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Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL – experience from Slovakia

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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary vascular disorder causing ischaemic attacks and strokes in middle-aged adults. Though the clinical spectrum includes some typical symptoms, recognition of the disease, especially at an earlier stage, is very difficult because of the highly variable manifestation and incomplete clinical picture. Characteristic brain MRI findings and the presence of pathogenic variants in the NOTCH3 gene are fundamental for CADASIL diagnosis. In this paper, we provide the first comprehensive report on CADASIL patients from Slovakia. Altogether, we identified 23 different pathogenic variants in 35 unrelated families. In our cohort of patients with clinical suspicion of CADASIL, we found a causal genetic defect and confirmed the diagnosis in 10.2% of cases. We present the case reports with up-to-date unpublished NOTCH3 variants and describe their phenotype–genotype correlation: p.(Cys65Phe), p.(Pro86Leu/Ser502Phe), p.(Arg156*), p.(Cys408Arg), p.(Tyr423Cys), p.(Asp1720His), and p.(Asp1893Thrfs*13). The most frequently described location for pathogenic variants was in exon 4, whereas the most common single variant was p.Arg1076Cys in exon 20. Based on the results of our study, we propose a re-evaluation of the criteria for the selection of patients suitable for NOTCH3 gene analysis. We hereby state that the currently used protocol of a high score requirement is not ideal for assessing molecular analysis, and it will be desirable to be less strict in criteria for genetic testing.

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Authors and Affiliations

  1. Department of Molecular and Biochemical Genetics, Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine of Comenius University, University Hospital, Mickiewiczova 13, 813 69, Bratislava, Slovakia

    M. Juhosová, J. Chandoga, S. Dallemule, P. Ďurina, D. Jarásková, P. Jungová, A. Pastoráková, R. Petrovič & D. Böhmer

  2. Department of Medical Genetics, University Hospital, Žilina, Slovakia

    F. Cisárik

  3. Department of Medical Genetics, University Hospital F.D. Roosvelta, Námestie Ludvíka Svobodu 1, 975 17, Banská Bystrica, Slovakia

    D. Kantarská

  4. Unilabs Slovensko, s. r. o., Ltd., Bratislava, Slovakia

    M. Kvasnicová, M. Mistrík & H. Zelinková

  5. Department of Clinical Genetics, University Hospital Trenčín, Trenčín, Slovakia

    A. Valachová

  6. Genet, s. r. o., Razusova 16, 949 01, Nitra, Slovakia

    J. Barošová

  7. 1st Department of Neurology, Faculty of Medicine of Comenius University, University Hospital, Bratislava, Slovakia

    J. Štofko

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  1. M. Juhosová
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Appendix

Appendix

Patients’ history and clinical findings were obtained from the medical records.

MRI findings were evaluated by the same neuroradiologist. MRI findings in CADASIL are the white matter hyperintensities (WMHs) in both T2 and FLAIR sequences, typically in the anterior temporal, frontal, and parietal lobe; external capsule; and corpus callosum. In particular, the rtgWMH in the anterior temporal lobes and corpus callosum distinguish CADASIL from vascular leukoaraiosis [39]. In addition, acute and chronic ischaemic lesions, enlarged perivascular spaces (EPVS), and signs of microbleeds are common findings. Brain atrophy was measured using the bi-caudal ratio (BCR).

Case 1

A 50-year-old woman has suffered from intermittent headaches associated with weak arms and finger paresthesias since the age of 33.

MRI showed extensive converging WMHs of both hemispheres, including the anterior temporal, frontal, and parietal lobes; the external capsules; and the corpus callosum. The occipital lobes were relatively unaffected. In addition, postischemic lesions in both the thalamus, pons Varoli, and EPVS were found.

Molecular-genetic analysis of the NOTCH3 gene confirmed the presence of pathogenic variant p.(Cys65Phe) in heterozygous form. A genealogical study was not possible because the patient offered no reliable clinical data concerning parents and relatives (including three underage sons).

Case 2

The 62-year-old female reported gait problems, lower limb weakness, and dizziness. A neurological examination revealed a spastic-paretic gait.

