The Cerebellum https://doi.org/10.1007/s12311-020-01173-z SHORT REPORTS Ataxia Associated with CADASIL: a Pathology-Confirmed Case Report and Literature Review Don Gueu Park 1 & Je Hong Min 1 & Seong hyang Sohn 2 & Young Bae Sohn 3 & Jung Han Yoon 1 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is primarily characterized by migraine, stroke, mood disturbances, and cognitive decline. Ataxia has seldom been reported as a presenting symptom. Here, we review reports of CADASIL presenting as ataxia and compare these to the first pathologically confirmed case of CADASIL presenting with progressive ataxia. A 50-year-old woman presented with progressive truncal ataxia. Brain magnetic resonance imaging (MRI) revealed white matter hyperintensities in the bilateral anterior temporal lobes, external capsules, and periventricular areas, but not the cerebellum. Electron microscopy of skin biopsy material revealed multiple granular osmiophilic materials. Genetic testing confirmed a c.4552C > A mutation in exon 25 of the NOTCH3 gene. CADASIL is a rare cause of progressive ataxia, and only four cases of CADASIL presenting with ataxia have been reported in the literature. We also discuss the possible pathophysiology of cerebellar ataxia associated with CADASIL. Keywords CADASIL . NOTCH3 . Exon 25 . Leu1518Met . Ataxia . Granular osmiophilic material Introduction Case Report Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is primarily characterized by migraine, stroke, mood disturbances, and cognitive decline. However, ataxia has rarely been reported as presenting symptom [1, 2]. Here, we report the first pathologically confirmed CADASIL patient with progressive ataxia, and we review ataxia associated with CADASIL. A 50-year-old woman presented with a 3-month history of progressive gait difficulties in the absence of any history of migraine, stroke, or vascular risk factors such as hypertension or diabetes. Her family and relatives had no history of cerebrovascular disease or dementia. In neurological examination, the patient was dysarthric, with wide-based unsteady gait and hyperreflexia in lower limbs. There was greater truncal ataxia than lower limb ataxia, and upper limb ataxia was not evident except for very mild limb dysmetria and dysdiadochokinesis in the left (Supplementary Video). Eye movement examinations were grossly normal, with normal saccades and smooth pursuit. All other neurological parameters were also unremarkable. Brain magnetic resonance imaging (MRI) revealed bilateral anterior temporal lobe, external capsule, and periventricular white matter lesions on fluid-attenuated inversion recovery (FLAIR) images (Fig. 1 a and b). Neuropsychological testing revealed mild cognitive impairment (MCI) with impaired visuospatial memory and fronto-executive function, and the Beck Depression Inventory (BDI) indicated mild depression. Nerve conduction studies of the upper and lower extremities revealed no evidence of peripheral neuropathy. Laboratory tests for vascular risk factors revealed mild dyslipidemia, but markers of leukodystrophy (the levels of arylsulfatases A and B and that Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12311-020-01173-z) contains supplementary material, which is available to authorized users. * Jung Han Yoon jhyoon@ajou.ac.kr 1 Department of Neurology, Ajou University School of Medicine, 164, World cup-ro, Yeontong-gu, Suwon-si, Gyeonggi-do 16499, South Korea 2 Laboratory of Cell Biology, Ajou University School of Medicine, Suwon, South Korea 3 Medical Genetics, Ajou University School of Medicine, Suwon, South Korea Cerebellum Fig. 1 Brain MRI images (A, B) and electron microscopy of skin biopsy material (C). Fluid attenuated inversion recovery (FLAIR) imaging revealed bilateral anterior temporal (a), external capsular, and periventricular lesions (b). The arrow indicates granular osmiophilic material (GOM) (c) a b c of very long-chain fatty acids) were negative. Genetic tests for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, and 17; dentatorubralpallidoluysian atrophy; and Friedreich ataxia were negative. A