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

doi:10.21203/rs.3.rs-3646797/v1

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Case Report

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

https://doi.org/10.21203/rs.3.rs-3646797/v1

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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).

CADASIL

NOTCH3

cysteine-sparing mutation

seizure

Pro572Leu

exon 11

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 on chromosome 19 (1), which can weaken arteriolar survivability to blood flow and pressure, making small vessels prone to spasm, blockage, and rupture (2, 3). Clinically, CADASIL typically presents as migraine with aura, subcortical ischemic events, mood disturbances, apathy, and cognitive impairment (4). It usually manifests as white matter hyperintensity (WMH), ischemic infarcts, microbleeds, and brain atrophy on brain magnetic resonance imaging (MRI), and granular osmiophilic material (GOM) deposition on skin biopsy (4).

NOTCH3 encodes a single-pass transmembrane protein expressed in arteriolar vascular smooth muscle cells (5–7), and its mutations affect the expression and normal function of this protein. Most NOTCH3 mutations are missense mutations that usually involve a cysteine residue, in which either an amino acid is substituted for a cysteine, or a cysteine replaces an amino acid (8). An odd number of cysteine residues are thought to cause protein misfolding, ultimately affecting trafficking, processing, ligand binding, and signal transduction (8). Cysteine-sparing NOTCH3 mutations have recently been discovered (9); however, their pathogenesis remains unclear. Current studies showed no differences in clinical manifestations; however, some studies revealed that white matter lesions and temporal lobes were less involved in patients with cysteine-sparing mutations than in those with cysteine-involving mutations (10–13).

Clinically, epileptic seizures appear to be a relatively rare symptom of CADASIL, with an overall incidence of 5–10% (4). Among the CADASIL cases with seizures, generalized seizures are the most common; however, focal seizures and status epilepticus are less commonly reported (14–16). Although CADASIL is a hereditary disease with familial aggregation, most seizures occur in sporadic cases (17, 18). Additionally, they mostly appear after a stroke (14). Studies have suggested that seizures may be triggered by ischemic lesions or white matter lesions, or may be an independent clinical manifestation of CADASIL; however, the specific mechanism is not yet clear (18).

Here, we report for the first time a case of CADASIL with a c.1715C > T, p. Pro572Leu mutation on exon 11 presenting as generalized tonic-clonic seizures (GTCSs) secondary to focal onset to broaden our understanding of CADASIL with cysteine-sparing mutations and epileptic seizures.

The proband was a right-handed female with a primary school education and a medical history of antral gastritis, tuberculosis, tracheitis, cholecystectomy, and somnipathy before 40 years of age. At age 45, both her long-term and short-term memory began to decline, forgetting family members’ phone numbers and what she wanted to do a moment ago. At the age of 50 years, her memory impairment gradually worsened. She experienced intermittent attacks of dizziness and migraine without aura, mainly located in the hemilateral temple and forehead, sometimes accompanied by vomiting, lasting for 30 min to 1 hour, with a frequency of two to three times a month, and usually recovered after sleep. At 60 years of age, her migraines worsened with increased intensity and frequency. When she was 62 years old, she gradually developed an imbalanced posture while walking and often leaned to the left. At the age of 65 years, she visited a local hospital because of a migraine. Brain Computed Tomography revealed several lacunar infarcts in the bilateral basal ganglia. T2 and FLAIR sequences of the brain MRI showed extensive WMH in the bilateral semioval center, paraventricular capsule, and external capsule (Fazekas grade 3) (Fig. 1, A-H) (19). She was diagnosed with migraine and lacunar infarcts, subsequently hospitalized for five days, and discharged with oral medication for one month (medication unknown). Six months before admission to our hospital, she had fallen twice, falling forward uncontrollably with a facial injury. At the age of 66, she was admitted to our hospital because of seizures twice in two months. The first seizure was nocturnal, and the witness reported stiffness of her four limbs, unconsciousness, eyes staring to the left, salivation, pale face, and a tongue bite. The seizure lasted for approximately 3–5 min, and the patient complained of chest and abdominal pain after recovery. She was diagnosed with secondary epilepsy, although a regular electroencephalogram (EEG) (lasting for 15 min) showed normal results. She was discharged from a local hospital with 1,200 mg/day oral valproate. Twenty days before admission, she reduced the valproate dose on her own to 600 mg per day due to “controlled seizures” and experienced a relapsed seizure attack during sleep, similar to the first one. Her primary care doctor referred her to our epilepsy center with 1,200 mg/day valproate.

