Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations

Abstract

Background:

Heterozygous HTRA1 mutations are the second most common cause of monogenic dominant cerebral small vessel disease (HTRA1-AD-cSVD or CADASIL2), after cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) due to NOTCH3 cysteine-altering mutations. However, there have been few studies of cohorts of HTRA1-AD-cSVD and whether it can be differentiated clinically and on neuroimaging from CADASIL is unclear.

Aims:

This retrospective study aims to characterize and compare the clinical and neuroimaging features of HTRA1-AD-cSVD with those of CADASIL.

Methods:

We identified 21 unrelated Taiwanese subjects carrying 15 heterozygous HTRA1 variants, all functionally validated as pathogenic through in vitro protease activity assays. HTRA1-AD-cSVD patients were compared with 406 CADASIL patients, including 44 cases carrying NOTCH3 mutations within the high-risk epidermal growth factor-like repeat domains (EGFr), 358 with moderate-risk EGFr mutations, and 4 with low-risk EGFr mutations. Multivariate regression analyses were conducted with adjustments for age at MRI examination and hypertension.

Results:

Stroke occurred in 81.0% of HTRA1-AD-cSVD patients, and 47.6% exhibited cognitive dysfunction. MRI revealed moderate-to-severe white matter hyperintensity (WMH) in the deep white matter and external capsule (modified Scheltens’ scale: 5.3 ± 1.0 and 4.1 ± 1.7), mild WMH in the temporal pole (1.0 ± 1.7), lacunes in 90.5%, ⩾10 cerebral microbleeds (CMBs) in 66.7%, and intracranial hemorrhage (ICH) lesions in 46.7%, indicating susceptibility to both ischemic and hemorrhagic strokes. Patients with HTRA1 loss-of-function mutations or protease domain missense mutations exhibited a higher prevalence of ⩾10 CMBs on SWI/T2* imaging (100% and 83.3%) compared to those with missense mutations outside this domain (20%). Symptom onset occurred earliest in patients with NOTCH3 high-risk EGFr mutations (49.2 ± 10.5 years), followed by those with heterozygous HTRA1 mutations (54.3 ± 10.7 years), and latest in NOTCH3 moderate-risk EGFr mutations carriers (59.7 ± 9.5 years). Temporal pole involvement was most prevalent in NOTCH3 high-risk EGFr mutations (88.6%), followed by NOTCH3 moderate-risk EGFr mutations (32.4%), and least common in heterozygous HTRA1 mutations (28.6%). Even after adjusting for age and hypertension, HTRA1-AD-cSVD patients exhibited significantly milder temporal pole WMH severity compared to NOTCH3 high-risk EGFr mutation carriers (adjusted p < 0.001). In addition, ICH lesions were more frequently observed in HTRA1-AD-cSVD patients (46.7%) than in patients with NOTCH3 high-risk or moderate-risk EGFr mutations (18.2% and 21.2%), although the difference was not statistically significant.

Conclusion:

HTRA1-AD-cSVD shares overlapping clinical and neuroimaging features with CADASIL. Temporal pole WMH involvement can occur in HTRA1-AD-cSVD but is more common in CADASIL. The high prevalence of ICH in HTRA1-AD-cSVD has been under-recognized.

Data access statement:

Data are available upon reasonable request from third parties.

Graphical abstract

Keywords

CADASIL cerebral small vessel disease intracranial hemorrhage MRI

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References

Nozaki

Nishizawa

Onodera

Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2014; 45: 3447–3453.

Hara

Shiga

Fukutake

, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009; 360: 1729–1739.

Verdura

Herve

Scharrer

, et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 2015; 138: 2347–2358.

Lee

Chung

Chao

, et al. Characterization of heterozygous HTRA1 mutations in Taiwanese patients with cerebral small vessel disease. Stroke 2018; 49: 1593–1601.

Nozaki

Kato

Nihonmatsu

, et al. Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. Neurology 2016; 86: 1964–1974.

Di Donato

Bianchi

Gallus

, et al. Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease. CNS Neurosci Ther 2017; 23: 759–765.

Uemura

Nozaki

Kato

, et al. HTRA1-related cerebral small vessel disease: a review of the literature. Front Neurol 2020; 11: 545.

