RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome

Kishore R Kumar^{1

2

3

4}, Andrea Cortese^{5

6}, Susan E Tomlinson^{3

7}, Stephanie Efthymiou⁵, Melina Ellis⁸, Danqing Zhu¹, Marion Stoll¹, Natalia Dominik⁵, Stephen Tisch^{7

9}, Michel Tchan^{3

10}, Kathy H C Wu^{9

11

12}, Sophie Devery¹¹, Penelope J Spring², Simon Hawke^{3

13

14}, Phillip Cremer^{3

15}, Karl Ng^{3

15}, Mary M Reilly⁵, Garth A Nicholson^{1

2

3

8}, Henry Houlden⁵, Marina Kennerson^{1

3

8}

Affiliations

¹ Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia.
² Neurology Department, Concord Repatriation General Hospital, Sydney, NSW, Australia.
³ Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁴ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁵ Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
⁶ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁷ Department of Neurology, St Vincent's Hospital, Darlinghurst, Sydney, Australia.
⁸ Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, Australia.
⁹ School of Medicine, University of New South Wales, Sydney, Australia.
¹⁰ Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia.
¹¹ St Vincent's Clinical Genomics, St Vincent's Hospital, Sydney, Australia.
¹² Discipline of Genetic Medicine, University of Sydney, Sydney, Australia.
¹³ Vascular Immunology Unit Department of Pathology, The University of Sydney, Sydney, NSW Australia.
¹⁴ Central West Neurology and Neurosurgery, Orange, NSW Australia.
¹⁵ Royal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australia.

PMID: 32949124
PMCID: PMC7586083
DOI: 10.1093/brain/awaa244

Comment

RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome

Kishore R Kumar et al. Brain. 2020.

. 2020 Oct 1;143(10):e82.

doi: 10.1093/brain/awaa244.

Authors

Affiliations

¹ Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia.
² Neurology Department, Concord Repatriation General Hospital, Sydney, NSW, Australia.
³ Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁴ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁵ Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
⁶ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁷ Department of Neurology, St Vincent's Hospital, Darlinghurst, Sydney, Australia.
⁸ Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, Australia.
⁹ School of Medicine, University of New South Wales, Sydney, Australia.
¹⁰ Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia.
¹¹ St Vincent's Clinical Genomics, St Vincent's Hospital, Sydney, Australia.
¹² Discipline of Genetic Medicine, University of Sydney, Sydney, Australia.
¹³ Vascular Immunology Unit Department of Pathology, The University of Sydney, Sydney, NSW Australia.
¹⁴ Central West Neurology and Neurosurgery, Orange, NSW Australia.
¹⁵ Royal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australia.

PMID: 32949124
PMCID: PMC7586083
DOI: 10.1093/brain/awaa244

No abstract available

PubMed Disclaimer

Figures

**Figure 1**
**Southern blot results, pedigrees and sural nerve biopsy findings.** (A) Southern blot results confirming *RCF1* biallelic AAGGG expansions. The number of repeats for each allele are shown in parentheses. Patients R19975 (821, 1015), R19982 (1070, 1070), R110358 (292, 1192), R60355 (526, 821), and R200002 (1128, 1128). Patient R19955 was heterozygous for the AAGGG expansion (1325). Patient R40143 was positive for the repeat primed (AAAAG) PCR, which are non-pathogenic expansions. We considered pathogenic repeat expansions >250. (B) Pedigrees of families with biallelic pathogenic *RCF1* expansions. Black filled symbols indicate affected individuals. Grey filled symbols indicate family members whose affected status is uncertain. Arrow indicates proband. Diagonal line indicates deceased individuals. M = allele with pathogenic RFC1 expansion; a dash indicates an allele without pathogenic RFC1 expansion. (C) Right sural nerve biopsy (Toluidine blue) from Patient R19977 showing a severe reduction in myelinated fibre density with only a few large myelinated fibres remaining in most fascicles. There were no inflammatory cell infiltrates. On the teased fibre preparation most fibres were of small diameter and thinly remyelinated. Ten per cent of fibres show evidence of previous demyelination/remyelination. Immunofluorescence stains for immunoglobulin, complement, fibrinogen and the Congo red stain for amyloid were negative. The findings are consistent with severe axonal loss consistent with a neuropathy or ganglionopathy.

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Comment on

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.
Cortese A, Tozza S, Yau WY, Rossi S, Beecroft SJ, Jaunmuktane Z, Dyer Z, Ravenscroft G, Lamont PJ, Mossman S, Chancellor A, Maisonobe T, Pereon Y, Cauquil C, Colnaghi S, Mallucci G, Curro R, Tomaselli PJ, Thomas-Black G, Sullivan R, Efthymiou S, Rossor AM, Laurá M, Pipis M, Horga A, Polke J, Kaski D, Horvath R, Chinnery PF, Marques W, Tassorelli C, Devigili G, Leonardis L, Wood NW, Bronstein A, Giunti P, Züchner S, Stojkovic T, Laing N, Roxburgh RH, Houlden H, Reilly MM. Cortese A, et al. Brain. 2020 Feb 1;143(2):480-490. doi: 10.1093/brain/awz418. Brain. 2020. PMID: 32040566 Free PMC article.

References

1. Akcimen F, Ross JP, Bourassa CV, Liao C, Rochefort D, Gama MTD, et al.Investigation of the RFC1 repeat expansion in a Canadian and a Brazilian ataxia cohort: identification of novel conformations. Front Genet 2019; 10: 1219. - PMC - PubMed
1. Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, et al.Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet 2019; 51: 649–58. - PMC - PubMed
1. Cortese A, Tozza S, Yau WY, Rossi S, Beecroft SJ, Jaunmuktane Z, et al.Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. Brain 2020; 143: 480–90. - PMC - PubMed
1. Kok C, Kennerson ML, Spring PJ, Ing AJ, Pollard JD, Nicholson GA.. A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am J Hum Genet 2003; 73: 632–7. - PMC - PubMed
1. Rafehi H, Szmulewicz DJ, Bennett MF, Sobreira NLM, Pope K, Smith KR, et al.Bioinformatics-based identification of expanded repeats: a non-reference intronic pentamer expansion in RFC1 causes CANVAS. Am J Hum Genet 2019; 105: 151–65. - PMC - PubMed

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RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome

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RFC1 expansions can mimic hereditary sensory neuropathy with cough and Sjögren syndrome

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