Objective: In this project, we aim to establish correlations between the length of the CAGexp, AO, and disease progression based on International Cooperative Ataxia Rating Scale, ICAR, score, and also aim to identify modifier genes for the variance in age of onset in Dutch MJD cases.

Background: Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3), is caused by a trinucleotide repeat expansion, CAGexp, encoding a long glutamine repeat stretch in the ataxin-3 gene. The CAGexp size is inversely correlated to the age at onset (AO) ​but only explains up to 60-70% of the variance in AO. However, it is less clear if and how the CAGexp also predicts the rate of disease progression or AO.

Methods: The ICAR scores of 44 Dutch MJD patients with CAGexp of 68±2 repeats and AO of 40±5 years, annually followed between 2002 and 2014, were used in mixed models with intercepts and random slopes. The genomic DNA of 16 early (E) and 16 (L) AO cases with an average of 11 and 12 years earlier and later AO than expected based on CAGexp length were exome sequenced. 100bp paired-end reads were generated on a HiSeq2000 platform. Variants were identified via an in-house bioinformatics pipeline and interpreted using Cartagenia Bench Lab.

Results: Each additional CAG repeat significantly increased the progression rate with 0.1213/year. No significant relationship was observed for disease progression rate and AO. Family analysis using the coding sequence data of 275 candidate genes identified rare non-synonymous variants in E cases in IPO5, UVRAG, ZRANB3, whereas variants in ODF1, HERC2, and UBE3B were detected in L cases that were not seen in the other group of the same family. A non-synonymous variant was identified in NSUN5 in a large family that led to an average delay in AO of 7,875 ± 4,840 years.

Conclusions: The progression rate of the ataxic manifestations measured by ICARS is linear in time and relatively slow. Larger expanded repeats were weakly associated with faster progression rates however faster disease progression was not associated with earlier AO. Putative candidate modifier genes of AO are identified that are currently being explored in one of the largest MJD cohorts in Europe. Functional studies to assess how NSUN5 can act as a genetic modifier of AO in MJD are pending.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-modifiers-of-the-age-of-onset-variance-and-disease-progression-in-a-dutch-cohort-of-machado-joseph-disease-patients/