Cerebellar atrophy is a characteristic sign of late-onset Tay-Sachs disease (LOTS). Other structural neuroimaging abnormalities are inconsistently reported. Our study aimed to perform a detailed whole-brain analysis and quantitatively characterize morphometric changes in LOTS patients. Fourteen patients (8 M/6F) with LOTS from three centers were included in this retrospective study. For morphometric brain analyses, we used deformation-based morphometry, voxel-based morphometry, surface-based morphometry, and spatially unbiased cerebellar atlas template. The quantitative whole-brain morphometric analysis confirmed the finding of profound pontocerebellar atrophy with most affected cerebellar lobules V and VI in LOTS patients. Additionally, the atrophy of structures mainly involved in motor control, including bilateral ventral and lateral thalamic nuclei, primary motor and sensory cortex, supplementary motor area, and white matter regions containing corticospinal tract, was present. The atrophy of the right amygdala, hippocampus, and regions of occipital, parietal and temporal white matter was also observed in LOTS patients in contrast with controls (p < 0.05, FWE corrected). Patients with dysarthria and those initially presenting with ataxia had more severe cerebellar atrophy. Our results show predominant impairment of cerebellar regions responsible for speech and hand motor function in LOTS patients. Widespread morphological changes of motor cortical and subcortical regions and tracts in white matter indicate abnormalities in central motor circuits likely coresponsible for impaired speech and motor function.

Advanced Therapies Program Division of Genetics and Metabolism Department of Pediatrics Medical School University of Minnesota Minneapolis Minnesota USA

Department of Experimental and Clinical Pharmacology University of Minnesota College of Pharmacy Minneapolis Minnesota USA

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Neurology LMU University Hospital LMU Munich Munich Germany

Department of Neuroradiology Medical School University of Minnesota Minneapolis Minnesota USA

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Radiology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Division of Clinical Behavioral Neuroscience Department of Pediatrics Medical School University of Minnesota Minneapolis Minnesota USA

Gene Therapy and Diagnostic Laboratory Department of Pediatrics Medical School University of Minnesota Minneapolis Minnesota USA

Zobrazit více v PubMed

Leal AF, Benincore-Flórez E, Solano-Galarza D, et al. Gm2 gangliosidoses: Clinical features, pathophysiological aspects, and current therapies. Int J Mol Sci. 2020;21(17):1–27. doi:10.3390/ijms21176213 PubMed DOI PMC

Toro C, Zainab M, Tifft CJ. The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment. Neurosci Lett. 2021;764:136195. doi:10.1016/j.neulet.2021.136195 PubMed DOI PMC

Barritt AW, Anderson SJ, Leigh PN, Ridha BH. Late-onset Tay–Sachs disease. Pract Neurol. 2017;17(5):396–399. doi:10.1136/practneurol-2017-001665 PubMed DOI

Mitsumoto H, Sliman RJ, Schafer IA, et al. Motor neuron disease and adult hexosaminidase a deficiency in two families: Evidence for multisystem degeneration. Ann Neurol. 1985;17(4):378–385. doi:10.1002/ana.410170413 PubMed DOI

Steiner KM, Brenck J, Goericke S, Timmann D. Cerebellar atrophy and muscle weakness: Late-onset Tay-Sachs disease outside Jewish populations. BMJ Case Rep. 2016;2016(C):2–3. doi:10.1136/bcr-2016-214634 PubMed DOI PMC

Peters AS, Markovic K, Schramm A, Schwab S, Heuss D. Late onset hexosaminidase A deficiency in a young adult. Eur J Neurol. 2008;15(7):2007–2008. doi:10.1111/j.1468-1331.2008.02170.x PubMed DOI

Deik A, Saunders-Pullman R. Atypical presentation of late-onset Tay-sachs disease. Muscle Nerve. 2014;49(5):768–771. doi:10.1002/mus.24146 PubMed DOI PMC

