The AAGGG repeat expansion in RFC1 associated with late-onset ataxia and sensory neuropathy: from genetic cause to defining the functional mechanism

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Late-onset ataxia is a common reason for neurological consultation, but its cause often remains idiopathic. Ataxia primarily results from cerebellar dysfunction but can also be caused by disorders affecting the large-fibre sensory neurons (sensory neuronopathy) or the vestibular system. When in combination, this more severe late onset ataxia is termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We identified a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) as a common cause of CANVAS and late-onset ataxia. The AAGGG repeat expansion does not lead to overt loss of function of RFC1, which is unexpected given the recessive pattern of inheritance of the disease and suggests that novel disease-causing mechanisms could be involved. The main objective of this project is to
investigate the molecular mechanisms underlying neurodegeneration in the presence of biallelic AAGGG expansions in RFC1. We will use a combined approach by taking advantage of in vitro experiments, Drosophila model as well as patients'-derived cell lines and tissues in order to test the presence of a dose-dependent gain-of-function of toxic pentapeptide repeat proteins encoded by the transcribed intronic repeated sequence and/or unconventional loss-of-function of tissue specific RFC1 isoforms, non-coding transcripts, neighboring and distant genes and/or reorganization 3D chromatin structure.

Technical Summary

Late-onset ataxia is a common reason for neurological consultation, but its cause often remains idiopathic. Ataxia primarily results from cerebellar dysfunction but can also be caused by disorders affecting the large-fibre sensory neurons (sensory neuronopathy) or the vestibular system. When in combination, this more severe late onset ataxia is termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We identified a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) as a common cause of CANVAS and late-onset ataxia. The AAGGG repeat expansion does not lead to overt loss of function of RFC1, which is unexpected given the recessive pattern of inheritance of the disease and suggests that novel disease-causing mechanisms could be involved. Main objective of this project is to
investigate the molecular mechanisms underlying neurodegeneration in the presence of biallelic AAGGG expansions in RFC1. We will use a combinational approach by taking advantage in vitro and Drosophila models as well as patients'-derived cell lines and tissues in order to test the presence of a dose-dependent gain-of-function of toxic pentapeptide repeat proteins encoded by the transcribed intronic repeated sequence and/or unconventional loss-of-function of tissue specific RFC1 isoforms, non-coding transcripts, neighbouring and distant genes and/or reorganization of topologically associated domains and 3D chromatin structure.

Planned Impact

The frequency of the repeat expansion in 20% of undiagnosed ataxia cases and almost over 90% of typical CANVAS cases together with a carrier rate in the healthy population of ~1% makes the AAGGG repeat expansion in RFC1 as the most common cause of late-onset recessive ataxia. Therefore, we predict that the results of the study will be of great interest to the neurogenetics community and to the field of repeat expansion disorders, both at clinical and laboratory level.
Repeat expansions are still relatively hard to find and they may account for a relatively large proportion of missing heritability in neurological and non-neurological disorders. The majority of repeat expansions were discovered by positional cloning approaches and next generation sequencing technologies have so far had a limited impact on their identification. Our approach has unravelled that a significant part of undiagnosed ataxia and sensory neuronopathy cases is caused by a recessive repeat expansion, and we think that, if combined with novel tools for analysis of STR from WGS data (eg Expansion Hunter), it could inspire other researchers in academia or other research institutions, such as Genomic England, in the discovery of other recessive repeat expansion disorders.
Understandably, given the early days of this novel repeat expansion, little is known about the associated disease-causing mechanisms of this as well as other penta- and exanucleotide repeat disorders. However, this area has gained great importance as shown by the exponential growth of work following the discovery of GGGGCC expansion in c9orf72 in ALS/FTD and we now stand in the unique position to be the first ones to address the same mechanistic questions in this common type of recessive ataxia.
If confirmed, our hypothesis of a dose (and age) dependent toxic gain-of-function of AAGGG repeat expansion in RFC1 will represent a completely novel pathogenic mechanisms underlying a late-onset recessive Mendelian disorder, with broader implications to the general field of neurodegenerative diseases.
Moreover, the modified protocol we designed for recursive directional ligation, given the independence of restriction digestion and subsequent ligation from the repeated unit sequence, has the potential to enable the generation of increased repeat sizes of any nucleotide sequence and could represent a useful tool to basic scientists working on repeat expansion disorders and non-coding repetitive DNA elements.
Finally, one of the main aims of the project is to establish in vitro, cellular and Drosophila models of the disease which will be of use not only to the academic community but also to the pharmaceutical industry in order to test possible ways of future therapeutic intervention.

