The diagnostic thus relies on the family history, the clinical presentation, the neuroimaging pattern, and the genetic tests. Overall, the genetic tests are currently successful in about 60 % of SCAs (see below). Time should be devoted to construct the family tree in order to determine the mode of inheritance. Families with a history of a predominant cerebellar syndrome during successive generations have a high likelihood to present a SCA when both sexes are affected. Anticipation (discussed below) is an additional argument. However, the family tree may be difficult to set when the other members of the family cannot be examined (following death, for instance) or in case of no apparent symptom in some family members (patients at a presymptomatic stage). The variable penetrance and a possible false paternity or adoption also need to be taken into account. The ethnic and geographical background is also a clue for the diagnosis.

Additional tests may be valuable for the differential diagnosis. Neurophysiological studies such as nerve conduction velocities (NCV) and visual-evoked potentials (VEP) are useful to determine the presence of a peripheral neuropathy and optical nerve disease, respectively. Motor-evoked potentials (MEP) confirm the involvement of the corticospinal tract, especially in SCA1. The presence of periodic leg movements (PLM) during sleep is detected by polysomnography.

Brain MRI is noninvasive and is considered as a technique of choice to assess the anatomy of the brain in dominant ataxias (Fig. 11.1). It is important to exclude other causes of ataxia which could mimic a degenerative disorder (brain tumor, stroke, malformation, immune disease, etc.). Although brain MRI may be totally normal at the beginning of the symptoms, it becomes a sensitive tool to quantify atrophy as the disorder evolves with time. The main morphological patterns are the following:

Some findings may be very suggestive of a given SCA. Dentate nuclei calcifications are observed in SCA20.

Volumetric studies are now available as routine procedures and allow to quantify the degree of regional atrophy and the progression with time.

Differential diagnosis of hereditary ataxia includes:

ADCAs are associated to mutations that include nucleotide expansions occurring in either expressed or non-expressed regions of the gene, point mutations, duplications, and deletions. The normal size of CAG repeat allele and of the full-penetrance disease-causing CAG expansion varies among the disorders (for reviews, see GeneReviews.org). Today, 50–60 % of the dominant hereditary ataxias can be identified with accurate and specific molecular genetic testing. This is the case for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, SCA17, and DRPLA. These disorders are characterized by CAG repeats within the coding region of the genes, translating into an elongated polyglutamine tract in the protein. Molecular genetic tests for CAG repeat length are highly specific and sensitive diagnostic tools, and further they are commercially available. However, pursuing tests for multiple genes simultaneously may seem less optimal than serial genetic testing, but their cost is decreasing. Molecular genetic testing results more specific than MRI findings in the hereditary ataxias and guidelines for genetic testing of hereditary ataxia have been published [13]. Testing is also available for some autosomal dominant forms of SCA that are not associated with repeat expansions (SCA5, SCA13, SCA14, SCA15, SCA27, SCA28, and 16q22-linked SCA). Interpretation of results can be an issue in the same case and should be done with caution, and the following aspects should be taken into account:

Generally autosomal dominant ataxia patients have an affected parent, although in some cases the family history is negative. For example, family history may not be obvious because of:

The risk to siblings depends on the genetic status of the proband’s parents. If one of the proband’s parents has a mutant allele, the risk for the sibs of inheriting the mutant allele is 50 %. Individuals with autosomal dominant ataxia have a 50 % chance of transmitting the mutant allele to each child.

At-risk asymptomatic adult can be tested for autosomal dominant cerebellar ataxia after identification of a specific disorder and mutation in their family. Such testing should be performed in the context of formal genetic counseling and will remain a predictive testing and not a diagnostic testing. The test will not predict the age of onset, the severity, the type of symptoms, or the rate of progression. However, molecular genetic testing of asymptomatic individuals younger than 18 years who are at risk for adult-onset disorders for which no effective treatment exists is not considered appropriate. Concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the recommendations of the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points.

Looking for the exact genetic mutation in patients with a cerebellar ataxia may be difficult, time consuming, and costly. The relatively uniform phenotype of many patients with cerebellar ataxia makes it difficult to decide which gene should be investigated first. Since conventional testing is expensive, many genes that are rarely involved in disease causation may not be tested. Thus, the development of novel technologies such as exome capture and next-generation DNA sequencing (NGS) is very interesting to screen the whole coding part of the genome in one experiment at reduced costs. This has been demonstrated to be a powerful diagnostic approach in the case of ataxia and Charcot–Marie–Tooth disease, which is a similarly heterogeneous disease [14]. The costs for this test decreased dramatically over the last year (it is about 1,000 USD). However, limitations need to be considered, in particular in the diagnosis of ataxia. In fact, currently NGS has a poor ability to sequence stretches of repetitive DNA such as the polyglutamine repeats.

Recently, systems biology approach based on whole-transcriptome gene expression analysis has been used to address the possible relationships among known SCA genes, predict their functions, identify overlapping pathways, and provide a framework for candidate gene discovery. Published results showed that two cerebellar gene coexpression modules were statistically enriched in SCA transcripts and contained established granule and Purkinje cell markers, respectively. One module includes genes involved in the ubiquitin–proteasome system and contains SCA genes usually associated with a complex phenotype, while the other module encloses many genes important for calcium homeostasis and signaling and contains SCA genes associated mostly with pure ataxia [15].

DNA banking is the storage of DNA (generally from white blood cells) for possible future use. Because it is likely that testing methodology will improve in the future, consideration should be given to banking DNA of affected individuals with dominant ataxias.

Prenatal diagnosis for some of the hereditary ataxias is possible by analyzing fetal DNA (from chorionic villus sampling at about 10–12 weeks’ gestation or amniocentesis, usually performed at about 15–18 weeks’ gestation) for disease-causing mutations. The disease-causing allele(s) of an affected family member must be identified before prenatal testing. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion regarding the purpose of the testing should be considered, like pregnancy termination rather than early diagnosis. Preimplantation genetic diagnosis may also be available when the disease-causing mutation has been identified.

Historically, SCA1 was linked to chromosome 6 in 1977. SCA1 was identified as the first disorder associated with a trinucleotide repeat expansion [16]. Current numbering of SCAs is based on the chronological order of the gene discovery.

Table 11.2 lists the SCAs and their respective locus, and Table 11.3 provides the normal repeat range, the intermediate repeat range, and the pathological repeat range. A number of 32 genetic loci have been discovered:

On the basis of the genetic mutation, three groups of SCAs can be considered (Fig. 11.2).