Ataxia comes from the greek word ‘a taxis’ which means without order or without coordination.

The hereditary ataxias are neurological disorders that can be inherited in autosomal dominant, recessive or X-linked manner, of which the incidence of latter two is rather rare.

The autosomal dominant ataxias also called as spinocerebellar ataxias and are characterized by degenerative changes in the brain and spinal cord which results in symptoms such as; awkward hand-eye movement, slow speech, involuntary eye movement, vision loss and cognitive impairment.

Just a couple of decades ago patients with hereditary ataxias had to undergo numerous investigations, several of which were invasive such as brain scans, spinal taps, peripheral nerve biopsies, and what was even worse was that a definitive diagnosis was still not reached. But post completion of the human genome project in 2003, the ensuing genetics revolution has changed all that. A simple DNA test on peripheral blood has afforded great relief to families in several ways; saving costs as well as pain of additional tests, better understanding of the disorder, understanding the risk for the family and genetic counselling.

Moreover not only is genetic testing helping in the diagnosis, but combining and correlating with clinical as well as pathological features is also aiding in the classification of the disorders to different categories. Molecular genetic testing is thus proving to be the rosetta stone for autosomal dominant ataxias.

Underlying Genetic cause for Spinocerebellar ataxias

Till date almost 29 dominantly inherited ataxias have been identifiedSCA1to 8, SCA10 to 19, SCA21 to 25, fibroblast growth factor14 (FGF14)–SCA, and dentatorubropallidoluysian atrophy(DRPLA), however the genes involved and underlying genetic mutations have not been identified in all (2). The genetic change that causes SCA types 1, 2, 3, 6, 7, 12, and 17 is a CAG trinucleotide repeat expansion in the respective gene. The CAG expansions encode poly glutamine repeats, the CAG pattern is repeated too many times, and disrupts the normal function of the protein made by the gene, hence these disorders are also known as polyglutamine expansion disorders. The exceptions are SCA 8, which is caused by a CTG repeat expansion; SCA10, which is caused by a ATTCT repeat expansion; TGGAA in SCA31 and GGCCTG in SCA36and SCA14 that is not caused by a repeat expansion at all. Other subtypes of autosomal dominant ataxia are caused by conventional mutations including insertions, Single Nucleotide variations and deletions, in the AFG3L2 gene for such as SCA28,ITPR1for SCA29/SCA16 or PRKCG forSCA14.

Why is Genetic Testing Important?

There is a significant overlap of symptoms among the different types of SCAs, genetic testing can help determine the type of SCA in an affected individual. It minimizes the length and impact of a potentially protracted diagnostic process. Most often just knowing what has afflicted the individual brings relief, much like the George Mallory argument, you would want to know because it is there and it is affecting you. And as already stated affords great relief in terms of pain of additional tests and cost saving. Identification of the specific type of SCA also provides an indication of the likely prognosis of the individual. It enables counselling and initiation of appropriate interventions and prepares the patient and the family to have some idea what to expect and what to watch out for. Predictive Genetic testing for adult at risk members in the absence of symptoms is a completely informed choice and should be provided only after appropriate counselling.

What is done in Genetic Testing & its interpretation

Genetic Testing determines the number of repeats (CAG or CTG or ATTCT) in the respective genes.

Molecular genetic testing for repeat length is a highly specific and highly sensitive diagnostic test.

The technology involved is polymerase chain reaction (PCR) to amplify the specific gene, followed by fragment analysis to determine the exact number of repeats.It is a definitive way to confirm the number of repeats, and is a more potent way to confirm the clinical diagnosis.Repeat sizes may be in the normal range, expanded or affected range, or in the intermediate range.

The repeat sizes in the intermediate range may or may not cause the disease phenotype (reduced penetrance), however they have the potential to expand into disease range in the next generation. An intermediate results needs to be analysed in conjunction with the clinical picture. Genetic analysis can be done in a directed manner considering both the clinical features and the frequency of the sub-type in the specific ethnic population.

Based on phenotypic classification by Harding (3)ataxia’s have been distinguished into three type; ADCA (autosomal dominant cerebellar ataxia) type I is ataxia plus impairment of other neuronal systems, and ADCA typeII is ataxia plus retinal degeneration and almost exclusivelyassociated with SCA7 mutations. ADCA type III described as“pure” cerebellar ataxias as a non life-limiting disease. Laboratories nowadays routinely offer panels for Spinocerebellar ataxia testing encompassing those with a high frequency in the population and clinical relevance.

Patients suspected of ataxia should be referred to a secondary centre, the clinical presentation and family history will determine the diagnostic algorithm.

Imaging studies and certain routine assays may form the first tier of diagnostic tests after secondary referral. Often it may so happen that the clinical presentation is so stark and clear-cut that genetic testing may be recommended in the first line itself.

Genetic Testing can identify almost 70 % of the cases affected with autosomal dominant ataxias. Genetic testing for autosomal dominant ataxias is the easiest way and gold standard to confirm the clinical diagnosis.

Since there is a considerable overlap between symptoms genetic testing can help identify the specific ataxia, which helps in prognostication as well as appropriate counselling and planning for the individual.
 

Contributed by Dr Aparna Bhanushali, PhD, Research Scientist & Senior Manager, R&D, SRL Limited and Dr B R Das, PhD Advisor & Mentor-R&D, Molecular Pathology & Clinical Research Services, SRL Limited.

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