Publications

10 25 50
 
Description NIH Inherited Neuropathy Consortium Pilot Award. Project title: Untangling the genomics of axonal Charcot- Marie-Tooth disease
Amount $50,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 01/2021 
End 12/2021
 
Description EAN training fellowship - Fellow visiting for 1 year 
Organisation University of Pavia
Country Italy 
Sector Academic/University 
PI Contribution Trainee neurologist (Dr Riccardo Curro') awarded with EAN training fellowship visiting the lab for 1 year and working on the MRC project. Training on clinical and lab techniques
Collaborator Contribution Carrying our clinical and lab research on RFC1 expansion disease
Impact Riccardo Currò ... Andrea Cortese. RFC1 expansions are a common cause of idiopathic sensory neuropathy. Accepted in Brain in January 2021
Start Year 2020
 
Description Genotype and phenotype spectrum of RFC1 CANVAS and disease spectrum 
Organisation Pitié-Salpêtrière Hospital
Country France 
Sector Hospitals 
PI Contribution As stated in the project proposal, we partnered with several centres around the world to fully define the genotype and phenotype spectrum RFC1 disease. We have tested over the last year over 2000 samples with ataxia and/or sensory neuropathy for RFC1 expansion sent to us from all across the world, as shown in the research output. Identification of novel population specific pathogenic configuration in RFC1
Collaborator Contribution Contribution with patients samples and clinical information.
Impact University of Perth Beecroft S. J., Cortese A., Sullivan R., Yau W. Y., Dyer Z., Wu T. Y., Mulroy E., Pelosi L., Rodrigues M., Taylor R., Mossman S., Leadbetter R., Cleland J.,Anderson T., Ravenscroft G., Laing N. G., Houlden H., Reilly M. M., Roxburgh R. H. (2020). A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. BRAIN (ONLINE), vol. 143, p. 2673-2680, ISSN: 1460-2156, doi: 10.1093/brain/awaa203 Scriba C. K., Beecroft S. J., Clayton J. S., Cortese A., Sullivan R., Yau W. Y., Dominik N., Rodrigues M., Walker E., Dyer Z., Wu T. Y., Davis M. R., Chandler D. C., Weisburd B., Houlden H., Reilly M. M., Laing N. G., Lamont P. J., Roxburgh R. H., Ravenscroft G. (2020). A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. BRAIN (ONLINE), vol. 143, p. 2904- 2910, ISSN: 1460-2156, doi: 10.1093/brain/awaa263 University of Sydney Kumar K. R*., Cortese A*., Tomlinson S. E., Efthymiou S., Ellis M., Zhu D., Stoll M., Dominik N., Tisch S., Tchan M., Wu K. H. C., Devery S., Spring P. J., Hawke S., Cremer P., Ng K., Reilly M. M., Nicholson G. A., Houlden H., Kennerson M. (2020). RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome. BRAIN (ONLINE), vol. 143, p. e82, ISSN: 1460-2156, doi: 10.1093/brain/awaa244 University of Tubingen and collaborators of ARCA consortium Traschütz A, Cortese A, Reich S, Dominik N, Faber J, Jacobi H, Hartmann AM, Rujescu D, Montaut S, Echaniz-Laguna A, Erer S, Schütz VC, Tarnutzer AA, Sturm M, Haack TB, Vaucamps-Diedhiou N, Puccio H, Schöls L, Klockgether T, van de Warrenburg BP, Paucar M, Timmann D, Hilgers RD, Gazulla J, Strupp M, Moris G, Filla A, Houlden H, Anheim M, Infante J, Basak AN, Synofzik M; RFC1 Study Group.Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. Neurology. 2021 Mar 2;96(9):e1369-e1382. doi: 10.1212/WNL.0000000000011528. Epub 2021 Jan 25. Paris - PItie'-Salpetriere Cortese A., Tozza S., Yau W. Y., Rossi S., Beecroft S. J., Jaunmuktane Z., Dyer Z., Ravenscroft G., Lamont P. J., Mossman S., Chancellor A., Maisonobe T., Pereon Y., Cauquil C., Colnaghi S., Mallucci [...] H., Houlden H., Reilly M. M. (2020). Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. BRAIN, vol. 143, p. 489-490, ISSN: 0006-8950, doi: 10.1093/brain/awz418
Start Year 2020
 