sequence analysis of the NOTCH3 gene (NM_00435.2) identified two heterozygous variants of unknown significance; one was c.4552C > A which changes leucine to methionine at position 1518 in exon 25, and the other was c.2567-4G > A in intron 16. However, the clinical significance of the c.4552C > A (p.Leu1518Met) variant has been classified as “likely benign” in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar). The c.25674G > A variant, another NOTCH3 variant in our case, exhibited a low minor allele frequency (T = 0.0000 (1/20326, ExAC)). In silico splice site analysis predicted no significant impact on splicing in both Human Splicing Finder (http://www.umd.be/ HSF/) and FSPLICE (http://www.softberry.com/berry.phtml). Familial segregation analysis was not possible due to patient refusal. Electron microscopy of skin biopsy material revealed multiple granular osmiophilic material (GOM) deposits in the basal lamina, characteristic of CADASIL (Fig. 1c). Discussion CADASIL is associated with a wide range of symptoms, but ataxia as the initial presentation of CADASIL has rarely been reported (Table 1). In a study that reported the clinical spectrum of CADASIL in seven affected families, a small portion of the 38 subjects who had histories of transient ischemic attacks or strokes had ataxia, although detailed case descriptions were not included [3]. More recently, Vedeler et al. reported a family in which three of four siblings exhibited progressive ataxia and spastic paraparesis associated with a NOTCH3 mutation [1]. In their report, the patients presented with spastic paraparesis, truncal ataxia, dysdiadochokinesis, broken smooth pursuit, or internuclear ophthalmoplegia. MRI showed bilateral white matter hyperintensities (WMH), but the cerebellum was intact and without evident atrophy. These cases had a NOTCH3 gene mutation at exon 19, but no information was given on pathological confirmation. In a recent report, Sari et al. [2] described a 41-year-old woman who presented with gait ataxia, dysarthria, dysdiadochokinesis, hallucinations, and seizures. Her brain MRI showed WMH and mild cerebellar atrophy, and genetic testing of the NOTCH3 gene revealed mutation in exon 33. However, the case in that report also lacked pathological confirmation. It is unusual that no white matter lesions or cerebellar atrophy have/has been noted in CADASIL patients presenting with ataxia, including our case (Table 1). MRI findings could be heterogeneous in CADASIL, and earlier brain MRI studies revealed evidence of infratentorial involvement (cerebellum and spinal Cerebellum Table 1 Summary of movement disorders in CADASIL patients Reference Sex/ Symptoms and signs onset age Brain imaging Genetic testing (NOTCH3) Vedeler et al., 2011 [1] WMH, no MRI lesions or cerebellar atrophy WMH, subcortical infarcts in both hemisphere and basal ganglia, no MRI lesions or cerebellar atrophy WMH, no MRI lesions or cerebellar atrophy c.3065G > T Not tested (p.Cys1022Phe); exon 19 WMH including the temporal lobe, hyperintensity lesions in left uncus, mild cerebellar atrophy c.6668C > T Not tested (p.Ala2223Val); exon 33 M/53 Spastic paraparesis, internuclear ophthalmoplegia, truncal ataxia M/55 Bilateral dysdiadochokinesis, truncal ataxia, spastic paraparesis, hyperreflexia M/71 Broken smooth pursuit, bilateral dysdiadochokinesis Sari et al., F/41 2019 [2] Our case F/60 Gait ataxia, dysarthria, dysdiadochokinesis, diplopia, abduction palsy in the left eye, skew deviation, cognitive decline, visual/auditory hallucinations, seizures Dysarthria, dysdiadochokinesis, gait ataxia GOM deposition evident on biopsy WMH including bilateral external capsule c.4552C > A + and temporal poles,no MRI lesions or (p.Leu1518Mcerebellar atrophy et); exon 25 c.2567-4G > A; intron 16 WMH, white matter hyperintensities cord) in CADASIL patients [4–6]. However, symptomatic CADASIL patients can have normal brain MRI features with only early abnormalities evident on brain single photon emission computed tomography (SPECT), transcranial Doppler (TCD), or 18 F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) [7, 