Uemura

Nozaki

Koyama

, et al. HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade. Front Neurol 2019; 10: 693.

Truebestein

Tennstaedt

Monig

, et al. Substrate-induced remodeling of the active site regulates human HTRA1 activity. Nat Struct Mol Biol 2011; 18: 386–388.

10.

Khaleeli

Jaunmuktane

Beaufort

, et al. A novel HTRA1 exon 2 mutation causes loss of protease activity in a Pakistani CARASIL patient. J Neurol 2015; 262: 1369–1372.

11.

Nishimoto

Shibata

Nihonmatsu

, et al. A novel mutation in the HTRA1 gene causes CARASIL without alopecia. Neurology 2011; 76: 1353–1355.

12.

Zhuo

Cong

Zhang

, et al. A novel heterozygous HTRA1 mutation is associated with autosomal dominant hereditary cerebral small vessel disease. Mol Genet Genomic Med 2020; 8: e1111.

13.

Zhang

Zheng

, et al. Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL. Ann Clin Transl Neurol 2022; 9: 1586–1595.

14.

Uemura

Kitahara

Kato

, et al. Inappropriate interpretation of non-pathogenic HTRA1 variant as pathogenic. Ann Clin Transl Neurol 2023; 10: 1261–1262.

15.

Liao

Hsiao

Fuh

, et al. Characterization of CADASIL among the Han Chinese in Taiwan: distinct genotypic and phenotypic profiles. PLoS ONE 2015; 10: e0136501.

16.

Duering

Biessels

Brodtmann

, et al. Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol 2023; 22: 602–618.

17.

Scheltens

Barkhof

Leys

, et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 1993; 114: 7–12.

18.

O’Sullivan

Jarosz

Martin

, et al. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology 2001; 56: 628–634.

19.

Hack

Gravesteijn

Cerfontaine

, et al. Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction. Brain 2023; 146: 2913–2927.

20.

Ando

Saito

Kitahara

, et al. “Chocolate chip sign” on susceptibility-weighted imaging: a novel neuroimaging biomarker for HTRA1-related cerebral small vessel disease. Neurol Genet 2025; 11: e200237.

21.

Bougea

Velonakis

Spantideas

, et al. The first Greek case of heterozygous cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy: an atypical clinico-radiological presentation. Neuroradiol J 2017; 30: 583–585.

22.

Favaretto

Margoni

Salviati

, et al. A new Italian family with HTRA1 mutation associated with autosomal-dominant variant of CARASIL: Are we pointing towards a disease spectrum? J Neurol Sci 2019; 396: 108–111.

23.

Tateoka

Onda

Hirota

, et al. Unusual case of cerebral small vessel disease with a heterozygous nonsense mutation in HTRA1. J Neurol Sci 2016; 362: 144–146.

24.

Ohta

Ozawa

Fujinaka

, et al. Cerebral small vessel disease related to a heterozygous nonsense mutation in HTRA1. Intern Med 2020; 59: 1309–1313.

25.

Liu

Zhu

Zhou

, et al. HTRA1-related autosomal dominant cerebral small vessel disease. Chin Med J 2020; 134: 178–184.

26.

Menezes Cordeiro

Nzwalo

, et al. Shifting the CARASIL paradigm: report of a non-Asian family and literature review. Stroke 2015; 46: 1110–1112.

27.

Chen

Meng

, et al. A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). J Int Med Res 2013; 41: 1445–1455.

28.

Guo

Peng

Ling

Microbleeds in heterozygous HTRA1-related cerebral small vessel disease. JAMA Neurol 2024; 81: 551–552.

29.

Kondo

Yoshinaga

Nakamura

, et al. Severe cerebral small vessel disease caused by the uniallelic p.A252T variant of HTRA1. Neurol Genet 2023; 9: e200047.

30.

Kitahara

Tsuboguchi

Uemura

, et al. Patients with heterozygous HTRA1-related cerebral small vessel disease misdiagnosed with other diseases: two case reports. Clin Neurol Neurosurg 2022; 223: 107502.

31.

Kobayashi

Kondo

Tazawa

, et al. HTRA1-related cerebral small-vessel disease causes cerebral microbleeds on the brainstem surface. J Neurol Sci 2024; 466: 123229.

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