Parkinsonism is a Late, Not Rare, Feature of CADASIL: A Study on Italian Patients Carrying the R1006C Mutation (original) (raw)

C erebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-vessel disease caused by mutations in the NOTCH3 gene. 1 The clinical spectrum includes migraine, recurrent transient ischemic attacks or stroke, cognitive decline, psychiatric manifestations, epileptic seizures, and cognitive impairment. 2 Parkinsonian features are not viewed as typical of the CADASIL phenotype and, so far, a clear parkinsonian syndrome has been rarely described. 3-5 Here, we report 5 CADASIL patients carrying the R1006C mutation affected by parkinsonism. Methods Since 1995, we observed 45 individuals belonging to 20 families sharing the R1006C mutation in the exon 19 of the NOTCH3 gene and originating from the district of Ascoli Piceno, Central Italy. 6 Among them, 5 presented parkinsonism and were included in the study. We also included, for comparison, 3 CADASIL patients with the same mutation and without parkinsonism. Brain MRI and 123 I-FP-CIT SPECT studies were performed in all subjects and myocardial 123 I-meta-iodobenzylguanidine (MIBG) scintigraphy in 4 patients with parkinsonism. Details of methodology of clinical and imaging studies are in the online-only Data Supplement. Results Clinical features of the patients are shown in Table 1, and imaging data are shown in Table 2 and the Figure in the online-only Data Supplement. Four patients were male and 1 was female; mean age±SD was 63.0±9.3 years, mean age at onset of CADASIL manifestations was 47.6±14.3 years, and that of parkinsonism 61.6±8.7. The severity of the parkinsonian syndrome was moderate in 4 patients and severe in case 3. Median Hoehn and Yahr stage was 3, median Unified Parkinson's Disease Rating Scale-Motor Section (UPDRS-III) score 19, median Rankin Scale score 2, and median Global Deterioration Scale score 5. Akinesia, rigidity, and postural instability were present in all patients, whereas rest tremor was always absent. Asymmetry of signs was observed only in case 1. Levodopa response was tested in 4 patients without benefit. In all patients, MRI showed widespread areas of increased signal in the periventricular white matter extended down to involve the external and internal capsules, consistent with ischemic lesions, detected on T2-weighted images or FLAIR sequences and associated with focal gliotic hyperintensities or lacunar lesions in the basal ganglia and thalami. Background and Purpose-To describe parkinsonism as a clinical manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Methods-We report 5 patients carrying the R1006C mutation in the exon 19 of NOTCH3 gene. All cases presented late onset, slowly progressive parkinsonism, not responsive to l-dopa. We performed brain MRI and 123 I-FP-CIT SPECT in all and in 3 additional patients carrying the same mutation but without parkinsonism. Four patients with parkinsonism underwent myocardial 123 I-meta-iodobenzylguanidine scintigraphy. Results-In all patients, brain MRI showed widespread ischemic lesions in the periventricular white matter, the internal and external capsules, the basal ganglia, and thalami. 123 I-FP-CIT SPECT showed symmetrical or asymmetrical reduction of tracer uptake in the putamen, with inconstant caudate involvement. Myocardial 123 I-meta-iodobenzylguanidine scintigraphy resulted normal. Nigrostriatal denervation was also demonstrated in 2 patients without parkinsonism. Conclusions-In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, parkinsonism may be a not rare, late onset manifestation. The clinical picture, the lack of response to dopaminergic treatment, and MRI findings suggest a vascular parkinsonism, which may be preceded by a protracted presymptomatic phase.