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Table of Contents    
ORIGINAL ARTICLE
Year : 2020  |  Volume : 68  |  Issue : 1  |  Page : 86-91

Spinocerebellar Ataxias in India: Three‑year Molecular Data from a Central Reference Laboratory


Research and Development, Mumbai, Maharashtra, India

Date of Web Publication28-Feb-2020

Correspondence Address:
Dr. Bibhu R Das
SRL Ltd, Prime Square Building, Plot No 1, S. V. Road, Goregaon (W), Mumbai - 400 062, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.279666

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 » Abstract 


Introduction: There is a great deal of heterogeneity, both phenotypically and genotypically among the autosomal dominant cerebellar ataxias (ADCA). Their prevalence also varies in different populations. Trinucleotide repeat expansions (CTG/CAG) have been shown predominantly to cause a number of ADCAs.
Aim: The present study describes the frequency of spinocerebellar ataxias (SCA) and the CAG repeat sizes among the different regions of India.
Settings and Design: Molecular data from our central reference laboratory were retrospectively analyzed for SCAs 1, 2, 3, 6, 7, 10, 12, 17 and DRPLA. Correlation between age at diagnosis and the CAG repeats of the expanded and the normal alleles were tested with the Spearman correlation test.
Results: The presence of SCAs vary according to geographical regions and ethnicities; SCA 12 was detected with the highest frequency (229/901), but was restricted to a specific ethnic population, followed by SCA 2 with a positivity of 12% (101/845). SCA 3 previously known as Machado-Joseph Disease had a prevalence of 4.05% (32/789), whereas SCA 1 was diagnosed in 30/773 (3.88%). No positivity was seen for SCA 10 from the 103 samples tested and for SCA 17 from the 131 samples tested either as a part of an extended panel or stand-alone.
Conclusion: In this report, we are able to expand the portrait of SCAs in India by presenting the largest ever molecular data from a central reference laboratory.


Keywords: Autosomal dominant, fragment analysis, India, molecular diagnosis, spinocerebellar ataxias
Key Messages: The frequency of specific ataxias varies within the different geographical regions in India. Molecular Testing can help determine the specific SCAs which enables prognosis, counselling, risk assessment of family members and in some cases also therapeutic management.


How to cite this article:
Bhanushali AA, Venkatesan R, Das BR. Spinocerebellar Ataxias in India: Three‑year Molecular Data from a Central Reference Laboratory. Neurol India 2020;68:86-91

How to cite this URL:
Bhanushali AA, Venkatesan R, Das BR. Spinocerebellar Ataxias in India: Three‑year Molecular Data from a Central Reference Laboratory. Neurol India [serial online] 2020 [cited 2020 Apr 4];68:86-91. Available from: http://www.neurologyindia.com/text.asp?2020/68/1/86/279666




The spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders that usually present with progressive gait impairment. The hereditary SCAs which show an autosomal dominant pattern of inheritance (AD-HCA) are predominantly caused due to an expansion of unstable triplet repeats in the genome, exception to which is the pentanucleotide repeat seen in SCA 10 and SCA 14 that is not caused by a repeat expansion at all.

Till date more than 41 different SCAs have been characterized. Globally, the prevalence AD-HCA were found to be between 0.0 and 5.6/105.[1] Highly variable prevalence for HCA has been reported across different populations reflecting the differences in their genetic make-up, even so large areas of the world remain without documented prevalence.[1]

Traditionally, the classification of ataxia has been based on neuropathological and clinical criteria,[2] in the last decade, however, molecular diagnosis has become a potent way to confirm the clinical diagnosis.[1] Moreover, since these disorders demonstrate evidence of anticipation, expansion of repeats in subsequent generations and repeat instability, molecular genetic testing enables these correlations. It also enables counselling and initiation of appropriate interventions as well as identification of at risk family members.

In the current report, we present 3-year molecular data from our central reference laboratory for SCA 1, 2, 3, 6, 7, 10, 12, 17 and DRPLA. Though there have been studies from India that have documented the prevalence of ataxias in different regions, the sample size has been small. Moreover, they have, they have queried only specific SCAs. To the best of our knowledge, this is the largest data set reported in the Indian population.


