Clinical and epidemiological profiles from a case series of 26 Brazilian CADASIL patients

Nogueira, Renata; Couto, Christian Marques; Oliveira, Pérola de; Martins, Bernardo José Alves Ferreira; Montanaro, Vinícius Viana Abreu

doi:10.1055/s-0042-1758756

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Original Article • Arq. Neuropsiquiatr. 81 (5) • 2023 • https://doi.org/10.1055/s-0042-1758756 copy

Clinical and epidemiological profiles from a case series of 26 Brazilian CADASIL patients

Perfil clínico e epidemiológico de uma série de casos de 26 pacientes com diagnóstico de CADASIL

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke. Despite being the most prevalent vascular hereditary disease, clinical data regarding the Brazilian population are scarce. Considering that the Brazilian population has one of the most heterogeneous genetic constitutions in the world, knowledge about genetic and epidemiological profiles is mandatory. The present study aimed to elucidate the epidemiological and clinical features of CADASIL in Brazil.

Methods

We performed a case series study comprising 6 rehabilitation hospitals in Brazil and reported the clinical and epidemiological data from the medical records of patients admitted from 2002 to 2019 with genetic confirmation.

Results

We enrolled 26 (16 female) patients in whom mutations in exons 4 and 19 were the most common. The mean age at the onset of the disease was of 45 years. Ischemic stroke was the first cardinal symptom in 19 patients. Cognitive impairment, dementia, and psychiatric manifestations were detected in 17, 6, and 16 patients respectively. In total, 8 patients had recurrent migraines, with aura in 6 (75%) of them. White matter hyperintensities in the temporal lobe and the external capsule were found in 20 (91%) and 15 patients (68%) respectively. The median Fazekas score was of 2. Lacunar infarcts, microbleeds, and larger hemorrhages were observed in 18 (82%), 9, and 2 patients respectively.

Conclusion

The present is the most extensive series of Brazilian CADASIL patients published to date, and we have reported the first case of microbleeds in the spinal cord of a CADASIL patient. Most of our clinical and epidemiological data are in accordance with European cohorts, except for microbleeds and hemorrhagic strokes, for which rates fall in between those of European and Asian cohorts.

Keywords:
CADASIL; Stroke; Epidemiology; Brazil; Receptor, Notch3

Family	Patients	Nucleotide change	Amino acid change	Exon	Exons sequenced
Family 1	Patients 1, 2, 3	c.3043T > C	p.1015Cys > Arg	19	Information not available
Family 2	Patients 4, 5	c.457C > T	p.153Arg > Cys	4	3 and 4
Family 3	Patients 6, 7	c.505C > T	p.169Arg > Cys	4	Information not available
Family 4	Patient 8	c.509A > G	p.170His > Arg	4	Information not available
Family 5	Patient 9	c.602G > A	p.201Cys > Tyr	4	3, 4 and 19
Family 6	Patient 10	c.509A > G	p.170His > Arg	4	Information not available
Family 7	Patient 11	c.397C > T	p.133Arg > Cys	4	Information not available
Family 8	Patient 12	c.2932A > C	p.978Ser > Arg	18	Information not available
Family 9	Patient 13	c.544C > T	p.182Arg > Cys	4	3 and 4
Family 10	Patient 14	c.397C > T	p.133Arg > Cys	4	3, 4 and 19
Family 11	Patient 15	c.457C > T	p.153Arg > Cys	4	3 and 4
Family 12	Patient 16	c.751T > A	p.251Cys > Ser	5	5
Family 13	Patient 17	c.634T > A	p.212Cys > Ser	4	3 and 4
Family 14	Patient 18	c.665G > A	p.222Cys > Tyr	4	3 and 4
Family 15	Patient 19	c.3058G > C	p.1020Ala > Pro	19	2, 3, 5, 6, 11, 18 and 19
Family 16	Patient 20	c.457C > T	p.153Arg > Cys	4	3 and 4
Family 17	Patient 21	c.457C > T	p.153Arg > Cys	4	3, 4 and 19
Family 18	Patient 22	c.1735T > C	p.579Cys > Arg	11	Information not available
Family 19	Patient 23	c.457C > T	p.153Arg > Cys	4	Information not available
Family 20	Patient 24	c.457C > T	p.153Arg > Cys	4	3 and 4
Family 21	Patient 25	c.434C > G	p.145Ser > Cys	4	3, 4 and 19
Family 22	Patient 26	c.397C > T	p.133Arg > Cys	4	3 and 4

