Facial nerve thinning is a hallmark and correlates with motor function in adults with spinal muscular atrophy

Facial nerve thinning is a hallmark and correlates with motor function in adults with spinal muscular atrophy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Facial nerve thinning is a hallmark and correlates with motor function in adults with spinal muscular atrophy Felipe Franco da Graça, Guilherme Soares de Oliveira Wertheimer, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8296422/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Spinal muscular atrophy (SMA) leads to progressive degeneration of lower motor neurons, yet reliable imaging biomarkers remain limited. We evaluated whether MRI-derived facial nerve morphometry distinguishes adult patients from healthy controls and reflects clinical status. Twenty-two adults with SMA types II and III and fourteen matched controls underwent 3T brain MRI using high-resolution balanced fast field echo sequences. Facial nerve diameters were measured bilaterally at the brainstem root entry zone and compared with clinical assessments including ambulation, facial weakness, the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Motor Function Measure (MFM-32). Patients showed consistently reduced facial nerve diameters, with the smallest values observed in non-ambulant individuals and in those with facial weakness. Facial diameters correlated with motor function, and the facial-to-trigeminal ratio demonstrated even stronger associations, emerging as a sensitive indicator of motor neuron loss. These findings support facial nerve morphometry as a promising and accessible biomarker for assessing disease involvement in adults with SMA. Figures Figure 1 Introduction Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by degeneration of lower motor neurons in the spinal cord and brainstem¹. With the advent of disease-modifying therapies, there is growing interest in biomarkers that directly reflect motor neuron integrity², especially in adults, where disease progression may be slow and clinical scales can be influenced by comorbidities³. Electrophysiological techniques such as CMAP-Scan Fit and motor unit number index (MUNIX) estimate motor unit loss⁴⁻⁵, while imaging studies usually focus on muscle fat fraction quantification. Those methods provide indirect information and may be time-consuming. High-resolution MRI enables reliable visualisation of cranial nerves, allowing quantitative morphometric analysis, particularly for nerves V and VII⁶. In amyotrophic lateral sclerosis (ALS), facial nerve thinning has been reported compared with controls, suggesting that cranial nerve morphometry may serve as a structural marker of motor neuron involvement⁷⁻⁸. In SMA types II and III, neurophysiological abnormalities of the facial nerve, including reduced CMAP and MUNIX values even without clinical weakness, have been described⁹. Based on these observations, we evaluated whether structural changes of the facial and trigeminal nerves can be identified in adults with SMA and whether such alterations correlate with clinical status and motor function. Methods We included 22 adults with genetically confirmed SMA and 14 healthy controls. None had neurological or psychiatric comorbidities. Controls had normal neurological examinations and no relevant family history. Patients were followed at the Neuromuscular Unit of the University of Campinas (UNICAMP). MRI was performed on a 3T Philips Achieva scanner. Standard T2-weighted images were obtained to rule out unrelated abnormalities. Cranial nerve imaging used an 8-channel head coil and a balanced fast field echo (bFFE) sequence with high spatial resolution (voxel size 0.58×0.58×1.00 mm³, interpolated to 0.28×0.28×0.5 mm³; reconstructed matrix 640×640; 75 slices; TR/TE 7.1/3.0 ms; flip angle 45°). Images were reviewed by a board-certified neuroradiologist blinded to clinical data. Facial and trigeminal nerve diameters were measured bilaterally at their root entry/exit zones, following established guidelines⁶, using ARIA software. A facial-to-trigeminal diameter ratio was also calculated. On the same day as MRI, a neurologist assessed ambulation and the presence of facial weakness. Motor function was evaluated by a physical therapist specialised in neuromuscular disorders using the HFMSE and MFM-32 scales. Both raters were blinded to imaging results. Statistical analyses used Mann–Whitney U