 » Materials and Methods Top


The present study included individuals who had been referred for molecular genetic testing based on clinical suspicion of SCA. Most of the samples have been interrogated as a part of the panel for SCA 1, 2, 3, 6, and 12. In some cases wherein the clinical indication or family history warranted interrogation of specific ataxia as per the referring clinician, it was done accordingly.

Briefly, genomic DNA was extracted from the collected EDTA whole blood using QIAamp® DNA extraction kit following the manufacturer's instructions (Qiagen, Germany). Capillary electrophoresis was performed for determining the repeat sizes after PCR amplification using previously reported protocols for all the SCAs[3],[4],[5],[6],[7],[8],[9] on the ABI-3500 Dx Genetic Analyzer. The study was approved by the institutional review committee and is in accordance with the declaration of Helsinki. Patient characteristics are given as Mean ± SD. Categorical variables, such as diagnosis and region of origin, were compared through Fisher exact test. CAG repeats in most loci did not show a normal distribution on the Shapiro-Wilk test. Correlation between age at diagnosis and the CAG repeats of the expanded and the normal alleles were tested with Spearman correlation test.


 » Results Top


[Table 1] denotes the samples tested for each SCA and the percent positivity. Almost 700 samples were tested as a part of the panel of SCA 1, 2, 3, 6, and 12. The total number of SCA 12 that have been tested is 901, and this is expected since the prevalence of SCA 12 is high in an ethnic population from Rajasthan in North India. The highest positivity also (25%) was seen for SCA 12 (229/901), followed by SCA 2 with a positivity of 12% (101/845). SCA 3 previously known as Machado-Joseph disease had a prevalence of 4.05% (32/789), whereas SCA 1 was diagnosed in 30/773 (3.88%). No positivity was seen for SCA 10 from the 103 samples tested and for SCA 17 from the 131 samples tested either as a part of an extended panel or stand-alone.
Table 1: Frequency of interrogated ataxias

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[Table 2] provides details of the positive samples for all the ataxias including DRPLA, the mean age at diagnosis, the mean allele sizes as well as the largest allele recorded for the ataxias and the number of individuals in the grey zone. The diagnosis of SCA 12 is seen predominantly in the fifth decade, whereas for SCA 1, 2, and 3 it is within third and fourth decades of life. Only two individuals have been diagnosed with SCA 6 in the current study with the mean age being 55.5 ± 7.77 years, whereas for DRPLA the mean age is 31.66 ± 15 years. Grey zone alleles or large mutable alleles were not seen for SCA 3, SCA 7, SCA 6 or DRPLA. In case of SCA 12, 28 individuals had CAG repeat sizes in the intermediate zone (males; 21, females; 7) with mean age at diagnosis being 65 ± 9.6 years and mean expanded allele size 46 ± 3 repeats. For SCA 1, there were 7 individuals with alleles in the grey zone (males; 5, females; 2) with mean expanded allele size 39 ± 2, the mean ages at diagnosis were 58.5 and 61.2 years for females and males, respectively. Only three individuals had intermediate (32 CAG repeats) in case of SCA 2. [Figure 1] and [Figure 2] indicate the prevalence of ataxias across the different zones in India.
Table 2: Details of positive samples

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Figure 1: The frequency of SCA 12, SCA 2, SCA 1, and SCA3 is indicated. (a) SCA 12 positivity across regions is indicated; (b) SCA 2 positivity across regions is indicated; (c) SCA 1 positivity across regions is indicated; (d) SCA 3 positivity across regions is indicated

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Figure 2: The frequency of ataxias in the zones has been indicated in this bar-chart (N; North, E; East, W; West, S; South, C; Central)

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 » Discussion Top


In this report, we are able to expand the portrait of SCAs in India by presenting the largest ever molecular data set from a central reference laboratory. Our data gives insight about the prevalence of SCAs in geographical zones within India, and also in determining. The age at diagnosis and allele sizes. We acknowledge the current limitation of the study wherein correlation with clinical details has not been done. In the current study, no positivity was seen for SCA 10 and SCA 17.

