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LETTERS TO THE EDITOR
Year : 2021  |  Volume : 24  |  Issue : 2  |  Page : 297-299
 

Autosomal dominant cerebral small vessel disease in HTRA1 gene mutation


Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India

Date of Submission03-May-2020
Date of Acceptance07-Jul-2020
Date of Web Publication07-Oct-2020

Correspondence Address:
Rohan R Mahale
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.AIAN_381_20

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How to cite this article:
Mahale RR, Agarwal A, Gautam J, Varghese N, Kovoor J, Mailankody P, Padmanabha H, Pavagada M. Autosomal dominant cerebral small vessel disease in HTRA1 gene mutation. Ann Indian Acad Neurol 2021;24:297-9

How to cite this URL:
Mahale RR, Agarwal A, Gautam J, Varghese N, Kovoor J, Mailankody P, Padmanabha H, Pavagada M. Autosomal dominant cerebral small vessel disease in HTRA1 gene mutation. Ann Indian Acad Neurol [serial online] 2021 [cited 2021 Jun 19];24:297-9. Available from: https://www.annalsofian.org/text.asp?2021/24/2/297/297447




Dear Sir,

Cerebral small vessel disease (SVD) is a heterogeneous group of disorders affecting small arteries, arterioles, veins, and/or capillaries of the brain. The most common symptoms seen with cerebral SVD are stroke and cognitive impairment. Brain imaging in cerebral SVD will show white matter lesions with lacunar infarct, microbleeds, and macrobleeds.[1] Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common autosomal dominant (AD) monogenic SVD caused by mutation in the NOTCH3 gene. AD SVD due to heterozygous mutation in the HTRA1 gene accounts for 5% of AD SVD cases.[2] Hereby, we report a woman who presented with cognitive impairment, mood disturbances, migraine without aura, parkinsonism, and positive family history of strokes, headache, and cognitive impairment in three generations suggesting AD inheritance. Genetic analysis showed heterozygous mutation of HTRA1 gene suggesting HTRA1-AD disease.

A 40-year-old woman presented with history of episodic headache of 3 years duration. Headache was holocranial, associated with nausea, no photophobia or phonophobia, moderate in intensity, episode lasting for 2 h, subsiding with analgesics with frequency of 2–3 per month. Headache was followed by the emergence of behavioral disturbance in the form of unprovoked aggression toward family members 6 months later. During the same time, she had two episodes of generalized tonic-clonic seizures and was started on valproic acid. She was on atypical antipsychotic for 3 months for behavioral change and showed improvement.

Two and half years later, she developed memory disturbances in the form of forgetting her daily chores, unable to dress herself, unconcerned urinary and fecal incontinence, disinhibition, and wandering behavior. There was no language or speech impairment. There was no myoclonus. She had slowness in walking with no freezing episodes. There were no falls due to postural instability or tremors in limbs. Her family history was significant for strokes, headache, and memory disturbances in 3 successive generations including her one male sibling, mother, and maternal grandfather. It started in their 40s and they died within their 50s after varying periods of bed-bound state. Systemic examination was unremarkable. Cognitive assessment was not possible as she had decreased attention span and perseverative behavior. Speech was normal. Cranial nerve assessment was normal. Motor examination showed mild rigidity in both lower limbs with brisk deep tendon reflexes. Plantar response was mute. Gait was short stepped, narrow based. Mild stooping was noted along with postural instability. Based on the clinical symptoms, family history of headache, stroke, and dementia, and examination findings, an inherited AD cerebral vasculopathy like CADASIL was considered. Routine blood investigations were normal. Serum vitamin B12, homocysteine, and thyroid hormones were normal. Brain magnetic resonance imaging (MRI) showed periventricular and subcortical T2 white matter hyperintensities sparing the external capsule and temporal lobe. Susceptibility-weighted imaging (SWI) showed multiple microbleeds in cortex and subcortical region. There was no contrast enhancement and intracranial vessels were normal [Figure 1]. Vasculitis profile and cerebrospinal fluid analysis was normal. Skin biopsy showed no amyloid deposits in blood vessels and electron microscopy was negative for granular osmiophilic material (GOM). Clinical exome sequencing showed heterozygous missense variation in exon 4 of the HTRA1 gene (chr10:g122506818G > A; Depth: 51x) resulting in the amino acid substitution of glutamine for arginine at codon 302 (NM_002775.4) (c.905G > A) (p.Arg302Gln). The observed variation lies in the trypsin-like peptidase domain of the HTRA1 protein. The p.Arg302Gln variant (R302Q) has not been reported in the 1000 genomes, ExAC. This variant has been predicted to be deleterious by in silico tools suggesting HTRA1-AD disease. Sanger sequencing has not been done in our patient. The affected sibling, mother, and maternal grandfather were deceased.
Figure 1: Brain magnetic resonance imaging (a) axial fluid-attenuated inversion recovery (FLAIR) image shows hyperintensity (red arrow) in periventricular white matter with prominent lateral ventricle sparing subcortical U fibers; (b) axial FLAIR image shows absence of signal change in anterior temporal lobe; (c) susceptibility-weighted image shows microbleeds (red arrow); (d) axial T2 image shows hyperintensity (red arrow) in periventricular white matter with prominent lateral ventricle sparing subcortical U fibers; (e) axial T2 image shows pontine hyperintense signal change (red arrow); (f) MR angiogram with normal intracranial arteries