tests and Spearman correlations, with significance set at p < 0.05. Results As shown in Table 1 , demographic characteristics were similar between SMA patients and controls. Facial nerve diameters were significantly reduced in SMA patients bilaterally (right: 1.15 mm vs 1.40 mm, p = 0.001; left: 1.14 mm vs 1.35 mm, p = 0.012). For the trigeminal nerve, a difference emerged only on the left side (3.16 mm vs 3.59 mm, p = 0.017), whereas right-side measurements did not differ significantly. Table 1 Demographic and clinical characteristics of patients with SMA and healthy controls Characteristic Patients (n = 22) Controls (n = 14) p-value Age, years, median (IQR) 31.5 (24.2–44.0) 35.5 (30.5–42.8) 0.570 Sex (M/F) 13 / 9 8 / 6 1.000 SMA type (II/III) 3 / 19 – – Disease duration, years, median (IQR) 28.5 (22.2–36.5) – – MFM-32, median (IQR) 34.9 (25.8–52.1) – – HFMSE, median (IQR) 8.0 (0–25.5) – – Ambulation (ambulantory / non-ambulantory) 6 / 16 – – Clinical facial weakness (present / absent) 4 / 18 – – Treatment status (untreated/treated with Nusinersen) 16/6 - - Values are shown as median (interquartile range) or absolute numbers. Comparisons between patients and controls were performed using Mann–Whitney U test (age) and Fisher’s exact test (sex). Within the SMA group, ambulant patients had larger facial nerve diameters than non-ambulant patients (right: 1.29 mm vs 1.14 mm, p = 0.039; left: 1.40 mm vs 1.10 mm, p = 0.003). Trigeminal measurements did not differ according to ambulation. The facial-to-trigeminal ratio was higher in ambulant individuals on both sides. Patients with clinically overt facial weakness showed marked reductions in facial diameters (right: 0.66 mm vs 1.23 mm, p = 0.009; left: 0.77 mm vs 1.19 mm, p = 0.019) and lower facial-to-trigeminal ratios, whereas trigeminal values remained similar between subgroups. Facial nerve diameters correlated positively with both functional scales. For MFM-32, correlations were ρ = 0.57 (p = 0.005) on the right and ρ = 0.65 (p = 0.001) on the left. For HFMSE, correlations were ρ = 0.65 (p = 0.001) on the right and ρ = 0.68 (p < 0.001) on the left. The facial-to-trigeminal ratio showed even stronger correlations with motor outcomes (ρ = 0.70–0.73, all p < 0.001). No associations were found between trigeminal measurements and motor function. Disease duration did not correlate with any imaging parameter. Discussion and Conclusions This study provides evidence that facial nerve thinning is a structural feature of adult SMA detectable through high-resolution MRI. Facial diameters distinguished patients from controls, varied with clinical severity, and correlated with established motor scales. The facial-to-trigeminal ratio enhanced these associations, likely because it normalises a motor-predominant nerve to a predominantly sensory one, thereby increasing sensitivity to motor neuron involvement. These results are consistent with neurophysiological evidence of facial motor impairment in SMA and parallel reports of facial nerve thinning in ALS⁷. Trigeminal measurements showed limited discriminatory ability and no functional correlations, consistent with the sensory predominance of this nerve. This pattern contrasts with sensory ganglionopathies such as RFC1/CANVAS, in which trigeminal but not facial nerve involvement is characteristic⁶. The lack of correlation with disease duration suggests that cranial nerve thinning relates more to disease severity than to chronological progression. Importantly, cranial nerve morphometry is simple, reproducible, and feasible even in centres without advanced neuroimaging protocols. In conclusion, facial nerve diameter and the facial-to-trigeminal ratio appear to be promising structural biomarkers of motor neuron involvement in adult SMA, including in patients without overt facial weakness. Their ease of acquisition and strong clinical correlations support further evaluation in larger and longitudinal cohorts to determine their potential role in monitoring disease progression and response to therapy. Declarations Compliance with Ethical Standards: All participants provided written informed consent, and the study was approved by the local Research Ethics Committee. The authors report no conflicts of interest. Author Contribution F.F.G. and M.C.F.J. performed study conceptualization and design, wrote the main manuscript text and prepared figures. F.F.G.,M.C.F.J. ,G.S.O.W., T.J.R.R., C.I., R.H.M. and E.Z. performed data collection and analysis and approved the final version to be submitted. Data Availability The data supporting the findings of this study are not publicly available due to restrictions related to medical confidentiality and patient privacy. De-identified data may be made available from the corresponding author upon reasonable request and subject to institutional and ethical approval. References Schroth M, Deans J, Arya K, Castro D, De Vivo DC, Gibbons MA, Ionita C, Kuntz NL, Lakhotia A, Knierbein EN, et al. Spinal muscular atrophy update in best practices: recommendations for diagnosis considerations. Neurol Clin Pract. 