Objective: To investigate the prevalence and neuroimaging findings of NOTCH3 p.R544C mutation in patients with Parkinsonism in Taiwan.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutation of NOTCH3 gene. Spectrum of clinical manifestation, includes recurrent stroke, migraine, cognitive impairment, psychiatric manifestations, and epileptic seizures. Parkinsonism has been descried as a rare clinical presentation of this disease. In Taiwan, more than 70% of CADASIL patients carry the mutation hot spot of p.R544C. We investigated the prevalence and their neuroimaging findings of NOTCH3 p.R544C mutation in patients with Parkinsonism in Taiwan

Method: This prospective study recruited 476 patients with Parkinsonism, included 417 Parkinson’s disease (PD), 23 vascular Parkinsonism (VP), and 36 drug-induced Parkinsonism (DIP). The p.R544C mutation was identified by polymerase chain reaction with confronting two-pair primers. Demographics, clinical features, and findings of neuroimaging studies were obtained for their special charts.

Results: We positively detected 5 of the total 476 Parkinsonism patients for p.R544C NOTCH3 mutation, included 3 PD and 2 VP patients. The prevalence of p.R544C NOTCH3 mutation was 1.05% of Parkinsonism in the study population; 0.7% (3/417) in PD, 8.7% (2/23) in VP, and 0% in DIP. The mean age at onset of 3 PD with the mutation was 56.3 ± 7.5 years, that was insignificantly younger than that of total PD patients (66 .0 ± 11.1 years, p=0.14) and 2 VP patients did not revealed difference in their mean age at onset (75.5 ± 0.5 v.s. 74.3 ± 8.5 years). Brain MRI in 2 VP patients with the mutation revealed a widespread ischemic lesion in the periventricular white matte, internal and external capsule, basal ganglia, and thalamus, but in those 3 PD patients did not revealed significant abnormality. ^99mTc-TRODAT-1 (TRODAT) SPECT imaging revealed markedly and asymmetrically reduced uptake of dopamine transporter at the bilateral striatum in all five mutation carriers.

Conclusion: Parkinsonian picture is not rarely clinical presentation in CADASIL patients and.R544C NOTCH3 mutation is underdiagnosed in Parkinsonism in Taiwan.  It merits to have genetic testing for p.R544C NOTCH3 mutation in Parkinsonism patients, especially in VP.

References: 1. Joutel C, Corpechoy C, Ducros A, et al. Notch3 mutations in CADASI, a hereditary adult-onset conditions causing stroke and dementia. Nature 1996;383:707-710.
2. Ragno M, Berbellini A, Caccho G, et al. Parkinsonism is a late, not rare, feature of CADASIL: a study on Italian patients carrying the R1006C mutation. Stroke 2013;44:1147-1149.
3. Tang SC, Cehn YR, Chi NF, et al. Prevalence and clinical characteristics of stroke patients with p.R544C NOTCH3 mutation in Taiwan. Ann Clin Trans Neurol 2019;6:121-128.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/prevalence-and-neuroimaging-presentations-of-parkinsonism-patients-with-p-r544c-notch3-mutation-in-taiwan/