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RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

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.

SUBMITTER: Maroofian R

PROVIDER: S-EPMC11224604 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Maroofian Reza R Sarraf Payam P O'Brien Thomas J TJ Kamel Mona M Cakar Arman A Elkhateeb Nour N Lau Tracy T Patil Siddaramappa Jagdish SJ Record Christopher J CJ Horga Alejandro A Essid Miriam M Selim Laila L Benrhouma Hanene H Ben Younes Thouraya T Zifarelli Giovanni G Pagnamenta Alistair T AT Bauer Peter P Khundadze Mukhran M Mirecki Andrea A Kamel Sara Mahmoud SM Elmonem Mohamed A MA Ghayoor Karimiani Ehsan E Jamshidi Yalda Y Offiah Amaka C AC Rossor Alexander M AM Youssef-Turki Ilhem Ben IB Hübner Christian A CA Munot Pinki P Reilly Mary M MM Brown André E X AEX Nagy Sara S Houlden Henry H

Brain : a journal of neurology 20240701 7

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 heredi ...[more]

PMID: 38527963

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Project description:IntroductionOnabotulinumtoxinA treatment for spasticity varies according to numerous factors and is individualized to meet treatment goals.ObjectiveTo explore real-world onabotulinumtoxinA utilization and effectiveness in patients with lower limb spasticity from the Adult Spasticity International Registry (ASPIRE) study.DesignTwo-year, multicenter, prospective, observational registry (NCT01930786).SettingFifty-four international clinical sites.PatientsAdults (naïve or non-naïve to botulinum toxin[s] treatment for spasticity, across multiple etiologies) with lower limb spasticity related to upper motor neuron syndrome.InterventionsOnabotulinumtoxinA administered at the clinician's discretion.Main outcome measuresOnabotulinumtoxinA treatment utilization, clinician- and patient-reported satisfaction.ResultsIn ASPIRE, 530 patients received ≥1 onabotulinumtoxinA treatment for lower limb spasticity (mean age, 52 years; stroke, 49.4%; multiple sclerosis, 20.4%). Equinovarus foot was treated most often (80.9% of patients), followed by flexed knee (26.0%), stiff extended knee (22.5%), and flexed toes (22.3%). OnabotulinumtoxinA doses ranged between 10 and 1100 U across all presentations. Electromyography (EMG) was most commonly used for injection localization (≥41.1% of treatment sessions). Despite low patient response on the satisfaction questionnaire, clinicians (94.6% of treatment sessions) and patients (84.5%) reported satisfaction/extreme satisfaction that treatment helped manage spasticity, and clinicians (98.3%) and patients (91.6%) would probably/definitely continue onabotulinumtoxinA treatment. These data should be interpreted with care. Twenty-one adverse events (AEs) in 18 patients (3.4%) were considered treatment-related. Sixty-seven patients (12.6%) reported 138 serious AEs; 3 serious AEs in two patients (0.4%) were considered treatment-related. No new safety signals were identified.ConclusionsASPIRE provides long-term observational data on the treatment of lower limb spasticity with onabotulinumtoxinA. Real-world data from this primary analysis can help to guide the clinical use of onabotulinumtoxinA to improve spasticity management.

Dataset Information

RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Publications

RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

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