Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity

Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity Publisher Pubmed

Maroofian R¹ ; Sarraf P^{2, 3} ; Obrien TJ^{4, 5} ; Kamel M⁶ ; Cakar A^{1, 7} ; Elkhateeb N⁸ ; Lau T¹ ; Patil SJ⁹ ; Record CJ¹ ; Horga A¹ ; Essid M¹⁰ ; Selim L⁶ ; Benrhouma H¹⁰ ; Younes TB¹⁰ Show All Authors

Maroofian R¹
Sarraf P^{2, 3}
Obrien TJ^{4, 5}
Kamel M⁶
Cakar A^{1, 7}
Elkhateeb N⁸
Lau T¹
Patil SJ⁹
Record CJ¹
Horga A¹
Essid M¹⁰
Selim L⁶
Benrhouma H¹⁰
Younes TB¹⁰
Zifarelli G¹¹
Pagnamenta AT¹²
Bauer P¹¹
Khundadze M¹³
Mirecki A¹³
Kamel SM¹⁴
Elmonem MA¹⁵
Karimiani EG^{16, 17}
Jamshidi Y¹⁶
Offiah AC¹⁸
Rossor AM¹
Youssefturki IB¹⁰
Hubner CA^{13, 19}
Munot P²⁰
Reilly MM¹
Brown AEX^{4, 5}
Nagy S^{1, 21}
Houlden H¹

Show Affiliations

1. Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
2. Department of Neuromuscular Diseases, Iranian Centre of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, 1416753955, Iran
3. Department of Neurology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, 1416753955, Iran
4. Institute of Clinical Sciences, Imperial College London, London, SW7 2AZ, United Kingdom
5. MRC Laboratory of Medical Sciences, London, W12 0HS, United Kingdom
6. Department of Pediatrics, Neurology and Metabolic Division, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, 4240310, Egypt
7. Neuromuscular Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, 34093, Turkey
8. Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, United Kingdom
9. Division of Medical Genetics, Mazumdar Shaw Medical Center, Narayana Hrudayalaya Hospital, Bangalore, 560099, India
10. LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, University of Tunis El Manar, Tunis, 1007, Tunisia
11. CENTOGENE GmbH, Rostock, 18055, Germany
12. NIHR Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, OX3 9DU, United Kingdom
13. Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, 07747, Germany
14. Department of Radiology, Cairo University, Cairo, 12613, Egypt
15. Department of Clinical and Chemical Pathology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, 12613, Egypt
16. Molecular and Clinical Sciences Institute, St. George's, University of London, London, SW17 0RE, United Kingdom
17. Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, 9187147578, Iran
18. Division of Clinical Medicine, School of Medicine & Population Health, University of Sheffield, Sheffield, S10 2RX, United Kingdom
19. Center for Rare Diseases, Jena University Hospital, Friedrich Schiller Universitat, Jena, 07747, Germany
20. Dubowitz Neuromuscular Centre, Great Ormond Street Hospital NHS Trust, London, WC1N 3JH, United Kingdom
21. Department of Neurology, University Hospital Basel, University of Basel, Basel, 4031, Switzerland

Source: Brain Published:2024

Abstract

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to the scarcity of supporting evidence. In this study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterization of Caenorhabditis elegans RTN2 homologous loss-of-function variants demonstrated morphological and behavioural differences compared with the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite RTN2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with RTN2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN. © 2024 The Author(s).

Style	Citing Format
MLA	Maroofian R, et al.. "Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity." Brain, vol. 147, no. 7, 2024, pp. 2334-2343.
APA	Maroofian R, Sarraf P, Obrien TJ, Kamel M, Cakar A, Elkhateeb N, Lau T, Patil SJ, Record CJ, Horga A, Essid M, Selim L, Benrhouma H, Younes TB, Zifarelli G, Pagnamenta AT, Bauer P, Khundadze M, Mirecki A, ... Houlden H (2024). Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity. Brain, 147(7), 2334-2343.
Chicago	Maroofian R, Sarraf P, Obrien TJ, Kamel M, Cakar A, Elkhateeb N, Lau T, et al.. "Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity." Brain 147, no. 7 (2024): 2334-2343.
Harvard	Maroofian R et al. (2024) 'Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity', Brain, 147(7), pp. 2334-2343.
Vancouver	Maroofian R, Sarraf P, Obrien TJ, Kamel M, Cakar A, Elkhateeb N, et al.. Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity. Brain. 2024;147(7):2334-2343.
BibTex	@article{ author = {Maroofian R and Sarraf P and Obrien TJ and Kamel M and Cakar A and Elkhateeb N and Lau T and Patil SJ and Record CJ and Horga A and Essid M and Selim L and Benrhouma H and Younes TB and Zifarelli G and Pagnamenta AT and Bauer P and Khundadze M and Mirecki A and Kamel SM and Elmonem MA and Karimiani EG and Jamshidi Y and Offiah AC and Rossor AM and Youssefturki IB and Hubner CA and Munot P and Reilly MM and Brown AEX and Nagy S and Houlden H}, title = {Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity}, journal = {Brain}, volume = {147}, number = {7}, pages = {2334-2343}, year = {2024} }
RIS	TY - JOUR AU - Maroofian R AU - Sarraf P AU - Obrien TJ AU - Kamel M AU - Cakar A AU - Elkhateeb N AU - Lau T AU - Patil SJ AU - Record CJ AU - Horga A AU - Essid M AU - Selim L AU - Benrhouma H AU - Younes TB AU - Zifarelli G AU - Pagnamenta AT AU - Bauer P AU - Khundadze M AU - Mirecki A AU - Kamel SM AU - Elmonem MA AU - Karimiani EG AU - Jamshidi Y AU - Offiah AC AU - Rossor AM AU - Youssefturki IB AU - Hubner CA AU - Munot P AU - Reilly MM AU - Brown AEX AU - Nagy S AU - Houlden H TI - Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity JO - Brain VL - 147 IS - 7 SP - 2334 EP - 2343 PY - 2024 ER -

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Abstract