Description Genotype and phenotype spectrum of RFC1 CANVAS and disease spectrum 
Organisation Sheffield Teaching Hospitals NHS Foundation Trust
Department Sheffield Podiatry Services
Country United Kingdom 
Sector Public 
PI Contribution As stated in the project proposal, we partnered with several centres around the world to fully define the genotype and phenotype spectrum RFC1 disease. We have tested over the last year over 2000 samples with ataxia and/or sensory neuropathy for RFC1 expansion sent to us from all across the world, as shown in the research output. Identification of novel population specific pathogenic configuration in RFC1
Collaborator Contribution Contribution with patients samples and clinical information.
Impact University of Perth Beecroft S. J., Cortese A., Sullivan R., Yau W. Y., Dyer Z., Wu T. Y., Mulroy E., Pelosi L., Rodrigues M., Taylor R., Mossman S., Leadbetter R., Cleland J.,Anderson T., Ravenscroft G., Laing N. G., Houlden H., Reilly M. M., Roxburgh R. H. (2020). A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. BRAIN (ONLINE), vol. 143, p. 2673-2680, ISSN: 1460-2156, doi: 10.1093/brain/awaa203 Scriba C. K., Beecroft S. J., Clayton J. S., Cortese A., Sullivan R., Yau W. Y., Dominik N., Rodrigues M., Walker E., Dyer Z., Wu T. Y., Davis M. R., Chandler D. C., Weisburd B., Houlden H., Reilly M. M., Laing N. G., Lamont P. J., Roxburgh R. H., Ravenscroft G. (2020). A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. BRAIN (ONLINE), vol. 143, p. 2904- 2910, ISSN: 1460-2156, doi: 10.1093/brain/awaa263 University of Sydney Kumar K. R*., Cortese A*., Tomlinson S. E., Efthymiou S., Ellis M., Zhu D., Stoll M., Dominik N., Tisch S., Tchan M., Wu K. H. C., Devery S., Spring P. J., Hawke S., Cremer P., Ng K., Reilly M. M., Nicholson G. A., Houlden H., Kennerson M. (2020). RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome. BRAIN (ONLINE), vol. 143, p. e82, ISSN: 1460-2156, doi: 10.1093/brain/awaa244 University of Tubingen and collaborators of ARCA consortium Traschütz A, Cortese A, Reich S, Dominik N, Faber J, Jacobi H, Hartmann AM, Rujescu D, Montaut S, Echaniz-Laguna A, Erer S, Schütz VC, Tarnutzer AA, Sturm M, Haack TB, Vaucamps-Diedhiou N, Puccio H, Schöls L, Klockgether T, van de Warrenburg BP, Paucar M, Timmann D, Hilgers RD, Gazulla J, Strupp M, Moris G, Filla A, Houlden H, Anheim M, Infante J, Basak AN, Synofzik M; RFC1 Study Group.Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. Neurology. 2021 Mar 2;96(9):e1369-e1382. doi: 10.1212/WNL.0000000000011528. Epub 2021 Jan 25. Paris - PItie'-Salpetriere Cortese A., Tozza S., Yau W. Y., Rossi S., Beecroft S. J., Jaunmuktane Z., Dyer Z., Ravenscroft G., Lamont P. J., Mossman S., Chancellor A., Maisonobe T., Pereon Y., Cauquil C., Colnaghi S., Mallucci [...] H., Houlden H., Reilly M. M. (2020). Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. BRAIN, vol. 143, p. 489-490, ISSN: 0006-8950, doi: 10.1093/brain/awz418
Start Year 2020
 
