CADASIL Type 2

Mendelian MONDO:0014768 Pathograph 41 Show in embeddings browser Hereditary Stroke Disorder Small Vessel Disease

CADASIL type 2 is the cerebral small vessel disease caused by pathogenic germline variants in HTRA1, which encodes the secreted, homotrimeric serine protease HTRA1. GeneReviews treats HTRA1 disorder as one phenotypic spectrum, and this entry follows it, carrying the two ends as subtypes. Heterozygous variants (HTRA1-CSVD, the autosomal dominant form named by MONDO:0014768) cause a later-onset disease, typically after age 40, with slowly progressive gait disturbance, lacunar stroke, mood change and cognitive decline on a background of confluent white matter hyperintensities, lacunes and cerebral microbleeds; intracerebral hemorrhage is not rare, penetrance is incomplete, and spine disease is common while alopecia is uncommon. Biallelic variants cause classic CARASIL, a recessive disease beginning between ages 20 and 40 with spastic gait disturbance, stroke-like episodes, pseudobulbar palsy, mood change and dementia, accompanied by premature scalp alopecia and lumbago from spondylosis. Truncating heterozygous alleles act by haploinsufficiency, and many heterozygous missense alleles interfere with the trimer-dependent activation of wild-type HTRA1. Loss of protease activity leads to accumulation of HTRA1 matrisome substrates in the small-artery wall, dysregulated TGF-beta and NOTCH3 signalling in vascular smooth muscle, loss of medial smooth muscle cells, intimal thickening with splitting of the internal elastic lamina, and chronic subcortical ischemia with white matter myelin loss. Diagnosis rests on HTRA1 molecular testing. Management is supportive; no mechanism-directed therapy is established.

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Mappings

MONDO

MONDO:0010829 cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2 Not Yet Curated

MONDO:0010829 is the biallelic HTRA1 disease (CARASIL, OMIM:600142). MONDO places it as the only descendant of MONDO:0014768, whose definition is any CADASIL caused by HTRA1 variation. This entry carries CARASIL as a subtype, so the recessive MONDO concept is narrower than the entry.

MONDO:0007432 cerebral arteriopathy with subcortical infarcts and leukoencephalopathy Not Yet Curated

MONDO:0007432 is the parent grouping term (OMIMPS:125310) that also subsumes CADASIL type 1 (NOTCH3, curated as CADASIL_Type_1) and ARCASIL. This entry curates HTRA1 only, so the parent is broader and must not be retired from the curation queue by this entry, matching how CADASIL_Type_1 maps it.

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Inheritance

Autosomal dominant HP:0000006

Heterozygous pathogenic variants cause HTRA1-CSVD. Each child of an affected heterozygote has a 50% risk of inheriting the variant. Penetrance is incomplete and appears lower for truncating alleles; many heterozygous carriers in CARASIL families are asymptomatic.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (5 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"HTRA1 disorder caused by heterozygous pathogenic variants is inherited in an autosomal dominant manner."

GeneReviews states dominant inheritance for the heterozygous form.

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Each sib of an affected individual has a 50% risk of inheriting the pathogenic variant from their affected parent."

Recurrence risk for the dominant form.

PMID:26063658 SUPPORT PRIMARY RESULT Human clinical

"A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family."

Segregation of a heterozygous variant with disease in a dominant family.

+ 2 more references

Autosomal recessive HP:0000007

Biallelic pathogenic variants cause classic CARASIL. Sibs of an affected individual have a 25% risk of being affected and a 50% risk of being heterozygous; heterozygous relatives may themselves develop HTRA1-CSVD, so the two forms can segregate in one family (semidominant pattern).

Autosomal recessive inheritance

Show evidence (3 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"HTRA1 disorder caused by biallelic pathogenic variants (i.e., the classic CARASIL phenotype) is inherited in an autosomal recessive manner."

GeneReviews states recessive inheritance for the biallelic form.

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"At conception, each sib of an affected individual has a 25% chance of inheriting both HTRA1 pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither pathogenic variant and not being at risk for HTRA1 disorder."

Recurrence risk for the recessive form.

PMID:34303089 SUPPORT PRIMARY RESULT Human clinical

"Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms."

Within one family the same allele causes CARASIL in homozygotes and CADASIL type 2 in heterozygotes.

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Subtypes

Heterozygous HTRA1 cerebral small vessel disease (CADASIL type 2) MONDO:0014768

HTRA1 hgnc:9476 Autosomal dominant inheritance

Heterozygous HTRA1 missense, nonsense or frameshift variants. Onset is usually after age 40 with slowly progressive gait disturbance, stroke, mood change and cognitive decline. Compared with CARASIL, onset is later, confluent white matter hyperintensities and alopecia are less frequent, and spine disease is seen in a majority rather than in all patients. Severity varies widely within families, and vascular risk factors are more frequent than in CARASIL.

Show evidence (2 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

""HTRA1 cerebral small vessel disease" (HTRA1-CSVD) refers to the milder phenotype associated with a heterozygous HTRA1 pathogenic variant."

GeneReviews defines the heterozygous end of the spectrum.

PMID:32719647 SUPPORT REVIEW SYNTHESIS Human clinical

"The symptomatic carriers show the elderly onset, lower frequency of extraneurological complications, and milder WMHs compared to those in CARASIL."

Literature review of 46 symptomatic carriers and 28 CARASIL patients contrasting the two forms.

Classic CARASIL (biallelic HTRA1) MONDO:0010829

HTRA1 hgnc:9476 Autosomal recessive inheritance

Homozygous or compound heterozygous HTRA1 variants, first described in Japanese families and since reported from China, India, Turkey, Europe and the Americas. Onset is between ages 20 and 40 with spastic gait disturbance, stroke-like episodes, pseudobulbar palsy, mood change and progressive dementia, without hypertension, together with premature scalp alopecia and acute lumbago with spondylosis.

Show evidence (3 references)

PMID:19387015 SUPPORT PRIMARY RESULT Human clinical

"CARASIL is associated with mutations in the HTRA1 gene."

Gene identification in five CARASIL families.

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"In this chapter, the term "classic CARASIL" refers to the more severe phenotype associated with biallelic pathogenic variants"

GeneReviews defines the biallelic end of the spectrum.

PMID:25712943 SUPPORT PRIMARY RESULT Human clinical

"The study revealed the presence of a homozygous c.496C>T substitution in HTRA1 in both siblings."

Homozygous HTRA1 variant in a non-Asian sibling pair with the typical phenotype.

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Pathophysiology

HTRA1 Haploinsufficiency

Nonsense and frameshift HTRA1 alleles are degraded by nonsense-mediated mRNA decay, so heterozygous carriers make about half the normal amount of HTRA1. In CARASIL, a homozygous nonsense allele abolished HTRA1 protein by the same route.

Downstream

HTRA1 Serine Protease Loss of Function Less HTRA1 protein means less protease activity in the vessel wall.

Show evidence (3 references)

PMID:34270682 SUPPORT PRIMARY RESULT Human clinical

"Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency."

Patient mRNA shows decay of the truncating allele.

PMID:32017060 SUPPORT PRIMARY RESULT In vitro / ex vivo

"We found a 50% reduction of HTRA1 expression in HTRA1 mutation carriers compared to the control."

Carrier fibroblasts express half the normal HTRA1.

PMID:19387015 SUPPORT PRIMARY RESULT Human clinical

"The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA."

A biallelic CARASIL nonsense allele removes HTRA1 protein by mRNA decay.

Dominant-Negative Disruption of HTRA1 Trimer Activation

HTRA1 works as a homotrimer in which each subunit activates its neighbour through the loop 3 sensor and loop D activation domains. Many missense proteins found in symptomatic heterozygotes either fail to form trimers or carry substitutions in loop D or loop 3, and inhibit the activity of co-expressed wild-type HTRA1. Most CARASIL missense proteins tested did not inhibit wild-type HTRA1.

protein homotrimerization GO:0070207 ↓ DECREASED

Downstream

HTRA1 Serine Protease Loss of Function The mutant subunit lowers the activity of wild-type HTRA1 as well as its own.

Show evidence (2 references)

PMID:27164673 SUPPORT PRIMARY RESULT In vitro / ex vivo

"Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers."

Two heterozygous-disease missense proteins fail to trimerize; this is the basis for the reduced homotrimerization annotation.

PMID:31316458 SUPPORT PRIMARY RESULT In vitro / ex vivo

"Together with our previous work, 10 of 11 hetero-HTRA1s and two of six CARASIL-HTRA1s were either defective in trimerization or had mutations in the LD or L3 domain (P = 0.006)."

Trimerization or activation-loop defects are typical of heterozygous-disease alleles.

HTRA1 Serine Protease Loss of Function

Disease alleles of both forms reduce HTRA1 serine protease activity, measured in casein assays of recombinant mutant proteins. HTRA1 is a primarily secreted protease that processes extracellular matrix proteins and regulates TGF-beta family signalling.

HTRA1 hgnc:9476

serine-type endopeptidase activity GO:0004252 ↓ DECREASED

Downstream

Vascular Matrisome Protein Accumulation HTRA1 substrates of the extracellular matrix are no longer cleared and accumulate in the small-artery wall.

Dysregulated TGF-beta Signaling HTRA1 normally controls TGF-beta bioavailability; mutant HTRA1 fails to do so.

Increased NOTCH3 Signaling in Vascular Smooth Muscle Loss of HTRA1 raises the NOTCH3 ligand JAG1 and NOTCH3 signalling in vascular smooth muscle cells.

Impaired Vascular Smooth Muscle Contractile Differentiation HTRA1 is required for smooth muscle cells to reach the contractile phenotype.

Endothelial NOX4-Driven Oxidative Stress Reduced HTRA1 in brain endothelial cells increases NOX4 and oxidative stress (one cell and mouse study).

Show evidence (3 references)

PMID:19387015 SUPPORT PRIMARY RESULT In vitro / ex vivo

"The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family."

CARASIL mutant proteins have low protease activity.

PMID:26063658 SUPPORT PRIMARY RESULT In vitro / ex vivo

"In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect."

Heterozygous-disease mutants lose activity.

PMID:29895533 SUPPORT PRIMARY RESULT In vitro / ex vivo

"All mutations significantly compromise the HTRA1 protease activities."

Seven further heterozygous alleles reduce protease activity.

Vascular Matrisome Protein Accumulation

HTRA1 matrisome substrates such as fibronectin (including its extra domain-A form), LTBP-4 and versican accumulate in the thickened intima of cerebral small arteries, in CARASIL autopsy tissue and in HTRA1-null mice. The same loss-of-function proteomic profile is seen in CADASIL vessels, where HTRA1 is sequestered in NOTCH3 deposits.

extracellular matrix disassembly GO:0022617 ↓ DECREASED

tunica intima of cerebral small arteries UBERON:0002523

Animal models

Htra1 knockout mouse Mouse recapitulates Matrisome substrates accumulate in the thickened intima.

Downstream

Intimal Thickening of Cerebral Small Arteries Accumulated matrix proteins form the thickened intima; lowering them normalizes vessel function in mice.

Reduced Cerebral Arterial Distensibility Matrisome accumulation stiffens the arterial wall; candesartan lowers the accumulation and restores distensibility.

Cerebral Vessel Ectasia Type III collagen, an HTRA1 substrate, accumulates in dilated leptomeningeal vessel walls.

Show evidence (2 references)

PMID:19387015 SUPPORT PRIMARY RESULT Human clinical

"Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta1 in the tunica media."

Matrix proteins accumulate in the intima of CARASIL cerebral small arteries.

PMID:29725820 SUPPORT PRIMARY RESULT In vitro / ex vivo

"Several of them were shown to be processed by HTRA1 in an in vitro proteolysis assay identifying them as novel substrates."

Accumulating vessel proteins are HTRA1 substrates, supporting reduced substrate breakdown.

Dysregulated TGF-beta Signaling

HTRA1 controls TGF-beta bioavailability, but the direction of the change in disease is contested. CARASIL mutant proteins fail to repress TGF-beta family signalling and TGF-beta1 accumulates in the tunica media of patient arteries; HTRA1 cleaves proTGF-beta1 in the endoplasmic reticulum; and HTRA1-null smooth muscle cells and a transgenic CARASIL mouse show increased SMAD2/3 signalling. Against this, HTRA1 also processes LTBP-1, and its loss attenuates TGF-beta signalling in fibroblasts, while carrier fibroblasts show no change in phospho-SMAD2/3. The node is therefore annotated as dysregulated rather than increased.

vascular associated smooth muscle cell CL:0000359

transforming growth factor beta receptor signaling pathway GO:0007179 ↕ DYSREGULATED

Animal models

Transgenic HtrA1 L364P mouse Mouse partially recapitulates Increased TGF-beta, SMAD2 and SMAD3 expression in the brain.

Downstream

Impaired Vascular Smooth Muscle Contractile Differentiation Combined over-activation of TGF-beta and NOTCH3 signalling represses contractile smooth muscle genes.

Premature Scalp Alopecia The gene-discovery study proposed loss of TGF-beta family repression as the link to alopecia. The mechanism in hair follicles has not been studied, so this edge is a hypothesis.

Scalp Alopecia in Heterozygotes Extended from the CARASIL alopecia hypothesis to the alopecia of heterozygous carriers; the hair follicle mechanism has not been studied in either form.

Lumbar Spondylosis The same study proposed the TGF-beta link for spondylosis. A homozygous R302Q rat develops vertebral osteophytes, supporting a direct skeletal effect of HTRA1 loss, but the intermediate steps are unknown.

Intervertebral Disk Degeneration Inferred by analogy with the CARASIL spine link; no study addresses the mechanism of spine disease in heterozygotes.

Show evidence (5 references)

PMID:21320870 SUPPORT PRIMARY RESULT In vitro / ex vivo

"HTRA1 binds and cleaves the pro-domain of proTGF-β1 in the endoplasmic reticulum (ER), and cleaved proTGF-β1 is degraded by ER-associated degradation."

Mechanism by which HTRA1 loss could raise mature TGF-beta1.

PMID:31796853 SUPPORT PRIMARY RESULT In vitro / ex vivo

"In addition, the loss of HTRA1 enhanced TGFβ-SMAD2/3 signaling activity."

Increased SMAD2/3 signalling in HTRA1-deficient smooth muscle cells.

PMID:35841197 SUPPORT PRIMARY RESULT Model organism

"Immunohistochemistry, RT-PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF-β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees."

Increased TGF-beta pathway expression in a transgenic L364P mouse brain.

+ 2 more references

Increased NOTCH3 Signaling in Vascular Smooth Muscle

Loss of HTRA1 increases JAG1 protein and NOTCH3 signalling activity in vascular smooth muscle cells, shown in HTRA1-silenced human umbilical artery smooth muscle cells and Htra1-deficient mice.

vascular associated smooth muscle cell CL:0000359

Notch signaling pathway GO:0007219 ↑ INCREASED

Downstream

Impaired Vascular Smooth Muscle Contractile Differentiation Excess HES and HEY repressors downstream of NOTCH3 and TGF-beta block contractile gene expression.

Show evidence (1 reference)

PMID:31796853 SUPPORT PRIMARY RESULT In vitro / ex vivo

"Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH3 signaling activity in VSMC."

Direct measurement of increased NOTCH3 signalling.

Impaired Vascular Smooth Muscle Contractile Differentiation

Without HTRA1, vascular smooth muscle cells stay immature or shift to the synthetic phenotype, with impaired vasoconstriction, more proliferation and migration, MMP9 activity and susceptibility to oxidative stress-induced death. Shown in cultured cells and Htra1-null mice; the aortic data come from a vessel not affected in patients.

vascular associated smooth muscle cell CL:0000359

vascular associated smooth muscle cell differentiation GO:0035886 ↓ DECREASED

Animal models

Htra1 knockout mouse Mouse recapitulates Smooth muscle cells remain immature with impaired vasoconstriction.

Downstream

Medial Smooth Muscle Cell Loss Synthetic modulation precedes and promotes smooth muscle cell death in Htra1-null aorta.

Show evidence (2 references)

PMID:31796853 SUPPORT PRIMARY RESULT Model organism

"As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice."

Immature smooth muscle phenotype in vivo.

PMID:29768431 SUPPORT PRIMARY RESULT Model organism

"HtrA1-/- VSMCs expressed less smooth muscle α-actin, and more vimentin and osteopontin, and responded to PDGF-BB more strongly than wild type VSMCs, indicating that HtrA1-/- VSMCs were in the synthetic phenotype."

Synthetic shift of aortic smooth muscle cells from Htra1-null mice.

Medial Smooth Muscle Cell Loss

The cardinal arterial lesion of both forms: extensive loss of medial smooth muscle cells in pial and perforating arteries and arterioles, even in arteries without sclerotic change. Seen at autopsy in CARASIL and, less severely, in heterozygous patients.

smooth muscle cell of the brain vasculature CL:0002590

tunica media of cerebral small arteries UBERON:0002522

Downstream

Chronic Subcortical Hypoperfusion Medial degeneration is proposed to disturb autoregulation and cause blood-flow fluctuation in the deep white matter. This is the autopsy authors' inference, not a measurement in patients.

Cerebral Vessel Ectasia Arteries that have lost their medial smooth muscle are centrifugally enlarged.

Cerebral Small Vessel Wall Fragility Loss of medial smooth muscle, together with splitting of the elastic lamina, leaves a wall prone to intramural bleeding.

Show evidence (3 references)

PMID:18021191 SUPPORT PRIMARY RESULT Human clinical

"We further revealed that arterial medial smooth muscle cells (SMCs) in patients with CARASIL were extensively lost, even in arteries without sclerotic changes."

Autopsy of two CARASIL brains.

PMID:27634960 SUPPORT PRIMARY RESULT Human clinical

"All 3 had similar cerebral arteriopathy showing myointimal proliferation, multi-layering and splitting of elastic laminae, and marked loss of medial smooth muscle cells."

Three genetically confirmed CARASIL autopsies.

PMID:29797751 SUPPORT PRIMARY RESULT Human clinical

"Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media."

Same lesion in a heterozygous R302Q patient.

Intimal Thickening of Cerebral Small Arteries

Myointimal proliferation and hyalinization thicken the intima of small penetrating and leptomeningeal arteries and narrow the lumen, in CARASIL, in heterozygous patients and in HTRA1-null mice and rats.

tunica intima of cerebral small arteries UBERON:0002523

Animal models

Htra1 knockout mouse Mouse recapitulates Intimal thickening and abnormal elastic lamina in cerebral arteries.

Htra1 R302Q knock-in rat (CRHTRA1) Rat recapitulates Arteriolar wall thickening with lumen stenosis.

Downstream

Chronic Subcortical Hypoperfusion Luminal narrowing of penetrating arteries is inferred to reduce flow to the deep white matter and basal ganglia; no source here measures flow distal to a stenosed patient artery.

Show evidence (3 references)

PMID:36524103 SUPPORT PRIMARY RESULT Human clinical

"The small arteries showed hyalinization, marked intimal thickening, narrowing of the lumen, and loss of smooth muscle cells (SMCs) in the tunica media with HE stain"

Surgical pathology from a heterozygous p.Q318H patient.

