causing over production of polyglutamine, can result in over five subtypes of the disease such as SCA2, DRPLA, Machado-Joseph, etc. There can also be repeats at CTG, ATTCT, TGGAA, GGCCTG sites, or non-repeat mutations. For example, mutation at site TTBK2 can result in SCA11; mutation at site ITPR1 can result in SCA15 and SCA16. In general, non-repeat mutations will result in an earlier onset and a slower progression compare to the repeat mutations. Evidences also suggest that people with SCA caused by non-repeat mutations can also suffer from mental retardations. By far, there is not a cure for SCA, thus the best we can do, for now, is to try to slow down the progression of the disease. The most traditional way of treating SCA is through physical therapies. Now studies on possible treatments of SCA are being done all over the world, and a few of them seem to be promising.
Table of Contents
General information about SCA
Distribution of SCA
The distribution of SCA also depends on the subtype of the disorder, however we do know that the most abundant subtype all over the world is SCA subtype 3 disorder. As stated in the summary, SCA3 counts for up to 50% of SCA cases worldwide. Even within the same subtype of the disorder, the distribution is slightly altered according to the geographic location in question. For example, SCA3 counts for over 80% of the cases, however its incidence rate in India, Mexico and a few other countries is small.
Causes of SCA
As mentioned above, SCA is an inherited disease caused by autosomal dominant, autosomal recessive and sex-lined mutations. The majority of SCA cases are cause by autosomal dominant mutations, which means if one of the parents has the mutated gene and is heterozygous, there is a 50% chance that their child also has the disorder. If the first generation with the mutated gene has a homozygous genotype, then the descendants will for sure have the disorder. Details on genetics will be discussed in the following section. Also, evidence collected from previous studies suggests that people with dominant mutation caused SCA tend to have a more rapid progression.
Onset and Symptoms of SCA
In general, SCA is a rare and potentially lethal genetic disorder with no cure. It is progressive, which means the patients’ condition keeps getting worse and worse until the point they can no longer breathe on their own. SCA affects motor functions all over the body. People with SCA gradually lose the ability to walk, talk, eat, or breathe. The most common causes of death among patients with SCA are infection and respiratory failure.
The age of onset ranges from infantile to adulthood. With different types of SCA, the onset age of people with SCA is slightly or significantly different to each other. SCA subtype 6 has a late onset whereas the onset age of SCA2 can be as early as in infantile.
Although symptoms of each subtypes of SCA vary in some degree, they have their common symptoms. Most of the time, SCA only affects cerebellum, however it can have effects on brain stem and spinal cord as well. SCA causes death of neurons at cerebellum, without these neurons, the body will not be able to function properly. The most obvious symptom is ataxia. Other than ataxia, people with SCA may experience sensory losses, tremor of different muscle, and so on.
Most of the cases, patients with SCA do not have problems with cognitive abilities.
Genetics of SCA
Types of Mutation
We have discussed in previous sections, the types of mutations that can result in SCA. Now it is time to get specific. So far, the results of previous studies lead to three main types of mutation which causes SCA. First of all, the majority of SCA patients are resultant from repeats of sites that are going to be translated into functional protein during the course of cell replication. This type of mutation is responsible for SCA subtypes 1, 2, 3, 6, 7, 17. Secondly, SCA can also occur with repeats of sites that are not going to be translated into functional protein. Pathology of SCA subtypes 8 and 12 suggests that they are caused by this type of mutation. Last but not least, SCA can also result from a third type of mutation, non-repeat mutations. This type of mutation is commonly referred to as point mutation, deletion and insertion. It is responsible for SCA subtypes 5, 11, 13, 15, 27, and 16q22-linked ADCA (SCA 4). People suffer from these types of SCA share some common properties. The progression of these subtypes of SCA is relative slow compare to those caused by repeat mutations. Also, the onset is considerably earlier than SCA resulted from repeated mutations.
Sites of Mutation
The mutation site for translated repeat mutation is at CAG. Untranslated repeats take place at sites CTG, AATCT, and it may also take place at site CAG. Non-repeat mutations, namingly mutations not resulted from extra repeats at the site of mutation, can take place at any site
Resulted Changes in Functional Proteins
CAG gene codes for polyglutamine, any extra repeats at the site results in abnormalities in polyglutamine production. Extra repeats in genes atxn-1, 2, 3, 7 and 10 results a segment of polyglutamine which does not cooperate with the system. SCA can also affect the genes control the production of voltage-gated calcium channel subunit, TATA box binding protein, and some other proteins shown in Table 1.
SCA2 in specific
The article by Magaña and his colleagues studied specifically and closely on a subtype of SCA, SCA2. They identified the mutation site of SCA2 and the effects that mutation have on the functional proteins. They also describe the symptoms and possible treatments of SCA2. This paper gives us a deep understanding on SCA2 in many perspectives.
Current Knowledge about SCA2
SCA2 is one of the most commonly found subtypes of SCA in the world. It is caused by extra repeats of CAG triplets at the end of ataxin-2 gene. Normal CAG repeat lengths range from 14 to 30, diseased CAG repeat lengths range from 33 to 77 with length 37 as the most commonly seen size in disease condition. SCA2 is considered to have a relative late onset, normally after 20s. However, in some cases where the repeat length of CAG is unusually long, the onset of the disease could happen during infantile. Under this kind of circumstance, the symptoms will be very severe too.
Causes of SCA2
The genetic cause of SCA2 was not found until 1996. By then, scientists start to learn the genetics of SCA2. Generally speaking, atxn-2 gene consists of 22 repeats of CAG alleles. More than 31, maybe up to 200, repeats are found in patients with SCA2, which results in an unstable state for CAG alleles. Also, it is believed in cases of SCA2, the unstable state of CAG alleles act as a catalyst to further enhance the mutation.
Symptoms of SCA2
The most commonly found symptoms of SCA2 includes progressive cerebellar syndrome, ataxic gait, cerebellar dysarthria, dysdiadochokinesia associated with slow saccadic movements, peripheral neuropathies, sleep disorders, and so on. One of the powerful tools to diagnosis SCA2 is check to see if the patient’s horizontal saccadic movements are normal. They get slower before any other symptoms’ development, and if they do the patient may have SCA2. Examination of lower and upper limb for reflex can also help to diagnosis because people will development areflexia or hyporeflexia in their limbs.
Possible Treatments of SCA
As stated before, there is no cure for SCA now and the only we can do is to slow down the progress of the disease. Physical rehabilitation is one of the traditional ways to help patients with movement disorders. It is based on the concept of neuroplasticity, which basically means the more we train the nerves, the better it functions. Physical rehabilitation has some achievements in terms of treating people with movement problems, however it is only a passive way to deal with progressive neurodegenerations. Of course, there are always other options in terms of treating a disease and scientists are constantly working on finding cures for diseases such as SCA. Research done on animal model shows that calcium-activated potassium channel (SK2) can possibly restore the normal function of Purkinje cells in the cerebellum, which is tempered in patients with SCA2. If this turns out applicable on human, this may be a way to stop the progress of SCA2. However, even this way cannot eliminate the disease. Gene silencing is another potential way to treat SCA2. By silencing the downstream of the mutated gene, the disease should be stopped in theory and it is not limited to SCA2, but many different types of SCA.