On admission, her vital signs were stable with a normal blood pressure of 112/80 mmHg. Neurological examination findings were normal, except for grade IV muscle strength in both lower limbs. The Mini-Mental State Examination (MMSE) score was 23 (losing 4 points for attention and calculation, and 3 points for language), and the Montreal Cognitive Assessment (MoCA) score was 15 (losing 4 points for attention and delayed recall, 2 points for visuospatial/executive functions, language, and abstract, and 1 point for naming). Laboratory examination showed no obvious abnormalities, except for a slightly decreased fibrinogen of 1.68 g/L (normal range, 2–4 g/L). Twenty-four-hour video EEG showed sporadic medium-amplitude sharp waves in the right temporal region (Fig. 1I). No microbleeds were observed on susceptibility-weighted imaging. Cerebral and jugular computed tomography angiography showed that the vertebral and base arteries were tortuous, the right vertebral artery was tiny, and the V1 segment artery was stiff, without any vascular stenosis.

Based on her typical neuroimaging and clinical symptoms, CADASIL was suspected and further confirmed by whole exome sequencing (WES), which revealed a c.1715C > T, p. Pro572Leu heterozygous mutation on exon 11 of NOTCH3 (Fig. 2, A). This missense variant was possibly pathogenic predicted by Rare Exome Variant Ensemble Learner. The pathogenicity of this missense variant predicted by multiple bioinformatics tools, and the population frequency of it evaluated in gene databases are shown in Table 1. Further, this mutation had been mentioned in the studies of Kim, H. et al, and Yoon, C. W. et al, which showed its pathogenicity (10, 20). After obtaining informed consent, skin biopsy was performed, and electron microscopy showed a normal structure of the skin and its subcutaneous connective tissue, two arterioles found in the subcutaneous adipose connective tissue, a few smooth muscle cell layers of arterioles, and no GOM deposition in the smooth muscle cells (Fig. 1J). On the 10th day after admission, the repeated MMSE score was 23 (losing 4 points for language and 3 points for attention and calculation), and the MoCA score was 21 (losing 3 points for visuospatial/executive functions and delayed recall, and 1 point for naming, attention, and abstract). The proband was discharged seizure-free and with ameliorated cognitive function, and with oral sustained-release sodium valproate (750 mg/day), aspirin (100 mg/night), atorvastatin calcium (10 mg/night), and donepezil (10 mg/day).

Table 1

The pathogenicity of Pro572Leu predicted by bioinformatics tools and the population frequency of it evaluated in gene databases
Missense variant	SIFT	Polyphen2_HVAR	Polyphen2_HDIV	ClinPred	LRT	MT	MA	FATHMM	PROVEAN	GERP	gnomAD_exome	gnomAD _genome	ExAc	1000 genomes
Pro572Leu	deleterious	Probably damaging ( > = 0.909)	Probably damaging ( > = 0.957)	deleterious	neutral	disease causing	Medium	deleterious	deleterious	4.51	0.003	0	0.002	0
Note: SIFT: Sorting Intolerant From Tolerant; PolyPhen2: Polymorphism Phenotyping v2; LRT: Likelihood Ratio Test; MT: Mutation Taster; MA: Mutation Assessor; FATHMM: Functional Analysis Through Hidden Markov Models; PROVEAN: Protein Variation Effect Analyzer; GERP: Genomic Evolutionary Rate Profiling; ExAc: the Exome Aggregation Consortium.

The patient did not have any vascular risk factors such as hypertension, diabetes, smoking, or drinking. Her father had migraines at age 55, cognitive impairment at age 74, and was sometimes unable to navigate his way home, although he could recognize his family members. He had bronchiectasis and emphysema at a young age and had no history of ischemic stroke, hypertension, or diabetes mellitus. He had smoked for 50 years (ten cigarettes per day), had no history of alcohol intake, and died of bowel cancer at 82. Her mother had migraines at around 65 years of age, ischemic stroke at 70 years of age with a history of hypertension and heart disease but no cognitive impairment, and died of lung cancer at 80. Her 43-year-old son had migraines without aura since age 37, mainly located in the occiput, with a frequency of once to twice a year, and appearing only after insufficient sleep and upper respiratory tract infection. At about the age of 40, his memory started to decline, not being able to remember things as fast as he used to. However, his MRI showed no obvious abnormality. He did not report a history of hypertension, diabetes, or drinking but had smoked cigarettes at a rate of one pack for 2–3 days for 13 years. The two daughters of the proband were all asymptomatic. Sanger sequencing was performed on the son, two daughters, one grandson and granddaughter of the proband, which confirmed that only her son carried the same mutation (Fig. 2B-F). The proband’s two sisters and one brother did not show similar symptoms and refused to undergo gene testing to verify whether they had the mutation or not. A pedigree map was established based on inquiries from the proband and her pedigree members (Fig. 2G).

