Objective: To present observations on abnormal expansion in both allele in ADCAs.

Background: Use of expansion in tandem repeats is restricted to only disease diagnosis in patients with Autosomal Dominant Cerebellar Ataxias (ADCAs). Here we discuss other consequences/effects of the tandem repeats – abnormal expansion in both alleles.   

Methods: We analysed our ataxia genetic screening data and a total of 2500 patients were considered. Trinucleotide repeats were analysed in patients with SCA1, 2, 3 and 12.

Results: Out of 105 SCA1 positive patients, two (1.9%) had homozygous allele carrying 48/48 and 54/43 trinucleotide repeats (TNRs). Of 213 SCA2 patients (0.94%) two carried 40/34 and 35/34TNRs, one of 205 SCA12 patients (0.49%) had 56/48 TNRs and none of 60 SCA 3 patients carried homozygous allele. Approximately one percent (0.86%) ADCA positive patients were found to be homozygous in our analysis. It has immense importance in terms of patient’s prognosis and the genetic counselling. Literature says that earlier age of onset and a more severe clinical manifestation occur in the homozygous patients where some reports says that second copy of the expanded allele does not significantly alter the disease process or severity. Homozygous patient carry two copies of the abnormal repeats, one of them is transferred to the progeny, it means that 100% progeny of such patients will be affected with same SCA. Further follow up of such cases and genetic analysis of their progeny will clarify the actual consequences.

Conclusions: Long term follow up of these patients is needed to detect the effect on the disease severity. This study emphasizes that geneticists must be careful at the time of reporting and must provide the status of both alleles and clinicians must counsel accordingly.

References: 1. Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD. Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain. 2003 Apr;126(Pt 4):946-55.

2. CH Zu¨hlke,, M Spranger, S Spranger, R Voigt , M Lanz, U Gehlken, F Hinrichs and E Schwinger; SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6; European Journal of Human Genetics (2003) 11, 629–632

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tandem-repeats-beyond-the-clinical-diagnosis-in-adcas/