2024;14(4):e200310. doi:10.1212/CPJ.0000000000200310 Gao C, Zhan Y, Chen H, Deng C. Application of biomarkers in spinal muscular atrophy. Int J Mol Sci. 2025;26:6887. doi:10.3390/ijms26146887 Piepers S, van den Berg LH, Brugman F, Schelhaas HJ, van der Pol WL, Dooijes D, et al. Assessing motor function in late-onset spinal muscular atrophy. Neuromuscul Disord. 2008;18(4):277-82. doi:10.1016/j.nmd.2008.01.008 Mendonça RH, Machado LMS, Heise CO, Polido GJ, Matsui C Jr, Silva AMS, et al. Motor unit number index (MUNIX) in children and adults with 5q-spinal muscular atrophy: variability and clinical correlations. Neuromuscul Disord. 2021;31(6):498-504. doi:10.1016/j.nmd.2021.02.019 Vacchiano V, Morabito F, Faini C, Nocera G, Not R, Scarpini G, et al. Motor unit number estimation via MScanFit MUNE in spinal muscular atrophy. Muscle Nerve. 2024;70(1):71-81. doi:10.1002/mus.28091 Lobo CC, Wertheimer GSO, Schmitt GS, Matos PCAAP, Rezende TJR, Silva JM, et al. Cranial nerve thinning distinguishes RFC1-related disorder from other late-onset ataxias. Mov Disord Clin Pract. 2024;11(1):45-52. doi:10.1002/mdc3.13930 Miyata M, Kakeda S, Hashimoto T, Ide S, Okada K, Adachi H, et al. Facial nerve atrophy in patients with amyotrophic lateral sclerosis: evaluation with fast imaging employing steady-state acquisition (FIESTA). J Magn Reson Imaging. 2020;51(3):757-66. doi:10.1002/jmri.26890 Mazón M, Costa JFV, Ten-Esteve A, Martí-Bonmatí L. Imaging biomarkers for the diagnosis and prognosis of neurodegenerative diseases: the example of amyotrophic lateral sclerosis. Front Neurosci. 2018;12:784. doi:10.3389/fnins.2018.00784 Barp A, Carraro E, Salmin F, Lizio A, Cheli M, Sansone V. Facial nerve vulnerability in spinal muscular atrophy and motor unit number index of the orbicularis oculi muscle. Muscle Nerve. 2023;67(5):401-6. doi:10.1002/mus.27809 Additional Declarations No competing interests reported. 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09:55:52","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38859,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8296422/v1/bf627a968fe4d2daa35a5af2.html"},{"id":98761627,"identity":"7b2d7c21-7d8b-4320-ba42-3eea8ae4d184","added_by":"auto","created_at":"2025-12-22 09:55:44","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":110694,"visible":true,"origin":"","legend":"\u003cp\u003eBrainstem images acquired with a balanced steady-state (bFFE) sequence illustrating the measurement of the left facial nerve diameter in a patient with spinal muscular atrophy (a) and in a healthy control (b). Panel (c) shows boxplots comparing facial nerve diameters between healthy controls and SMA patients, while panel (d) compares diameters between ambulatory and non-ambulatory patients. Panel (e) depicts the correlation between left facial nerve diameter and MFM-32 scores, and panel (f) shows the correlation between the left facial-to-trigeminal ratio and MFM-32 scores.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8296422/v1/e192c9baea39de804863172a.jpeg"},{"id":100547809,"identity":"751d5bc8-a8f6-435f-844e-c436d84cc856","added_by":"auto","created_at":"2026-01-19 08:16:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":467762,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8296422/v1/da734deb-5be6-4d3a-8528-7797ebb16260.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Facial nerve thinning is a hallmark and correlates with motor function in adults with spinal muscular atrophy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by degeneration of lower motor neurons in the spinal cord and brainstem¹. With the advent of disease-modifying therapies, there is growing interest in biomarkers that directly reflect motor neuron integrity², especially in adults, where disease progression may be slow and clinical scales can be influenced by comorbidities³. Electrophysiological techniques such as CMAP-Scan Fit and motor unit number index (MUNIX) estimate motor unit loss⁴⁻⁵, while imaging studies usually focus on muscle fat fraction quantification. Those methods provide indirect information and may be time-consuming.