Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic <i>HTRA1</i> variants

Muthusamy, Karthik; Ferrer, Alejandro; Klee, Eric W.; Wierenga, Klaas J.; Gavrilova, Ralitza H.

doi:10.1002/mgg3.1799

Cited by 5 publications

(9 citation statements)

References 11 publications

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Section: Imaging Presentations: Difference From Childhood Leukodystro...mentioning

confidence: 99%

“…Hereditary cerebral small vessel diseases (CSVD) are a heterogeneous group of disorders that result in progressive white matter changes in imaging, along with multiple lacunar infarcts and microhemorrhages ( 83 ). Though the initial manifestation tends to be recurrent transient ischemic attacks or stroke with a step ladder pattern of neurologic decline, clinical features eventually progress to involve cognitive decline, behavioral issues, gait dysfunction, and bladder disturbances ( 83 ). Common genetic vascular leukoencephalopathies are cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1 -related CSVD, cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), SNORD118 -related leukoencephalopathy with cysts and calcifications (LCC), FOXC1/FOXF2 -related disorders , CTC1 -related cerebroretinal microangiopathy with calcifications and cysts, TREX1 -related vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations, methylenetetrahydrofolate reductase deficiency, homocystinuria, and Fabry disease ( 84 ).…”

Section: Imaging Presentations: Difference From Childhood Leukodystro...mentioning

confidence: 99%

“…Clinical manifestations are heterogenous with symptom onset usually from the third to fourth decade in most disorders. Diagnosis is challenging, as the clinical and imaging findings significantly overlap with sporadic CSVD due to vascular risk factors such as hypertension, hyperlipidemia, and diabetes mellitus which are quite common in the adult population ( 83 ).…”

Section: Imaging Presentations: Difference From Childhood Leukodystro...mentioning

confidence: 99%

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Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions

Muthusamy¹,

Sivadasan²,

Dixon³

et al. 2023

Front. Neurol.

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Adult-onset leukodystrophies though individually rare are not uncommon. This group includes several disorders with isolated adult presentations, as well as several childhood leukodystrophies with attenuated phenotypes that present at a later age. Misdiagnoses often occur due to the clinical and radiological overlap with common acquired disorders such as infectious, immune, inflammatory, vascular, metabolic, and toxic etiologies. Increased prevalence of non-specific white matter changes in adult population poses challenges during diagnostic considerations. Clinico-radiological spectrum and molecular landscape of adult-onset leukodystrophies have not been completely elucidated at this time. Diagnostic approach is less well-standardized when compared to the childhood counterpart. Absence of family history and reduced penetrance in certain disorders frequently create a dilemma. Comprehensive evaluation and molecular confirmation when available helps in prognostication, early initiation of treatment in certain disorders, enrollment in clinical trials, and provides valuable information for the family for reproductive counseling. In this review article, we aimed to formulate an approach to adult-onset leukodystrophies that will be useful in routine practice, discuss common adult-onset leukodystrophies with usual and unusual presentations, neuroimaging findings, recent advances in treatment, acquired mimics, and provide an algorithm for comprehensive clinical, radiological, and genetic evaluation that will facilitate early diagnosis and consider active treatment options when available. A high index of suspicion, awareness of the clinico-radiological presentations, and comprehensive genetic evaluation are paramount because treatment options are available for several disorders when diagnosed early in the disease course.

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Section: Imaging Presentations: Difference From Childhood Leukodystro...mentioning

confidence: 99%

Section: Imaging Presentations: Difference From Childhood Leukodystro...mentioning

confidence: 99%

Section: Imaging Presentations: Difference From Childhood Leukodystro...mentioning

confidence: 99%

See 1 more Smart Citation

Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions

Muthusamy¹,

Sivadasan²,

Dixon³

et al. 2023

Front. Neurol.

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“…Clinicoradiographic characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers may overlap with sporadic CSVD. 27 Presently, there are no specific imaging signs for symptomatic carriers. White matter hyperintensities (WMHs, 100%), lacunar infarctions (LIs, 75%), and cerebral microbleeds (CMBs, 55.77%) were the most common imaging manifestations ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…Most pathogenic and likely pathogenic heterozygous HTRA1 gene variants of symptomatic carriers were missense variants, and some of them were nonsense variants, 30–35 frameshift variants, 27 , 30 , 36 and splice site variants. 6 , 36 , 37 The variant sites of the heterozygous HTRA1 gene were mostly located in exon 4 (50.91%), and the trypsin-like serine protease domain was the most common domain in HtrA1 protease (61.82%).…”

Section: Introductionmentioning

confidence: 99%

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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Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants

Muthusamy

Ferrer

Klee

et al. 2021

Molec Gen & Gen Med

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Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 5 publications

References 11 publications

Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions

Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions

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

Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants

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