SCA 12

The highest positivity was seen for SCA 12 (25%), almost 80% of the samples were from North India [Figure 1] and 11% from West India. Interestingly, when these were further analyzed, SCA 12 samples from all regions belonged to the same ethnic community. The prevalence of SCA 12 in the founder Agrawal community from Rajasthan has been well documented.[10] Though worldwide, the incidence of SCA 12 is quite low, it has been identified in different populations across the globe.[11] SCA 12 was first described in a single large American pedigree of German ancestry, and then by Fujigasaka et al. in a family with Indian ancestry.[12] Subsequently, Srivastava et al. identified five smaller pedigrees with expanded trinucleotides (CAG repeats) in the PPP2R2B gene in the affected members ranging from 55 to 69, whereas the size of the normal alleles ranged from 7 to 31, the smallest expanded allele with phenotypic correlation has been 51 CAG repeats.[13] In the current study, the mean expanded allele sizes were 55 CAG repeats and the largest allele size documented was 68 repeats. In addition, we found almost 28 individuals with repeats ranging from 36 to 50, which were classified as grey zones, as the unambiguous normal range of PPP2R2B-CAG has been found to be 4-31 repeats. There has been a recent report identification of CAG -46 repeats as the shortest pathogenic allele in PPP2R2B. Concerns regarding the cut-off pathogenic length have remained,[14] even in our study it is possible that these individuals may be affected with late-onset as the mean age at diagnosis for the grey zone individuals is 65 ± 9 versus 57 ± 9 years for those detected with repeats in the pathogenic range (≥51 CAG). Interestingly, 3 of the 28 individuals in grey zone showed bialleleic expansion 48/48 repeats; age 66 years, 47/48 repeats; age 67 years, 43/44 repeats; age 55 years. In their paper on clinical behaviors of SCA 12 and intermediate allele sizes, Srivastava et al.[14] have opined that CAG repeats greater than 43 can lead to molecular events leading to neurodegeneration and can be considered as the shortest pathogenic length for the SCA 12 phenotype. It would be interesting to follow up these patients in terms of clinical progression and prognosis. Notably a wide heterogeneity in the age at diagnosis among patients harboring the same repeat length was seen, as indicated by Srivastava et al.[14]

SCA 2

In our study, 12% of the diagnosed cases were of SCA 2, the second most diagnosed ataxia, with the highest cases being from North India (49%), followed by the West region (30%). South India accounted for 4% and Central India accounted for 14%. Two studies from Kolkata[15],[16] and Delhi reported SCA 2 as the most common mutation[17], another study from NIMHANS on a relatively large population size (318 probands) indicated SCA 2 as the second most common ataxia (22.9%), and SCA 1 with the highest frequency.[18] SCA 2 has been seen with an almost similar frequency as indicated in the current report in Taiwan (10.8%)[19], but accounted only for 6% of the diagnosed case in a study from Australia which examined 88 pedigrees with multiple affected members.[20] SCA 2 was also the second most common SCA in Brazil.[21] SCA 2 is indicated to be the most widespread gene worldwide second only to SCA 3; it is the most frequent cause of HCA in Cantabria, Cuba,[22] and also some other countries such as UK[22] and Korea.[23]

The largest expanded allele in the current study was 66 CAG repeats and the expanded alleles ranged from 37 to 66 CAG, which is similar to that documented by the study from NIMHANS.[18] A preponderance of homozygous 22 CAG allele as seen in other populations has been found in our study also.

In a study on Cubans where the prevalence of SCA2 is high, a significantly higher frequency of large alleles (>25 CAG) repeats were seen as compared with the Japanese, Caucasian or even the North Indian population.[24] In the present study, only 14 individuals were seen with larger allele sizes which is significantly different (P< 0.0001) as compared with the Cuban population.[24]

Interestingly, three individuals with grey zone repeats (32 CAG) were seen in our study, whereas none were documented in the study from NIMHANS.[18] The mean age at diagnosis in our study is 36.1 years, with negative correlation between age at diagnosis and expanded CAG repeats (R2, -0.69). A similar inverse correlation was also seen in the Brazilian population (R2, -0.65) with mean age at onset being 29.7 years.