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation."

Intimal thickening in HTRA1-null mice.

PMID:41142321 SUPPORT PRIMARY RESULT Model organism

"At 12 months, histopathological analyses revealed marked thickening of the cerebral arteriolar walls with concomitant lumen stenosis."

Wall thickening with stenosis in the homozygous R302Q rat.

Internal Elastic Lamina Splitting

The internal elastic lamina of small cerebral arteries is split, multilayered and wavy in CARASIL and in heterozygous patients, and abnormal in HTRA1-null mice. In one heterozygous patient with intracerebral hemorrhage, blood had tracked beneath the internal elastic lamina.

elastic fiber assembly GO:0048251 ⚠ ABNORMAL

cerebral artery UBERON:0004449

Downstream

Cerebral Small Vessel Wall Fragility Bleeding beneath a split internal elastic lamina forms intramural, dissection-like hemorrhage.

Show evidence (2 references)

PMID:27634960 SUPPORT PRIMARY RESULT Human clinical

"All 3 had similar cerebral arteriopathy showing myointimal proliferation, multi-layering and splitting of elastic laminae, and marked loss of medial smooth muscle cells."

Elastic lamina splitting in three CARASIL autopsies.

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation."

Abnormal elastic lamina in HTRA1-null mice.

Reduced Cerebral Arterial Distensibility

Cerebral arteries of HTRA1-null mice are less distensible, and cortical blood flow is reduced; both normalize when candesartan lowers matrisome accumulation. Not yet measured in patients.

cerebral artery UBERON:0004449

Animal models

Htra1 knockout mouse Mouse recapitulates Reduced cerebral arterial distensibility and cortical blood flow.

Downstream

Chronic Subcortical Hypoperfusion Stiffer arteries accompany reduced cerebral blood flow, and both are rescued together in mice.

Show evidence (1 reference)

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex."

Reduced distensibility in HTRA1-null mice.

Cerebral Vessel Ectasia

Small arteries are centrifugally enlarged in CARASIL autopsies and dilated in HTRA1-null mice, and leptomeningeal veins around the midbrain are disproportionately dilated with type III collagen in their walls in HTRA1-related disease. The dilated extraparenchymal vessels appear as hypointense dots on susceptibility-weighted MRI (the chocolate chip sign).

cerebral and leptomeningeal small vessels UBERON:0001981

Show evidence (2 references)

PMID:40017561 SUPPORT PRIMARY RESULT Human clinical

"Histopathologic analysis revealed pronounced dilation of leptomeningeal veins with type III collagen accumulation specifically, in HRSVD brains."

Autopsy evidence of vessel dilation with collagen accumulation.

PMID:40017561 SUPPORT PRIMARY RESULT Human clinical

"Three-dimensional SWI reconstruction and 7T MRI confirmed these dots as dilated extraparenchymal vessels."

The SWI dots correspond to dilated vessels.

Cerebral Small Vessel Wall Fragility

The smooth-muscle-depleted, elastically disrupted small-artery wall is prone to rupture, giving cerebral microbleeds and intracerebral hemorrhage. In heterozygous patients microbleeds and hemorrhagic lesions are frequent, and a hematoma specimen showed intramural, dissection-like bleeding.

brain UBERON:0000955

Downstream

Cerebral Microbleeds Fragile small vessels leak, leaving microbleeds.

Intracerebral Hemorrhage Rupture of fragile small arteries causes intracerebral hemorrhage.

Show evidence (1 reference)

PMID:36524103 SUPPORT PRIMARY RESULT Human clinical

"This phenomenon indicated that the fragility of the vascular wall may lead to not only thrombosis but also hemorrhage in this disease."

Authors' interpretation of the hemorrhage pathology.

Endothelial NOX4-Driven Oxidative Stress

In a single study, HtrA1 knockdown in mouse brain endothelial cells raised NOX4, oxidative stress and apoptosis and lowered tight-junction proteins, and blood from four heterozygous patients showed reduced HTRA1 and claudin-5 with increased NOX4 expression. An emerging hypothesis.

brain microvascular endothelial cell CL:2000044

response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

Blood-Brain Barrier Leakage Endothelial HtrA1 loss disrupts barrier integrity in mice; a NOX4 inhibitor mitigates it.

Show evidence (1 reference)

PMID:42169653 SUPPORT PRIMARY RESULT In vitro / ex vivo

"HtrA1 overexpression in bEnd.3 cells enhanced viability, decreased oxidative stress and apoptosis and elevated tight junction protein expression, whereas HtrA1 knockdown exacerbated these effects."

Knockdown raises oxidative stress in brain endothelial cells.

Blood-Brain Barrier Leakage

Dynamic contrast-enhanced MRI in 13 patients with HTRA1-related disease showed higher whole-brain gadolinium leakage (Ktrans) than in healthy controls, together with a lower water exchange rate across the barrier, and AAV-mediated endothelial HtrA1 knockdown disrupted barrier integrity in mice. The step from leakage to plasma-protein extravasation and white matter injury has not been shown in this disease.

brain microvascular endothelial cell CL:2000044

maintenance of blood-brain barrier GO:0035633 ↓ DECREASED

blood brain barrier UBERON:0000120

Show evidence (3 references)

PMID:38787758 SUPPORT PRIMARY RESULT Human clinical

"In HTRA1-related cSVD, both higher Ktrans in the whole brain and lower kw in multiple brain regions were observed."

Increased gadolinium leakage in patients with HTRA1-related disease.

PMID:36625892 SUPPORT PRIMARY RESULT Human clinical

"Compared with the healthy controls, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients"

Altered barrier water exchange in nine heterozygous patients.

PMID:42169653 SUPPORT PRIMARY RESULT Model organism

"In mice, AAV-mediated HtrA1 suppression in cerebrovascular endothelial cells increased NOX4 and caspase3 levels, disrupted blood-brain barrier (BBB) integrity"

Barrier disruption after endothelial knockdown in mice.

Chronic Subcortical Hypoperfusion

Reduced and unstable perfusion of the deep white matter and basal ganglia, supplied by the diseased penetrating arteries. Cortical blood flow is reduced in HTRA1-null mice; in patients hypoperfusion is inferred from the vascular pathology and the distribution of lacunes and white matter lesions.

cerebral white matter UBERON:0002437

Downstream

Cerebral White Matter Myelin Loss The CARASIL autopsy study attributes the diffuse leukoencephalopathy to the arterial medial degeneration and its effect on flow.

Lacunar Stroke Ischemia in the territory of a diseased penetrating artery produces a lacunar infarct; inferred from the shared small-vessel pathology.

Stroke-like Episodes Clinical stroke-like episodes are the acute expression of subcortical ischemia; inferred, not measured.

Show evidence (1 reference)

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex."

Reduced cerebral blood flow in HTRA1-null mice.

Cerebral White Matter Myelin Loss

Diffuse and focally intense myelin pallor of the cerebral white matter with sparing of the U-fibres is the histological correlate of the leukoencephalopathy, described in CARASIL and resembled in heterozygous HTRA1 disease, and myelin basic protein is lost in affected regions of the homozygous R302Q rat. The myelin loss here is secondary to the arteriopathy (a leuko-vasculopathy), so conformance is declared at the module's convergent myelin node only, not at its oligodendrocyte trigger nodes.

oligodendrocyte CL:0000128

myelin maintenance GO:0043217 ↓ DECREASED

cerebral white matter UBERON:0002437

Animal models

Htra1 R302Q knock-in rat (CRHTRA1) Rat partially recapitulates Loss of myelin basic protein in focal MRI-hyperintense regions.

Downstream

Leukoencephalopathy Myelin loss is the tissue substrate of the white matter hyperintensities seen on MRI.

Gait Disturbance Disruption of deep white matter tracts is taken to cause the gait disturbance; the HTRA1 sources report the two together without testing the link.

Cognitive Impairment White matter disease is taken to underlie the subcortical cognitive decline; inferred from the general small vessel disease model rather than shown in HTRA1 cohorts.

Spasticity Spasticity with pyramidal signs is attributed to involvement of descending motor tracts in the deep white matter; inferred, not tested in the HTRA1 sources.

Pseudobulbar Paralysis Pseudobulbar palsy is attributed to bilateral corticobulbar tract involvement by the white matter disease; inferred, not tested in the HTRA1 sources.

Apathy Apathy is taken to reflect disruption of frontal-subcortical white matter connections; inferred from the general small vessel disease model rather than shown in HTRA1 cohorts.

Show evidence (3 references)

PMID:32196841 SUPPORT REVIEW SYNTHESIS Human clinical

"Histological ﬁndings demonstrate diﬀuse and focally intensive myelin pallor in the white matter sparing U-ﬁbres, resembling CARASIL"

Consensus statement on the white matter histology of heterozygous HTRA1 disease, likened to CARASIL. The ligature characters are copied from the cached PDF text.

PMID:41142321 SUPPORT PRIMARY RESULT Model organism

"Further immunolabeling revealed loss of myelin basic protein in these affected regions"

Myelin basic protein loss in MRI-hyperintense regions of the homozygous R302Q rat.

PMID:41142321 SUPPORT BACKGROUND Human clinical

"Post-mortem histological analyses show a diffuse loss of white matter with cortical U-fiber sparing"

Introduction of the rat study summarizing CARASIL autopsy findings.

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Pathograph

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Phenotypes

Blood 2

Cerebral Microbleeds Cerebral hemorrhage HP:0001342

Show evidence (3 references)

PMID:40607620 SUPPORT PRIMARY RESULT Human clinical

"lacunes in 90.5%, ⩾10 cerebral microbleeds (CMBs) in 66.7%, and intracranial hemorrhage (ICH) lesions in 46.7%"

Microbleed burden in heterozygous patients.

PMID:39270409 SUPPORT PRIMARY RESULT Human clinical

"Brainstem surface on T2*WI low showed dot-like lesions, which are not generally observed in patients with stroke and can be characteristic of HTRA1-CSVD associated with heterozygous variant."

Brainstem-surface dots in four heterozygous patients.

PMID:32719647 SUPPORT REVIEW SYNTHESIS Human clinical

"In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds."

Microbleeds in CARASIL.

Intracerebral Hemorrhage HP:0001342

Show evidence (2 references)

PMID:40607620 SUPPORT PRIMARY RESULT Human clinical

"The high prevalence of ICH in HTRA1-AD-cSVD has been under-recognized."

Hemorrhage is common in heterozygous disease.

PMID:36524103 SUPPORT PRIMARY RESULT Human clinical

"Brain CT showed massive cerebral hemorrhage in the left basal ganglia, and the hemorrhage volume was about 70 mL"

Severe hemorrhage in a heterozygous patient.

Cardiovascular 3

Stroke-like Episodes HP:0002401

Show evidence (3 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Forty-four percent of affected individuals have stroke-like episodes before age 40 years."

Classic CARASIL.

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"A majority of affected individuals have a stroke-like episode after age 40 years."

Heterozygous form.

PMID:40607620 SUPPORT PRIMARY RESULT Human clinical

"Stroke occurred in 81.0% of HTRA1-AD-cSVD patients, and 47.6% exhibited cognitive dysfunction."

Frequency in 21 heterozygous patients.

Lacunar Stroke HP:0032325

Show evidence (2 references)

PMID:21215656 SUPPORT REVIEW SYNTHESIS Human clinical

"The most characteristic findings on brain magnetic resonance imaging are diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus."

CARASIL imaging review.

PMID:40607620 SUPPORT PRIMARY RESULT Human clinical

"lacunes in 90.5%, ⩾10 cerebral microbleeds (CMBs) in 66.7%, and intracranial hemorrhage (ICH) lesions in 46.7%"

Lacune frequency in heterozygous patients.

Dilated Perivascular Spaces Dilation of Virchow-Robin spaces HP:0012520

Show evidence (1 reference)

PMID:36047879 SUPPORT PRIMARY RESULT Human clinical

"T2‐weighted images of the brain revealing visible perivascular spaces in the basal ganglia and deep brain white matter"

Perivascular spaces in a heterozygous pedigree.

Digestive 1

Pseudobulbar Paralysis HP:0007024

Show evidence (2 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years."

Classic CARASIL.

PMID:36530220 SUPPORT PRIMARY RESULT Human clinical

"At 30 years, she developed emotional instability and pseudobulbar palsy."

Young-onset patient in a p.A252T family.

Head and Neck 2

Premature Scalp Alopecia VERY_FREQUENT Alopecia of scalp HP:0002293

Show evidence (2 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic."

GeneReviews.

PMID:32719647 SUPPORT REVIEW SYNTHESIS Human clinical

"The frequency both of alopecia of younger onset and lumbago/spondylosis deformans was significantly higher in CARASIL than symptomatic carriers (alopecia of younger onset: CARASIL 85.7% vs. symptomatic carriers 13.2%, p < 0.01"

Pooled literature frequencies.

Scalp Alopecia in Heterozygotes OCCASIONAL Alopecia of scalp HP:0002293

Show evidence (3 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Spondylosis and alopecia are seen in a minority of individuals with HTRA1-CSVD."

GeneReviews.

PMID:29895533 SUPPORT PRIMARY RESULT Human clinical

"3 have leukoencephalopathy in anterior temporal poles, and 2 patients have alopecia"

Two of nine heterozygous patients.

PMID:36524103 SUPPORT PRIMARY RESULT Human clinical

"In addition, asymptomatic carrier F1-V-6 developed alopecia at age 24 years, with very slight/minimal leukoencephalopathy in the region near the frontal horn of the lateral ventricle"

Early alopecia in a heterozygous carrier.

Limbs 1

Knee Osteoarthritis HP:0005086

Show evidence (1 reference)

PMID:11889251 SUPPORT PRIMARY RESULT Human clinical

"Severe degenerative changes in the lumbar spine and knee joints were seen on radiographs."

Two CARASIL sisters.

Musculoskeletal 3

Spasticity HP:0001257

Show evidence (2 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years."

GeneReviews attributes the CARASIL gait disturbance to spasticity.

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"consideration of medication (baclofen or tizanidine) for spasticity"

Spasticity is a managed feature of HTRA1 disorder.

Lumbar Spondylosis VERY_FREQUENT HP:0034931

Sequelae: Low Back Pain

Show evidence (3 references)

PMID:32719647 SUPPORT REVIEW SYNTHESIS Human clinical

"lumbago/spondylosis deformans: CARASIL 100% vs. symptomatic carriers 60.0%, p < 0.01"

Pooled literature frequency.

PMID:11889251 SUPPORT PRIMARY RESULT Human clinical

"Severe degenerative changes in the lumbar spine and knee joints were seen on radiographs."

Two CARASIL sisters.

PMID:24535794 SUPPORT PRIMARY RESULT Human clinical

"Patients with degenerated spine and progressive clinical symptoms must be evaluated or reevaluated for other central nervous system symptoms and signs to rule out other diseases or syndromes."

Degenerated spine in a homozygous R370X patient.

Intervertebral Disk Degeneration FREQUENT HP:0008419

Show evidence (4 references)

PMID:32719647 SUPPORT REVIEW SYNTHESIS Human clinical

"lumbago/spondylosis deformans: CARASIL 100% vs. symptomatic carriers 60.0%, p < 0.01"

Pooled literature frequency in symptomatic carriers.

PMID:36047879 SUPPORT PRIMARY RESULT Human clinical

"T2‐weighted cervical and lumbar MRI revealed multilevel degenerative disease, including disc herniation, canal stenosis, and degeneration of vertebral bodies"

Spine imaging in a heterozygous pedigree.

PMID:34303089 SUPPORT PRIMARY RESULT Human clinical

"All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation."

Disc degeneration in all heterozygotes of one family.

+ 1 more reference

Nervous System 13

Leukoencephalopathy VERY_FREQUENT HP:0002352

Show evidence (3 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings."

GeneReviews lists deep white matter change as the defining CARASIL finding.

PMID:32719647 SUPPORT REVIEW SYNTHESIS Human clinical

"On brain MRIs, the frequency of confluent WMHs was significantly higher in CARASIL patients than symptomatic carriers (CARASIL 100% vs. symptomatic carriers 81.3%, p = 0.011)."

Pooled literature frequencies for both forms.

PMID:26138950 SUPPORT PRIMARY RESULT Human clinical

"At the last follow-up MRI, all patients had hyperintense lesions on T2-weighted images of the frontal white matter, anterior temporal lobe, external capsules, and thalami."

Seven genetically confirmed CARASIL patients.

Gait Disturbance HP:0001288

Show evidence (3 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"The most frequent initial symptom in individuals with HTRA1-CSVD is slowly progressive gait disturbance after age 40 years, which may be followed by the development of mood changes and cognitive dysfunction."

Heterozygous form.

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years."

Classic CARASIL.

PMID:32719647 SUPPORT REVIEW SYNTHESIS Human clinical

"gait disturbance was significantly less frequent in symptomatic carriers (67.4%) than CARASIL (92.6%) (p = 0.019)"

Pooled literature frequencies.

Cognitive Impairment HP:0100543

Sequelae: Dementia

Show evidence (2 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years."

Classic CARASIL.

PMID:40607620 SUPPORT PRIMARY RESULT Human clinical

"Stroke occurred in 81.0% of HTRA1-AD-cSVD patients, and 47.6% exhibited cognitive dysfunction."

Heterozygous series.

Dementia HP:0000726

Show evidence (2 references)

PMID:21215656 SUPPORT REVIEW SYNTHESIS Human clinical

"The main clinical manifestations of CARASIL are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation."

Dementia in CARASIL.

PMID:36300346 SUPPORT PRIMARY RESULT Human clinical

"HTRA1 carriers an increased all-cause dementia risk (OR, 2.17; 95% CI, 1.28-3.41)"

Population-based association in heterozygous variant carriers.

Apathy HP:0000741

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years."

GeneReviews names apathy among CARASIL mood changes.

Irritability HP:0000737

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years."

GeneReviews names irritability among CARASIL mood changes.

Depression HP:0000716

Show evidence (1 reference)

PMID:29895533 SUPPORT PRIMARY RESULT Human clinical

"Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior"

Psychiatric features in heterozygous patients.

Delusion HP:0000746

Show evidence (1 reference)

PMID:29895533 SUPPORT PRIMARY RESULT Human clinical

"Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior"

Psychiatric features in heterozygous patients.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:36530220 SUPPORT PRIMARY RESULT Human clinical

"At 38 years, she had recurrent episodes of stroke and showed dysarthria, hemiparesis, and gait disturbance."

Patient 3, homozygous p.A252T.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:36530220 SUPPORT PRIMARY RESULT Human clinical

"She became a wheelchair user because of spastic paresis and cerebellar ataxia at 48 years."

Single patient report.

Parkinsonism HP:0001300

Show evidence (1 reference)

PMID:36530220 SUPPORT PRIMARY RESULT Human clinical

"At 48 years, he developed cognitive decline and parkinsonism."

Patient 6, heterozygous p.A252T; single patient.

Brain Atrophy HP:0012444

Show evidence (2 references)

PMID:26138950 SUPPORT PRIMARY RESULT Human clinical

"The atrophy advanced, followed by white matter lesion progression."