Clinical features	Patients: n (%)
All patients	26
Male gender	10 (38%)
Positive family history*	19 (73%)
Asymptomatic	2 (8%)
Cardinal symptoms	24 (92%)
Migraine**	8 (31%)
Without aura	1 (13%)
With aura	6 (75%)
TIA or stroke	21 (81%)
Ischemic stroke	21 (100%)
Hemorrhagic stroke	1 (5%)
Cognitive impairment	17 (65%)
Mild cognitive impairment	11 (65%)
Dementia	6 (35%)
Psychiatric symptoms	16 (61%)
Other neurological symptoms	22 (92%)
Seizure	3 (12%)
Encephalopathy	1 (4%)
Pseudobulbar palsy	6 (23%)
Pyramidal signs	22 (85%)
Apraxic gait	6 (23%)
Bulbar signs	7 (27%)
Vascular risk factors
No cardiovascular risk factors	8 (31%)
Past or current alcohol consumption*	3 (12%)
Past or current smoker*	6 (23%)
Dyslipidemia**	8 (31%)
Diabetes mellitus**	1(4%)
Hypertension**	10 (38%)
Disability
mRS: 0-2	17 (65%)
mRS: 3-5	9 (35%)
Antiaggregation therapy	14 (54%)

First major clinical symptom	Patients: n (%)	Mean age (years)
All patients	26	45
No major clinical symptom	4 (15%)	41
Transient ischemic attack/Stroke	19 (73%)	44.2
Encephalopathy	1 (4%)	51
Seizure	1 (4%)	68
Progressive gait disorder	1 (4%)	57

	SWI, T2* or b0		T2 or FLAIR					T2 or FLAIR
	Intracerebral hemorrhage (n)		Lacunar stroke image					White matter hyperintensities
Patient	Microbleeds	Larger hemorrhage	BG	FPM	EC	IC	Pons	TL	PV	EC	IC	EC > IC	BT	FAZEKAS score	SVD score
Patient 1	17	0	+	+	–	–	+	+	+	+	+	+	+	1	3
Patient 2	0	0	–	–	–	–	–	+	–	+	–	+	+	1	1
Patient 3	N/A		N/A					N/A						N/A	N/A
Patient 4	0	0	–	–	–	–	–	+	–	–	–	–	–	0	0
Patient 5	0	0	+	+	–	–	+	+	+	–	+	–	+	3	2
Patient 6	0	0	+	–	–	–	–	+	+	+	+	+	+	3	2
Patient 7	0	0	–	–	–	–	–	+	+	–	–	–	–	2	1
Patient 8	N/A		N/A					N/A						N/A	N/A
Patient 9	0	0	–	–	–	–	–	–	–	–	–	–	–	2	1
Patient 10	15	0	+	+	–	+	+	+	+	–	–	–	–	2	3
Patient 11	N/A		N/A					N/A						N/A	N/A
Patient 12	28	1	+	+	+	–	+	–	+	+	+	+	+	3	4
Patient 13	11	0	+	–	–	–	–	+	+	+	–	+	–	1	3
Patient 14	13	0	+	–	–	+	–	+	+	–	–	–	+	2	3
Patient 15	0	0	+	+	+	–	–	+	+	+	+	+	+	1	2
Patient 16	4	0	+	+	+	+	+	+	+	+	–	+	+	3	4
Patient 17	N/A		+	–	–	–	–	+	+	+	–	+	–	2	N/A
Patient 18	0	0	+	+	+	+	+	+	+	+	+	–	+	2	3
Patient 19	13^§ § Walnut kernel microbleed sign.	0	–	–	–	–	–	+	+	–	–	–	–	2	2
Patient 20	N/A		N/A					N/A						N/A	N/A
Patient 21	18	0	+	+	–	+	+	+	+	+	+	+	+	2	3
Patient 22	N/A		+	+	+	–	+	+	+	+	+	–	–	3	N/A
Patient 23	0	0	+	+	–	+	+	+	+	+	+	–	+	3	3
Patient 24	2	0	+	+	+	+	+	+	+	+	+	+	–	3	4
Patient 25	7	1	+	+	+	+	+	+	+	+	+	+	+	3	4
Patient 26	0	0	–	+	–	–	–	+	+	–	–	–	–	2	1

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[1] Address for correspondence Renata Nogueira (email: rnogueira.p@gmail.com).