One year later, we followed up the proband and found that she was seizure-free. Her migraines were less frequent and intense than she had previously experienced. Her cognitive functions did not show obvious improvement or deterioration, with an MMSE score of 23 (losing 3 points for orientation, 2 points for language, 1 point for attention and calculation, and recall) and MoCA score of 22 (losing 4 points for delayed recall, 2 points for visuospatial/executive functions, and 1 point for naming and orientation). Additionally, to further evaluate the retinal structure and microvasculature, optical coherence tomography and optical coherence tomography and angiography were performed, which revealed no obvious abnormalities. The specific parameters of retinal structure and microvasculature in the proband are summarized in Fig. 3.

Here, we firstly describe a case of CADASIL with NOTCH3 c.1715C > T, p. Pro572Leu mutation on exon 11 presenting as GTCSs secondary to focal onset (temporal lobe).

The proband was admitted to the hospital due to seizures twice. We suspected the diagnosis of CADASIL based on her extensive and typically located WMH and lacunar infarcts on MRI, and a history of migraine and cognitive impairment. WES confirmed as NOTCH3 Pro572Leu mutation on exon 11, which was possibly pathogenic predicted by multiple bioinformatics tools, and reproducible because it had appeared in the studies of Kim et al and Yoon, C. W. et al (10, 20), and existed the phenomenon of family segregation, for her son carrying the same mutation while her two daughters not. Although the skin biopsy of our proband did not reveal typical GOM deposition, which has 100% specificity for CADASIL diagnosis, we still considered the diagnosis of CADASIL based on its relatively low sensitivity of 45–96% (21, 22).

Recent studies have compared CADASIL patients with cysteine-involving mutations to those with cysteine-sparing mutations. For example, a meta-analysis including 752 patients with CADASIL found no significant differences in clinical manifestations and phenotype severity, but the onset was considerably earlier in patients with cysteine-sparing mutations than in those with cysteine-involving mutations (43 vs. 51 years) (13). In contrast, Hu et al. conducted a comparative study of 42 patients (28 cysteine-involving and 14 cysteine-sparing) and found that patients with cysteine-sparing mutations had later symptom onset (51.36 ± 7.06 years vs. 44.96 ± 8.82 years) (11). For the range of WMH, cysteine-sparing cases presented milder lesions in the temporal lobes evaluated by modified Schelten’s scale (23) than patients with cysteine-involving mutations (1.50 ± 1.74 vs. 3.11 ± 2.32, scores of 0–6 indicating the size and number of WMH in the temporal lobes) (11). A study by Kim et al., which enrolled 79 patients with NOTCH3 mutations (55 cysteine-involving and 24 cysteine-sparing) showed a higher rate of anterior temporal lobe hyperintensities in the cysteine-involving group than in the cysteine-sparing group (67.3%, 25.0%, respectively, p = 0.001), although both groups showed similar clinical signs and symptoms (10). Additionally, Muino et al. studied 34 probands with cysteine-sparing mutations and found that all probands had severe WMH, but 91% did not have anterior temporal pole involvement (12). Therefore, WMH with less involvement of the temporal lobes may be a key characteristic of cysteine-sparing mutations; however, whether the age of onset is lower remains unclear. Our proband, who had a Pro572Leu mutation, showed signs and symptoms that were highly consistent with the above manifestations, including cognitive impairment at the age of 45 years as onset and severe WMH-sparing temporal lobes (Fazekas grade 3) on MRI. However, gait disturbances with falls and epileptic seizures are both infrequently reported on exon 11 mutations of NOTCH3. Accumulation of clinical data regarding cysteine-sparing mutations is required to draw further conclusions.

Although CADASIL is associated with a variety of clinical symptoms, epileptic seizures are rare. Our proband demonstrated GTCSs with right temporal epileptiform discharges on interictal VEEG, similar to four cases involving cysteine-involving mutations (Arg544Cys, Arg182Cys, and Arg207Cys) on exons 11 and 4 which all presented as focal discharge on EEG and GTCS on symptom (17, 18, 24, 25). The GTCS may be caused by the rapid propagation of focal-onset epileptiform discharges to bilateral cerebral hemispheres and whole neural networks (18). Therefore, the seizure type in our proband was classified as GTCS secondary to focal onset. Whether this type of seizure is more common requires further investigation. During the one-year follow-up, she was seizure-free with continuous valproate, although the dosage was still self-reduced.

