Autosomal Dominant Cerebral Small Vessel Disease in HTRA1 Gene Mutation

Mahale, Rohan; Agarwal, Aakash; Gautam, Jyothi; Varghese, Nibu; Kovoor, J.M.E.; Mailankody, Pooja; Padmanabha, Hansashree; Pavagada, Mathuranath

doi:10.4103/aian.aian_381_20

Cited by 2 publications

(1 citation statement)

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“…Given the diagnosis of CARASIL was established, whole exome sequencing as well as CNV-seq was employed for the diagnosis of this patient. A heterozygous missense mutation c.905G>A (p.Arg302Gln) was detected ( Figure 2B ), and the variant was likely pathogenic according to the ACMG classification ( Mahale et al, 2021 ). No Notch 3 mutation was observed.…”

Section: Case Reportmentioning

confidence: 99%

Case report: Heterozygous mutation in HTRA1 causing typical cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

Li,

Jia,

Xin

et al. 2023

Front. Genet.

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Background: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive disorder characterized by baldness, recurrent ischemic stroke, lumbago, headache, and dementia which is closely related to homozygous mutations of the high-temperature requirement serine peptidase A1 (HTRA1) gene. Heterozygous mutations of HTRA1 are usually considered to be non-pathogenic. Although it has been revealed that only a few patients with heterozygous mutations could present some manifestations, their clinical symptoms were atypical, milder, and always with a lower frequency of extra-neurological features. Here, a rare patient with heterozygous mutation of HTRA1 who had all typical features of CARASIL as well as severe clinical symptoms and rapid progression was initially reported in our study.Case presentation: A 43-year-old female patient presented with a gradual onset of headache and cognitive decline. As time progressed, her headache intensified and symptoms of dementia began to manifest gradually. During her early years, she had thinning hair and subsequently experienced two occurrences of ischemic strokes in her thirties. Furthermore, she also had a history of lumbago and urinary retention before visiting our hospital. The patient’s magnetic resonance imaging revealed the presence of widespread white matter lesions, infarctions, and microbleeds, in addition to lumbar disc herniation and degenerative lesions. The observed clinical characteristics had a strong correlation with CARASIL, and the patient was diagnosed with a heterozygous missense mutation of 905G>A (Arg302Gln) in the HTRA1 gene. The patient has been under continuous follow-up for a duration exceeding 3 years subsequent to her release from the hospital. She underwent cystostomy, and symptoms of bulbar paralysis developed in a progressive way. Currently, there has been a notable decrease in motor function and activities of daily living, resulting in the individual being confined to bed for a duration exceeding 1 year.Conclusion: This case suggests that patients carrying a heterozygous mutation in G905A may also have typical clinical features of CARASIL, which allows us to have a more comprehensive understanding of CARASIL.

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Section: Case Reportmentioning

confidence: 99%

Case report: Heterozygous mutation in HTRA1 causing typical cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

Li,

Jia,

Xin

et al. 2023

Front. Genet.

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Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease

Xu¹,

Li²,

Li³

et al. 2023

IJGM

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High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166–182 aa and 274–302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.

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Autosomal Dominant Cerebral Small Vessel Disease in HTRA1 Gene Mutation

Cited by 2 publications

References 8 publications

Case report: Heterozygous mutation in HTRA1 causing typical cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

Case report: Heterozygous mutation in HTRA1 causing typical cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease

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