Progressive atrophy in CARASIL.

PMID:36530220 SUPPORT PRIMARY RESULT Human clinical

"MRI showed cerebral atrophy, white matter hyperintensities (WMHs), and microbleeds"

Atrophy in a heterozygous carrier.

Migraine HP:0002076

Show evidence (1 reference)

PMID:36047879 SUPPORT REVIEW SYNTHESIS Human clinical

"Although migraine has been considered a hallmark of CADASIL, patients with heterozygous HTRA1‐related CSVD can also present with this symptom"

Discussion statement citing earlier reports.

Constitutional 1

Low Back Pain HP:0003419

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic."

GeneReviews.

🧬

Genetic Associations

HTRA1

Gene: HTRA1 hgnc:9476 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

PMID:19387015 SUPPORT PRIMARY RESULT Human clinical

"Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1."

Founding CARASIL alleles.

PMID:26063658 SUPPORT PRIMARY RESULT Human clinical

"There was a highly significant difference in the number of likely deleterious variants in cases compared to controls"

Case-control burden supports causality of heterozygous variants.

PMID:34270682 SUPPORT PRIMARY RESULT Human clinical

"Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism."

Heterozygous truncating alleles are pathogenic.

+ 2 more references

💊

Medical Actions

Antiplatelet and Antihypertensive Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: antiplatelet agent NCIT:C1327 antihypertensive agent NCIT:C270

Platform: Small molecule

GeneReviews suggests considering antiplatelet and antihypertensive therapy for those with cerebral microbleeds. Severe intracerebral hemorrhage in heterozygous patients, especially with marked microbleeds or antiplatelet use, argues for caution. Strict control of vascular risk factors is proposed to prevent vascular events in heterozygous carriers.

Show evidence (3 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Consideration of anti-platelet therapy and anti-hypertensive therapy for those with cerebral microbleeds"

GeneReviews management.

PMID:36524103 SUPPORT PRIMARY RESULT Human clinical

"Two patients in our study experienced severe ICH, which reminds the clinicians of the risk of hemorrhage for these patients, especially for those who had marked microbleed and/or were on antiplatelet medications."

Hemorrhage risk qualifies antiplatelet use.

PMID:36530220 SUPPORT PRIMARY RESULT Human clinical

"suggesting that strict control of vascular risk factors can prevent vascular events in uniallelic HTRA1 carriers"

Rationale for vascular risk factor control.

Antispasticity Medication

Action: Pharmacotherapy NCIT:C15986

Agent: baclofen CHEBI:2972 tizanidine CHEBI:63629

Platform: Small molecule

Baclofen or tizanidine may be considered for spasticity.

Target Phenotypes: Spasticity HP:0001257

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"consideration of medication (baclofen or tizanidine) for spasticity"

GeneReviews management.

Physical Therapy and Mobility Aids

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy, walking aids and home adaptations for gait disturbance.

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"physical therapy, walking aids, and home adaptations for those with gait disturbance"

GeneReviews management.

Avoidance of Smoking and High-Salt Diet

Action: lifestyle modification Ontology label: Lifestyle Therapy NCIT:C15900

Platform: Behavioral / lifestyle

Smoking and a high-salt diet are listed by GeneReviews as circumstances to avoid because they may hasten arteriosclerosis.

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."

GeneReviews agents and circumstances to avoid.

Supportive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

A wig or hairpiece for alopecia, standard treatment for spinal spondylosis and mood disorder, and emotional support and counselling for affected individuals and families.

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"wig or hairpiece for those with alopecia; standard treatment for spinal spondylosis and mood disorder; supportive care including emotional support and counseling for affected individuals and their families"

GeneReviews management.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counselling covers dominant (50%) and recessive (25%) recurrence risks, the possibility that heterozygous relatives of CARASIL patients develop disease, and the availability of prenatal and preimplantation testing once the familial variants are known.

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Once the HTRA1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HTRA1 disorder are possible."

GeneReviews genetic counseling.

Candesartan (Preclinical)

Action: Pharmacotherapy NCIT:C15986

Agent: candesartan CHEBI:3347

Platform: Small molecule

The angiotensin II receptor blocker candesartan reduced matrisome accumulation and normalized arterial distensibility and cerebral blood flow in HTRA1-null mice. This is a mouse result; no clinical trial in HTRA1 disease is reported in the cited sources.

Mechanism Target:

Vascular Matrisome Protein Accumulation — Candesartan lowers matrisome protein accumulation in the arterial intima of HTRA1-null mice.

Show evidence (1 reference)

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow."

Preclinical rescue in mice.

Show evidence (1 reference)

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network."

Preclinical mouse evidence only.

🌍

Environmental Factors

Tobacco smoking

GeneReviews advises avoiding smoking because it may hasten arteriosclerosis. In UK Biobank, cardiovascular risk burden was associated with increased stroke risk in HTRA1 variant carriers.

Show evidence (2 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."

GeneReviews agents and circumstances to avoid.

PMID:36300346 SUPPORT PRIMARY RESULT Human clinical

"Cardiovascular risk burden was associated with increased stroke risk in NOTCH3 and HTRA1 carriers."

Vascular risk factors modify penetrance in heterozygous carriers.

Mechanism Target:

EXACERBATES Intimal Thickening of Cerebral Small Arteries — Smoking is advised against because it may accelerate the arteriosclerotic change of the small arteries.

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."

GeneReviews links smoking to arteriosclerosis progression.

High-salt diet

GeneReviews advises avoiding a high-salt diet because it may hasten arteriosclerosis.

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."

GeneReviews agents and circumstances to avoid.

Mechanism Target:

EXACERBATES Intimal Thickening of Cerebral Small Arteries — A high-salt diet is advised against because it may accelerate small-artery arteriosclerosis.

Show evidence (1 reference)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."

GeneReviews links high salt intake to arteriosclerosis progression.

🔬

Diagnosis

HTRA1 molecular genetic testing

The diagnosis is established by finding a heterozygous or biallelic pathogenic HTRA1 variant, usually on a small vessel disease gene panel or exome after NOTCH3. Because not every rare missense variant is pathogenic, protease activity, trimer formation and segregation are assessed for novel missense variants, and mRNA analysis can confirm decay of truncating alleles.

genetic testing NCIT:C15709

Results: Heterozygous (HTRA1-CSVD) or biallelic (CARASIL) pathogenic HTRA1 variant(s).

Show evidence (3 references)

PMID:20437615 SUPPORT REVIEW SYNTHESIS Human clinical

"The diagnosis of HTRA1 disorder is established in a proband by identification of either a heterozygous or biallelic pathogenic variant(s) in HTRA1 on molecular genetic testing."

GeneReviews diagnostic criterion.

PMID:32196841 SUPPORT REVIEW SYNTHESIS Human clinical

"In order to establish pathogenicity of a HTRA1 variant, the activity of the mutated enzyme and its ability to form trimers should be evaluated, as well as whether it segregates with disease within a family."

Consensus advice on variant interpretation.

PMID:36261288 SUPPORT PRIMARY RESULT Human clinical

"Third, HTRA1 genetic testing is performed in the remaining patients without mutations in NOTCH3."

Proposed testing order in adult-onset monogenic small vessel disease.

Brain MRI

MRI shows confluent white matter hyperintensities, lacunes and microbleeds. Early CARASIL lesions involve the frontal white matter, external capsule and pons, and an arc-shaped pontine to middle cerebellar peduncle lesion appears late. On susceptibility-weighted imaging, five or more hypointense dots around the midbrain (the chocolate chip sign) distinguished HTRA1-related disease from other small vessel disease. CARASIL is suspected in recurrent unexplained lacunar strokes with severe white matter hyperintensities, especially with premature alopecia, lumbago or spondylosis.

magnetic resonance imaging procedure NCIT:C16809

Results: Confluent white matter hyperintensities, lacunes, microbleeds, arc sign (advanced CARASIL), chocolate chip sign on SWI.

Show evidence (3 references)

PMID:26138950 SUPPORT PRIMARY RESULT Human clinical

"The arc sign was a characteristic finding for CARASIL in the advanced stage."

Characteristic late CARASIL imaging sign.

PMID:40017561 SUPPORT PRIMARY RESULT Human clinical

"A threshold of 5 or more dots, termed the Chocolate Chip Sign, demonstrated optimal sensitivity and specificity for differentiating HRSVD (area under the curve [AUC]: 0.817; 95% confidence interval [CI]: 0.624–1.00; Figure 2D, eTable 4), which remained significant even after adjusting for..."

SWI sign distinguishing HTRA1-related disease.

PMID:32196841 SUPPORT REVIEW SYNTHESIS Human clinical

"CARASIL should be suspected in cases of recurrent unexplained lacunar strokes with severe WMHs"

Consensus clinical and imaging trigger for testing.

📊

Prevalence

Published HTRA1 disorder cases (literature review to 2020)

Cases/families reported in the literature

No population prevalence has been measured for either form. A 2020 literature review assembled 46 symptomatic heterozygous carriers and 28 CARASIL patients. Among Japanese patients with severe or familial cerebral small vessel disease, HTRA1 variants were the second most common monogenic cause after NOTCH3; in a Taiwanese cohort heterozygous HTRA1 variants explained 2.08% (7/337) of small vessel disease, and 4.97% of probands with familial small vessel disease of unknown aetiology in a European cohort.

Show evidence (4 references)

PMID:32719647 SUPPORT REVIEW SYNTHESIS Human clinical

"Forty-six symptomatic carriers and 28 patients with CARASIL were investigated."

Size of the published case series available to the review.

PMID:29895533 SUPPORT PRIMARY RESULT Human clinical

"Heterozygous HTRA1 mutations account for 2.08% (7 of 337) of SVD in Taiwan."

Proportion of small vessel disease explained by heterozygous HTRA1 variants in one cohort.

PMID:26063658 SUPPORT PRIMARY RESULT Human clinical

"Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging."

Proportion of familial small vessel disease probands with heterozygous HTRA1 variants.

+ 1 more reference

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from CADASIL Type 2:

CADASIL type 1 (NOTCH3)

Overlapping Features Shares dominant inheritance, stroke, cognitive decline, white matter hyperintensities, lacunes and microbleeds. Anterior temporal pole involvement is more common in NOTCH3 disease, and spine disorders more common in heterozygous HTRA1 disease; only genetic testing reliably separates them.

Show evidence (2 references)

PMID:40607620 SUPPORT PRIMARY RESULT Human clinical

"Temporal pole WMH involvement can occur in HTRA1-AD-cSVD but is more common in CADASIL."

Imaging overlap and difference.

PMID:36047879 SUPPORT PRIMARY RESULT Human clinical

"Patients with heterozygous HTRA1‐related CSVD had a higher proportion of spine disorders and a lower proportion of WMH involving the anterior temporal lobe compared with CADASIL."

Distinguishing features from NOTCH3 CADASIL.

Sporadic cerebral small vessel disease

Overlapping Features Heterozygous HTRA1 disease resembles age- and hypertension-related small vessel disease apart from its familial occurrence.

Show evidence (1 reference)

PMID:26063658 SUPPORT PRIMARY RESULT Human clinical

"They are similar to those of sporadic small vessel disease, except for their familial nature."

Clinical resemblance to sporadic disease.

🐁

Animal Models

Htra1 knockout mouse

Htra1-null mice develop CARASIL-like cerebral arteriopathy with intimal thickening, abnormal elastic lamina, vasodilation and accumulation of matrisome proteins, with reduced arterial distensibility and cortical blood flow. Their smooth muscle cells fail to mature to the contractile phenotype. One study found normal cerebral arteries and an aortic phenotype in the same knockout, and no leukoencephalopathy on myelin stain.

Species

Mouse

Genotype

Htra1-/- (homozygous null)

Publication

PMID:34779414

Pathograph links

Vascular Matrisome Protein Accumulation recapitulates fidelity: moderate observes: tissue Matrisome substrates accumulate in the thickened intima.

Limitations: Models the biallelic null state, so it informs CARASIL more than heterozygous disease, and mice lack the decades of vascular risk exposure that modify human penetrance.

Show evidence (1 reference)

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated."

Direct observation in the model.

Intimal Thickening of Cerebral Small Arteries recapitulates fidelity: moderate observes: tissue Intimal thickening and abnormal elastic lamina in cerebral arteries.

Limitations: An independent study of the same knockout reported normal cerebral arteries, so the cerebral phenotype may depend on background or age.

Show evidence (2 references)

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation."

Cerebral arteriopathy in the model.

+ 1 more reference

Impaired Vascular Smooth Muscle Contractile Differentiation recapitulates fidelity: unknown observes: cellular Smooth muscle cells remain immature with impaired vasoconstriction.

Limitations: Shown partly in aortic and umbilical-artery smooth muscle rather than cerebral small arteries.

Show evidence (1 reference)

PMID:31796853 SUPPORT PRIMARY RESULT Model organism

"As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice."

In vivo smooth muscle phenotype.

Reduced Cerebral Arterial Distensibility recapitulates fidelity: unknown observes: tissue Reduced cerebral arterial distensibility and cortical blood flow.

Limitations: Not yet measured in patients, so fidelity to human disease is unknown.

Show evidence (1 reference)

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex."

Functional vascular readout in the model.

Show evidence (1 reference)

PMID:34779414 SUPPORT PRIMARY RESULT Model organism

"Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation."

Model characterization.

Htra1 R302Q knock-in rat (CRHTRA1)

At 12 months the rat shows cerebral arteriolar wall thickening with lumen stenosis, enlarged perivascular spaces, loss of myelin basic protein in hyperintense regions, cognitive deficit, gait disturbance and vertebral osteophytes, with TGF-beta and matrix remodelling changes in the brain transcriptome.

Species

Rat

Genotype

Homozygous Htra1 p.R302Q knock-in

Publication

PMID:41142321

Pathograph links

Intimal Thickening of Cerebral Small Arteries recapitulates fidelity: moderate observes: tissue Arteriolar wall thickening with lumen stenosis.

Limitations: Homozygous model of a variant that is pathogenic in humans when heterozygous; a single study at one age.

Show evidence (1 reference)

PMID:41142321 SUPPORT PRIMARY RESULT Model organism

"At 12 months, histopathological analyses revealed marked thickening of the cerebral arteriolar walls with concomitant lumen stenosis."

Direct observation in the model.

Cerebral White Matter Myelin Loss partially recapitulates fidelity: unknown observes: tissue Loss of myelin basic protein in focal MRI-hyperintense regions.

Limitations: Focal rather than the diffuse confluent leukoencephalopathy of patients.

Show evidence (1 reference)

PMID:41142321 SUPPORT PRIMARY RESULT Model organism

"Further immunolabeling revealed loss of myelin basic protein in these affected regions"

Myelin readout in the model.

Show evidence (1 reference)

PMID:41142321 SUPPORT PRIMARY RESULT Model organism

"Behavioral testing in CRHTRA1 rats revealed significant cognitive deficit and gait disturbances."

Behavioural phenotype of the model.

Transgenic HtrA1 L364P mouse

Mice expressing a CARASIL allele show cognitive deficits, loss of normal structure in some small cerebral arteries, thickened small-vessel walls with lumen stenosis on electron microscopy, abnormal myelin and increased TGF-beta, SMAD2 and SMAD3 expression.

Species

Mouse

Genotype

Transgenic expression of human HTRA1 p.L364P

Publication

PMID:35841197

Pathograph links

Dysregulated TGF-beta Signaling partially recapitulates fidelity: unknown observes: molecular Increased TGF-beta, SMAD2 and SMAD3 expression in the brain.

Limitations: A transgene expressing the mutant on a wild-type background models neither the null nor the heterozygous human genotype; whole-brain expression does not localize the change to vascular cells.

Show evidence (1 reference)

PMID:35841197 SUPPORT PRIMARY RESULT Model organism

"Immunohistochemistry, RT-PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF-β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees."

Pathway readout in the model.

Show evidence (1 reference)

PMID:35841197 SUPPORT PRIMARY RESULT Model organism

"The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure."

Vascular phenotype of the model.