Description Genotype and phenotype spectrum of RFC1 CANVAS and disease spectrum 
Organisation University Hospital Tuebingen
Country Germany 
Sector Academic/University 
PI Contribution As stated in the project proposal, we partnered with several centres around the world to fully define the genotype and phenotype spectrum RFC1 disease. We have tested over the last year over 2000 samples with ataxia and/or sensory neuropathy for RFC1 expansion sent to us from all across the world, as shown in the research output. Identification of novel population specific pathogenic configuration in RFC1
Collaborator Contribution Contribution with patients samples and clinical information.
Impact University of Perth Beecroft S. J., Cortese A., Sullivan R., Yau W. Y., Dyer Z., Wu T. Y., Mulroy E., Pelosi L., Rodrigues M., Taylor R., Mossman S., Leadbetter R., Cleland J.,Anderson T., Ravenscroft G., Laing N. G., Houlden H., Reilly M. M., Roxburgh R. H. (2020). A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. BRAIN (ONLINE), vol. 143, p. 2673-2680, ISSN: 1460-2156, doi: 10.1093/brain/awaa203 Scriba C. K., Beecroft S. J., Clayton J. S., Cortese A., Sullivan R., Yau W. Y., Dominik N., Rodrigues M., Walker E., Dyer Z., Wu T. Y., Davis M. R., Chandler D. C., Weisburd B., Houlden H., Reilly M. M., Laing N. G., Lamont P. J., Roxburgh R. H., Ravenscroft G. (2020). A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. BRAIN (ONLINE), vol. 143, p. 2904- 2910, ISSN: 1460-2156, doi: 10.1093/brain/awaa263 University of Sydney Kumar K. R*., Cortese A*., Tomlinson S. E., Efthymiou S., Ellis M., Zhu D., Stoll M., Dominik N., Tisch S., Tchan M., Wu K. H. C., Devery S., Spring P. J., Hawke S., Cremer P., Ng K., Reilly M. M., Nicholson G. A., Houlden H., Kennerson M. (2020). RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome. BRAIN (ONLINE), vol. 143, p. e82, ISSN: 1460-2156, doi: 10.1093/brain/awaa244 University of Tubingen and collaborators of ARCA consortium Traschütz A, Cortese A, Reich S, Dominik N, Faber J, Jacobi H, Hartmann AM, Rujescu D, Montaut S, Echaniz-Laguna A, Erer S, Schütz VC, Tarnutzer AA, Sturm M, Haack TB, Vaucamps-Diedhiou N, Puccio H, Schöls L, Klockgether T, van de Warrenburg BP, Paucar M, Timmann D, Hilgers RD, Gazulla J, Strupp M, Moris G, Filla A, Houlden H, Anheim M, Infante J, Basak AN, Synofzik M; RFC1 Study Group.Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. Neurology. 2021 Mar 2;96(9):e1369-e1382. doi: 10.1212/WNL.0000000000011528. Epub 2021 Jan 25. Paris - PItie'-Salpetriere Cortese A., Tozza S., Yau W. Y., Rossi S., Beecroft S. J., Jaunmuktane Z., Dyer Z., Ravenscroft G., Lamont P. J., Mossman S., Chancellor A., Maisonobe T., Pereon Y., Cauquil C., Colnaghi S., Mallucci [...] H., Houlden H., Reilly M. M. (2020). Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. BRAIN, vol. 143, p. 489-490, ISSN: 0006-8950, doi: 10.1093/brain/awz418
Start Year 2020
 