\u003c/p\u003e \u003cp\u003eHigh-resolution MRI enables reliable visualisation of cranial nerves, allowing quantitative morphometric analysis, particularly for nerves V and VII⁶. In amyotrophic lateral sclerosis (ALS), facial nerve thinning has been reported compared with controls, suggesting that cranial nerve morphometry may serve as a structural marker of motor neuron involvement⁷⁻⁸. In SMA types II and III, neurophysiological abnormalities of the facial nerve, including reduced CMAP and MUNIX values even without clinical weakness, have been described⁹. Based on these observations, we evaluated whether structural changes of the facial and trigeminal nerves can be identified in adults with SMA and whether such alterations correlate with clinical status and motor function.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eWe included 22 adults with genetically confirmed SMA and 14 healthy controls. None had neurological or psychiatric comorbidities. Controls had normal neurological examinations and no relevant family history. Patients were followed at the Neuromuscular Unit of the University of Campinas (UNICAMP).\u003c/p\u003e\u003cp\u003eMRI was performed on a 3T Philips Achieva scanner. Standard T2-weighted images were obtained to rule out unrelated abnormalities. Cranial nerve imaging used an 8-channel head coil and a balanced fast field echo (bFFE) sequence with high spatial resolution (voxel size 0.58×0.58×1.00 mm³, interpolated to 0.28×0.28×0.5 mm³; reconstructed matrix 640×640; 75 slices; TR/TE 7.1/3.0 ms; flip angle 45°). Images were reviewed by a board-certified neuroradiologist blinded to clinical data. Facial and trigeminal nerve diameters were measured bilaterally at their root entry/exit zones, following established guidelines⁶, using ARIA software. A facial-to-trigeminal diameter ratio was also calculated.\u003c/p\u003e\u003cp\u003eOn the same day as MRI, a neurologist assessed ambulation and the presence of facial weakness. Motor function was evaluated by a physical therapist specialised in neuromuscular disorders using the HFMSE and MFM-32 scales. Both raters were blinded to imaging results. Statistical analyses used Mann–Whitney U tests and Spearman correlations, with significance set at p \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, demographic characteristics were similar between SMA patients and controls. Facial nerve diameters were significantly reduced in SMA patients bilaterally (right: 1.15 mm vs 1.40 mm, p = 0.001; left: 1.14 mm vs 1.35 mm, p = 0.012). For the trigeminal nerve, a difference emerged only on the left side (3.16 mm vs 3.59 mm, p = 0.017), whereas right-side measurements did not differ significantly.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of patients with SMA and healthy controls\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients (n = 22)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControls (n = 14)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, median (IQR)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.5 (24.2–44.0)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.5 (30.5–42.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.570\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (M/F)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 / 9\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 / 6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSMA type (II/III)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 / 19\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration, years, median (IQR)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.5 (22.2–36.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMFM-32, median (IQR)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.9 (25.8–52.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHFMSE, median (IQR)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.0 (0–25.