Measuring disease progression in Friedreich's Ataxia

Abstract

Friedreich’s Ataxia (FRDA) is the commonest autosomal recessive ataxia worldwide, affecting 1 in 40,000. Biologically, there is a deficit in an essential mitochondrial protein, frataxin, caused by a GAA trinucleotide repeat expansion mutations in the frataxin (FXN) gene. The size of the GAA repeat expansion determines phenotypic features, including age at onset and individual variation in the progression of FRDA. The condition is not solely characterized by neurodegeneration, but the differential vulnerability of various organs such as heart, pancreas, skeletal muscles to frataxin expression makes it a rather complex and multisystem disease. The neuropathology initially targets the proprioceptive system (dorsal root ganglia, posterior columns, and spinocerebellar tracts of the spinal cord), followed by atrophy of the cerebellar dentate nuclei and efferent fibres, while later in the disease, the corticospinal tracts degenerate. This combination of sensory neuronopathy and progressive pyramidal weakness is responsible for the typical combination of signs and symptoms specific to FRDA. Unsurprisingly, advanced FRDA patients present with sensory, cerebellar, and pyramidal features that are difficult to disentangle clinically. The clinical rating scales (the Friedreich Ataxia Rating Scale [FARS] and the Scale for the Assessment and Rating of Ataxia [SARA]) widely used as outcome measures in clinical trials are much more accurate in the assessment of already established motor deficits in ambulatory FRDA patients. However, the sensitivity of these scales to detect small improvements (or stabilizations) over short assessment intervals is low, and this diminishes significantly in non-ambulant patients. Rating scales are therefore not ideally suited as outcome measures in therapeutic trials for what is a rare disease. In this project, I explored whether electrophysiological measures of corticospinal tract integrity and sensory neuronopathy could be used to quantify disease progression in FRDA. Specifically, I studied 15-30 Hz intermuscular coherence, also known as beta band intermuscular coherence (BIMC), a relatively new marker of upper motor neuron (UMN) function, and motor evoked potential (MEP) central motor conduction time (CMCT), an established marker of UMN function using transcranial magnetic stimulation (TMS), in healthy volunteers and patients with FRDA. I correlated the electrophysiological abnormalities with their GAA repeat size, serial measurements of FARS scores as well as blood Frataxin levels. A few patients had their skin fibroblasts cultured and analysed for quantitative proteomics, to look at alteration in neuroprotective pathway proteins. I concluded that BIMC is lost very early in the condition and thus not a good method of monitoring progression. Instead, BIMC might have an application in screening for the onset of subclinical disease in asymptomatic individuals with a genetic diagnosis of FRDA, identifying when to initiate disease modifying therapy in such patients. MEP CMCTs showed significant changes with time in patients and thus appear to be a promising method of quantifying disease progression in clinical trials. As a multi-system disease, the combination of a range of surrogate measures is likely to be significantly more sensitive at detecting disease progression than any measure in isolation. Future studies should aim to extend the preliminary results presented here to develop statistical methods of combining such multi-modal data that will allow quantification of subclinical progression of disease, sufficiently robust to be incorporated as primary outcome measures in clinical trials.