Description Genotype and phenotype spectrum of RFC1 CANVAS and disease spectrum 
Organisation University of Lubeck
Country Germany 
Sector Academic/University 
PI Contribution As stated in the project proposal, we partnered with several centres around the world to fully define the genotype and phenotype spectrum RFC1 disease. We have tested over the last year over 2000 samples with ataxia and/or sensory neuropathy for RFC1 expansion sent to us from all across the world, as shown in the research output. Identification of novel population specific pathogenic configuration in RFC1
Collaborator Contribution Contribution with patients samples and clinical information.
Impact University of Perth Beecroft S. J., Cortese A., Sullivan R., Yau W. Y., Dyer Z., Wu T. Y., Mulroy E., Pelosi L., Rodrigues M., Taylor R., Mossman S., Leadbetter R., Cleland J.,Anderson T., Ravenscroft G., Laing N. G., Houlden H., Reilly M. M., Roxburgh R. H. (2020). A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. BRAIN (ONLINE), vol. 143, p. 2673-2680, ISSN: 1460-2156, doi: 10.1093/brain/awaa203 Scriba C. K., Beecroft S. J., Clayton J. S., Cortese A., Sullivan R., Yau W. Y., Dominik N., Rodrigues M., Walker E., Dyer Z., Wu T. Y., Davis M. R., Chandler D. C., Weisburd B., Houlden H., Reilly M. M., Laing N. G., Lamont P. J., Roxburgh R. H., Ravenscroft G. (2020). A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. BRAIN (ONLINE), vol. 143, p. 2904- 2910, ISSN: 1460-2156, doi: 10.1093/brain/awaa263 University of Sydney Kumar K. R*., Cortese A*., Tomlinson S. E., Efthymiou S., Ellis M., Zhu D., Stoll M., Dominik N., Tisch S., Tchan M., Wu K. H. C., Devery S., Spring P. J., Hawke S., Cremer P., Ng K., Reilly M. M., Nicholson G. A., Houlden H., Kennerson M. (2020). RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome. BRAIN (ONLINE), vol. 143, p. e82, ISSN: 1460-2156, doi: 10.1093/brain/awaa244 University of Tubingen and collaborators of ARCA consortium Traschütz A, Cortese A, Reich S, Dominik N, Faber J, Jacobi H, Hartmann AM, Rujescu D, Montaut S, Echaniz-Laguna A, Erer S, Schütz VC, Tarnutzer AA, Sturm M, Haack TB, Vaucamps-Diedhiou N, Puccio H, Schöls L, Klockgether T, van de Warrenburg BP, Paucar M, Timmann D, Hilgers RD, Gazulla J, Strupp M, Moris G, Filla A, Houlden H, Anheim M, Infante J, Basak AN, Synofzik M; RFC1 Study Group.Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. Neurology. 2021 Mar 2;96(9):e1369-e1382. doi: 10.1212/WNL.0000000000011528. Epub 2021 Jan 25. Paris - PItie'-Salpetriere Cortese A., Tozza S., Yau W. Y., Rossi S., Beecroft S. J., Jaunmuktane Z., Dyer Z., Ravenscroft G., Lamont P. J., Mossman S., Chancellor A., Maisonobe T., Pereon Y., Cauquil C., Colnaghi S., Mallucci [...] H., Houlden H., Reilly M. M. (2020). Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. BRAIN, vol. 143, p. 489-490, ISSN: 0006-8950, doi: 10.1093/brain/awz418
Start Year 2020
 