{ }

Source YAML

click to show

name: CADASIL Type 2
category: Mendelian
creation_date: '2026-10-28T00:00:00Z'
synonyms:
- CADASIL2
- CADASIL type 2
- HTRA1 CADASIL
- CADASIL caused by mutation in HTRA1
- HTRA1 disorder
- HTRA1-related cerebral small vessel disease
- HTRA1 cerebral small vessel disease
- HTRA1-CSVD
- HTRA1-related autosomal dominant cerebral small vessel disease
- CARASIL
- Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy
- Maeda syndrome
description: >-
  CADASIL type 2 is the cerebral small vessel disease caused by pathogenic germline variants in HTRA1,
  which encodes the secreted, homotrimeric serine protease HTRA1. GeneReviews treats HTRA1 disorder as
  one phenotypic spectrum, and this entry follows it, carrying the two ends as subtypes. Heterozygous
  variants (HTRA1-CSVD, the autosomal dominant form named by MONDO:0014768) cause a later-onset disease,
  typically after age 40, with slowly progressive gait disturbance, lacunar stroke, mood change and
  cognitive decline on a background of confluent white matter hyperintensities, lacunes and cerebral
  microbleeds; intracerebral hemorrhage is not rare, penetrance is incomplete, and spine disease is
  common while alopecia is uncommon. Biallelic variants cause classic CARASIL, a recessive disease
  beginning between ages 20 and 40 with spastic gait disturbance, stroke-like episodes, pseudobulbar
  palsy, mood change and dementia, accompanied by premature scalp alopecia and lumbago from spondylosis.
  Truncating heterozygous alleles act by haploinsufficiency, and many heterozygous missense alleles
  interfere with the trimer-dependent activation of wild-type HTRA1. Loss of protease activity leads to
  accumulation of HTRA1 matrisome substrates in the small-artery wall, dysregulated TGF-beta and NOTCH3
  signalling in vascular smooth muscle, loss of medial smooth muscle cells, intimal thickening with
  splitting of the internal elastic lamina, and chronic subcortical ischemia with white matter myelin
  loss. Diagnosis rests on HTRA1 molecular testing. Management is supportive; no mechanism-directed
  therapy is established.
disease_term:
  preferred_term: CADASIL type 2
  term:
    id: MONDO:0014768
    label: cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2
parents:
- Hereditary Stroke Disorder
- Small Vessel Disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010829
      label: cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0010829 is the biallelic HTRA1 disease (CARASIL, OMIM:600142). MONDO places it as the only
      descendant of MONDO:0014768, whose definition is any CADASIL caused by HTRA1 variation. This entry
      carries CARASIL as a subtype, so the recessive MONDO concept is narrower than the entry.
  - term:
      id: MONDO:0007432
      label: cerebral arteriopathy with subcortical infarcts and leukoencephalopathy
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0007432 is the parent grouping term (OMIMPS:125310) that also subsumes CADASIL type 1
      (NOTCH3, curated as CADASIL_Type_1) and ARCASIL. This entry curates HTRA1 only, so the parent is
      broader and must not be retired from the curation queue by this entry, matching how CADASIL_Type_1
      maps it.
references:
- reference: PMID:20437615
  title: HTRA1 Disorder.
  tags:
  - GeneReviews
  findings: []
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Heterozygous pathogenic variants cause HTRA1-CSVD. Each child of an affected heterozygote has a 50%
    risk of inheriting the variant. Penetrance is incomplete and appears lower for truncating alleles;
    many heterozygous carriers in CARASIL families are asymptomatic.
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "HTRA1 disorder caused by heterozygous pathogenic variants is inherited in an autosomal dominant manner."
    explanation: GeneReviews states dominant inheritance for the heterozygous form.
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Each sib of an affected individual has a 50% risk of inheriting the pathogenic variant from their affected parent."
    explanation: Recurrence risk for the dominant form.
  - reference: PMID:26063658
    reference_title: Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family."
    explanation: Segregation of a heterozygous variant with disease in a dominant family.
  - reference: PMID:34270682
    reference_title: Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower."
    explanation: Reduced penetrance of heterozygous truncating alleles.
  - reference: PMID:31316458
    reference_title: HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Most carriers for HTRA1 mutations are asymptomatic, but more than 10 mutations have been reported in symptomatic carriers."
    explanation: Background statement that most heterozygous carriers are asymptomatic, i.e. incomplete penetrance.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic pathogenic variants cause classic CARASIL. Sibs of an affected individual have a 25% risk
    of being affected and a 50% risk of being heterozygous; heterozygous relatives may themselves develop
    HTRA1-CSVD, so the two forms can segregate in one family (semidominant pattern).
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "HTRA1 disorder caused by biallelic pathogenic variants (i.e., the classic CARASIL phenotype) is inherited in an autosomal recessive manner."
    explanation: GeneReviews states recessive inheritance for the biallelic form.
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "At conception, each sib of an affected individual has a 25% chance of inheriting both HTRA1 pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither pathogenic variant and not being at risk for HTRA1 disorder."
    explanation: Recurrence risk for the recessive form.
  - reference: PMID:34303089
    reference_title: "One Disease with two Faces: Semidominant Inheritance of a Novel HTRA1 Mutation in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms."
    explanation: Within one family the same allele causes CARASIL in homozygotes and CADASIL type 2 in heterozygotes.
has_subtypes:
- name: HTRA1-CSVD
  display_name: Heterozygous HTRA1 cerebral small vessel disease (CADASIL type 2)
  classification: inheritance
  subtype_term:
    preferred_term: CADASIL type 2
    term:
      id: MONDO:0014768
      label: cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2
  description: >-
    Heterozygous HTRA1 missense, nonsense or frameshift variants. Onset is usually after age 40 with slowly
    progressive gait disturbance, stroke, mood change and cognitive decline. Compared with CARASIL, onset is
    later, confluent white matter hyperintensities and alopecia are less frequent, and spine disease is seen
    in a majority rather than in all patients. Severity varies widely within families, and vascular risk
    factors are more frequent than in CARASIL.
  genes:
  - preferred_term: HTRA1
    term:
      id: hgnc:9476
      label: HTRA1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "\"HTRA1 cerebral small vessel disease\" (HTRA1-CSVD) refers to the milder phenotype associated with a heterozygous HTRA1 pathogenic variant."
    explanation: GeneReviews defines the heterozygous end of the spectrum.
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The symptomatic carriers show the elderly onset, lower frequency of extraneurological complications, and milder WMHs compared to those in CARASIL."
    explanation: Literature review of 46 symptomatic carriers and 28 CARASIL patients contrasting the two forms.
- name: CARASIL
  display_name: Classic CARASIL (biallelic HTRA1)
  classification: inheritance
  subtype_term:
    preferred_term: CARASIL
    term:
      id: MONDO:0010829
      label: cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2
  description: >-
    Homozygous or compound heterozygous HTRA1 variants, first described in Japanese families and since
    reported from China, India, Turkey, Europe and the Americas. Onset is between ages 20 and 40 with spastic
    gait disturbance, stroke-like episodes, pseudobulbar palsy, mood change and progressive dementia,
    without hypertension, together with premature scalp alopecia and acute lumbago with spondylosis.
  genes:
  - preferred_term: HTRA1
    term:
      id: hgnc:9476
      label: HTRA1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:19387015
    reference_title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "CARASIL is associated with mutations in the HTRA1 gene."
    explanation: Gene identification in five CARASIL families.
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In this chapter, the term \"classic CARASIL\" refers to the more severe phenotype associated with biallelic pathogenic variants"
    explanation: GeneReviews defines the biallelic end of the spectrum.
  - reference: PMID:25712943
    reference_title: "Shifting the CARASIL paradigm: report of a non-Asian family and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The study revealed the presence of a homozygous c.496C>T substitution in HTRA1 in both siblings."
    explanation: Homozygous HTRA1 variant in a non-Asian sibling pair with the typical phenotype.
prevalence:
- population: Published HTRA1 disorder cases (literature review to 2020)
  measure_type: CASES_IN_LITERATURE
  notes: >-
    No population prevalence has been measured for either form. A 2020 literature review assembled 46
    symptomatic heterozygous carriers and 28 CARASIL patients. Among Japanese patients with severe or
    familial cerebral small vessel disease, HTRA1 variants were the second most common monogenic cause
    after NOTCH3; in a Taiwanese cohort heterozygous HTRA1 variants explained 2.08% (7/337) of small vessel
    disease, and 4.97% of probands with familial small vessel disease of unknown aetiology in a European cohort.
  evidence:
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Forty-six symptomatic carriers and 28 patients with CARASIL were investigated."
    explanation: Size of the published case series available to the review.
  - reference: PMID:29895533
    reference_title: Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Heterozygous HTRA1 mutations account for 2.08% (7 of 337) of SVD in Taiwan."
    explanation: Proportion of small vessel disease explained by heterozygous HTRA1 variants in one cohort.
  - reference: PMID:26063658
    reference_title: Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging."
    explanation: Proportion of familial small vessel disease probands with heterozygous HTRA1 variants.
  - reference: PMID:36261288
    reference_title: High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "CADASIL accounted for nearly 60% of the patients, followed by HTRA1-related CSVD in approximately a quarter of the patients."
    explanation: HTRA1 is the second most frequent monogenic cause in a Japanese cohort.
genetic:
- name: HTRA1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: HTRA1
    term:
      id: hgnc:9476
      label: HTRA1
  notes: >-
    Heterozygous disease alleles include missense variants such as p.R166L, p.G283E, p.P285L, p.R302Q and
    p.T319I, and nonsense or frameshift variants that undergo nonsense-mediated decay. Heterozygous missense
    variants cluster in the linker region and the loop 3/loop D activation domains, whereas CARASIL missense
    variants lie more often elsewhere in the protease domain. The same allele can cause CARASIL when
    homozygous and HTRA1-CSVD when heterozygous (p.P275L, p.A252T). Not every rare missense variant is
    pathogenic; protease activity, trimer formation and segregation are used to establish pathogenicity.
    The local ClinGen cache holds no gene-disease validity record for HTRA1, so no validity tier is
    recorded.
  evidence:
  - reference: PMID:19387015
    reference_title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1."
    explanation: Founding CARASIL alleles.
  - reference: PMID:26063658
    reference_title: Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "There was a highly significant difference in the number of likely deleterious variants in cases compared to controls"
    explanation: Case-control burden supports causality of heterozygous variants.
  - reference: PMID:34270682
    reference_title: Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism."
    explanation: Heterozygous truncating alleles are pathogenic.
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Missense mutations in symptomatic carriers were frequently located in the linker region or L3/LD domain, whereas missense mutations in CARASIL patients were more frequently located in the protease domain and rarely in the L3/LD domain."
    explanation: Allele location differs between the two forms.
  - reference: PMID:36530220
    reference_title: Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "However, our study revealed that patients with uniallelic p.A252T can have severe and young-onset CSVD."
    explanation: An allele first reported homozygous in CARASIL also causes disease when heterozygous.
pathophysiology:
- name: HTRA1 Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Nonsense and frameshift HTRA1 alleles are degraded by nonsense-mediated mRNA decay, so heterozygous
    carriers make about half the normal amount of HTRA1. In CARASIL, a homozygous nonsense allele abolished
    HTRA1 protein by the same route.
  evidence:
  - reference: PMID:34270682
    reference_title: Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency."
    explanation: Patient mRNA shows decay of the truncating allele.
  - reference: PMID:32017060
    reference_title: HTRA1 expression profile and activity on TGF-β signaling in HTRA1 mutation carriers.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "We found a 50% reduction of HTRA1 expression in HTRA1 mutation carriers compared to the control."
    explanation: Carrier fibroblasts express half the normal HTRA1.
  - reference: PMID:19387015
    reference_title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA."
    explanation: A biallelic CARASIL nonsense allele removes HTRA1 protein by mRNA decay.
  downstream:
  - target: HTRA1 Serine Protease Loss of Function
    description: Less HTRA1 protein means less protease activity in the vessel wall.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32017060
      reference_title: HTRA1 expression profile and activity on TGF-β signaling in HTRA1 mutation carriers.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Our results suggest that each heterozygous HTRA1 missense mutation displays a different and peculiar HTRA1 expression pattern and that CSVD phenotype may also result from 50% of HTRA1 expression."
      explanation: Authors propose that halved HTRA1 expression is sufficient for disease; protease activity was not measured here.
- name: Dominant-Negative Disruption of HTRA1 Trimer Activation
  biological_scale: MOLECULAR
  description: >-
    HTRA1 works as a homotrimer in which each subunit activates its neighbour through the loop 3 sensor and
    loop D activation domains. Many missense proteins found in symptomatic heterozygotes either fail to form
    trimers or carry substitutions in loop D or loop 3, and inhibit the activity of co-expressed wild-type
    HTRA1. Most CARASIL missense proteins tested did not inhibit wild-type HTRA1.
  biological_processes:
  - preferred_term: protein homotrimerization
    term:
      id: GO:0070207
      label: protein homotrimerization
    modifier: DECREASED
  evidence:
  - reference: PMID:27164673
    reference_title: Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers."
    explanation: Two heterozygous-disease missense proteins fail to trimerize; this is the basis for the reduced homotrimerization annotation.
  - reference: PMID:31316458
    reference_title: HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Together with our previous work, 10 of 11 hetero-HTRA1s and two of six CARASIL-HTRA1s were either defective in trimerization or had mutations in the LD or L3 domain (P = 0.006)."
    explanation: Trimerization or activation-loop defects are typical of heterozygous-disease alleles.
  downstream:
  - target: HTRA1 Serine Protease Loss of Function
    description: The mutant subunit lowers the activity of wild-type HTRA1 as well as its own.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27164673
      reference_title: Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity"
      explanation: Mixing assays show inhibition of wild-type protease activity by heterozygous-disease mutants.
    - reference: PMID:31316458
      reference_title: HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Conclusions: HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade of HTRA1."
      explanation: Authors' conclusion linking the trimer defect to reduced activation of HTRA1.
- name: HTRA1 Serine Protease Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Disease alleles of both forms reduce HTRA1 serine protease activity, measured in casein assays of
    recombinant mutant proteins. HTRA1 is a primarily secreted protease that processes extracellular matrix
    proteins and regulates TGF-beta family signalling.
  genes:
  - preferred_term: HTRA1
    term:
      id: hgnc:9476
      label: HTRA1
  molecular_functions:
  - preferred_term: serine-type endopeptidase activity
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:19387015
    reference_title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family."
    explanation: CARASIL mutant proteins have low protease activity.
  - reference: PMID:26063658
    reference_title: Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect."
    explanation: Heterozygous-disease mutants lose activity.
  - reference: PMID:29895533
    reference_title: Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "All mutations significantly compromise the HTRA1 protease activities."
    explanation: Seven further heterozygous alleles reduce protease activity.
  downstream:
  - target: Vascular Matrisome Protein Accumulation
    description: HTRA1 substrates of the extracellular matrix are no longer cleared and accumulate in the small-artery wall.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34779414
      reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated."
      explanation: HTRA1 substrates accumulate in cerebral arteries of HTRA1-null mice.
    - reference: PMID:29725820
      reference_title: CADASIL brain vessels show a HTRA1 loss-of-function profile.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Indeed, a comparison with the brain vessel proteome of HTRA1 knockout mice (n = 5) revealed a highly significant overlap of 18 enriched proteins (p = 2.2 × 10-16), primarily representing secreted and extracellular matrix factors."
      explanation: HTRA1-null brain vessels are enriched for secreted and matrix proteins, several shown to be HTRA1 substrates.
  - target: Dysregulated TGF-beta Signaling
    description: HTRA1 normally controls TGF-beta bioavailability; mutant HTRA1 fails to do so.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19387015
      reference_title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family."
      explanation: CARASIL mutants lose the ability to repress TGF-beta family signalling.
    - reference: PMID:25369932
      reference_title: Cerebral small vessel disease-related protease HtrA1 processes latent TGF-β binding protein 1 and facilitates TGF-β signaling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Cleavage occurs at physiological protease concentrations, is prevented under HtrA1-deficient conditions as well as by CARASIL mutations and disrupts both LTBP-1 binding to fibronectin and its incorporation into the extracellular matrix."
      explanation: Loss of HTRA1 cleavage of LTBP-1 alters TGF-beta bioavailability, here towards attenuated signalling.
  - target: Increased NOTCH3 Signaling in Vascular Smooth Muscle
    description: Loss of HTRA1 raises the NOTCH3 ligand JAG1 and NOTCH3 signalling in vascular smooth muscle cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31796853
      reference_title: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH3 signaling activity in VSMC."
      explanation: HTRA1 silencing in human arterial smooth muscle cells increases JAG1 and NOTCH3 activity.
  - target: Impaired Vascular Smooth Muscle Contractile Differentiation
    description: HTRA1 is required for smooth muscle cells to reach the contractile phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased JAG1-NOTCH3 signalling
    - Increased TGF-beta-SMAD2/3 signalling
    evidence:
    - reference: PMID:31796853
      reference_title: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Here we report that HTRA1 is essential for VSMC differentiation into the contractile phenotype."
      explanation: Cell and Htra1-null mouse data establish the requirement.
  - target: Endothelial NOX4-Driven Oxidative Stress
    description: Reduced HTRA1 in brain endothelial cells increases NOX4 and oxidative stress (one cell and mouse study).
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42169653
      reference_title: Endothelial NOX4‑driven oxidative stress inhibition reverses HtrA1 deficiency‑induced blood‑brain barrier disruption and cognitive impairment.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In mice, AAV-mediated HtrA1 suppression in cerebrovascular endothelial cells increased NOX4 and caspase3 levels"
      explanation: Endothelial knockdown of HtrA1 in mice raises NOX4.
- name: Vascular Matrisome Protein Accumulation
  biological_scale: TISSUE
  description: >-
    HTRA1 matrisome substrates such as fibronectin (including its extra domain-A form), LTBP-4 and versican
    accumulate in the thickened intima of cerebral small arteries, in CARASIL autopsy tissue and in
    HTRA1-null mice. The same loss-of-function proteomic profile is seen in CADASIL vessels, where HTRA1 is
    sequestered in NOTCH3 deposits.
  locations:
  - preferred_term: tunica intima of cerebral small arteries
    term:
      id: UBERON:0002523
      label: tunica intima
  biological_processes:
  - preferred_term: extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: DECREASED
  evidence:
  - reference: PMID:19387015
    reference_title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta1 in the tunica media."
    explanation: Matrix proteins accumulate in the intima of CARASIL cerebral small arteries.
  - reference: PMID:29725820
    reference_title: CADASIL brain vessels show a HTRA1 loss-of-function profile.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Several of them were shown to be processed by HTRA1 in an in vitro proteolysis assay identifying them as novel substrates."
    explanation: Accumulating vessel proteins are HTRA1 substrates, supporting reduced substrate breakdown.
  downstream:
  - target: Intimal Thickening of Cerebral Small Arteries
    description: Accumulated matrix proteins form the thickened intima; lowering them normalizes vessel function in mice.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34779414
      reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL."
      explanation: The authors place matrisome accumulation upstream of the arteriopathy in HTRA1-null mice.
  - target: Reduced Cerebral Arterial Distensibility
    description: Matrisome accumulation stiffens the arterial wall; candesartan lowers the accumulation and restores distensibility.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34779414
      reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow."
      explanation: Accumulation and distensibility respond together to treatment; causality is inferred.
  - target: Cerebral Vessel Ectasia
    description: Type III collagen, an HTRA1 substrate, accumulates in dilated leptomeningeal vessel walls.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40017561
      reference_title: "\"Chocolate Chip Sign\" on Susceptibility-Weighted Imaging: A Novel Neuroimaging Biomarker for HTRA1-Related Cerebral Small Vessel Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "We propose that the loss of HTRA1 function, a key characteristic of HRSVD, disrupts the degradation of its substrates, including type III collagen, leading to excessive collagen accumulation and subsequent dilation of vascular walls."
      explanation: Authors' proposed mechanism linking substrate accumulation to vessel dilation, based on autopsy histology.
- name: Dysregulated TGF-beta Signaling
  biological_scale: CELLULAR
  description: >-
    HTRA1 controls TGF-beta bioavailability, but the direction of the change in disease is contested. CARASIL
    mutant proteins fail to repress TGF-beta family signalling and TGF-beta1 accumulates in the tunica media
    of patient arteries; HTRA1 cleaves proTGF-beta1 in the endoplasmic reticulum; and HTRA1-null smooth
    muscle cells and a transgenic CARASIL mouse show increased SMAD2/3 signalling. Against this, HTRA1 also
    processes LTBP-1, and its loss attenuates TGF-beta signalling in fibroblasts, while carrier fibroblasts
    show no change in phospho-SMAD2/3. The node is therefore annotated as dysregulated rather than increased.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:21320870
    reference_title: Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "HTRA1 binds and cleaves the pro-domain of proTGF-β1 in the endoplasmic reticulum (ER), and cleaved proTGF-β1 is degraded by ER-associated degradation."
    explanation: Mechanism by which HTRA1 loss could raise mature TGF-beta1.
  - reference: PMID:31796853
    reference_title: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "In addition, the loss of HTRA1 enhanced TGFβ-SMAD2/3 signaling activity."
    explanation: Increased SMAD2/3 signalling in HTRA1-deficient smooth muscle cells.
  - reference: PMID:35841197
    reference_title: HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF-β/Smad signaling pathway in CARASIL model mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Immunohistochemistry, RT-PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF-β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees."
    explanation: Increased TGF-beta pathway expression in a transgenic L364P mouse brain.
  - reference: PMID:25369932
    reference_title: Cerebral small vessel disease-related protease HtrA1 processes latent TGF-β binding protein 1 and facilitates TGF-β signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Hence, our data suggest an attenuation of TGF-β signaling caused by a lack of HtrA1-mediated LTBP-1 processing as mechanism underlying CARASIL pathogenesis."
    explanation: Supports dysregulation but in the opposite direction (attenuation), from fibroblast and mouse tissue data.
  - reference: PMID:32017060
    reference_title: HTRA1 expression profile and activity on TGF-β signaling in HTRA1 mutation carriers.
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Moreover, we showed no changes in TGF-β signaling pathway downstream intermediate, Phospho Smad2/3."
    explanation: Fibroblasts from four heterozygous carriers showed no change in phospho-SMAD2/3.
  downstream:
  - target: Impaired Vascular Smooth Muscle Contractile Differentiation
    description: Combined over-activation of TGF-beta and NOTCH3 signalling represses contractile smooth muscle genes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31796853
      reference_title: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "However, their combined over-activation led to an additive accumulation of HES and HEY proteins, which repressed the expression of contractile VSMC marker genes."
      explanation: TGF-beta and NOTCH3 over-activation jointly block contractile differentiation.
  - target: Premature Scalp Alopecia
    description: >-
      The gene-discovery study proposed loss of TGF-beta family repression as the link to alopecia. The
      mechanism in hair follicles has not been studied, so this edge is a hypothesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19387015
      reference_title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis."
      explanation: Authors' proposed link; not demonstrated in hair follicles.
  - target: Scalp Alopecia in Heterozygotes
    description: >-
      Extended from the CARASIL alopecia hypothesis to the alopecia of heterozygous carriers; the hair
      follicle mechanism has not been studied in either form.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Lumbar Spondylosis
    description: >-
      The same study proposed the TGF-beta link for spondylosis. A homozygous R302Q rat develops vertebral
      osteophytes, supporting a direct skeletal effect of HTRA1 loss, but the intermediate steps are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19387015
      reference_title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis."
      explanation: Authors' proposed link for the skeletal feature.
    - reference: PMID:41142321
      reference_title: A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Micro-computed tomography of spinal vertebrae revealed pronounced increases in osteophyte formation."
      explanation: Vertebral osteophytes in the homozygous R302Q rat; the rat transcriptome also showed TGF-beta pathway changes.
  - target: Intervertebral Disk Degeneration
    description: Inferred by analogy with the CARASIL spine link; no study addresses the mechanism of spine disease in heterozygotes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased NOTCH3 Signaling in Vascular Smooth Muscle
  biological_scale: CELLULAR
  description: >-
    Loss of HTRA1 increases JAG1 protein and NOTCH3 signalling activity in vascular smooth muscle cells, shown
    in HTRA1-silenced human umbilical artery smooth muscle cells and Htra1-deficient mice.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:31796853
    reference_title: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH3 signaling activity in VSMC."
    explanation: Direct measurement of increased NOTCH3 signalling.
  downstream:
  - target: Impaired Vascular Smooth Muscle Contractile Differentiation
    description: Excess HES and HEY repressors downstream of NOTCH3 and TGF-beta block contractile gene expression.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31796853
      reference_title: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "However, their combined over-activation led to an additive accumulation of HES and HEY proteins, which repressed the expression of contractile VSMC marker genes."
      explanation: NOTCH3 over-activation contributes to repression of contractile genes.
- name: Impaired Vascular Smooth Muscle Contractile Differentiation
  biological_scale: CELLULAR
  description: >-
    Without HTRA1, vascular smooth muscle cells stay immature or shift to the synthetic phenotype, with
    impaired vasoconstriction, more proliferation and migration, MMP9 activity and susceptibility to
    oxidative stress-induced death. Shown in cultured cells and Htra1-null mice; the aortic data come from
    a vessel not affected in patients.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: vascular associated smooth muscle cell differentiation
    term:
      id: GO:0035886
      label: vascular associated smooth muscle cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:31796853
    reference_title: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice."
    explanation: Immature smooth muscle phenotype in vivo.
  - reference: PMID:29768431
    reference_title: Loss of HtrA1 serine protease induces synthetic modulation of aortic vascular smooth muscle cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "HtrA1-/- VSMCs expressed less smooth muscle α-actin, and more vimentin and osteopontin, and responded to PDGF-BB more strongly than wild type VSMCs, indicating that HtrA1-/- VSMCs were in the synthetic phenotype."
    explanation: Synthetic shift of aortic smooth muscle cells from Htra1-null mice.
  downstream:
  - target: Medial Smooth Muscle Cell Loss
    description: Synthetic modulation precedes and promotes smooth muscle cell death in Htra1-null aorta.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29768431
      reference_title: Loss of HtrA1 serine protease induces synthetic modulation of aortic vascular smooth muscle cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Loss of HtrA1 therefore skews VSMCs toward the synthetic phenotype, induces MMP9 expression, and expedites cell death."
      explanation: Mouse aortic evidence; cerebral arteries of these mice were normal, so the step to cerebral medial cell loss is inferred.
- name: Medial Smooth Muscle Cell Loss
  biological_scale: CELLULAR
  description: >-
    The cardinal arterial lesion of both forms: extensive loss of medial smooth muscle cells in pial and
    perforating arteries and arterioles, even in arteries without sclerotic change. Seen at autopsy in
    CARASIL and, less severely, in heterozygous patients.
  cell_types:
  - preferred_term: smooth muscle cell of the brain vasculature
    term:
      id: CL:0002590
      label: smooth muscle cell of the brain vasculature
  locations:
  - preferred_term: tunica media of cerebral small arteries
    term:
      id: UBERON:0002522
      label: tunica media
  evidence:
  - reference: PMID:18021191
    reference_title: Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We further revealed that arterial medial smooth muscle cells (SMCs) in patients with CARASIL were extensively lost, even in arteries without sclerotic changes."
    explanation: Autopsy of two CARASIL brains.
  - reference: PMID:27634960
    reference_title: "Histopathologic Analysis of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL): A Report of a New Genetically Confirmed Case and Comparison to 2 Previous Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "All 3 had similar cerebral arteriopathy showing myointimal proliferation, multi-layering and splitting of elastic laminae, and marked loss of medial smooth muscle cells."
    explanation: Three genetically confirmed CARASIL autopsies.
  - reference: PMID:29797751
    reference_title: Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media."
    explanation: Same lesion in a heterozygous R302Q patient.
  downstream:
  - target: Chronic Subcortical Hypoperfusion
    description: >-
      Medial degeneration is proposed to disturb autoregulation and cause blood-flow fluctuation in the deep
      white matter. This is the autopsy authors' inference, not a measurement in patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18021191
      reference_title: Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Because of the medial and adventitial degeneration, CARASIL brains likely receive marked fluctuations in blood flow because of deviations in the structural and functional basis of autoregulation mechanisms."
      explanation: Authors' inference from autopsy histology.
  - target: Cerebral Vessel Ectasia
    description: Arteries that have lost their medial smooth muscle are centrifugally enlarged.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18021191
      reference_title: Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "In CARASIL, conversely, most of the arteries were centrifugally enlarged and some were collapsed."
      explanation: Enlargement is seen alongside smooth muscle loss in the same autopsies; the causal direction is inferred.
  - target: Cerebral Small Vessel Wall Fragility
    description: >-
      Loss of medial smooth muscle, together with splitting of the elastic lamina, leaves a wall prone to
      intramural bleeding.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36524103
      reference_title: "Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "This phenomenon indicated that the fragility of the vascular wall may lead to not only thrombosis but also hemorrhage in this disease."
      explanation: Authors relate the smooth-muscle-depleted, dissection-like arteries of a heterozygous patient to hemorrhage.
- name: Intimal Thickening of Cerebral Small Arteries
  biological_scale: TISSUE
  description: >-
    Myointimal proliferation and hyalinization thicken the intima of small penetrating and leptomeningeal
    arteries and narrow the lumen, in CARASIL, in heterozygous patients and in HTRA1-null mice and rats.
  locations:
  - preferred_term: tunica intima of cerebral small arteries
    term:
      id: UBERON:0002523
      label: tunica intima
  evidence:
  - reference: PMID:36524103
    reference_title: "Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The small arteries showed hyalinization, marked intimal thickening, narrowing of the lumen, and loss of smooth muscle cells (SMCs) in the tunica media with HE stain"
    explanation: Surgical pathology from a heterozygous p.Q318H patient.
  - reference: PMID:34779414
    reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation."
    explanation: Intimal thickening in HTRA1-null mice.
  - reference: PMID:41142321
    reference_title: A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "At 12 months, histopathological analyses revealed marked thickening of the cerebral arteriolar walls with concomitant lumen stenosis."
    explanation: Wall thickening with stenosis in the homozygous R302Q rat.
  downstream:
  - target: Chronic Subcortical Hypoperfusion
    description: >-
      Luminal narrowing of penetrating arteries is inferred to reduce flow to the deep white matter and basal
      ganglia; no source here measures flow distal to a stenosed patient artery.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Internal Elastic Lamina Splitting
  biological_scale: TISSUE
  description: >-
    The internal elastic lamina of small cerebral arteries is split, multilayered and wavy in CARASIL and in
    heterozygous patients, and abnormal in HTRA1-null mice. In one heterozygous patient with intracerebral
    hemorrhage, blood had tracked beneath the internal elastic lamina.
  locations:
  - preferred_term: cerebral artery
    term:
      id: UBERON:0004449
      label: cerebral artery
  biological_processes:
  - preferred_term: elastic fiber assembly
    term:
      id: GO:0048251
      label: elastic fiber assembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27634960
    reference_title: "Histopathologic Analysis of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL): A Report of a New Genetically Confirmed Case and Comparison to 2 Previous Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "All 3 had similar cerebral arteriopathy showing myointimal proliferation, multi-layering and splitting of elastic laminae, and marked loss of medial smooth muscle cells."
    explanation: Elastic lamina splitting in three CARASIL autopsies.
  - reference: PMID:34779414
    reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation."
    explanation: Abnormal elastic lamina in HTRA1-null mice.
  downstream:
  - target: Cerebral Small Vessel Wall Fragility
    description: Bleeding beneath a split internal elastic lamina forms intramural, dissection-like hemorrhage.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36524103
      reference_title: "Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Furthermore, bleeding beneath the internal elastic lamina, forming an intramural hemorrhage-like structure, was observed in a few small arteries"
      explanation: Histological association in one heterozygous patient.
- name: Reduced Cerebral Arterial Distensibility
  biological_scale: TISSUE
  description: >-
    Cerebral arteries of HTRA1-null mice are less distensible, and cortical blood flow is reduced; both
    normalize when candesartan lowers matrisome accumulation. Not yet measured in patients.
  locations:
  - preferred_term: cerebral artery
    term:
      id: UBERON:0004449
      label: cerebral artery
  evidence:
  - reference: PMID:34779414
    reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex."
    explanation: Reduced distensibility in HTRA1-null mice.
  downstream:
  - target: Chronic Subcortical Hypoperfusion
    description: Stiffer arteries accompany reduced cerebral blood flow, and both are rescued together in mice.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34779414
      reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex."
      explanation: Co-occurrence of reduced distensibility and reduced cortical blood flow; direction inferred.
- name: Cerebral Vessel Ectasia
  biological_scale: TISSUE
  description: >-
    Small arteries are centrifugally enlarged in CARASIL autopsies and dilated in HTRA1-null mice, and
    leptomeningeal veins around the midbrain are disproportionately dilated with type III collagen in their
    walls in HTRA1-related disease. The dilated extraparenchymal vessels appear as hypointense dots on
    susceptibility-weighted MRI (the chocolate chip sign).
  locations:
  - preferred_term: cerebral and leptomeningeal small vessels
    term:
      id: UBERON:0001981
      label: blood vessel
  evidence:
  - reference: PMID:40017561
    reference_title: "\"Chocolate Chip Sign\" on Susceptibility-Weighted Imaging: A Novel Neuroimaging Biomarker for HTRA1-Related Cerebral Small Vessel Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Histopathologic analysis revealed pronounced dilation of leptomeningeal veins with type III collagen accumulation specifically, in HRSVD brains."
    explanation: Autopsy evidence of vessel dilation with collagen accumulation.
  - reference: PMID:40017561
    reference_title: "\"Chocolate Chip Sign\" on Susceptibility-Weighted Imaging: A Novel Neuroimaging Biomarker for HTRA1-Related Cerebral Small Vessel Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Three-dimensional SWI reconstruction and 7T MRI confirmed these dots as dilated extraparenchymal vessels."
    explanation: The SWI dots correspond to dilated vessels.
- name: Cerebral Small Vessel Wall Fragility
  biological_scale: TISSUE
  description: >-
    The smooth-muscle-depleted, elastically disrupted small-artery wall is prone to rupture, giving cerebral
    microbleeds and intracerebral hemorrhage. In heterozygous patients microbleeds and hemorrhagic lesions are
    frequent, and a hematoma specimen showed intramural, dissection-like bleeding.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:36524103
    reference_title: "Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "This phenomenon indicated that the fragility of the vascular wall may lead to not only thrombosis but also hemorrhage in this disease."
    explanation: Authors' interpretation of the hemorrhage pathology.
  downstream:
  - target: Cerebral Microbleeds
    description: Fragile small vessels leak, leaving microbleeds.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40607620
      reference_title: Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "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"
      explanation: The authors read the hemorrhagic imaging burden as susceptibility of the vessels to bleeding.
  - target: Intracerebral Hemorrhage
    description: Rupture of fragile small arteries causes intracerebral hemorrhage.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36524103
      reference_title: "Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "This phenomenon indicated that the fragility of the vascular wall may lead to not only thrombosis but also hemorrhage in this disease."
      explanation: >-
        The authors propose, from the dissection-like pathology of one heterozygous patient, that wall
        fragility leads to hemorrhage; the statement is hedged and is an interpretation rather than a
        demonstrated rupture.
- name: Endothelial NOX4-Driven Oxidative Stress
  biological_scale: CELLULAR
  description: >-
    In a single study, HtrA1 knockdown in mouse brain endothelial cells raised NOX4, oxidative stress and
    apoptosis and lowered tight-junction proteins, and blood from four heterozygous patients showed reduced
    HTRA1 and claudin-5 with increased NOX4 expression. An emerging hypothesis.
  cell_types:
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:42169653
    reference_title: Endothelial NOX4‑driven oxidative stress inhibition reverses HtrA1 deficiency‑induced blood‑brain barrier disruption and cognitive impairment.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "HtrA1 overexpression in bEnd.3 cells enhanced viability, decreased oxidative stress and apoptosis and elevated tight junction protein expression, whereas HtrA1 knockdown exacerbated these effects."
    explanation: Knockdown raises oxidative stress in brain endothelial cells.
  downstream:
  - target: Blood-Brain Barrier Leakage
    description: Endothelial HtrA1 loss disrupts barrier integrity in mice; a NOX4 inhibitor mitigates it.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42169653
      reference_title: Endothelial NOX4‑driven oxidative stress inhibition reverses HtrA1 deficiency‑induced blood‑brain barrier disruption and cognitive impairment.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "The NOX4 inhibitor GLX351322 partially restored endothelial function, mitigated BBB damage and alleviated behavioral impairment."
      explanation: Pharmacological NOX4 inhibition reduces barrier damage in HtrA1-deficient mice.
- name: Blood-Brain Barrier Leakage
  conforms_to: "blood_brain_barrier_breakdown#Blood-Brain Barrier Permeability Increase"
  biological_scale: TISSUE
  description: >-
    Dynamic contrast-enhanced MRI in 13 patients with HTRA1-related disease showed higher whole-brain
    gadolinium leakage (Ktrans) than in healthy controls, together with a lower water exchange rate across the
    barrier, and AAV-mediated endothelial HtrA1 knockdown disrupted barrier integrity in mice. The step from
    leakage to plasma-protein extravasation and white matter injury has not been shown in this disease.
  cell_types:
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  locations:
  - preferred_term: blood brain barrier
    term:
      id: UBERON:0000120
      label: blood brain barrier
  biological_processes:
  - preferred_term: maintenance of blood-brain barrier
    term:
      id: GO:0035633
      label: maintenance of blood-brain barrier
    modifier: DECREASED
  evidence:
  - reference: PMID:38787758
    reference_title: Heterogeneous blood-brain barrier dysfunction in cerebral small vessel diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In HTRA1-related cSVD, both higher Ktrans in the whole brain and lower kw in multiple brain regions were observed."
    explanation: Increased gadolinium leakage in patients with HTRA1-related disease.
  - reference: PMID:36625892
    reference_title: Decreased water exchange rate across blood-brain barrier in hereditary cerebral small vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Compared with the healthy controls, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients"
    explanation: Altered barrier water exchange in nine heterozygous patients.