MRI showed enormous WMHs of both hemispheres including the temporal, frontal, and parietal lobes; the internal and external capsules; and the corpus callosum. The white matter of the cerebellum and the pons Varoli was also affected. Postischemic lesions were seen in both the thalamus and pons Varoli; moreover, EPVS were present.

The patient was found to carry pathogenic variant p.(Cys65Phe) in heterozygous form.

Family history: The mother died of a stroke at the age of 60, her mother’s brother as a 50-year-old remained immobile, and one of her two brothers suffered from migraines. All adult relatives suffered from high blood pressure. Their genetic testing is not available.

Case 3

A 68-year-old man who suffered from constant headaches and rapidly progressing dementia (Mini-Mental State Examination score was 16/30), other physical examination was normal.

MRI showed extensive converging WMHs of both hemispheres including the anterior temporal, frontal, and parietal lobes; the external capsule; and the corpus callosum. In addition, small acute ischaemic hemispherical lesions, the postischemic lesions in both the thalamus and the brainstem, EPVSs, signs of microbleeds, and cerebral atrophy (BCR = 18.7 mm) were seen.

Sanger sequencing of exon 8 confirmed the presence of heterozygous variant p.(Cys408Arg) in both, proband and daughter.

Family history: From his numerous family members, only his 32-year-old asymptomatic daughter accepted genetic counseling, DNA analysis, and MRI examination. MRI revealed numerous small WMHs in both hemispheres including anterior temporal, frontal, and parietal lobes and furthermore very small lesions in the corpus callosum.

figure a

Case 3: 68-years-old man: WMHs bilaterally in frontal and parietal lobes, EPVSs (MRI, FLAIR sequence)

figure b

Case 3: 32-year-old asymptomatic daughter: Numerous small WMHs in both hemispheres (MRI, FLAIR sequence)

Case 4

A 60-year-old man suffered from recurrent transient ischaemic attacks (TIAs), progressive cognitive decline, short-term memory loss, and speech disorders and finally developed completed cerebral ischemia with right hemiparesis and aphasia.

MRI showed extensive confluent WMHs in both hemispheres and in the brain stem. WMHs were found predominantly in the anterior temporal, frontal, and parietal lobes; the external capsules; but not in the corpus callosum. Important EPVS were present.

Genetic counseling revealed typical hallmarks of CADASIL, and the variant p.(Tyr423Cys) was found by NOTCH3 sequencing with a Pescini score of 11 points.

Family history: No neurological diseases were depicted in his ancestors. His younger brothers suffered from some psychiatric disease. However, genetic counseling was not accepted from their part. The patient had two sons and one daughter. No clinical symptoms related to CADASIL disease were detected in the daughter and younger son.

The older son (40-year-old) suffered from “pulling sensations” in his head, concentration difficulties, attention deficit, and memory disorders, tinnitus auris, and bilateral hypacusis perceptiva.

MRI of the brain showed multiple supratentorial lesions of ischaemic etiology.

DNA analysis of exon 8 resulted in finding the p.(Tyr423Cys) variant in heterozygous form. This case study supports the pathogenic significance of the novel variant.

Case 5

A 58-year-old woman has suffered from recurrent TIAs since the age of 30. Later, other symptoms typical of CADASIL were associated, such as migraine attacks with aura, paraesthesias, leg cramps, anxiety, depression, and memory loss.

MRI showed bilaterally numerous non-confluent supratentorial WMHs in the temporal, frontal, and parietal lobes and marked lesions in the corpus callosum. In addition, EPVS and cerebral atrophy (BCR = 18.3 mm) were detected.

Genetic counseling revealed two variants p.(Pro86Leu)/p.(Ser502Phe) in the heterozygous form with a Pescini score of 14 points.

Family history: The mother overcame a stroke twice and died at the age of 69, in addition to suffering from migraines and dementia. Her 3 brothers died young at the age of 35, 45, and 50 from unknown causes. The patient’s 2 children (son and daughter) also suffer from headaches and migraines.

Case 6

A 45-year-old woman was treated for a long time for headaches with common analgesics that were effective.

MRI showed bilateral supratentorial multiple partially merging WMHs in the anterior temporal, frontal, and parietal lobe; external capsule; and a small lesion in the corpus callosum.