Description Genotype and phenotype spectrum of RFC1 CANVAS and disease spectrum 
Organisation University of Perth
Country Australia 
Sector Academic/University 
PI Contribution As stated in the project proposal, we partnered with several centres around the world to fully define the genotype and phenotype spectrum RFC1 disease. We have tested over the last year over 2000 samples with ataxia and/or sensory neuropathy for RFC1 expansion sent to us from all across the world, as shown in the research output. Identification of novel population specific pathogenic configuration in RFC1
Collaborator Contribution Contribution with patients samples and clinical information.
Impact University of Perth Beecroft S. J., Cortese A., Sullivan R., Yau W. Y., Dyer Z., Wu T. Y., Mulroy E., Pelosi L., Rodrigues M., Taylor R., Mossman S., Leadbetter R., Cleland J.,Anderson T., Ravenscroft G., Laing N. G., Houlden H., Reilly M. M., Roxburgh R. H. (2020). A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. BRAIN (ONLINE), vol. 143, p. 2673-2680, ISSN: 1460-2156, doi: 10.1093/brain/awaa203 Scriba C. K., Beecroft S. J., Clayton J. S., Cortese A., Sullivan R., Yau W. Y., Dominik N., Rodrigues M., Walker E., Dyer Z., Wu T. Y., Davis M. R., Chandler D. C., Weisburd B., Houlden H., Reilly M. M., Laing N. G., Lamont P. J., Roxburgh R. H., Ravenscroft G. (2020). A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. BRAIN (ONLINE), vol. 143, p. 2904- 2910, ISSN: 1460-2156, doi: 10.1093/brain/awaa263 University of Sydney Kumar K. R*., Cortese A*., Tomlinson S. E., Efthymiou S., Ellis M., Zhu D., Stoll M., Dominik N., Tisch S., Tchan M., Wu K. H. C., Devery S., Spring P. J., Hawke S., Cremer P., Ng K., Reilly M. M., Nicholson G. A., Houlden H., Kennerson M. (2020). RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome. BRAIN (ONLINE), vol. 143, p. e82, ISSN: 1460-2156, doi: 10.1093/brain/awaa244 University of Tubingen and collaborators of ARCA consortium Traschütz A, Cortese A, Reich S, Dominik N, Faber J, Jacobi H, Hartmann AM, Rujescu D, Montaut S, Echaniz-Laguna A, Erer S, Schütz VC, Tarnutzer AA, Sturm M, Haack TB, Vaucamps-Diedhiou N, Puccio H, Schöls L, Klockgether T, van de Warrenburg BP, Paucar M, Timmann D, Hilgers RD, Gazulla J, Strupp M, Moris G, Filla A, Houlden H, Anheim M, Infante J, Basak AN, Synofzik M; RFC1 Study Group.Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. Neurology. 2021 Mar 2;96(9):e1369-e1382. doi: 10.1212/WNL.0000000000011528. Epub 2021 Jan 25. Paris - PItie'-Salpetriere Cortese A., Tozza S., Yau W. Y., Rossi S., Beecroft S. J., Jaunmuktane Z., Dyer Z., Ravenscroft G., Lamont P. J., Mossman S., Chancellor A., Maisonobe T., Pereon Y., Cauquil C., Colnaghi S., Mallucci [...] H., Houlden H., Reilly M. M. (2020). Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. BRAIN, vol. 143, p. 489-490, ISSN: 0006-8950, doi: 10.1093/brain/awz418
Start Year 2020
 
