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Spinocerebellar ataxia (SCA) is a neurodegenerative disease characterized by progressive degeneration of the cerebellum and other regions of the brain like brain stem, spinal cord, and basal ganglia to various degrees with neuronal loss and secondary degeneration of white matter tracts. Patients with SCA display loss of coordination of limb and trunk (limb and truncal ataxia), speech (dysarthria), eye movements (nystagmus), dysphagia, extrapyramidal sign (dystonia, rigidity, and bradykinesia), pyramidal sign, and autonomic disorder. There are total of 28 genetically distinct varieties of dominant SCA have been reported. Amongst these, a dozen defective genes have been discovered. Genetic testing can now be carried out to diagnose the type of ataxia a person has. SCA can be divided into acquired (non-genetic) ataxia and hereditary ataxia. MRI is recommended to diagnose the SPA. If a treatable cause is not discovered, a genetic test should be done. In about 60 percent of the cases, the genetic test will determine the type of ataxia.
Spinocerebellar ataxia (SCA) is a neurodegenerative disease characterized by progressive degeneration of the cerebellum and other regions of the brain like brain stem, spinal cord, and basal ganglia to various degrees with neuronal loss and secondary degeneration of white matter tracts. The word ataxia is derived from the Greek word "ataxis" which means "without order." Medically, this term implies a lack of coordination. The center for coordination is the cerebellum, which is at the base of the skull, below and behind the cerebral hemispheres. It has nerve fiber connections to other nervous system structures like the cerebral hemisphere, brain stem, and spinal cord. The cerebellum receives signals from these structures, integrates the information, and controls the smoothness of motor activity in the body. A complex motor activity, such as shooting a basketball, balancing, directional control, proper force, timing, velocity control, and appropriate termination of movement. The cerebellum functions as an error corrector and detector. So, any condition that interferes with normal cerebellar function causes ataxia. Patients with SCA display loss of coordination of limb and trunk (limb and truncal ataxia, speech (dysarthria), eye movements (nystagmus), dysphagia, extrapyramidal sign (dystonia, rigidity, and bradykinesia), pyramidal sign, and autonomic disorder.
Classifications of Spinocerebellar Ataxia
There are total of 28 genetically distinct varieties of dominant SCA have been reported. Among these, a dozen defective genes have been discovered. Genetic testing can now be carried out to diagnose the type of ataxia a person has. It can also be used to confirm whether an "at-risk" person is carrying the defective gene. Unfortunately, there are many families with ataxia who have but unidentified gene mutations. Many individuals with ataxia of unknown type have no family history of ataxia and genetic testing is negative. These sporadic ataxias occur randomly in the general population and there are no specific tests to identify them.
Categories of Spinocerebellar Ataxia
i) Acquired (Non-genetic) Ataxia
This type of ataxia usually results from some type of environmental factors such as a brain trauma, tumor or chemical exposure. For example, head injury or stroke can cause ataxia. Exposure to
Acquired ataxia is not passed on in families, so the children of an affected person are not at an increased risk to get the ataxia. Multiple system atrophy (MSA) is a common cause of adult onset ataxia whose cause is unknown and which is usually not inherited.
high levels of alcohol can lead to ataxia.
ii) Hereditary Ataxia
There are a number of different genes that can cause ataxia and most are located on autosomal chromosomes. Chromosomes are made up of nucleotides. These nucleotides are identified by letters and linked together in chains. A group of nucleotides together form genesband there are thousands of genes located on each chromosome. Many of the genes that lead to dominant forms of ataxia have a mutation resulting from expanded sections in these nucleotide chains called "trinucleotide repeat expansions." For instance, in SCA 1, a gene mutation on the sixth chromosome results in extra copies of a series of nucleotides C-A-G. In some conditions, the number of trinucleotide repeats is linked to the severity of the disease and the age of onset.
The hereditary ataxias are due to a gene defect or mutation and are divided into:
a) Dominantly inherited ataxias, which are passed from an affected parent to child, with each child has a 50-50 chance of inheriting the abnormal gene.
b) Recessively inherited ataxias, in which the ataxia is hidden in the genes of both healthy parents, and the child can develop the disease only if the child inherits the defective gene from both parents.
c) X-linked recessive ataxias, due to a genetic defect on the X-chromosome. The ataxia occurs only in males and
is carried by females who themselves are not affected.
Inheritance of Dominant Spinocerebellar Ataxia
Most of the types of SCA are inherited in an autosomal dominant pattern which means each son or daughter of an affected person has a 1 in 2, or 50% chance of inheriting SCA. SCA affects males and females equally. Each type of SCA is caused by a change (mutation) in a specific gene that is needed for normal functioning of brain.
Genes are the basic units of heredity, and contain the set of instructions that determine the growth and development of the body. Genes are composed of DNA (deoxyribonucleic acid). It is estimated that every cell contains about 30,000 genes. Genes are packaged on chromosomes-threadlike structures within cells that can be seen with a microscope (genes cannot be seen under the microscope). Each person inherits half of their chromosomes from their father, and half from mother. Every human has 23 pairs of chromosomes that contain two copies of each gene.
The genetic change that causes SCA types 1, 2, 3, 6, 7, 12, and 17 is called a CAG repeat expansion. CAG represents a specific pattern of DNA. In these types of SPA, the CAG pattern is repeated too many times, and disrupts the normal function of the protein made by the gene. The exceptions are SCA 8 due to a CTG repeat expansion; SCA10, which is caused by an ATTCT repeat expansion; and SCA14 that is not caused by a repeat expansion at all. SCA14 is caused by point mutation in the PRKCG gene. There is genetic testing for SCA types 1, 2, 3, 6, 7, 8, 10, 12, 14 and 17 and genetic testing will be available soon for other types of SCA as the genes for more types of SCA are discovered.