  - reference: PMID:42169653
    reference_title: Endothelial NOX4‑driven oxidative stress inhibition reverses HtrA1 deficiency‑induced blood‑brain barrier disruption and cognitive impairment.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "In mice, AAV-mediated HtrA1 suppression in cerebrovascular endothelial cells increased NOX4 and caspase3 levels, disrupted blood-brain barrier (BBB) integrity"
    explanation: Barrier disruption after endothelial knockdown in mice.
- name: Chronic Subcortical Hypoperfusion
  biological_scale: TISSUE
  description: >-
    Reduced and unstable perfusion of the deep white matter and basal ganglia, supplied by the diseased
    penetrating arteries. Cortical blood flow is reduced in HTRA1-null mice; in patients hypoperfusion is
    inferred from the vascular pathology and the distribution of lacunes and white matter lesions.
  locations:
  - preferred_term: cerebral white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  evidence:
  - reference: PMID:34779414
    reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex."
    explanation: Reduced cerebral blood flow in HTRA1-null mice.
  downstream:
  - target: Cerebral White Matter Myelin Loss
    description: >-
      The CARASIL autopsy study attributes the diffuse leukoencephalopathy to the arterial medial degeneration
      and its effect on flow.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18021191
      reference_title: Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "We thus consider that diffuse leukoencephalopathy in CARASIL may be caused by arterial medial SMC loss with mural ECM reduction."
      explanation: Authors' proposed vascular cause of the white matter disease.
  - target: Lacunar Stroke
    description: Ischemia in the territory of a diseased penetrating artery produces a lacunar infarct; inferred from the shared small-vessel pathology.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Stroke-like Episodes
    description: Clinical stroke-like episodes are the acute expression of subcortical ischemia; inferred, not measured.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cerebral White Matter Myelin Loss
  conforms_to: "cns_myelin_failure#Deficient or Unstable CNS Myelin Sheath"
  biological_scale: TISSUE
  description: >-
    Diffuse and focally intense myelin pallor of the cerebral white matter with sparing of the U-fibres is the
    histological correlate of the leukoencephalopathy, described in CARASIL and resembled in heterozygous
    HTRA1 disease, and myelin basic protein is lost in affected regions of the homozygous R302Q rat. The
    myelin loss here is secondary to the arteriopathy (a leuko-vasculopathy), so conformance is declared at
    the module's convergent myelin node only, not at its oligodendrocyte trigger nodes.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  locations:
  - preferred_term: cerebral white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  biological_processes:
  - preferred_term: myelin maintenance
    term:
      id: GO:0043217
      label: myelin maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:32196841
    reference_title: "Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Histological ﬁndings demonstrate diﬀuse and focally intensive myelin pallor in the white matter sparing U-ﬁbres, resembling CARASIL"
    explanation: Consensus statement on the white matter histology of heterozygous HTRA1 disease, likened to CARASIL. The ligature characters are copied from the cached PDF text.
  - reference: PMID:41142321
    reference_title: A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Further immunolabeling revealed loss of myelin basic protein in these affected regions"
    explanation: Myelin basic protein loss in MRI-hyperintense regions of the homozygous R302Q rat.
  - reference: PMID:41142321
    reference_title: A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Post-mortem histological analyses show a diffuse loss of white matter with cortical U-fiber sparing"
    explanation: Introduction of the rat study summarizing CARASIL autopsy findings.
  downstream:
  - target: Leukoencephalopathy
    description: Myelin loss is the tissue substrate of the white matter hyperintensities seen on MRI.
    causal_link_type: DIRECT
  - target: Gait Disturbance
    description: >-
      Disruption of deep white matter tracts is taken to cause the gait disturbance; the HTRA1 sources report
      the two together without testing the link.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cognitive Impairment
    description: >-
      White matter disease is taken to underlie the subcortical cognitive decline; inferred from the general
      small vessel disease model rather than shown in HTRA1 cohorts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spasticity
    description: >-
      Spasticity with pyramidal signs is attributed to involvement of descending motor tracts in the
      deep white matter; inferred, not tested in the HTRA1 sources.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pseudobulbar Paralysis
    description: >-
      Pseudobulbar palsy is attributed to bilateral corticobulbar tract involvement by the white matter
      disease; inferred, not tested in the HTRA1 sources.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Apathy
    description: >-
      Apathy is taken to reflect disruption of frontal-subcortical white matter connections; inferred from
      the general small vessel disease model rather than shown in HTRA1 cohorts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Neurological
  name: Leukoencephalopathy
  frequency: VERY_FREQUENT
  description: >-
    Confluent white matter hyperintensities, early in the frontal white matter, external capsule and pons and
    later extending through the hemispheres and thalami. In a literature review confluent hyperintensities were
    present in all CARASIL patients and in 81.3% of symptomatic carriers. In advanced CARASIL an arc-shaped
    lesion runs from the pons to the middle cerebellar peduncles (arc sign).
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings."
    explanation: GeneReviews lists deep white matter change as the defining CARASIL finding.
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "On brain MRIs, the frequency of confluent WMHs was significantly higher in CARASIL patients than symptomatic carriers (CARASIL 100% vs. symptomatic carriers 81.3%, p = 0.011)."
    explanation: Pooled literature frequencies for both forms.
  - reference: PMID:26138950
    reference_title: Characteristic features and progression of abnormalities on MRI for CARASIL.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At the last follow-up MRI, all patients had hyperintense lesions on T2-weighted images of the frontal white matter, anterior temporal lobe, external capsules, and thalami."
    explanation: Seven genetically confirmed CARASIL patients.
- category: Neurological
  name: Gait Disturbance
  description: >-
    The most frequent first symptom of both forms. In CARASIL it is spastic and begins between ages 20 and 40;
    in heterozygotes it is slowly progressive and begins after age 40. A literature review found it in 92.6%
    of CARASIL patients and 67.4% of symptomatic carriers.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most frequent initial symptom in individuals with HTRA1-CSVD is slowly progressive gait disturbance after age 40 years, which may be followed by the development of mood changes and cognitive dysfunction."
    explanation: Heterozygous form.
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years."
    explanation: Classic CARASIL.
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "gait disturbance was significantly less frequent in symptomatic carriers (67.4%) than CARASIL (92.6%) (p = 0.019)"
    explanation: Pooled literature frequencies.
- category: Neurological
  name: Spasticity
  description: >-
    Spasticity with bilateral pyramidal signs underlies the gait disturbance of CARASIL and is also seen in
    heterozygous patients with severe disease.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years."
    explanation: GeneReviews attributes the CARASIL gait disturbance to spasticity.
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "consideration of medication (baclofen or tizanidine) for spasticity"
    explanation: Spasticity is a managed feature of HTRA1 disorder.
- category: Neurological
  name: Stroke-like Episodes
  description: >-
    Stroke-like episodes occur before age 40 in 44% of CARASIL patients and after age 40 in a majority of
    heterozygous patients. Stroke occurred in 81.0% of a Taiwanese series of 21 heterozygous patients.
  phenotype_term:
    preferred_term: Stroke-like episode
    term:
      id: HP:0002401
      label: Stroke-like episode
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Forty-four percent of affected individuals have stroke-like episodes before age 40 years."
    explanation: Classic CARASIL.
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A majority of affected individuals have a stroke-like episode after age 40 years."
    explanation: Heterozygous form.
  - reference: PMID:40607620
    reference_title: Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Stroke occurred in 81.0% of HTRA1-AD-cSVD patients, and 47.6% exhibited cognitive dysfunction."
    explanation: Frequency in 21 heterozygous patients.
- category: Neurological
  name: Lacunar Stroke
  description: >-
    Multiple lacunar infarcts in the basal ganglia, thalamus and deep white matter; lacunes were present in
    90.5% of 21 heterozygous patients.
  phenotype_term:
    preferred_term: Lacunar infarction
    term:
      id: HP:0032325
      label: Lacunar stroke
  evidence:
  - reference: PMID:21215656
    reference_title: "Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most characteristic findings on brain magnetic resonance imaging are diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus."
    explanation: CARASIL imaging review.
  - reference: PMID:40607620
    reference_title: Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "lacunes in 90.5%, ⩾10 cerebral microbleeds (CMBs) in 66.7%, and intracranial hemorrhage (ICH) lesions in 46.7%"
    explanation: Lacune frequency in heterozygous patients.
- category: Neurological
  name: Cognitive Impairment
  description: >-
    Cognitive dysfunction begins between ages 20 and 50 in CARASIL and later in heterozygotes; 47.6% of a
    Taiwanese heterozygous series had cognitive dysfunction. In UK Biobank, carriers of HTRA1 variants had an
    increased risk of all-cause dementia.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years."
    explanation: Classic CARASIL.
  - reference: PMID:40607620
    reference_title: Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Stroke occurred in 81.0% of HTRA1-AD-cSVD patients, and 47.6% exhibited cognitive dysfunction."
    explanation: Heterozygous series.
  sequelae:
  - target: Dementia
    description: Cognitive decline progresses to dementia in CARASIL.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21215656
      reference_title: "Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: "ischemic stroke or stepwise deterioration in brain functions, progressive dementia"
      explanation: The CARASIL review describes stepwise deterioration of brain function with progressive dementia; the progression from impairment to dementia is inferred from that course.
- category: Neurological
  name: Dementia
  description: >-
    Progressive dementia is a main manifestation of CARASIL. In UK Biobank, carriers of putatively pathogenic
    HTRA1 variants had an increased risk of all-cause dementia.
  phenotype_term:
    preferred_term: Dementia
    term:
      id: HP:0000726
      label: Dementia
  evidence:
  - reference: PMID:21215656
    reference_title: "Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The main clinical manifestations of CARASIL are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation."
    explanation: Dementia in CARASIL.
  - reference: PMID:36300346
    reference_title: Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "HTRA1 carriers an increased all-cause dementia risk (OR, 2.17; 95% CI, 1.28-3.41)"
    explanation: Population-based association in heterozygous variant carriers.
- category: Behavioral/Psychiatric
  name: Apathy
  description: Apathy is one of the mood changes of CARASIL and follows gait disturbance in heterozygotes.
  phenotype_term:
    preferred_term: Apathy
    term:
      id: HP:0000741
      label: Apathy
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years."
    explanation: GeneReviews names apathy among CARASIL mood changes.
- category: Behavioral/Psychiatric
  name: Irritability
  description: Irritability is one of the mood changes of CARASIL.
  phenotype_term:
    preferred_term: Irritability
    term:
      id: HP:0000737
      label: Irritability
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years."
    explanation: GeneReviews names irritability among CARASIL mood changes.
- category: Behavioral/Psychiatric
  name: Depression
  subtype: HTRA1-CSVD
  description: In a Taiwanese series, four of nine heterozygous patients had psychiatric symptoms including depression.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:29895533
    reference_title: Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior"
    explanation: Psychiatric features in heterozygous patients.
- category: Behavioral/Psychiatric
  name: Delusion
  subtype: HTRA1-CSVD
  description: Delusions were among the psychiatric symptoms of four of nine heterozygous patients in a Taiwanese series.
  phenotype_term:
    preferred_term: Delusion
    term:
      id: HP:0000746
      label: Delusion
  evidence:
  - reference: PMID:29895533
    reference_title: Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior"
    explanation: Psychiatric features in heterozygous patients.
- category: Neurological
  name: Pseudobulbar Paralysis
  description: >-
    Pseudobulbar palsy begins between ages 20 and 50 in CARASIL and was seen with emotional instability in a
    young-onset member of a family carrying p.A252T.
  phenotype_term:
    preferred_term: Pseudobulbar palsy
    term:
      id: HP:0007024
      label: Pseudobulbar paralysis
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years."
    explanation: Classic CARASIL.
  - reference: PMID:36530220
    reference_title: Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At 30 years, she developed emotional instability and pseudobulbar palsy."
    explanation: Young-onset patient in a p.A252T family.
- category: Neurological
  name: Dysarthria
  subtype: CARASIL
  description: Dysarthria accompanied recurrent strokes in a homozygous p.A252T CARASIL patient.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:36530220
    reference_title: Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At 38 years, she had recurrent episodes of stroke and showed dysarthria, hemiparesis, and gait disturbance."
    explanation: Patient 3, homozygous p.A252T.
- category: Neurological
  name: Ataxia
  subtype: CARASIL
  description: Cerebellar ataxia with spastic paresis was reported in one homozygous p.A252T CARASIL patient.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:36530220
    reference_title: Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She became a wheelchair user because of spastic paresis and cerebellar ataxia at 48 years."
    explanation: Single patient report.
- category: Neurological
  name: Parkinsonism
  subtype: HTRA1-CSVD
  description: One heterozygous p.A252T carrier developed parkinsonism with cognitive decline at age 48.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:36530220
    reference_title: Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At 48 years, he developed cognitive decline and parkinsonism."
    explanation: Patient 6, heterozygous p.A252T; single patient.
- category: Neuroimaging
  name: Cerebral Microbleeds
  description: >-
    Microbleeds on susceptibility-weighted or T2* imaging, frequent in heterozygous patients (10 or more in 66.7%
    of 21 Taiwanese patients) and characteristically dotting the brainstem surface. Some of the brainstem-surface
    dots are dilated extraparenchymal vessels rather than hemorrhages (the chocolate chip sign).
  phenotype_term:
    preferred_term: Cerebral microbleeds
    term:
      id: HP:0001342
      label: Cerebral hemorrhage
  evidence:
  - reference: PMID:40607620
    reference_title: Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "lacunes in 90.5%, ⩾10 cerebral microbleeds (CMBs) in 66.7%, and intracranial hemorrhage (ICH) lesions in 46.7%"
    explanation: Microbleed burden in heterozygous patients.
  - reference: PMID:39270409
    reference_title: HTRA1-related cerebral small-vessel disease causes cerebral microbleeds on the brainstem surface.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Brainstem surface on T2*WI low showed dot-like lesions, which are not generally observed in patients with stroke and can be characteristic of HTRA1-CSVD associated with heterozygous variant."
    explanation: Brainstem-surface dots in four heterozygous patients.
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds."
    explanation: Microbleeds in CARASIL.
- category: Neurological
  name: Intracerebral Hemorrhage
  subtype: HTRA1-CSVD
  description: >-
    Intracranial hemorrhagic lesions were present in 46.7% of 21 heterozygous patients, more often than in
    CADASIL, and severe basal ganglia and lobar hemorrhages are reported in heterozygous pedigrees.
  phenotype_term:
    preferred_term: Intracerebral hemorrhage
    term:
      id: HP:0001342
      label: Cerebral hemorrhage
  evidence:
  - reference: PMID:40607620
    reference_title: Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The high prevalence of ICH in HTRA1-AD-cSVD has been under-recognized."
    explanation: Hemorrhage is common in heterozygous disease.
  - reference: PMID:36524103
    reference_title: "Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Brain CT showed massive cerebral hemorrhage in the left basal ganglia, and the hemorrhage volume was about 70 mL"
    explanation: Severe hemorrhage in a heterozygous patient.
- category: Neuroimaging
  name: Brain Atrophy
  description: Brain atrophy advances in CARASIL and is seen on MRI in heterozygous carriers.
  phenotype_term:
    preferred_term: Brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
  evidence:
  - reference: PMID:26138950
    reference_title: Characteristic features and progression of abnormalities on MRI for CARASIL.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The atrophy advanced, followed by white matter lesion progression."
    explanation: Progressive atrophy in CARASIL.
  - reference: PMID:36530220
    reference_title: Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "MRI showed cerebral atrophy, white matter hyperintensities (WMHs), and microbleeds"
    explanation: Atrophy in a heterozygous carrier.
- category: Neuroimaging
  name: Dilated Perivascular Spaces
  subtype: HTRA1-CSVD
  description: Visible perivascular spaces in the basal ganglia and deep white matter in heterozygous patients.
  phenotype_term:
    preferred_term: Dilated perivascular spaces
    term:
      id: HP:0012520
      label: Dilation of Virchow-Robin spaces
  evidence:
  - reference: PMID:36047879
    reference_title: Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "T2‐weighted images of the brain revealing visible perivascular spaces in the basal ganglia and deep brain white matter"
    explanation: Perivascular spaces in a heterozygous pedigree.
- category: Neurological
  name: Migraine
  subtype: HTRA1-CSVD
  description: Migraine is reported in some heterozygous patients, which can cause confusion with CADASIL type 1.
  phenotype_term:
    preferred_term: Migraine
    term:
      id: HP:0002076
      label: Migraine
  evidence:
  - reference: PMID:36047879
    reference_title: Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although migraine has been considered a hallmark of CADASIL, patients with heterozygous HTRA1‐related CSVD can also present with this symptom"
    explanation: Discussion statement citing earlier reports.
- category: Integumentary
  name: Premature Scalp Alopecia
  subtype: CARASIL
  frequency: VERY_FREQUENT
  description: >-
    Scalp alopecia before age 30 is characteristic of classic CARASIL; a literature review found alopecia of
    younger onset in 85.7% of CARASIL patients. It is not universal, and CARASIL without alopecia is reported.
  phenotype_term:
    preferred_term: Premature scalp alopecia
    term:
      id: HP:0002293
      label: Alopecia of scalp
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic."
    explanation: GeneReviews.
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The frequency both of alopecia of younger onset and lumbago/spondylosis deformans was significantly higher in CARASIL than symptomatic carriers (alopecia of younger onset: CARASIL 85.7% vs. symptomatic carriers 13.2%, p < 0.01"
    explanation: Pooled literature frequencies.
- category: Integumentary
  name: Scalp Alopecia in Heterozygotes
  subtype: HTRA1-CSVD
  frequency: OCCASIONAL
  description: >-
    Alopecia is seen in a minority of heterozygous patients: 13.2% of symptomatic carriers in a literature
    review, 2 of 9 in a Taiwanese series and 1 of 22 in a Chinese series. Early-onset alopecia can precede
    other signs, including in an asymptomatic carrier.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0002293
      label: Alopecia of scalp
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Spondylosis and alopecia are seen in a minority of individuals with HTRA1-CSVD."
    explanation: GeneReviews.
  - reference: PMID:29895533
    reference_title: Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "3 have leukoencephalopathy in anterior temporal poles, and 2 patients have alopecia"
    explanation: Two of nine heterozygous patients.
  - reference: PMID:36524103
    reference_title: "Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In addition, asymptomatic carrier F1-V-6 developed alopecia at age 24 years, with very slight/minimal leukoencephalopathy in the region near the frontal horn of the lateral ventricle"
    explanation: Early alopecia in a heterozygous carrier.
- category: Musculoskeletal
  name: Lumbar Spondylosis
  subtype: CARASIL
  frequency: VERY_FREQUENT
  description: >-
    Spondylosis deformans and disc herniation of the lumbar spine, present in all CARASIL patients in a
    literature review, often with lumbago before age 30. The homozygous R302Q rat develops vertebral osteophytes.
  phenotype_term:
    preferred_term: Lumbar spondylosis
    term:
      id: HP:0034931
      label: Lumbar spondylosis
  evidence:
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "lumbago/spondylosis deformans: CARASIL 100% vs. symptomatic carriers 60.0%, p < 0.01"
    explanation: Pooled literature frequency.
  - reference: PMID:11889251
    reference_title: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Severe degenerative changes in the lumbar spine and knee joints were seen on radiographs."
    explanation: Two CARASIL sisters.
  - reference: PMID:24535794