Hölzer HT, Boschann F, Hennermann JB, et al. Cerebellar atrophy on top of motor neuron compromise as indicator of late-onset GM2 gangliosidosis. J Neurol. 2021;268(6):2259–2262. doi:10.1007/s00415-021-10492-y PubMed DOI PMC

Neudorfer O, Pastores GM, Zeng BJ, Gianutsos J, Zaroff CM, Kolodny EH. Late-onset Tay-Sachs disease: Phenotypic characterization and genotypic correlation in 21 affected patients. Genetics in Medicine. 2005;7(2):119–123. doi:10.1097/01.GIM.0000154300.84107.75 PubMed DOI

Streifler J, Golomb M, Gadoth N. Psychiatric features of adult GM2 gangliosidosis. British Journal of Psychiatry. 1989;155(SEP.):410–413. doi:10.1192/bjp.155.3.410 PubMed DOI

Májovská J, Hennig A, Nestrasil I, et al. Pontocerebellar atrophy is the hallmark neuroradiological finding in late-onset Tay-Sachs disease. Neurological Sciences. 2022;43(5):3273–3281. doi:10.1007/s10072-021-05757-3 PubMed DOI

Rowe OE, Rangaprakash D, Weerasekera A, et al. Magnetic resonance imaging and spectroscopy in late-onset GM2-gangliosidosis. Mol Genet Metab. 2021;133(4):386–396. doi:10.1016/j.ymgme.2021.06.008 PubMed DOI PMC

Inglese M, Nusbaum AO, Pastores GM, Gianutsos J, Kolodny EH, Gonen O. MR imaging and proton spectroscopy of neuronal injury in late-onset G M2 gangliosidosis. American Journal of Neuroradiology. 2005;26(8):2037–2042. PubMed PMC

Nestrasil I, Ahmed A, Utz JM, Rudser K, Whitley CB, Jarnes-Utz JR. Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. Mol Genet Metab. 2018;123(2):97–104. doi:10.1016/j.ymgme.2017.12.432 PubMed DOI PMC

Gaser C, Nenadic I, Buchsbaum BR, Hazlett EA, Buchsbaum MS. Deformation-based morphometry and its relation to conventional volumetry of brain lateral ventricles in MRI. Neuroimage. 2001;13(6):1140–1145. doi:10.1006/nimg.2001.0771 PubMed DOI

Dahnke R, Yotter RA, Gaser C. Cortical thickness and central surface estimation. Neuroimage. 2013;65:336–348. doi:10.1016/j.neuroimage.2012.09.050 PubMed DOI

Diedrichsen J A spatially unbiased atlas template of the human cerebellum. Neuroimage. 2006;33(1):127–138. doi:10.1016/j.neuroimage.2006.05.056 PubMed DOI

Diedrichsen J, Zotow E. Surface-based display of volume-averaged cerebellar imaging data. PLoS One. 2015;10(7):1–18. doi:10.1371/journal.pone.0133402 PubMed DOI PMC

Kalincik T, Vaneckova M, Tyblova M, et al. Volumetric MRI Markers and Predictors of Disease Activity in Early Multiple Sclerosis: A Longitudinal Cohort Study. PLoS One. 2012;7(11):1–8. doi:10.1371/journal.pone.0050101 PubMed DOI PMC

Salimi-Khorshidi G, Smith SM, Nichols TE. Adjusting the effect of nonstationarity in cluster-based and TFCE inference. Neuroimage. 2011;54(3):2006–2019. doi:10.1016/j.neuroimage.2010.09.088 PubMed DOI

Voevodskaya O The effects of intracranial volume adjustment approaches on multiple regional MRI volumes in healthy aging and Alzheimer’s disease. Front Aging Neurosci. 2014;6(OCT). doi:10.3389/fnagi.2014.00264 PubMed DOI PMC

Lindig T, Bender B, Kumar VJ, et al. Pattern of Cerebellar Atrophy in Friedreich’s Ataxia—Using the SUIT Template. Cerebellum. 2019;18(3):435–447. doi:10.1007/s12311-019-1008-z PubMed DOI

