Objective: To report clinical and genetic outcomes of rare combinatiorial triplet repeat expansion(TRE), SCA mutations in patients.

Background: The presence of more than one TRE-SCA in a patient is rare incidence. Previously, we have reported combination of SCA2 and 12 gene mutation a single patient. Similar coexistence have been earlier reported e.g. SCA2 and 10, SCA3 with SCA17, similarly, SCA-8 mutation has been reported in combinations with SCA6, SCA3 and SCA1.from different part of world.

Methods: We provide clinical and genetic description of the four unrelated index cases.

Results: Combination of SCA2 and 3: A 35 year old patient who harbored both ATXN2 and ATXN3 gene had two years history of progressive cerebellar ataxia, slurring of speech of one year duration. Neurologically,only features of cerebellar ataxia were obserevd. Brain MRI revealed mild cerebral, diffuse cerebellar and mild brain stem atrophy. (Mild SCA phenotype). Combination of SCA1 and 2: Two unrelated patients who were carrying mutation in both ATXN1 and ATXN2 gene presented with symptoms of gait ataxia, tremor, and dysarthria. Finger nose test was abnormal. Both the patients had hyperreflexia, slow saccades. Age at onset was inversely correlated with CAG repeats. Varying degree of disease severity was noted in both the patients. (SCA2 phenotype). Combination of SCA2 and 12: A 30 year old female presented with complaints of progressive gait ataxia, dysarthria and tremors from last five years. Neurological examination revealed abnormal finger nose test, impaired tandem gait, decreased reflexes in both upper and lower limbs and slow saccades and broken pursuits. This patient had mutations in both SCA2 and SCA12 genes. (SCA2 phenotype).

Conclusions: This is the first report of multiple cases of combinatorial mutation (one at least SCA2, the most common SCA in India)from single centre and co-occurence of two coding region asssociated CAG rpeat mutations. Our study suggests that combinatorial mutation are rare events and genetic possibilities of such events (due to population over-prevalence of one particular SCA) can not be ruled clinically unless a panel based SCA screening has been undertaken. Increased clinically severity is not accounted by the combination hitherto however, a long term follow up of such patients should be done to look for development of new features.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/co-occurrence-of-two-triplet-repeat-associated-sca-mutations-a-dilemma-in-clinical-diagnosis-prognosis-and-genetic-counselling-and-clinical-significance/