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmbulation (ambulantory / non-ambulantory)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 / 16\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical facial weakness (present / absent)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 / 18\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e–\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment status (untreated/treated with Nusinersen)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16/6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eValues are shown as median (interquartile range) or absolute numbers. Comparisons between patients and controls were performed using Mann–Whitney U test (age) and Fisher’s exact test (sex).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eWithin the SMA group, ambulant patients had larger facial nerve diameters than non-ambulant patients (right: 1.29 mm vs 1.14 mm, p = 0.039; left: 1.40 mm vs 1.10 mm, p = 0.003). Trigeminal measurements did not differ according to ambulation. The facial-to-trigeminal ratio was higher in ambulant individuals on both sides.\u003c/p\u003e \u003cp\u003ePatients with clinically overt facial weakness showed marked reductions in facial diameters (right: 0.66 mm vs 1.23 mm, p = 0.009; left: 0.77 mm vs 1.19 mm, p = 0.019) and lower facial-to-trigeminal ratios, whereas trigeminal values remained similar between subgroups.\u003c/p\u003e \u003cp\u003eFacial nerve diameters correlated positively with both functional scales. For MFM-32, correlations were ρ = 0.57 (p = 0.005) on the right and ρ = 0.65 (p = 0.001) on the left. For HFMSE, correlations were ρ = 0.65 (p = 0.001) on the right and ρ = 0.68 (p \u0026lt; 0.001) on the left. The facial-to-trigeminal ratio showed even stronger correlations with motor outcomes (ρ = 0.70–0.73, all p \u0026lt; 0.001). No associations were found between trigeminal measurements and motor function. Disease duration did not correlate with any imaging parameter.\u003c/p\u003e "},{"header":"Discussion and Conclusions","content":"\u003cp\u003eThis study provides evidence that facial nerve thinning is a structural feature of adult SMA detectable through high-resolution MRI. Facial diameters distinguished patients from controls, varied with clinical severity, and correlated with established motor scales. The facial-to-trigeminal ratio enhanced these associations, likely because it normalises a motor-predominant nerve to a predominantly sensory one, thereby increasing sensitivity to motor neuron involvement.\u003c/p\u003e\u003cp\u003eThese results are consistent with neurophysiological evidence of facial motor impairment in SMA and parallel reports of facial nerve thinning in ALS⁷. Trigeminal measurements showed limited discriminatory ability and no functional correlations, consistent with the sensory predominance of this nerve. This pattern contrasts with sensory ganglionopathies such as RFC1/CANVAS, in which trigeminal but not facial nerve involvement is characteristic⁶.\u003c/p\u003e\u003cp\u003eThe lack of correlation with disease duration suggests that cranial nerve thinning relates more to disease severity than to chronological progression. Importantly, cranial nerve morphometry is simple, reproducible, and feasible even in centres without advanced neuroimaging protocols.\u003c/p\u003e\u003cp\u003eIn conclusion, facial nerve diameter and the facial-to-trigeminal ratio appear to be promising structural biomarkers of motor neuron involvement in adult SMA, including in patients without overt facial weakness. Their ease of acquisition and strong clinical correlations support further evaluation in larger and longitudinal cohorts to determine their potential role in monitoring disease progression and response to therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eCompliance with Ethical Standards:\u003c/p\u003e\n\u003cp\u003eAll participants provided written informed consent, and the study was approved by the local Research Ethics Committee. The authors report no conflicts of interest.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eF.F.G. and M.C.F.J. performed study conceptualization and design, wrote the main manuscript text and prepared figures. F.F.G.,M.C.F.J. ,G.S.O.W., T.J.R.R., C.I., R.H.M. and E.Z. performed data collection and analysis and approved the final version to be submitted.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting the findings of this study are not publicly available due to restrictions related to medical confidentiality and patient privacy. De-identified data may be made available from the corresponding author upon reasonable request and subject to institutional and ethical approval.