Cocozza S, Costabile T, Pontillo G, et al. Cerebellum and cognition in Friedreich ataxia: a voxel-based morphometry and volumetric MRI study. J Neurol. 2020;267(2):350–358. doi:10.1007/s00415-019-09582-9 PubMed DOI

Hu J, Chen X, Li M, et al. Pattern of cerebellar grey matter loss associated with ataxia severity in spinocerebellar ataxias type 3: a multi-voxel pattern analysis. Brain Imaging Behav. 2022;16(1):379–388. doi:10.1007/s11682-021-00511-x PubMed DOI

Reetz K, Dogan I, Rolfs A, et al. Investigating function and connectivity of morphometric findings — Exemplified on cerebellar atrophy in spinocerebellar ataxia 17 (SCA17). Neuroimage. 2012;62(3):1354–1366. doi:10.1016/j.neuroimage.2012.05.058 PubMed DOI PMC

Hernandez-Castillo CR, Diaz R, Vaca-Palomares I, et al. Extensive cerebellar and thalamic degeneration in spinocerebellar ataxia type 10. Parkinsonism Relat Disord. 2019;66(August):182–188. doi:10.1016/j.parkreldis.2019.08.011 PubMed DOI

Jeyakumar M, Smith D, Eliott-Smith E, et al. An inducible mouse model of late onset Tay-Sachs disease. Neurobiol Dis. 2002;10(3):201–210. doi:10.1006/nbdi.2002.0511 PubMed DOI

Miklyaeva EI, Dong W, Bureau A, et al. Late onset Tay-Sachs disease in mice with targeted disruption of the Hexa gene: Behavioral changes and pathology of the central nervous system. Brain Res. 2004;1001(1–2):37–50. doi:10.1016/j.brainres.2003.11.067 PubMed DOI

Sarna JR, Larouche M, Marzban H, Sillitoe RV., Rancourt DE, Hawkes R. Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease. Journal of Comparative Neurology. 2003;456(3):279–291. doi:10.1002/cne.10522 PubMed DOI

Walkley SU, Sikora J, Micsenyi M, Davidson C, Dobrenis K. Lysosomal compromise and brain dysfunction: examining the role of neuroaxonal dystrophy. Biochem Soc Trans. 2010;38(6):1436–1441. doi:10.1042/BST0381436 PubMed DOI PMC

Lin YC, Hsu CCH, Wang PN, Lin CP, Chang LH. The Relationship Between Zebrin Expression and Cerebellar Functions: Insights From Neuroimaging Studies. Front Neurol. 2020;11(April):1–12. doi:10.3389/fneur.2020.00315 PubMed DOI PMC

Walkley SU, Sikora J, Misceney M, Davidson C, Dobrenis K. 乳鼠心肌提取 HHS Public Access. Physiol Behav. 2018;176(5):139–148. doi:10.4049/jimmunol.1801473.The DOI

Lefter S, O’ Mahony O, Sweeney B, Ryan AM. Late-Onset Tay-Sachs Disease in an Irish Family. Mov Disord Clin Pract. 2021;8(1):106–110. doi:10.1002/mdc3.13096 PubMed DOI PMC

Beh SC, Nations S, Pascual JM, Vernino S. Ataxia and weakness in a young woman. Arch Neurol. 2012;69(7):924–927. doi:10.1001/archneurol.2012.1207 PubMed DOI

Godeiro C, Felicio AC, Benites V, Chieia MA, Oliveira ASB. Late-onset hexosaminidase A deficiency mimicking primary lateral sclerosis. Arq Neuropsiquiatr. 2009;67(1):105–106. doi:10.1590/S0004-282X2009000100024 PubMed DOI

Hund E, Grau A, Fogel W, et al. Progressive cerebellar ataxia, proximal neurogenic weakness and ocular motor disturbances: Hexosaminidase A deficiency with late clinical onset in four siblings. J Neurol Sci. 1997;145(1):25–31. doi:10.1016/S0022-510X(96)00233-X PubMed DOI