Description Genotype and phenotype spectrum of RFC1 CANVAS and disease spectrum 
Organisation University of Sydney
Country Australia 
Sector Academic/University 
PI Contribution As stated in the project proposal, we partnered with several centres around the world to fully define the genotype and phenotype spectrum RFC1 disease. We have tested over the last year over 2000 samples with ataxia and/or sensory neuropathy for RFC1 expansion sent to us from all across the world, as shown in the research output. Identification of novel population specific pathogenic configuration in RFC1
Collaborator Contribution Contribution with patients samples and clinical information.
Impact University of Perth Beecroft S. J., Cortese A., Sullivan R., Yau W. Y., Dyer Z., Wu T. Y., Mulroy E., Pelosi L., Rodrigues M., Taylor R., Mossman S., Leadbetter R., Cleland J.,Anderson T., Ravenscroft G., Laing N. G., Houlden H., Reilly M. M., Roxburgh R. H. (2020). A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. BRAIN (ONLINE), vol. 143, p. 2673-2680, ISSN: 1460-2156, doi: 10.1093/brain/awaa203 Scriba C. K., Beecroft S. J., Clayton J. S., Cortese A., Sullivan R., Yau W. Y., Dominik N., Rodrigues M., Walker E., Dyer Z., Wu T. Y., Davis M. R., Chandler D. C., Weisburd B., Houlden H., Reilly M. M., Laing N. G., Lamont P. J., Roxburgh R. H., Ravenscroft G. (2020). A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. BRAIN (ONLINE), vol. 143, p. 2904- 2910, ISSN: 1460-2156, doi: 10.1093/brain/awaa263 University of Sydney Kumar K. R*., Cortese A*., Tomlinson S. E., Efthymiou S., Ellis M., Zhu D., Stoll M., Dominik N., Tisch S., Tchan M., Wu K. H. C., Devery S., Spring P. J., Hawke S., Cremer P., Ng K., Reilly M. M., Nicholson G. A., Houlden H., Kennerson M. (2020). RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome. BRAIN (ONLINE), vol. 143, p. e82, ISSN: 1460-2156, doi: 10.1093/brain/awaa244 University of Tubingen and collaborators of ARCA consortium Traschütz A, Cortese A, Reich S, Dominik N, Faber J, Jacobi H, Hartmann AM, Rujescu D, Montaut S, Echaniz-Laguna A, Erer S, Schütz VC, Tarnutzer AA, Sturm M, Haack TB, Vaucamps-Diedhiou N, Puccio H, Schöls L, Klockgether T, van de Warrenburg BP, Paucar M, Timmann D, Hilgers RD, Gazulla J, Strupp M, Moris G, Filla A, Houlden H, Anheim M, Infante J, Basak AN, Synofzik M; RFC1 Study Group.Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. Neurology. 2021 Mar 2;96(9):e1369-e1382. doi: 10.1212/WNL.0000000000011528. Epub 2021 Jan 25. Paris - PItie'-Salpetriere Cortese A., Tozza S., Yau W. Y., Rossi S., Beecroft S. J., Jaunmuktane Z., Dyer Z., Ravenscroft G., Lamont P. J., Mossman S., Chancellor A., Maisonobe T., Pereon Y., Cauquil C., Colnaghi S., Mallucci [...] H., Houlden H., Reilly M. M. (2020). Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. BRAIN, vol. 143, p. 489-490, ISSN: 0006-8950, doi: 10.1093/brain/awz418
Start Year 2020
 
Description Natural history of SORD neuropathy 
Organisation University of Miami
Country United States 
Sector Academic/University 
PI Contribution Enrolment of cases from UK and Europe. testing of sorbitol level
Collaborator Contribution Enrolment of cases from USA
Impact Active recruitment of cases. Abstract accepted will be presented at 2021 AAN and 2021 PNS meeting
Start Year 2020
 
Title Treatment and Detection of Inherited Neuropathies and Associated Disorders 
Description The present disclosure relates to methods of detecting and treating inherited neuropathy. In various aspects, the method comprises detecting the presence of a mutation in the sorbitol dehydrogenase (SORD) gene in a sample from a subject. In various embodiments, the SORD mutation is a DNA variant classified as pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) criteria. 
IP Reference WO2020227430A1 
Protection Patent application published
Year Protection Granted 2020
Licensed Commercial In Confidence
Impact Potential treatment of patients with SORD neuropathy with aldose reductase inhibitors.
 
Description Invited Seminar during the 5th Asian Oceanic Inherited Neuropathy Consortium (AOINC) Virtual Symposium- Friday 13 November 2020- 10 am - 12.30 pm. Title:'Repeats and retrogenes: novel hidden causes of inherited neuropathies" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Neurologists, paediatricians, researchers from several countries in East Asia and Oceania attended the meeting. Raised awareness of recent findings and novel causes of neuropathy. Fostering identification of patients with potentially treatable SORD neuropathy. Plans for collaborative studies including clinicians from developing countries
Year(s) Of Engagement Activity 2020
URL http://asianoceanicinc.org/wp-content/uploads/2020/10/Virtual-AOINC-Symposium-Program_FINAL-2020-11-...
 
Description New, frequent and increasing numbers of repeat expansion disorders in neurology" a 6th Congress of the European Academy of Neurology - 1st Virtual Congress 23 - 26 May 2020. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Educational course on recently identified repeat expansion. The course was well attended and received positive feedback. Audience reported change in view, fostering identification of cases and providing more patients with a genetic diagnosis.
Year(s) Of Engagement Activity 2020
URL https://www.ean.org/congress-2020