Anticipation and Penetrance
Most of the types of SCA are characterized by a phenomenon called anticipation. Anticipation refers to an earlier age of symptoms and increasing severity of disease from generation to generation in the family. In other words, an affected child can have more severe disease symptoms than their affected parent. With the recent discovery of the genetic cause of many SCA types, it has been found that the repeat size can change when passed from parent to child. For example, if a parent has a specific repeat size of gene on genetic testing, a child may have a larger number of repeats. Anticipation cannot be predicted. In most types of SCA, there is a general association between repeat size, age of onset and severity of symptoms. Generally, the larger the repeat size, the younger is the age that a person will develop symptoms of SCA. The repeat size cannot be used to predict the exact age when a person will develop symptoms, or exactly what those symptoms will be like.
The term penetrance refers to the proportion of individuals with the gene for SCA who will actually develop the symptoms. In all types of SCA, penetrance is very high which means that almost everyone with a repeat expansion will develop symptoms of SCA at some point in their lifetime. In some cases, however, a person with a repeat expansion may die of other causes before showing the symptoms of SCA. For reasons that are not completely understood, some people with a repeat expansion may never develop symptoms of SCA ("non-penetrance"). Further research is needed to understand why non-penetrance happens in SCA.
Symptoms of Ataxia
Symptoms of ataxia appear either suddenly or gradually. When symptoms come on suddenly, possible causes include:
â€¢ Head trauma
â€¢ Cardiac or respiratory arrest
â€¢ An infection such as chicken pox or an abscess
â€¢ Exposure to certain drugs or toxins such as seizure medication or alcohol
â€¢ Tumor in the cerebellum, either from childhood brain cancer or metastases from other sites
When symptoms appear gradually, the causes may be:
â€¢ Deficiencies in vitamin E or B-12
â€¢ Multiple sclerosis (which also can appear suddenly)
â€¢ Exposure to certain drugs or toxins (chronic alcohol use, lead, and cadmium)
â€¢ Congenital abnormalities such as deformity of the cerebellum or genetic biochemical defects
â€¢ Remote effects of cancer somewhere in the body
â€¢ Slow-growing tumors
â€¢Degenerative disorders (SPA, both hereditary and sporadic)
Strokes, tumors, abscesses, and trauma are prone to affect just one side of the cerebellum and thus cause one-sided ataxia. A person with one-sided cerebellar lesion may be considerably disabled, but still has one side that is normal and functions well.
Conditions involving both sides of the cerebellum or its connections cause imbalance, gait ataxia, right and left extremities incoordination, and slurred speech. These include drug toxicity, alcohol abuse, vitamin deficiency, and the SCA. All of these conditions result in temporary or permanent loss of functioning of nerve cell and may lead to nerve cell death and shrinkage of the spinal cord, brain stem, and cerebellum. Some ataxias happen in individuals without any family history of ataxia. These sporadic ataxias are as disabling as the hereditary ataxias and can be lethal too.
Most people do not know what ataxia is and may overlook the early symptoms. Anyone with progressive gait disorder or imbalance should be checked or evaluated by a neurologist. MRI is highly recommended in all cases. If a treatable cause is not discovered, a genetic test should be done. In about 60 percent of the cases, the genetic test will determine the type of ataxia.
Figure 6 A number of typical brain imaging appearances. (a) T1 sagittal MR scan showing isolated cerebellar atrophy in a patient with SCA 6. The brainstem and supratentorial structures are spared in this disorder, which is usually characterized by a relatively uncomplicated cerebellar syndrome. This scan would do equally well for a patient with SCA 10, SCA 14, GSS, coeliac disease or paraneoplastic cerebellar degeneration; (b) T2 axial MR scan of an 18-year-old boy with Wilson's disease, showing generalized cerebral atrophy and patchy high signal in the putamen and head of caudate; (c) T2 axial MR of 15 year-old boy with adrenoleukodystrophy, showing diffuse high signal in the posterior white matter of both cerebral hemispheres; (d) T2 axial MRI of a 37-yearold man showing the pulvinar sign of variant CJD; note the presence of high signal in the pulvinar of the thalamus (arrow); (e) T2 axial MRI of a 59-yearold woman with sporadic CJD showing the 'hockey stick' sign (arrow), a result of abnormal high signal in the caudate and putamen; (f) T2 axial section through the brain stem of a 64-year-old woman showing pontine and cerebellar atrophy and the characteristic 'hot cross bun' sign of multiple system atrophy in the brain stem (arrow).
The decision to be tested with DNA testing for dominant SCA is very personal. Members of the same family may have different feelings about the genetic testing. It is important to respect each person's feelings. For at-risk persons who do not have symptoms of SCA, the main benefit of presymptomatic testing is psychological, since there is currently no medical intervention (for example, early treatment, specific diet, or lifestyle changes) that can slow or prevent SCA. The test results have important implications for many life decisions after that.
The professional support services such as a therapist, psychologist, religious professional or psychiatrist can be visited by a person to discuss about the effects of the positive genetic test. This is particularly important if a person have had prior problems with depression, anxiety or stress.
If the affected person has not yet started a family, or is thinking about having more children, it is important to consider how the test result may impact the family planning decisions. For example, some people feel that if they are test positive, they will not have children. Individuals who already have children may feel guilty about having had children because they may develop SCA someday.
I would like to thank Professor Perumal Ramasamy for providing guidance and support in this scientific medical writing.