Inzelberg R, Korczyn AD. Parkinsonism in adult‐onset GM2 gangliosidosis. Movement Disorders. 1994;9(3):375–377. doi:10.1002/mds.870090325 PubMed DOI

Stendel C, Gallenmüller C, Peters K, et al. Paranoid delusion as lead symptom in two siblings with late-onset Tay–Sachs disease and a novel mutation in the HEXA gene. J Neurol. 2015;262(4):1072–1073. doi:10.1007/s00415-015-7729-0 PubMed DOI

Paw BH, Kaback MM, Neufeld EF. Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase. Proc Natl Acad Sci U S A. 1989;86(7):2413–2417. doi:10.1073/pnas.86.7.2413 PubMed DOI PMC

Neudorfer O, Pastores GM, Zeng BJ, Gianutsos J, Zaroff CM, Kolodny EH. Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med. 2005;7(2):119–123. doi:10.1097/01.gim.0000154300.84107.75 PubMed DOI

Fernandesa M, Bernard Boulay Feige Kaplan P d. Chronic Variant GM2 Gangliosidosis Splicing Defects MRNA Quantitation.; 1997. http://www.karger.ch

Riboldi GM, Lau H. Diagnostic tips from a video series and literature review of patients with late-onset tay-sachs disease. Tremor and Other Hyperkinetic Movements. 2022;12(1). doi:10.5334/tohm.726 PubMed DOI PMC

Foundas AL, Bollich AM, Feldman J, et al. Aberrant auditory processing and atypical planum temporale in developmental stuttering. Neurology. 2004;63(9):1640–1646. doi:10.1212/01.WNL.0000142993.33158.2A PubMed DOI

Fox PT, Ingham RJ, Ingham JC, Zamarripa F, Xiong JH, Lancaster JL. Brain correlates of stuttering and syllable production: A PET performance-correlation analysis. Brain. 2000;123(10):1985–2004. doi:10.1093/brain/123.10.1985 PubMed DOI

Shapiro BE, Natowicz MR. LETTERS psychogenic aphonia: Spectacular recovery after motor cortex transcranial magnetic stimulation. J Neurol Neurosurg Psychiatry. 2009;80(1):94. doi:10.1136/jnnp.2008.154302 PubMed DOI

Grim KK, Phillips GD, Renner DR. Dysarthria and Stutter as Presenting Symptoms of Late-Onset Tay-Sachs Disease in Three Siblings. Mov Disord Clin Pract. 2015;2(3):289–290. doi:10.1002/mdc3.12194 PubMed DOI PMC

Jahnová H, Poupětová H, Jirečková J, et al. Amyotrophy, cerebellar impairment and psychiatric disease are the main symptoms in a cohort of 14 Czech patients with the late-onset form of Tay–Sachs disease. J Neurol. 2019;266(8):1953–1959. doi:10.1007/s00415-019-09364-3 PubMed DOI

Starowicz-Filip A, Prochwicz K, Klosowska J, et al. Cerebellar Functional Lateralization From the Perspective of Clinical Neuropsychology. Front Psychol. 2021;12:775308. doi:10.3389/fpsyg.2021.775308 PubMed DOI PMC

Jovicich J, Czanner S, Han X. 基因的改变NIH Public Access. Genomics. 2009;94(1):20–31. doi:10.1016/j.neuroimage.2009.02.010.MRI-derived PubMed DOI

Stonnington CM, Tan G, Klöppel S, et al. Interpreting scan data acquired from multiple scanners: A study with Alzheimer’s disease. Neuroimage. 2008;39(3):1180–1185. doi:10.1016/j.neuroimage.2007.09.066 PubMed DOI PMC

Wittens MMJ, Allemeersch GJ, Sima DM, et al. Inter- and Intra-Scanner Variability of Automated Brain Volumetry on Three Magnetic Resonance Imaging Systems in Alzheimer’s Disease and Controls. Front Aging Neurosci. 2021;13. doi:10.3389/fnagi.2021.746982 PubMed DOI PMC