Case report: CADASIL with cysteine-sparing P572L mutation on exon 11 presenting as focal onset epilepsy

Abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease. It is caused by a NOTCH3 mutation and usually involves changes in cysteine residues. The clinical manifestations of CADASIL with cysteine-sparing mutations and seizures require further clarification because of the limited number of cases reported. Case presentation: The proband, a 66-year-old female, was admitted for secondary generalized tonic-clonic seizures (GTCSs) twice. Magnetic resonance imaging (MRI) showed severe white matter hyperintensity (WMH) sparing the temporal lobes and lacunar infarcts in the basal ganglia, but without microbleeds or brain atrophy, prompting the suspicion of CADASIL. Her medical history revealed that she had cognitive impairment for 31 years, migraine without aura for 26 years, and gait disturbances for six months before admission. Interictal video electroencephalogram revealed sporadic medium-amplitude sharp waves in the right temporal region. Although skin biopsy showed no granular osmiophilic material deposition, whole exome sequencing confirmed a c.1715C>T, p. Pro572Leu mutation on exon 11 of NOTCH3, and the diagnosis of CADASIL was made. Her son was confirmed to take the same mutation presented migraines without aura and mild cognitive impairment, but with normal MRI, while sanger sequencing denied the mutation in her two daughters. Consistent with relevant literature, WMH with less involvement of the temporal lobes may be characteristic of cysteine-sparing mutations. The lower incidence of epileptic seizures in CADASIL may be due to ischemic lesions and white matter lesions in the cortex or subcortex, or an independent clinical manifestation. In addition, GTCSs secondary to focal onset may be more common in patients with CADASIL. Conclusion: We firstly described a CADASIL patient with cysteine-sparing P572L mutation on exon 11 of NOTCH3 in detail and then provides novel insights on cysteine-sparing mutations in CADASIL, especially the presentation of GTCSs secondary to focal onset (temporal lobe).