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSchroth M, Deans J, Arya K, Castro D, De Vivo DC, Gibbons MA, Ionita C, Kuntz NL, Lakhotia A, Knierbein EN, et al. Spinal muscular atrophy update in best practices: recommendations for diagnosis considerations. Neurol Clin Pract. 2024;14(4):e200310. doi:10.1212/CPJ.0000000000200310\u003c/li\u003e\n \u003cli\u003eGao C, Zhan Y, Chen H, Deng C. Application of biomarkers in spinal muscular atrophy. Int J Mol Sci. 2025;26:6887. doi:10.3390/ijms26146887\u003c/li\u003e\n \u003cli\u003ePiepers S, van den Berg LH, Brugman F, Schelhaas HJ, van der Pol WL, Dooijes D, et al. Assessing motor function in late-onset spinal muscular atrophy. Neuromuscul Disord. 2008;18(4):277-82. doi:10.1016/j.nmd.2008.01.008\u003c/li\u003e\n \u003cli\u003eMendon\u0026ccedil;a RH, Machado LMS, Heise CO, Polido GJ, Matsui C Jr, Silva AMS, et al. Motor unit number index (MUNIX) in children and adults with 5q-spinal muscular atrophy: variability and clinical correlations. Neuromuscul Disord. 2021;31(6):498-504. doi:10.1016/j.nmd.2021.02.019\u003c/li\u003e\n \u003cli\u003eVacchiano V, Morabito F, Faini C, Nocera G, Not R, Scarpini G, et al. Motor unit number estimation via MScanFit MUNE in spinal muscular atrophy. Muscle Nerve. 2024;70(1):71-81. doi:10.1002/mus.28091\u003c/li\u003e\n \u003cli\u003eLobo CC, Wertheimer GSO, Schmitt GS, Matos PCAAP, Rezende TJR, Silva JM, et al. Cranial nerve thinning distinguishes RFC1-related disorder from other late-onset ataxias. Mov Disord Clin Pract. 2024;11(1):45-52. doi:10.1002/mdc3.13930\u003c/li\u003e\n \u003cli\u003eMiyata M, Kakeda S, Hashimoto T, Ide S, Okada K, Adachi H, et al. Facial nerve atrophy in patients with amyotrophic lateral sclerosis: evaluation with fast imaging employing steady-state acquisition (FIESTA). J Magn Reson Imaging. 2020;51(3):757-66. doi:10.1002/jmri.26890\u003c/li\u003e\n \u003cli\u003eMaz\u0026oacute;n M, Costa JFV, Ten-Esteve A, Mart\u0026iacute;-Bonmat\u0026iacute; L. Imaging biomarkers for the diagnosis and prognosis of neurodegenerative diseases: the example of amyotrophic lateral sclerosis. Front Neurosci. 2018;12:784. doi:10.3389/fnins.2018.00784\u003c/li\u003e\n \u003cli\u003eBarp A, Carraro E, Salmin F, Lizio A, Cheli M, Sansone V. Facial nerve vulnerability in spinal muscular atrophy and motor unit number index of the orbicularis oculi muscle. Muscle Nerve. 2023;67(5):401-6. doi:10.1002/mus.27809\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8296422/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8296422/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSpinal muscular atrophy (SMA) leads to progressive degeneration of lower motor neurons, yet reliable imaging biomarkers remain limited. We evaluated whether MRI-derived facial nerve morphometry distinguishes adult patients from healthy controls and reflects clinical status. Twenty-two adults with SMA types II and III and fourteen matched controls underwent 3T brain MRI using high-resolution balanced fast field echo sequences. Facial nerve diameters were measured bilaterally at the brainstem root entry zone and compared with clinical assessments including ambulation, facial weakness, the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Motor Function Measure (MFM-32). Patients showed consistently reduced facial nerve diameters, with the smallest values observed in non-ambulant individuals and in those with facial weakness. Facial diameters correlated with motor function, and the facial-to-trigeminal ratio demonstrated even stronger associations, emerging as a sensitive indicator of motor neuron loss. These findings support facial nerve morphometry as a promising and accessible biomarker for assessing disease involvement in adults with SMA.\u003c/p\u003e","manuscriptTitle":"Facial nerve thinning is a hallmark and correlates with motor function in adults with spinal muscular atrophy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:54:05","doi":"10.21203/rs.3.rs-8296422/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8149b5d5-d458-41c3-91e3-2ecb84e31877","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-17T06:09:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-22 09:54:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8296422","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8296422","identity":"rs-8296422","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}