8]. Previous 18F-FDG PET studies reported crossed cerebellar diaschisis [9] or hypometabolism of both bilateral cerebellar hemispheres in CADASIL patients compared with controls [10]. Impaired cerebrovascular reactivity is an early pathogenic feature of CADASIL. The vasodilator acetazolamide increased overall cerebral blood flow (including in the cerebellum) and improved CADASIL symptoms [11]. We speculate that vascular endothelial dysfunction may trigger the chronic ischemia or hypoperfusion that precedes infarction in CADASIL patients [12]. It is also possible that the prevalence of ataxia in patients with CADASIL has been underestimated; cerebellar signs may be masked by spastic paresis or Parkinsonism caused by subcortical infarcts. It may be worth noting that truncal ataxia was dominant rather than limb ataxia, in all reported ataxic cases of CADASIL including our case. It implies greater vermian than hemispheric cerebellar involvement, or it could be explained by a dentate lesion similar to that seen in dentatorubralpallidoluysian atrophy (DRPLA), which exhibits truncalpredominant ataxia. In support of this, an MR imaging study showed significantly lower T2 signal intensity in dentate nucleus of CADASIL patients compared with control [13]. Previous studies have shown that low T2 signal intensity in caudate and putamen of CADASIL patients was due to iron deposition [14], which was associated with the disease severity [15]. However, additional studies are required to clarify whether low signal intensity in dentate nucleus is associated with ataxia in these patients. It can be challenging to differentiate frontal gait disorder from cerebellar gait ataxia [16], and we acknowledge that the patient’s gait disturbances could be partially due to frontal gait disorder. However, because the presence of dysarthria, subtle dysdiadochokinesis, and limb dysmetria cannot be explained solely by the frontal lobe lesions seen in this patient, we believe that the patient’s manifestations are more easily explained by cerebellar ataxia than by frontal gait disorder alone. Since movement disorders are increasingly recognized as network disorders, the involvement of fronto-ponto-cerebellar fibers could contribute to gait and limb abnormalities [17, 18]. The symptoms and signs may be more evident in follow-up examinations, which could help with the interpretation. The c.4552C > A mutation in exon 25 of NOTCH3 may not be a pathogenic mutation. All pathogenic mutations in NOTCH3 are thought to occur within the epidermal growth factor-like repeats encoded by exons 2–24, but an earlier report indicated that the c.4544 T > C mutation in exon 25 might cause CADASIL by increasing canonical NOTCH3 signaling via an unusual mechanism without pathological GOM deposition [19]. No family with CADASIL caused by mutations in exon 25 has yet been reported. Recently, a possible association of an exon 33 mutation with CADASIL was reported in a Turkish family [2]. Conclusion This case indicates that ataxia may be a presenting neurological symptom of CADASIL in the absence of its other Cerebellum classical clinical features. Clinicians should consider CADASIL during the differential diagnosis of progressive ataxia, even when all typical clinical features of CADASIL are absent. Further cases of ataxia bearing the p.Leu1518Met mutation are needed to demonstrate the pathogenicity of this exon 25 NOTCH3 mutation. Authors’ Contributions JHY contributed to the study conception and design. Material preparation and data collection were performed by DGP, JHM, SHS, and YBS. The first draft of manuscript was written by DGP and JHY, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Information This research was partly supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (No. NRF2017R1C1B5018378 (J.H.Y), NRF-2018M3A9E8023859 (J.H.Y). 7. 8. 9. 10. 11. Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflict of interest. 12. Ethical Approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. 13. References 14. 1. Vedeler C, Bindoff L. A family with atypical CADASIL. J Neurol. 