    reference_title: Mutation in the HTRA1 gene in a patient with degenerated spine as a component of CARASIL syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Patients with degenerated spine and progressive clinical symptoms must be evaluated or reevaluated for other central nervous system symptoms and signs to rule out other diseases or syndromes."
    explanation: Degenerated spine in a homozygous R370X patient.
  sequelae:
  - target: Low Back Pain
    description: Spondylosis and disc disease cause the acute lumbago of CARASIL.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21215656
      reference_title: "Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "attacks of severe low back pain or spondylosis deformans/disk herniation"
      explanation: Low back pain is reported together with the spine lesions that cause it.
- category: Musculoskeletal
  name: Low Back Pain
  subtype: CARASIL
  description: Acute mid- to lower-back pain (lumbago) before age 30 is characteristic of classic CARASIL.
  phenotype_term:
    preferred_term: Lumbago
    term:
      id: HP:0003419
      label: Low back pain
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic."
    explanation: GeneReviews.
- category: Musculoskeletal
  name: Intervertebral Disk Degeneration
  subtype: HTRA1-CSVD
  frequency: FREQUENT
  description: >-
    Degeneration of vertebrae and discs, disc herniation and canal stenosis of the cervical and lumbar spine.
    Reported frequencies in heterozygous patients range from 60.0% (literature review) to most patients in a
    Chinese series; all heterozygotes in a semidominant family had disc degeneration.
  phenotype_term:
    preferred_term: Spondylosis and intervertebral disc degeneration
    term:
      id: HP:0008419
      label: Intervertebral disk degeneration
  evidence:
  - reference: PMID:32719647
    reference_title: "HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "lumbago/spondylosis deformans: CARASIL 100% vs. symptomatic carriers 60.0%, p < 0.01"
    explanation: Pooled literature frequency in symptomatic carriers.
  - reference: PMID:36047879
    reference_title: Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "T2‐weighted cervical and lumbar MRI revealed multilevel degenerative disease, including disc herniation, canal stenosis, and degeneration of vertebral bodies"
    explanation: Spine imaging in a heterozygous pedigree.
  - reference: PMID:34303089
    reference_title: "One Disease with two Faces: Semidominant Inheritance of a Novel HTRA1 Mutation in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation."
    explanation: Disc degeneration in all heterozygotes of one family.
  - reference: PMID:27164673
    reference_title: Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases"
    explanation: Spondylosis in every manifesting heterozygote of this series.
- category: Musculoskeletal
  name: Knee Osteoarthritis
  subtype: CARASIL
  description: Degenerative knee joint disease is reported alongside the spine disease in CARASIL patients.
  phenotype_term:
    preferred_term: Knee joint degeneration
    term:
      id: HP:0005086
      label: Knee osteoarthritis
  evidence:
  - reference: PMID:11889251
    reference_title: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Severe degenerative changes in the lumbar spine and knee joints were seen on radiographs."
    explanation: Two CARASIL sisters.
environmental:
- name: Tobacco smoking
  description: >-
    GeneReviews advises avoiding smoking because it may hasten arteriosclerosis. In UK Biobank, cardiovascular
    risk burden was associated with increased stroke risk in HTRA1 variant carriers.
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."
    explanation: GeneReviews agents and circumstances to avoid.
  - reference: PMID:36300346
    reference_title: Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Cardiovascular risk burden was associated with increased stroke risk in NOTCH3 and HTRA1 carriers."
    explanation: Vascular risk factors modify penetrance in heterozygous carriers.
  influences_mechanisms:
  - target: Intimal Thickening of Cerebral Small Arteries
    environmental_effect: EXACERBATES
    description: Smoking is advised against because it may accelerate the arteriosclerotic change of the small arteries.
    evidence:
    - reference: PMID:20437615
      reference_title: HTRA1 Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."
      explanation: GeneReviews links smoking to arteriosclerosis progression.
- name: High-salt diet
  description: GeneReviews advises avoiding a high-salt diet because it may hasten arteriosclerosis.
  exposure_term:
    preferred_term: dietary sodium chloride
    term:
      id: ECTO:9001347
      label: exposure to sodium chloride
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."
    explanation: GeneReviews agents and circumstances to avoid.
  influences_mechanisms:
  - target: Intimal Thickening of Cerebral Small Arteries
    environmental_effect: EXACERBATES
    description: A high-salt diet is advised against because it may accelerate small-artery arteriosclerosis.
    evidence:
    - reference: PMID:20437615
      reference_title: HTRA1 Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."
      explanation: GeneReviews links high salt intake to arteriosclerosis progression.
diagnosis:
- name: HTRA1 molecular genetic testing
  description: >-
    The diagnosis is established by finding a heterozygous or biallelic pathogenic HTRA1 variant, usually on a
    small vessel disease gene panel or exome after NOTCH3. Because not every rare missense variant is
    pathogenic, protease activity, trimer formation and segregation are assessed for novel missense variants,
    and mRNA analysis can confirm decay of truncating alleles.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: Heterozygous (HTRA1-CSVD) or biallelic (CARASIL) pathogenic HTRA1 variant(s).
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The diagnosis of HTRA1 disorder is established in a proband by identification of either a heterozygous or biallelic pathogenic variant(s) in HTRA1 on molecular genetic testing."
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:32196841
    reference_title: "Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In order to establish pathogenicity of a HTRA1 variant, the activity of the mutated enzyme and its ability to form trimers should be evaluated, as well as whether it segregates with disease within a family."
    explanation: Consensus advice on variant interpretation.
  - reference: PMID:36261288
    reference_title: High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Third, HTRA1 genetic testing is performed in the remaining patients without mutations in NOTCH3."
    explanation: Proposed testing order in adult-onset monogenic small vessel disease.
- name: Brain MRI
  description: >-
    MRI shows confluent white matter hyperintensities, lacunes and microbleeds. Early CARASIL lesions involve the
    frontal white matter, external capsule and pons, and an arc-shaped pontine to middle cerebellar peduncle
    lesion appears late. On susceptibility-weighted imaging, five or more hypointense dots around the midbrain
    (the chocolate chip sign) distinguished HTRA1-related disease from other small vessel disease. CARASIL is
    suspected in recurrent unexplained lacunar strokes with severe white matter hyperintensities, especially with
    premature alopecia, lumbago or spondylosis.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Confluent white matter hyperintensities, lacunes, microbleeds, arc sign (advanced CARASIL), chocolate chip sign on SWI.
  evidence:
  - reference: PMID:26138950
    reference_title: Characteristic features and progression of abnormalities on MRI for CARASIL.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The arc sign was a characteristic finding for CARASIL in the advanced stage."
    explanation: Characteristic late CARASIL imaging sign.
  - reference: PMID:40017561
    reference_title: "\"Chocolate Chip Sign\" on Susceptibility-Weighted Imaging: A Novel Neuroimaging Biomarker for HTRA1-Related Cerebral Small Vessel Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "A threshold of 5 or more dots, termed the Chocolate Chip Sign, demonstrated optimal sensitivity and specificity for differentiating HRSVD (area under the curve [AUC]: 0.817; 95% confidence interval [CI]: 0.624–1.00; Figure 2D, eTable 4), which remained significant even after adjusting for disease duration and hypertension (Table 2)."
    explanation: SWI sign distinguishing HTRA1-related disease.
  - reference: PMID:32196841
    reference_title: "Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CARASIL should be suspected in cases of recurrent unexplained lacunar strokes with severe WMHs"
    explanation: Consensus clinical and imaging trigger for testing.
treatments:
- name: Antiplatelet and Antihypertensive Therapy
  description: >-
    GeneReviews suggests considering antiplatelet and antihypertensive therapy for those with cerebral
    microbleeds. Severe intracerebral hemorrhage in heterozygous patients, especially with marked microbleeds
    or antiplatelet use, argues for caution. Strict control of vascular risk factors is proposed to prevent
    vascular events in heterozygous carriers.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antiplatelet agent
      term:
        id: NCIT:C1327
        label: Antiplatelet Agent
    - preferred_term: antihypertensive agent
      term:
        id: NCIT:C270
        label: Antihypertensive Agent
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Consideration of anti-platelet therapy and anti-hypertensive therapy for those with cerebral microbleeds"
    explanation: GeneReviews management.
  - reference: PMID:36524103
    reference_title: "Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Two patients in our study experienced severe ICH, which reminds the clinicians of the risk of hemorrhage for these patients, especially for those who had marked microbleed and/or were on antiplatelet medications."
    explanation: Hemorrhage risk qualifies antiplatelet use.
  - reference: PMID:36530220
    reference_title: Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "suggesting that strict control of vascular risk factors can prevent vascular events in uniallelic HTRA1 carriers"
    explanation: Rationale for vascular risk factor control.
- name: Antispasticity Medication
  description: Baclofen or tizanidine may be considered for spasticity.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
    - preferred_term: tizanidine
      term:
        id: CHEBI:63629
        label: tizanidine
  target_phenotypes:
  - preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "consideration of medication (baclofen or tizanidine) for spasticity"
    explanation: GeneReviews management.
- name: Physical Therapy and Mobility Aids
  description: Physical therapy, walking aids and home adaptations for gait disturbance.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "physical therapy, walking aids, and home adaptations for those with gait disturbance"
    explanation: GeneReviews management.
- name: Avoidance of Smoking and High-Salt Diet
  description: >-
    Smoking and a high-salt diet are listed by GeneReviews as circumstances to avoid because they may hasten
    arteriosclerosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: lifestyle modification
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis."
    explanation: GeneReviews agents and circumstances to avoid.
- name: Supportive Care
  description: >-
    A wig or hairpiece for alopecia, standard treatment for spinal spondylosis and mood disorder, and emotional
    support and counselling for affected individuals and families.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "wig or hairpiece for those with alopecia; standard treatment for spinal spondylosis and mood disorder; supportive care including emotional support and counseling for affected individuals and their families"
    explanation: GeneReviews management.
- name: Genetic Counseling
  description: >-
    Counselling covers dominant (50%) and recessive (25%) recurrence risks, the possibility that heterozygous
    relatives of CARASIL patients develop disease, and the availability of prenatal and preimplantation testing
    once the familial variants are known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20437615
    reference_title: HTRA1 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Once the HTRA1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HTRA1 disorder are possible."
    explanation: GeneReviews genetic counseling.
- name: Candesartan (Preclinical)
  description: >-
    The angiotensin II receptor blocker candesartan reduced matrisome accumulation and normalized arterial
    distensibility and cerebral blood flow in HTRA1-null mice. This is a mouse result; no clinical trial in
    HTRA1 disease is reported in the cited sources.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: candesartan
      term:
        id: CHEBI:3347
        label: candesartan
  target_mechanisms:
  - target: Vascular Matrisome Protein Accumulation
    description: Candesartan lowers matrisome protein accumulation in the arterial intima of HTRA1-null mice.
    evidence:
    - reference: PMID:34779414
      reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow."
      explanation: Preclinical rescue in mice.
  evidence:
  - reference: PMID:34779414
    reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network."
    explanation: Preclinical mouse evidence only.
animal_models:
- name: Htra1 knockout mouse
  species: Mouse
  genotype: Htra1-/- (homozygous null)
  publication: PMID:34779414
  description: >-
    Htra1-null mice develop CARASIL-like cerebral arteriopathy with intimal thickening, abnormal elastic lamina,
    vasodilation and accumulation of matrisome proteins, with reduced arterial distensibility and cortical
    blood flow. Their smooth muscle cells fail to mature to the contractile phenotype. One study found normal
    cerebral arteries and an aortic phenotype in the same knockout, and no leukoencephalopathy on myelin stain.
  modeled_mechanisms:
  - target: Vascular Matrisome Protein Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Matrisome substrates accumulate in the thickened intima.
    limitations: >-
      Models the biallelic null state, so it informs CARASIL more than heterozygous disease, and mice lack the
      decades of vascular risk exposure that modify human penetrance.
    evidence:
    - reference: PMID:34779414
      reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated."
      explanation: Direct observation in the model.
  - target: Intimal Thickening of Cerebral Small Arteries
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Intimal thickening and abnormal elastic lamina in cerebral arteries.
    limitations: >-
      An independent study of the same knockout reported normal cerebral arteries, so the cerebral phenotype
      may depend on background or age.
    evidence:
    - reference: PMID:34779414
      reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation."
      explanation: Cerebral arteriopathy in the model.
    - reference: PMID:29768431
      reference_title: Loss of HtrA1 serine protease induces synthetic modulation of aortic vascular smooth muscle cells.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Although their cerebral arteries were normal, the thoracic aorta was affected in HtrA1-/- mice."
      explanation: A second study found no cerebral arteriopathy in the knockout.
  - target: Impaired Vascular Smooth Muscle Contractile Differentiation
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: Smooth muscle cells remain immature with impaired vasoconstriction.
    limitations: Shown partly in aortic and umbilical-artery smooth muscle rather than cerebral small arteries.
    evidence:
    - reference: PMID:31796853
      reference_title: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice."
      explanation: In vivo smooth muscle phenotype.
  - target: Reduced Cerebral Arterial Distensibility
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: TISSUE
    description: Reduced cerebral arterial distensibility and cortical blood flow.
    limitations: Not yet measured in patients, so fidelity to human disease is unknown.
    evidence:
    - reference: PMID:34779414
      reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex."
      explanation: Functional vascular readout in the model.
  evidence:
  - reference: PMID:34779414
    reference_title: Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation."
    explanation: Model characterization.
- name: Htra1 R302Q knock-in rat (CRHTRA1)
  species: Rat
  genotype: Homozygous Htra1 p.R302Q knock-in
  publication: PMID:41142321
  description: >-
    At 12 months the rat shows cerebral arteriolar wall thickening with lumen stenosis, enlarged perivascular
    spaces, loss of myelin basic protein in hyperintense regions, cognitive deficit, gait disturbance and
    vertebral osteophytes, with TGF-beta and matrix remodelling changes in the brain transcriptome.
  modeled_mechanisms:
  - target: Intimal Thickening of Cerebral Small Arteries
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Arteriolar wall thickening with lumen stenosis.
    limitations: Homozygous model of a variant that is pathogenic in humans when heterozygous; a single study at one age.
    evidence:
    - reference: PMID:41142321
      reference_title: A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "At 12 months, histopathological analyses revealed marked thickening of the cerebral arteriolar walls with concomitant lumen stenosis."
      explanation: Direct observation in the model.
  - target: Cerebral White Matter Myelin Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: UNKNOWN
    model_scale: TISSUE
    description: Loss of myelin basic protein in focal MRI-hyperintense regions.
    limitations: Focal rather than the diffuse confluent leukoencephalopathy of patients.
    evidence:
    - reference: PMID:41142321
      reference_title: A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Further immunolabeling revealed loss of myelin basic protein in these affected regions"
      explanation: Myelin readout in the model.
  - target: Lumbar Spondylosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: UNKNOWN
    model_scale: TISSUE
    description: Vertebral osteophytes on micro-CT.
    limitations: Osteophytes along cervical, thoracic and lumbar vertebrae; disc degeneration and pain were not assessed.
    evidence:
    - reference: PMID:41142321
      reference_title: A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Micro-computed tomography of spinal vertebrae revealed pronounced increases in osteophyte formation."
      explanation: Skeletal readout in the model.
  evidence:
  - reference: PMID:41142321
    reference_title: A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Behavioral testing in CRHTRA1 rats revealed significant cognitive deficit and gait disturbances."
    explanation: Behavioural phenotype of the model.
- name: Transgenic HtrA1 L364P mouse
  species: Mouse
  genotype: Transgenic expression of human HTRA1 p.L364P
  publication: PMID:35841197
  description: >-
    Mice expressing a CARASIL allele show cognitive deficits, loss of normal structure in some small cerebral
    arteries, thickened small-vessel walls with lumen stenosis on electron microscopy, abnormal myelin and
    increased TGF-beta, SMAD2 and SMAD3 expression.
  modeled_mechanisms:
  - target: Dysregulated TGF-beta Signaling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: UNKNOWN
    model_scale: MOLECULAR
    description: Increased TGF-beta, SMAD2 and SMAD3 expression in the brain.
    limitations: >-
      A transgene expressing the mutant on a wild-type background models neither the null nor the
      heterozygous human genotype; whole-brain expression does not localize the change to vascular cells.
    evidence:
    - reference: PMID:35841197
      reference_title: HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF-β/Smad signaling pathway in CARASIL model mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Immunohistochemistry, RT-PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF-β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees."
      explanation: Pathway readout in the model.
  evidence:
  - reference: PMID:35841197
    reference_title: HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF-β/Smad signaling pathway in CARASIL model mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure."
    explanation: Vascular phenotype of the model.
differential_diagnoses:
- name: CADASIL type 1 (NOTCH3)
  description: >-
    Shares dominant inheritance, stroke, cognitive decline, white matter hyperintensities, lacunes and
    microbleeds. Anterior temporal pole involvement is more common in NOTCH3 disease, and spine disorders more
    common in heterozygous HTRA1 disease; only genetic testing reliably separates them.
  evidence:
  - reference: PMID:40607620
    reference_title: Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Temporal pole WMH involvement can occur in HTRA1-AD-cSVD but is more common in CADASIL."
    explanation: Imaging overlap and difference.
  - reference: PMID:36047879
    reference_title: Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Patients with heterozygous HTRA1‐related CSVD had a higher proportion of spine disorders and a lower proportion of WMH involving the anterior temporal lobe compared with CADASIL."
    explanation: Distinguishing features from NOTCH3 CADASIL.
- name: Sporadic cerebral small vessel disease
  description: >-
    Heterozygous HTRA1 disease resembles age- and hypertension-related small vessel disease apart from its
    familial occurrence.
  evidence:
  - reference: PMID:26063658
    reference_title: Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "They are similar to those of sporadic small vessel disease, except for their familial nature."
    explanation: Clinical resemblance to sporadic disease.
notes: >-
  Lump/split decision. MONDO lists CARASIL (MONDO:0010829) as the only descendant of MONDO:0014768, and the
  GeneReviews chapter treats heterozygous and biallelic HTRA1 disease as one phenotypic spectrum ("HTRA1
  disorder"). The two forms share the same initiating lesion (loss of HTRA1 protease activity), the same
  arteriopathy (medial smooth muscle loss, intimal thickening, elastic lamina splitting), seen at autopsy in
  both, and can segregate in one family from a single allele. They are therefore curated as one entry with
  HTRA1-CSVD and CARASIL subtypes, the precedent used for the dominant and recessive COL4A2 forms in
  Brain_Small_Vessel_Disease_2. The European Academy of Neurology consensus describes heterozygous disease as a
  different form of heritable small vessel disease rather than CARASIL; the subtype split records that
  difference, and subtype-specific features (age at onset, alopecia, spine disease) are scoped with subtype.
  The heterozygous missense mechanism (interference with trimer activation) differs from that of most CARASIL
  missense alleles, and is carried as its own pathophysiology node. The deep research report recommended
  keeping CARASIL out of this entry; that recommendation was considered and not followed for the reasons
  above. Orphanet records were not fetched because the Orphadata bulk files are not present locally.