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The majority of hereditary SVD is of dominant inheritance. This includes CADASIL, high temperature requirement A serine peptidase 1 (HTRA1)-AD disease, collagen 4A1 and collagen 4A2 microangiopathy,[3] cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, and pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL). Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive SVD and Fabry's disease is of X-linked inheritance.[4] AD SVD due to heterozygous mutation in the HTRA1 gene accounts for 5% of AD SVD cases. Autosomal dominant SVD due to heterozygous mutation in the HTRA1 gene presents with later age of stroke onset (around 60 years), cognitive impairment, and less frequent alopecia and spondylosis deformans.[4] CARASIL is caused by homozygous mutation in the HTRA1 gene. CARASIL patients present with recurrent strokes at the age of 20 to 40 years with vascular dementia at the age of 30–40 years, premature alopecia, depression, gait disturbance, and severe back pain due to lumbar disc herniation and spondylosis deformans. Brain imaging shows diffuse WMH with lacunar infarcts and multiple microbleeds [Table 1].[5]
Table 1: Clinical and radiological features of monogenic cerebral SVD

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HTRA1 gene at the long arm of chromosome 10 (10q26) codes for a serine protease which has several domains—insulin-like growth factor binding domain, Kazal-like serine protease inhibitor domain, trypsin-like serine protease domain, and PDZ domain from the N-terminal to the C-terminal. The gene product has a role in regulating cellular proliferation. The vascular lesions may be due to the dysregulation of transforming growth factor (TGF-β) signaling. TGF-β binding protein is an important component of the extracellular matrix, and substrate of proteolytic HTRA1 activity. The HTRA1 gene mutation causes reduced HTRA1 proteolytic activity and does not repress signaling by TGF-β causing vasculopathy.[6]

Wu et al. (2018) reported a family with suspected CADASIL who were NOTCH3 gene negative. Direct sequencing showed a heterozygous missense mutation in HTRA1 Exon4 c.905G>A p.Arg302Gln (R 302Q). Single nucleotide polymorphism (SNP) genotyping assay of the candidate gene in proband symptomatic sisters showed that HTRA1 gene had the same SNP, suggesting that this heterozygous missense mutation is the reason for their familial SVD.[4] Donato et al. (2017) detected heterozygous HTRA1 mutations in nine patients from five families with SVD. The genomic variants were p.Ser136Gly (kazal-like protein domain), p.Gly206Glu (serine protease protein domain), p.Gln151Lys (kazal-like protein domain), p.Val175Met (none), and p.Gly295Arg (serine protease protein domain). The patients were > 40 years at onset and had stroke, cognitive impairment, gait disturbances with no alopecia or spondylosis deformans.[7] Verdura et al. (2015) conducted a whole-exome sequencing to identify candidate genes in an AD SVD family in which known SVD genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial SVD of unknown etiology, using high throughput multiplex polymerase chain reaction and next-generation sequencing. A heterozygous HTRA1 variant (R166L) was identified in all affected members of the index family and ten probands of 201 additional unrelated and affected probands (4.97%). They concluded that about 5% of familial SVDs are associated with deleterious heterozygous mutations of HTRA1. HTRA1 mutations can be second cause of AD SVD after CADASIL.[2] Nozaki et al. (2016) reported four heterozygous missense mutations (p.G283E, p.P285L, p.R302Q, and p.T319I) in eight patients from 113 patients with SVD. Three mutations (p.G283E, p.R302Q, and p.T319I) were novel. Four patients had p.R302Q similar to our patient. Patients with p.R302Q had stroke, cognitive impairment in all, alopecia in two, and spondylosis deformans in all patients. HTRA1 mutants in these manifesting heterozygotes decreased wild-type HTRA1 protease activity [Table 2].[8]
Table 2: Clinical features of published R302Q HTRA1 mutation

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Patients presenting with familial AD SVD who are negative for notch3 gene mutation need testing for mutation in HTRA1 gene. HTRA1 mutations can be second cause of AD SVD after CADASIL.[2]

Acknowledgements

Authors are thankful to the MedGenome Labs Ltd. Bangalore, India for conducting the genetic analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: Insights from neuroimaging. Lancet Neurol 2013;12:483-97.  Back to cited text no. 1
    
2.
Verdura E, Herve D, Scharrer E, Amador MD, Guyant-Marechal ML, Philippi A, et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 205;138:2347-58.  Back to cited text no. 2
    
3.
Revesz T, Holton JL, Lashley T, Plant G, Frangione B, Rostagno A, et al. Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol 2009;118:115-30.  Back to cited text no. 3
    
4.
Wu X, Li C, Mao J, Li L, Liu Y, Hou Y. Heterozygous HTRA1 missense mutation in CADASIL-like family disease. Braz J Med Biol Res 2018;51:e6632.  Back to cited text no. 4
    
5.
Nozaki H, Nishizawa M, Onodera O. Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2014;45:3447-53.  Back to cited text no. 5
    
6.
Zhuo Z-l, Cong L, Zhang J, Zhao X-t. A novel heterozygous HTRA1 mutation is associated with autosomal dominant hereditary cerebral small vessel disease. Mol Genet Genomic Med 2020;8:e1111.  Back to cited text no. 6
    
7.
Di Donato I, Bianchi S, Gallus GN, Cerase A, Taglia I, Pescini F, et al. Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease. CNS Neurosci Ther 2017;23:759-65.  Back to cited text no. 7
    
8.
Nozaki H, Kato T, Nihonmatsu M, Saito Y, Mizuta I, Noda T, et al. Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes in CARASIL. Neurology 2016;86:1964-74.  Back to cited text no. 8
    


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