2011;258(10):1888–9. https://doi.org/10.1007/s00415-011-6023-z. 2. Sari US, Kisabay A, Batum M, Tarhan S, Dogan N, Coskunoglu A, et al. CADASIL with atypical clinical symptoms, magnetic resonance imaging, and novel mutations: two case reports and a review of the literature. J Mol Neurosci. 2019;68(4):529–38. https://doi. org/10.1007/s12031-019-01313-z. 3. Chabriat H, Vahedi K, Iba-Zizen MT, Joutel A, Nibbio A, Nagy TG, et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet. 1995;346(8980):934–9. https:// doi.org/10.1016/s0140-6736(95)91557-5. 4. Jing XZ, Jiang W, Gan L, Zhu WA, Dong M, Yu P, et al. CADASIL with spinal cord involvement: a case report and literature review. J Neurol. 2019;266(9):2330–3. https://doi.org/10. 1007/s00415-019-09436-4. 5. Bersano A, Bedini G, Markus HS, Vitali P, Colli-Tibaldi E, Taroni F, et al. The role of clinical and neuroimaging features in the diagnosis of CADASIL. J Neurol. 2018;265(12):2934–43. https://doi. org/10.1007/s00415-018-9072-8. 6. Motolese F, Rossi M, Gangemi E, Bersano A, Scelzo E, Di Lazzaro V, et al. CADASIL as multiple sclerosis mimic: a 48-year-old man with severe leukoencephalopathy and spinal cord involvement. Mult Scler Relat Disord. 2020;41:102014. https://doi.org/10.1016/ j.msard.2020.102014. 15. 16. 17. 18. 19. Miranda M, Dichgans M, Slachevsky A, Urbina F, Mena I, Venegas P, et al. CADASIL presenting with a movement disorder: a clinical study of a Chilean kindred. Mov Disord. 2006;21(7): 1008–12. https://doi.org/10.1002/mds.20879. Moreton FC, Cullen B, Delles C, Santosh C, Gonzalez RL, Dani K, et al. Vasoreactivity in CADASIL: comparison to structural MRI and neuropsychology. J Cereb Blood Flow Metab. 2018;38(6): 1085–95. https://doi.org/10.1177/0271678X17710375. Tatsch K, Koch W, Linke R, Poepperl G, Peters N, Holtmannspoetter M, et al. Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL: an 18F-FDG PET study. J Nucl Med. 2003;44(6): 862–9. Su J, Huang Q, Ren S, Xie F, Zhai Y, Guan Y, et al. Altered brain glucose metabolism assessed by (18)F-FDG PET imaging is associated with the cognitive impairment of CADASIL. Neuroscience. 2019;417:35–44. https://doi.org/10.1016/j.neuroscience.2019.07. 048. Huang L, Yang Q, Zhang L, Chen X, Huang Q, Wang H. Acetazolamide improves cerebral hemodynamics in CADASIL. J Neurol Sci. 2010;292(1–2):77–80. https://doi.org/10.1016/j.jns. 2010.01.023. Liem MK, Lesnik Oberstein SA, Haan J, Boom R, Ferrari MD, Buchem MA, et al. Cerebrovascular reactivity is a main determinant of white matter hyperintensity progression in CADASIL. AJNR Am J Neuroradiol. 2009;30(6):1244–7. https://doi.org/10. 3174/ajnr.A1533. Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology. 2001;218(2):443–51. https://doi.org/10.1148/radiology.218.2.r01fe24443. Liem MK, Lesnik Oberstein SA, Versluis MJ, Maat-Schieman ML, Haan J, Webb AG, et al. 7 T MRI reveals diffuse iron deposition in putamen and caudate nucleus in CADASIL. J Neurol Neurosurg Psychiatry. 2012;83(12):1180–5. https://doi.org/10.1136/jnnp2012-302545. Sun C, Wu Y, Ling C, Xie Z, Kong Q, Fang X, et al. Deep gray matter Iron deposition and its relationship to clinical features in cerebral autosomal dominant Arteriopathy with subcortical infarcts and leukoencephalopathy patients: a 7.0-T magnetic resonance imaging study. Stroke. 2020;51(6):1750–7. https://doi.org/10.1161/ strokeaha.119.028812. Pirker W, Katzenschlager R. Gait disorders in adults and the elderly: a clinical guide. Wien Klin Wochenschr. 2017;129(3–4):81–95. https://doi.org/10.1007/s00508-016-1096-4. Thompson PD. Frontal lobe ataxia. Handb Clin Neurol. 2012;103: 619–22. https://doi.org/10.1016/b978-0-444-51892-7.00044-9. Holtbernd F, Eidelberg D. Functional brain networks in movement disorders: recent advances. Curr Opin Neurol. 2012;25(4):392– 401. https://doi.org/10.1097/WCO.0b013e328355aa94. Fouillade C, Chabriat H, Riant F, Mine M, Arnoud M, Magy L, et al. Activating NOTCH3 mutation in a patient with small-vesseldisease of the brain. Hum Mutat. 2008;29(3):452. https://doi.org/ 10.1002/humu.9527. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.