Objective: To report the case of a patient with parkinsonism as initial symptom, secondary to an specific NOTCH3 pathogenic variant.Objective: To report the case of a patient with parkinsonism as initial symptom, secondary to an specific NOTCH3 pathogenic variant.

Background: Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is the most common hereditary cerebral small vessel disease [1-2]. Parkinsonism, has been rarely reported in patients with CADASIL, and it is considered a late manifestation.

Method: Case Report.

Results: A 65-year-old woman presents to the neurology consult because of long-standing tremor. Her family history included her mother deceased at age 51 due to a hemorrhagic stroke, and migraine headaches in her sister, daughter, and granddaughter. She reports that tremor started at age 30, primarily at rest and kinetic in the left upper limb, and was followed by progressive rigidity impairing writing. At age 40, she noted right lower limb stiffness without compromising ability to walk; and at 45 a low-frequency horizontal head tremor, without dystonic posturing. She reported that since age 63 she had been experiencing migraine-like headaches and short-term memory disturbances. Examination revealed mild cognitive impairment (Montreal Cognitive Assesment score 24/30 points), bilateral and asymmetric parkinsonism (MDS-UPDRS III score 39 points). MRI revealed severe ischemic damage in deep white matter and basal ganglia, suggestive of CADASIL (Figure 1) without other abnormalities. Genetic testing confirmed the presence of the pathogenic variant c.1732C>T (p.Arg578Cys) in the NOTCH3 gene. She was started on galantamine and cognitive rehabilitation with mild improvement in executive function (MoCA score: 27/30 points) and on levodopa/carbidopa for 2 months, without improvement of tremor and was suspended due to side effects. Genetic testing revealed the presence of the same variant in NOTCH3 in her sister and her daughter. There have been no reports of the NOTCH3 c.1732C>T variant presenting with early-onset parkinsonism, with most cases of this variant reporting the classic CADASIL phenotype of stroke and migraine.[3-4] Also, our case represents the second genetically-confirmed CADASIL case in Mexico.[5]

Conclusion: Albeit rare, the CADASIL genotype may include early-onset parkinsonism without levodopa response.[6]

Figure 1.

References: 1. Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44(5):731-739. doi:10.1002/ana.410440506
2. Ragno M, Berbellini A, Cacchiò G, et al. Parkinsonism is a late, not rare, feature of CADASIL: a study on Italian patients carrying the R1006C mutation. Stroke. 2013;44(4):1147-1149. doi:10.1161/STROKEAHA.111.000458
3. Guo W, Xu B, Sun H, et al. Case Report: Progressive Asymmetric Parkinsonism Secondary to CADASIL Without Dementia. Front Neurol. 2022;12:760164. Published 2022 Jan 10. doi:10.3389/fneur.2021.760164
4. Erro R, Lees AJ, Moccia M, et al. Progressive parkinsonism, balance difficulties, and supranuclear gaze palsy. JAMA Neurol. 2014;71(1):104-107. doi:10.1001/jamaneurol.2013.5149
5. Barinagarrementeria F, Arauz A, Mine M. First Mexican Family with CADASIL: A Novel Mutation in the NOTCH3 Gene (P07.242), Neurology Feb 2013, 80 (7 Supplement) P07.242.
6. Ramirez J, Dilliott AA, Binns MA, et al. Parkinson’s Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities. Mov Disord. 2020;35(11):2090-2095. doi:10.1002/mds.28171

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/early-onset-parkinsonism-as-presenting-manifestation-of-cadasil-in-a-mexican-woman-with-notch3-c-1732ct-pathogenic-variant/