SCA 3

SCA 3 was found to be the third most frequent ataxia (4.05%) in our study, of which the Western region contributed to almost 56% of the diagnosed cases, 16% were from the South, followed by 13% from the Northern region, 9% from the Eastern region and 6% from the Central region. The frequency of SCA 3 in the current study is a little lower than that reported by Salim et al. in Indians (5%)[17] and significantly lower than seen in Portuguese (58%)[25] or Spanish cohort (15%).[26] SCA 3 is the most common SCA accounting for 214 (59.6%) and 337 patients (62.5%) in the Brazilian study group.[21]

In the current study, the age at diagnosis is 39.63 ± 13 years which is similar to the patients from EUROSCA (40 ± 12), USA (40 ± 11) and Japan (41 ± 15). The Azores patients presented an earlier age at onset (37 ± 12), whereas the French had a later age at onset (44 ± 12).[27] The age at onset in the Brazilian population was much lower at 34 ± 11 years.[21]

As is described in recent publications, the CAG repeats for normal alleles is 11-44 and the pathogenic range has been indicated to be >55. Large varieties in clinical features are seen in individuals with >52 CAG repeats. In the current study, we did not find any alleles in the intermediate zone, that is, >45 to 49/54. The presence of large normal alleles >31 CAG repeats were seen in four individuals; interestingly, all the four individuals also showed biallelic large repeats, the repeat sizes in these individuals were 35/35, 37/37, 40/42, and 40/41. The frequency of the large alleles is significantly lower in the current study (0.005) than in the Chinese, Japanese, or Czech population.[28] A weak inverse correlation (R2, -0.45) is seen between expanded repeat sizes and age at diagnosis. One reason that may explain this is the presence of modifier elements. For example, the hypermethylation of the ATXN2 gene correlates with earlier onset of SCA 3 symptoms.

SCA 1

SCA 1 was first reported by Schut[29] in a large US family of Russian origin. In our study, the frequency of SCA 1 is 3.88%, which is similar to that seen in the Korean population (3.9%). In the Taiwanese cohort, the frequency was 5.4%. In another study where 75 Chinese families were evaluated for autosomal dominant SCAs the frequency of SCA 1 was 7%.[30] In comparison, other studies from India have reported a higher prevalence of SCA1; a high prevalence of SCA1 was seen in an ethnic Tamil community (7.2%)[31] from India; another study also from South India reported a frequency of 32.4% and was the most common mutation seen in 34 of the 105 families[18]; and a frequency of 10.53% was seen in the study from North India.[32]

In our study, the allele ranges were from 24 to 60, whereas in the report from South India[18], the mean allele sizes were from 30 to 75. In addition, the study[18] documented almost 15 patients with intermediate range of expansion (34-36 repeats). The incidence of high-end normal alleles have been proposed to associate with predisposition of the respective SCAs in many populations. However, only one patient was seen with intermediate expansion in our cohort, seven individuals with allele range between 39 and 40 were found, which would be causative if they are pure uninterrupted CAG repeats without CAT interruptions. An inverse correlation was seen between the allele size and age at diagnosis (R2,-0.65), which was not very strong.

Interestingly while this paper was being written, the first case of SCA 5 was reported from India, which noted a mutation in the SPTBN2 gene after a detailed genetic analysis of approximately 900 genes. The SPTBN2 gene is associated with SCA 5.[33]

In summary, neurological disorders form a significant proportion of NCDs (non-communicable disease); it is important to determine the prevalence and incidence of neurological disorders, which in turn enable planning for neurology-related health services, testing, counseling, and management.

As 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. Identification of the specific type of SCA also provides an indication of the likely prognosis of the individual. It enables counseling, initiation of appropriate interventions and in some instances pharmacological treatment. Genetic testing can also help identify at risk family members.

We have seen the presence of SCAs vary according to geographical regions and ethnicities, SCA 12 was detected with the highest frequency, but was restricted to a specific ethnic population, SCA 2 was the second most common mutation, with largest positivity from the Northern region, following which SCA 3 mutation were seen which were predominantly from the Western region which could be due to the Portuguese influence in these areas. Ages at diagnosis and inverse correlation with allele sizes were all as expected. Though we acknowledge that this report has limitations in terms of clinical correlations, nevertheless, this is one of the largest data set on a Pan India basis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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