Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia.

Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.

Corticosteroids and pulmonary rehabilitation reducing long-term morbidity in a patient with post-COVID-19 pneumonitis: A case study.

BACKGROUND: Whilst research efforts have focussed on treatment during the acute phase, little work has focussed on the long-term sequelae of COVID-19 infection. This case described a patient who remained symptomatic several weeks after discharge from hospital with what was diagnosed as a COVID-19 infection. There were significant deficits shown in his functional exercise testing, his pulmonary functions testing and there was evidence of fibrotic changes on his radiology. METHODS: As part of a multidisciplinary clinic, he was started on steroids and a tailored pulmonary rehabilitation course over a course of 6-8 weeks. Thereafter, his exercise testing, pulmonary function tests and radiology were all repeated to see progress. RESULTS: On completing the course of corticosteroids and concurrent personalised pulmonary rehabilitation, there was a dramatic improvement in the patient's symptom severity, radiology and pulmonary function. The most significant improvement noted was in his exercise testing, namely a 6-min walk test and 1 min of sit-to-stands. Before treatment, he had a Medical Reserch Council (MRC) score of 2, and after it returned to his baseline of 0. DISCUSSION: Using corticosteroids and exercise training that allowed quantitative evaluation throughout the stages of recovery was a valuable tool to gauge progress and response to treatment. These therapies present opportunity to prevent the development of irreversible pulmonary fibrosis that could prove to be a major breakthrough in reducing long-term morbidity and improving the quality of life of those affected.