Parkinson, MH; (2017) Clinical and genetic studies in autosomal recessive ataxias. Doctoral thesis , UCL (University College London).

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Abstract

167 patients with the recessive repeat expansion disorder Friedreich’s ataxia (FRDA) were recruited as part of the European FRDA Consortium for Translational Studies (EFACTS) and underwent longitudinal clinical assessment including validated and standardized clinical and functional rating scales. The mean age at onset was 13.7±9.6 years (range 1-55) and disease duration 20.5±11.2 years (range 3-55). The smaller repeat expansion (GAA1 size) correlated with age at onset, Activities of Daily Living (ADL), Scale for the Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxic Symptoms (INAS) count & Spinocerebellar Degeneration Functional Score (SDFS). 125 patients were seen after 1 year, and 116 after 2 years. Disease progression could be measured using these rating scales: SARA increased over 2 years by 1.3±3.1, ADL by 2.0±3.2 and SDFS by 0.3±0.6. There was no statistical difference in INAS count. A majority of patients could not complete the Spinocerebellar Ataxia Functional Index (SCAFI) which was deemed inappropriate in FRDA. Two novel FXN mutations were identified, as well as a probable macrodeletion. No compound heterozygous exonic deletions were found amongst 1768 cases referred with a possible diagnosis of FRDA, indicating that these deletions are extremely rare. Twenty-six patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) were recruited (mean age onset 15.0±17.4, range 0-51); mean disease duration 28.5±12.9, range 8-56). Loss of mobility, dysarthria, dysphagia, ataxia, sensory loss, square wave jerks and saccadic dysmetria were less common in ARSACS compared to FRDA; nystagmus, spasticity and hyperreflexia were more common. Nine novel SACS mutations were identified. Retinal Nerve Fibre Layer (RNFL) thickening on ocular coherence tomography (OCT) was found to be a specific (99.4%) and sensitive (100%) marker of ARSACS with positive predictive value of 94.4%, amongst 191 patients with ataxia, using a cut-off thickness of 119μm.

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