Seizures in CADASIL cohorts have been investigated in several studies. Desmond et al. showed that 5.7% (6/105) of patients with CADASIL presented with epileptic seizures, which were the initial symptoms in three (2.9%) patients (26). Another observational report indicated that 10% (10/102) of CADASIL patients developed seizures during disease progression, and nine of them presented with GTCSs, and only one with focal seizure, but the onset was not described (14). Additionally, a study of 73 CADASIL patients with an Arg544Cys mutation on exon 11 revealed that the incidence of seizures was only 1.4% (27), and patients presented with GTCS secondary to focal onset (17). Interestingly, seizures tended to be more common in CADASIL patients with cysteine-sparing NOTCH3 mutations. Muino et al. found that seizures occurred in three out of five CADASIL patients with cysteine-sparing mutations during the course of the disease (12): one patient presented with generalized seizures with spike waves in the whole cerebrum on EEG, one presented with generalized tonic seizures with paroxymal spikes and waves predominantly in the left hemisphere on EEG, and one did not describe the seizure type (28, 29). Consistently, our proband, with a cysteine-sparing mutation, presented with secondary GTCSs during the disease course. However, whether epileptic seizures are more common in patients with CADASIL with cysteine-sparing NOTCH3 mutations requires further investigation in studies with larger sample sizes.

Regarding the pathophysiological mechanism of seizures in CADASIL, the hallmark ischemic cortical or white matter lesions on MRI have been specifically noted and discussed. Ischemic lesions, which are epileptogenic, have been identified as an important risk factor for late-onset epilepsy in patients with sporadic stroke (14, 30), and recurrent seizures can further aggravate existing ischemic injury. A study by Dichgans et al. showed that nine of ten patients with CADASIL that had seizures had a history of ischemic stroke (14). Furthermore, a postmortem study using high-resolution 7-Tesla MRI combined with neuropathological detection of the brain confirmed a large number of intracortical infarcts in patients with CADASIL, which were invisible on the last in vivo 1.5 T MRI (31). On the other hand, white matter lesions adjacent to the cortex may also be epileptogenic (15, 32). Gasparini et al. found that the temporal lobe is predominantly involved in epilepsy associated with white matter lesions (33). Consistent with this, our proband had right temporal epileptiform discharges, which may have propagated to the whole brain and presented as GTSCs. Along with her extensive cortical white matter lesions, although not involving the temporal lobe, lacunar infarcts in the bilateral basal ganglia probably collectively contributed to the seizures, or epileptic seizure itself was one of the manifestations of CADASIL caused by NOTCH3 mutation on exon 11.

This is the first report on a CADASIL patient with cysteine-sparing P572L mutation on exon 11 of NOTCH3 who presented GTCSs secondary to focal onset (temporal lobe). We highlight that in epilepsy with unknown etiology, when typical clinical and neuroimaging manifestations of CADASIL are present, genetic testing should be performed in time for early diagnosis. Relatively milder or temporal lobe-sparing WMH may be highly specific for CADASIL patients with cysteine-sparing mutations. Epileptic seizures are rare in CADASIL, which may be triggered by ischemic lesions and white matter lesions in cortex or subcortex, and may be one of the manifestations of CADASIL. Additionally, GTCSs secondary to focal onset may be more common in patients with CADASIL.

CADASIL	cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
MRI	magnetic resonance imaging
GTCSs	generalized tonic-clonic seizures
WMH	white matter hyperintensity
GOM	granular osmiophilic material
EEG	electroencephalogram
MMSE	Mini-Mental State Examination
MoCA	Montreal Cognitive Assessment
WES	whole exome sequencing

Ethics approval and consent to participate

Procedures in the current case followed the principle of the Helsinki Declaration and were approved by the Ethics Committee on Human Research of Tongji Hospital.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report.

Availability of data and materials

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Competing interests

The authors have no conflicts of interest to declare.

Funding

This work was supported by the National Natural Science Foundation of China [81974279], China Association Against Epilepsy Fund for Epilepsy Research-UCB Fund [2020020A], National Key Project of Common and Frequently Occurring Diseases [2022YFC2503800], Natural Science Foundation of Hubei Province [2022CFB279], and Health Commission of Hubei Province [ZY2021M025].

Authors' contributions

YG wrote the draft of the manuscript. HL collected and analyzed the clinical and imaging data. ZG and MW followed up the proband and her pedigree. YT evaluated the patient’s ocular vessels and provided the proband’s optical coherence tomography and optical coherence tomography angiography data. HK gave the main idea and edited the whole manuscript. All authors contributed to the article and approved the submitted version.

Acknowledgements

The authors would like to thank the patient and her pedigree for participation.

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

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