Garcia Moreno, Hector; (2024) Natural history and biomarkers in spinocerebellar ataxia type 3/Machado-Joseph disease and xeroderma pigmentosum. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is the most common autosomal dominant cerebellar ataxia worldwide, and it is caused by a CAG repeat expansion in exon 10 of the ATXN3/MJD1 gene. Disease modifying therapies are an unmet need in SCA3/MJD and other ataxic disorders, and their clinical development will require the conduct of clinical trials. Natural history studies such as the EUROSCA-NHS and the ESMI study are instrumental in the characterisation and validation of clinical outcome measures and biomarkers for clinical trials in SCA3/MJD. In Chapter 3, I present the longitudinal analysis of several clinical outcomes and four plasma biomarkers (neurofilament light chain –NfL– total tau, glial fibrillary acidic protein, and ubiquitin carboxy-terminal hydrolase L1), in SCA3/MJD participants recruited through the ESMI study. SARA total score, ADL total score and SCAFI-9HPT show a significant progression in ataxic patients, with their rates being significantly different from the change observed in controls. Plasma NfL levels are able to differentiate ataxic patients, preataxic carriers, and controls, but none of the groups show significant progression in their plasma concentrations during the follow-up period. In ataxic patients, baseline plasma NfL concentrations predict worse scores in several of the clinical outcomes. In Chapter 4, I investigate potential genetic biomarkers in SCA3/MJD: the rs7158733 SNP (A1118/C1118), and the pattern of interruptions in the ATXN3/MJD1 repeat tract. SCA3/MJD patients carrying the A1118 SNP in cis with the expanded allele present with an age of onset, on average, 7.61 years earlier than patients with the C1118 SNP. In addition, this difference is larger for participants with shorter CAG repeat tracts. Most alleles carry the canonical ATXN3/MJD1 sequence, and additional interruptions in the CAG repeat tract are a rare event. Xeroderma pigmentosum (XP) is an autosomal recessive disorder due to defects in DNA repair processes, and characterised by cutaneous, ophthalmological and neurological symptoms, as well as an increased risk of cancer. In Chapter 5, I present the natural history study in patients with XP. I characterise the XP neurological disease in the different complementation groups, detecting significant progression in SARA total scores for the XPA and XPD groups. I show that more severe mutations in these two groups are associated with a faster progression in SARA total. In addition, I describe the asymptomatic XP neurological disease in the XPC, XPE and XPV groups, which were traditionally thought to be free of neurological features. In summary, the results reported in this thesis contribute to the characterisation of clinical outcomes and biomarkers in SCA3/MJD and XP, which will ultimately support the design of clinical trials in these two devastating conditions.

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