Her CADASIL score was 8 points, and the cysteine-sparing p.Gln151Glu variant was detected.

Family history: The mother suffered from chronic headaches.

Case 7

The 55-year-old man has overcome recurrent TIAs and cerebral ischemia since he was 46 years old. The patient had several risk factors such as atherosclerosis, obesity, arterial hypertension, hyperhomocysteinemia, and hypercholesterolemia.

MRI revealed vast confluent WMHs, including the anterior temporal, frontal, parietal, and occipital lobes; external capsules; corpus callosum; and pons Varoli. In addition, postischemic lesion in the left thalamus, EPVS, and brain atrophy (BCR = 19.2 mm) were present.

Though Pescini’s score reached only 8 points. The proband was heterozygous for a novel nonsense variant p.(Arg156*).

Family history: His mother died at the age of 49 from cerebellar hemorrhage.

figure c

Case 7: A Confluent WMHs bilaterally, EPVS, and cerebral atrophy (MRI, FLAIR sequence). B WMHs in the corpus callosum and medial surface of frontal and parietal lobes (MRI, FLAIR sequence)

Case 8

The youngest patient was a 20-year-old woman with a heterozygous form of these p.Ser497Leu/p.Ala1020Pro variants confirmed. She overcame TIA with right-sided hemiparesis and hemianopsia at the age of 19. Moreover, she suffered from headaches, nausea, paraesthesia, sensory disturbances, and memory problems.

MRI revealed 2 postischemic lesions—one older minor in the left thalamus and the other one in the calcarine sulcus of the left occipital lobe.

Co-segregated variants p.Ser497Leu/p.Ala1020Pro were detected and transmitted from her 52-year-old father, who suffered from frequent headaches, vertigo, vomiting, and diabetes. MRI of the brain showed only a few isolated small WMHs bilaterally in the frontal and parietal lobes.

Family history: Serious psychiatric illnesses were diagnosed in her two brothers.

figure d

Case 8: Ischaemic lesion in the left calcarine sulcus (MRI, DWI sequence)

Case 9

A 35-year-old female overcame left-sided hemiparesis.

MRI showed a large ischaemic lesion in the basal ganglia on the right. In addition, bilaterally small WMHs were seen bilaterally in the frontal and parietal lobes, and these were not present in the temporal, occipital lobes, or in the corpus callosum.

The Pescini score was high (20 p.). The DNA analysis of NOTCH3 confirmed the presence of co-segregated variants p.Ser497Leu/p.Ala1020Pro in heterozygous form.

Family history: The father overcame a stroke at the age of 40 and suffered from severe dementia. Her brother died of a stroke at the age of 60. The 58-year-old mother had no health problems, but the co-segregated variants were confirmed.

Case 10

A 33-year-old woman suffered from her childhood from migraines with aura.

MRI showed several small WMHs bilaterally in the frontal and parietal lobes and occasionally in the corpus callosum.

The co-segregated genetic variants p.Ser497Leu/p.Ala1020Pro in homozygous form were detected, and in both parents, heterozygous forms of variants were present. The Pescini score was 10 points.

Case 11

A 34-year-old man suffering from epileptic seizures from the age of 29.

MRI revealed vast confluent WMHs, including the anterior temporal, frontal, and parietal lobes, not in external capsules, and the corpus callosum.

Variant c.5158G > C, p.(Asp1720His) was detected.

Family history: The familiar variant was not identified in the proband’s father. Proband inherited this variant from his mother, whose brain MRI showed WMHs in both hemispheres and pons Varoli.

Case 12

A 55-year-old female suffered from headaches, dizziness, and concentration disorders.

MRI showed excessively confluent bilateral WMHs in both hemispheres—temporal, frontal, parietal lobes, external capsules, and the corpus callosum, also in the pons Varoli.

The variant c.5691delA, p.(Asp1898Thrfs*13) was detected.

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Juhosová, M., Chandoga, J., Cisárik, F. et al. Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL – experience from Slovakia. Neurogenetics 24, 1–16 (2023). https://doi.org/10.1007/s10048-022-00704-6

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  • DOI: https://doi.org/10.1007/s10048-022-00704-6

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