📚

References & Deep Research

References

PMID:20437615

HTRA1 Disorder.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Lump/split decision. MONDO lists CARASIL (MONDO:0010829) as the only descendant of MONDO:0014768, and the GeneReviews chapter treats heterozygous and biallelic HTRA1 disease as one phenotypic spectrum ("HTRA1 disorder"). The two forms share the same initiating lesion (loss of HTRA1 protease activity), the same arteriopathy (medial smooth muscle loss, intimal thickening, elastic lamina splitting), seen at autopsy in both, and can segregate in one family from a single allele. They are therefore curated as one entry with HTRA1-CSVD and CARASIL subtypes, the precedent used for the dominant and recessive COL4A2 forms in Brain_Small_Vessel_Disease_2. The European Academy of Neurology consensus describes heterozygous disease as a different form of heritable small vessel disease rather than CARASIL; the subtype split records that difference, and subtype-specific features (age at onset, alopecia, spine disease) are scoped with subtype. The heterozygous missense mechanism (interference with trimer activation) differs from that of most CARASIL missense alleles, and is carried as its own pathophysiology node. The deep research report recommended keeping CARASIL out of this entry; that recommendation was considered and not followed for the reasons above. Orphanet records were not fetched because the Orphadata bulk files are not present locally.

Create: CADASIL_Type_2 · 2026-10-28T02:12:39Z · View source

New entry for HTRA1-related cerebral small vessel disease (MONDO:0014768), written as one entry with two subtypes: HTRA1-CSVD (heterozygous, autosomal dominant, MONDO:0014768) and CARASIL (biallelic, autosomal recessive, MONDO:0010829, mapped as skos:narrowMatch). The lump follows the GeneReviews chapter "HTRA1 Disorder" (PMID:20437615), which treats both as one spectrum, MONDO's placement of CARASIL as the only child of MONDO:0014768, shared autopsy arteriopathy in both forms, and a semidominant family (PMID:34303089). The parent grouping MONDO:0007432 is mapped as skos:broadMatch, matching CADASIL_Type_1. The European Academy of Neurology consensus describes heterozygous disease as a separate form; this is recorded in notes. Deep research: claude_code (research/CADASIL_Type_2-deep-research-claude_code.md). Its reference validation resolved 49/49 identifiers; the one quoted claim checked (a synonym phrase attributed to PMID:27164673) was not found in the abstract and was not used. Term validation flagged four mislabelled CURIEs (annotations written as labels) and one obsolete GO term (GO:0005615); none was bound. The report recommended keeping CARASIL out of the entry; that was not followed, for the reasons above. preflight-dr returned PASS (HTRA1 mentioned 68 times). The GeneReviews chapter is tagged and cited for clinical characteristics, diagnosis, management (including smoking and high-salt diet as circumstances to avoid) and genetic counseling with recurrence risks. Additional references were found by PubMed search (HTRA1 with CARASIL/CADASIL/small vessel). Fetched but not cited: PMID:25116877, PMID:33313782, PMID:21482952, PMID:30447605 and PMID:40499346 (no cached abstract text), PMID:38466301 (no abstract), PMID:25770224 (correspondence; its point is covered by the TGF-beta node's REFUTE item), PMID:36035235 (UK Biobank, no significant HTRA1 phenotype associations), PMID:33963955 (genotype-phenotype review not needed for a specific claim) and PMID:39613464 (endothelial cell-line study overlapping PMID:42169653). Other report citations cached during report validation but not used were removed. Orphanet records were not fetched because the Orphadata bulk files are not present locally and disk space was limited. ClinGen has no HTRA1 gene-disease validity record in the local cache, so no tier is set. Pathophysiology: 17 nodes, each tagged with one biological scale, from HTRA1 haploinsufficiency and dominant-negative trimer disruption to protease loss of function, matrisome accumulation, dysregulated TGF-beta signalling (contested direction, with a REFUTE item), NOTCH3 over-activation, impaired smooth muscle differentiation, medial smooth muscle loss, intimal thickening, elastic lamina splitting, reduced distensibility, vessel ectasia, wall fragility, endothelial oxidative stress, blood-brain barrier leakage, chronic subcortical hypoperfusion and white matter myelin loss. Uncited edges carry a description saying the link is inferred. Conformance: "Blood-Brain Barrier Leakage" conforms to blood_brain_barrier_breakdown#Blood-Brain Barrier Permeability Increase (human DCE-MRI leakage, PMID:38787758, plus mouse knockdown); "Cerebral White Matter Myelin Loss" conforms to cns_myelin_failure#Deficient or Unstable CNS Myelin Sheath, which that module allows for secondary myelin loss when histology shows it (EAN consensus myelin pallor; rat MBP loss), and conformance is declared at that node only. Considered and rejected: aortopathy_tgfbeta_dysregulation (aorta-specific), fibrotic_response (matrisome accumulation here comes from failed degradation, not myofibroblast deposition), glymphatic_dysfunction (no HTRA1 evidence), neuroinflammation_glial_activation (not evidenced), corticospinal_tract_axonopathy and focal_axonal_injury_wallerian_degeneration (no tract-specific evidence), osteoarthritis_cartilage_degradation (spine and knee disease is reported clinically but no chondrocyte mechanism is shown), atherogenesis (no lipid mechanism), loss_of_proteostasis (intracellular scope). Validation: just validate passed; count-verified-snippets 176/176; check-genereviews TAGGED; entity refs, causal targets, logical rules, coarse phenotypes, enum values, duplicate keys, block-scalar comments, delivery system and qualifier terms clean; whole-tree snippet length, title snippets, reference titles, snippet grading, retired support prose, folded hyphens and environmental evidence clean; gene-activity grounding reports nothing for this file. 16 of 26 phenotypes are causally connected; the rest (mostly single-patient or psychiatric features) have no supported upstream node. validate-disorders passed. Review response (optional findings). The PMID:36530220 knee-pain item was removed from Knee Osteoarthritis, since pain does not establish joint degeneration; the radiograph finding in PMID:11889251 remains. The explanation on the wall-fragility to intracerebral-hemorrhage edge now says the source's statement is a hedged interpretation from one patient's pathology.

Claude Code ▸

CADASIL Type 2 (HTRA1-related autosomal dominant cerebral small vessel disease): research report

claude-haiku-5-5, claude-opus-5-5 13 citations 2026-10-28T01:32:54.037516

The local GeneReviews cache gives me the clinical baseline. Next I'm searching the primary literature on heterozygous HTRA1 disease for PMIDs and abstract quotes.

I have the main primary papers identified. Now I'm pulling exact PMIDs and abstract text from PubMed so the citations can be checked.

Shell network calls need approval, so I'm switching to fetching PubMed pages directly.

PubMed pages hit a captcha, so I'm using the NCBI E-utilities endpoint for abstracts instead.

CADASIL Type 2 (HTRA1-related autosomal dominant cerebral small vessel disease): research report

Target: MONDO:0014768 · OMIM:616779 · causal gene HTRA1 (HGNC:9476, written hgnc:9476 in this repo), chromosome 10q26.13 · Mendelian, autosomal dominant

Provenance: prepared 2026-10-28. - The clinical baseline comes from the GeneReviews HTRA1 Disorder chapter (PMID:20437615), which is already in references_cache/. - Primary-paper quotes were taken from PubMed abstracts through NCBI E-utilities, using a fetch tool that summarises pages. Treat every quoted string as a lead. Run just fetch-reference PMID:<id> and check the snippet against the cached abstract before it goes into YAML. - Every ontology CURIE suggested below is unverified and must be looked up before binding. CLAUDE.md requires this.

0. Note on the existing KB stub (`kb/disorders/CADASIL_Type_2.yaml`)

Synonyms that belong to a different disease. The current entry lists CARASIL and Maeda syndrome as synonyms. Those names refer to the recessive, biallelic HTRA1 disease (CARASIL, OMIM:600142), which has its own MONDO term. MONDO:0014768 / OMIM:616779 is the heterozygous, autosomal dominant disease.
Recommendation: keep CARASIL out of synonyms. Mention it only in description/notes, or as a related entity, as one end of the "HTRA1 disorder" spectrum.
Description: the current text covers both conditions. It should be rewritten to describe the dominant disease.

1. Disease information

Overview. CADASIL2 is an adult-onset hereditary cerebral small vessel disease (CSVD) caused by heterozygous pathogenic variants in HTRA1. HTRA1 encodes high-temperature requirement A serine peptidase 1, a secreted, trimeric PDZ-domain serine protease.

Clinical picture: - Typical features are progressive gait disturbance, lacunar strokes, cognitive decline and mood change, on a background of confluent white-matter hyperintensities, lacunes and microbleeds. - Compared with CARASIL, onset is later and extraneurological features (alopecia, spondylosis) are milder and less frequent.

Supporting sources: - GeneReviews (PMID:20437615): "'HTRA1 cerebral small vessel disease' (HTRA1-CSVD) refers to the milder phenotype associated with a heterozygous HTRA1 pathogenic variant." - Verdura et al., Brain 2015 (PMID:26063658), the defining paper: onset is later than in CARASIL or CADASIL, CARASIL's typical extraneurological features are absent, and the disease otherwise resembles sporadic SVD.

Identifiers

System	ID	Status
MONDO	MONDO:0014768 (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2)	Given in the brief; matches the KB stub
OMIM	616779	Given
Orphanet	ORPHA:482077 (HTRA1-related autosomal dominant cerebral small vessel disease)	Taken from OMIM/GenCC cross-references; confirm in ORPHA cache (`just fetch-reference ORPHA:482077`)
MedGen	C4225242 / 895965	From a MedGen page found in search; verify
ICD-10	I67.8 (other specified cerebrovascular disease) applies generically; there is no specific code	—
GeneReviews	HTRA1 Disorder, PMID:20437615 (NBK32533)	Cached

Synonyms: CADASIL2; CADASIL type 2; HTRA1-CSVD; HTRA1-related autosomal dominant CSVD (HTRA1-AD-cSVD); "symptomatic/manifesting heterozygotes of CARASIL" (older usage, e.g. PMID:27164673).

Data basis: aggregated disease-level resources (OMIM, GeneReviews, Orphanet) plus case series, systematic reviews and population biobank studies (UK Biobank, BioBank Japan). No EHR-derived phenotype profile exists.

2. Etiology

Causal factor. Heterozygous germline HTRA1 variants: missense variants clustered in the protease domain, and also nonsense and frameshift variants. Variant classes and mechanism are covered in §4.

Genetic risk and modifiers - Variant position and pathogenicity score affect severity. Systematic review (PMID:33963955): "clinical phenotype severity was independently related to the pathogenicity score (CADD score; p < 0.05)". Also: "patients with mutations in exon 4 (p = 0.0001) presented with more severe clinical symptoms". - Common HTRA1 variation (polygenic arm, separate from the Mendelian disease): - rs2293871 is associated with extreme CSVD MRI burden and with small-vessel ischaemic stroke (PMID:30859180). - A common variant that raises circulating HTRA1 increases ischaemic stroke risk (PMID:39196222). - Semidominance. Within one consanguineous family, the same allele (p.Pro275Leu) produced CARASIL when homozygous and CADASIL2 when heterozygous (PMID:34303089): "CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities".

Environmental and lifestyle risk factors - Vascular risk burden increases penetrance. UK Biobank (PMID:36300346): "Cardiovascular risk burden is associated with the penetrance of such variants." - Smoking and high-salt diet. GeneReviews advises avoiding both because they "may hasten the progression of arteriosclerosis". - Smoking in common-variant stroke susceptibility. An HTRA1 × smoking interaction has been reported for stroke susceptibility in Chinese Han cohorts (PMID:33746601). This concerns common variants, not the Mendelian disease. - Hypertension is a frequent comorbidity in case series. Strict risk-factor control is proposed as protective (PMID:36530220): "strict control of vascular risk factors can prevent vascular events in uniallelic HTRA1 carriers."

Protective factors: none established. Control of vascular risk factors is the only plausible modifiable protection.

Gene–environment interaction: the vascular-risk-burden × carrier-status effect on stroke (PMID:36300346) is the best-supported interaction.

3. Phenotypes

Main sources: - GeneReviews (PMID:20437615) - Uemura et al. 2020 review of 46 symptomatic carriers vs 28 CARASIL patients (PMID:32719647) - Chinese series of 21 HTRA1-AD-cSVD patients compared with CADASIL (PMID:40607620) - Comparison of Chinese HTRA1-CSVD with CADASIL (PMID:36047879)

HPO IDs are suggestions and must be checked against the cache or OAK before binding.

Phenotype	Suggested HPO	Onset / course	Frequency and evidence
Leukoencephalopathy / confluent WMH	HP:0002352 Leukoencephalopathy	Adult; progressive	Near-universal on MRI. One study found a lower WMH proportion than in CADASIL (PMID:36047879)
Gait disturbance (often the first symptom)	HP:0001288 Gait disturbance	After age 40; slowly progressive	GeneReviews: "The most frequent initial symptom in individuals with HTRA1-CSVD is slowly progressive gait disturbance after age 40 years"
Spasticity / pyramidal signs	HP:0001257 Spasticity	Adult; progressive	Common; treated with baclofen or tizanidine per GeneReviews
Stroke (lacunar ischaemic) / stroke-like episodes	HP:0001297 Stroke (narrower lacunar term to be checked)	After 40	GeneReviews: "A majority of affected individuals have a stroke-like episode after age 40 years." PMID:40607620: "Stroke occurred in 81.0% of HTRA1-AD-cSVD patients"
Lacunes on MRI	(radiological; consider an HP lacunar-infarct term)	—	"lacunes in 90.5%" (PMID:40607620)
Cerebral microbleeds, including brainstem-surface "chocolate chip sign"	HP:0002170? (verify the microbleed term)	—	"⩾10 cerebral microbleeds (CMBs) in 66.7%" (PMID:40607620). The SWI chocolate chip sign around the midbrain reached AUC 0.817 (PMID:40017561; also PMID:39270409, PMID:40866829)
Cognitive impairment / vascular dementia	HP:0100543 Cognitive impairment; HP:0000726 Dementia	Later course	"47.6% exhibited cognitive dysfunction" (PMID:40607620)
Mood change: apathy, irritability, depression	HP:0000741 Apathy; HP:0000737 Irritability; HP:0000716 Depression	Follows gait onset	GeneReviews ("may be followed by the development of mood changes and cognitive dysfunction")
Pseudobulbar palsy / dysarthria	HP:0007024 Pseudobulbar paralysis; HP:0001260 Dysarthria	Advanced	Mainly CARASIL; seen in some heterozygotes
Spondylosis / lumbar disc disease, low back pain	HP:0003419 Low back pain; spondylosis term to verify	Variable	GeneReviews: "Spondylosis and alopecia are seen in a minority of individuals with HTRA1-CSVD." PMID:36047879: more spine disorders than in CADASIL
Alopecia	HP:0001596 Alopecia	Can be early (PMID:40499346)	Minority
Urinary incontinence / urgency	HP:0000020	Advanced	Reported in case series
Small-fibre neuropathy (rare)	HP:0003487? (verify)	—	Single report (PMID:33313782)

Quality of life. Gait failure, cognitive decline and apathy drive disability. No EQ-5D or SF-36 data specific to HTRA1 were found.

Age at onset. Symptomatic carriers start significantly later than CARASIL patients (PMID:32719647): "The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL". Onset is usually in the 5th–6th decade. Young-onset severe disease is reported with p.A252T (PMID:36530220).

4. Genetic and molecular information

Gene. HTRA1 (HGNC:9476; OMIM *602194). It has an N-terminal IGFBP/Kazal module, a trypsin-like serine protease domain (catalytic triad H220/D250/S328) and a C-terminal PDZ domain. Activity depends on homotrimer formation and an inter-subunit activation cascade involving loops L3, LD and L1.

Variant classes and mechanism

Missense variants in the protease domain, enriched in exon 4. Two dominant-negative routes have been described: inability to form stable trimers, or trimers that cannot pass on activation.
PMID:27164673 (Nozaki 2016): "These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity". Also: "G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers."
PMID:31316458 (Uemura 2019): "10 of 11 hetero-HTRA1s and two of six CARASIL-HTRA1s were either defective in trimerization". Also: "eight of 11 hetero-HTRA1s … inhibited WT protease activity".
Examples: p.R166L (the Verdura founder family), p.G283E, p.P285L, p.R302Q (recurrent in Japan), p.T319I, p.A252T (also reported biallelic in CARASIL; severe when uniallelic, PMID:36530220), p.R274Q (knock-in mouse).
Nonsense and frameshift variants: haploinsufficiency through nonsense-mediated decay. PMID:34270682 (Brain 2021): "Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified". mRNA showed "a degradation of the mutated allele". The authors conclude "heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism".
Supporting data: carriers' cells show about 50% HTRA1 expression (PMID:32017060): "CSVD phenotype may also result from 50% of HTRA1 expression."

Functional consequence. Loss of function in every case: haploinsufficiency for null alleles, dominant-negative for many missense alleles. In repo terms this is LOSS_OF_FUNCTION or DOMINANT_NEGATIVE in functional_impact_category, depending on the variant.

Classification. ClinVar holds many P/LP heterozygous HTRA1 variants. A curated P/LP review is PMID:37016629.

ClinGen / GenCC. GenCC lists HTRA1 for Orphanet:482077. The ClinGen gene–disease validity tier for the AD disease was not retrieved. Check just list-gene-validity and the CGGV cache before recording any tier, and never assign one yourself.

Allele frequency and germline status. All variants are germline. Rare damaging HTRA1 variants occur in roughly 1 in 450 UK Biobank participants (medRxiv 2021 preprint), so carrier frequency in the population is far higher than clinical disease prevalence.

Modifier genes: none established. A patient with coexisting NOTCH3 and HTRA1 variants has been reported (PMID:40634305).

Epigenetics: HTRA1 methylation in blood has been studied as a marker of preclinical stroke risk in the general population (PMID:36581876). It is not specific to CADASIL2.

Chromosomal abnormalities: not a recognised mechanism.

5. Environmental information

Exposures: no causal environmental agent or infection.
Lifestyle: smoking, high salt intake and the general vascular risk burden (hypertension, diabetes, dyslipidaemia) modify penetrance and progression (PMID:36300346; PMID:20437615).

6. Mechanism and pathophysiology

Ordered causal chain

Heterozygous HTRA1 variant. A null allele leads to NMD and roughly 50% HTRA1 protein (PMID:34270682, PMID:32017060). A missense allele leads to a defective trimer or a trimer that blocks the activation cascade, reducing activity of the wild-type subunits (dominant-negative; PMID:27164673, PMID:31316458).
Reduced extracellular HTRA1 protease activity in the cerebral small-vessel wall results in failure to cleave matrisome substrates.
Demonstrated in Htra1-/- mice (PMID:34779414).
Shown by proteomics in human CADASIL vessels (PMID:29725820), where HTRA1 is sequestered by NOTCH3 aggregates. This is the convergent "HTRA1 loss" mechanism.
Matrisome accumulation in the vessel wall (fibronectin, LTBP-4, EDA-fibronectin, versican and others) leads to intimal thickening and abnormal elastic lamina.
Shown in knockout and R274Q knock-in mice (PMID:34779414; LMU dissertation 2022).
Inferred for human heterozygotes from CARASIL autopsy and mouse data.
Branch: dysregulated TGF-β family signalling. The direction is disputed.
Original CARASIL work found mutant HTRA1 "failed to repress" TGF-β family signalling, implying increased signalling (Hara 2009, PMID:19387015).
Beaufort 2014 (PMID:25369932) found HTRA1 processes LTBP-1 and that its loss attenuates TGF-β signalling.
No change in pSMAD2/3 in carrier cells (PMID:32017060).
Increased TGF-β/SMAD in a lentiviral mutant endothelial model (PMID:39613464).
Treat this step as contested.
Vascular smooth muscle cell (VSMC) dysfunction. Loss of HTRA1 leads to impaired contractile maturation and a shift to the synthetic phenotype, with MMP9 induction, VSMC death and medial degeneration.
PMID:31796853: "HTRA1 is essential for VSMC differentiation into the contractile phenotype." JAG1/NOTCH3 signalling also increases.
PMID:29768431: "Loss of HtrA1 therefore skews VSMCs toward the synthetic phenotype, induces MMP9 expression, and expedites cell death."
Evidence: in vitro and mouse.
Branch: endothelial oxidative stress. HTRA1 deficiency leads to NOX4-driven ROS, blood–brain barrier disruption and cognitive impairment.
Mouse and in vitro work, 2026 (PMID:42169653). This is an emerging hypothesis.
Arteriopathy of the small penetrating arteries (wall thickening, loss of VSMCs, vasodilation/ectasia, reduced distensibility) results in impaired autoregulation and reduced cerebral blood flow.
Shown in mice: candesartan "normalized the vascular distensibility and cerebral blood flow" (PMID:34779414).
Human autopsy of a heterozygote: PMID:29797751.
Chronic hypoperfusion of the deep white matter and focal occlusion lead to leukoencephalopathy and lacunar infarcts. Fragile walls lead to microbleeds, preferentially on the brainstem surface (PMID:39270409).
Disruption of white-matter tracts and lacunes produces gait disturbance and spasticity, then cognitive and mood dysfunction, pseudobulbar signs and dementia.
Extraneurological branch (inferred): HTRA1 roles in bone and cartilage, and possibly in hair follicles, may explain spondylosis, disc disease and alopecia. The mechanism is not established.

Ontology suggestions (verify each)

GO terms:
serine-type endopeptidase activity GO:0004252 (molecular function; decreased)
proteolysis GO:0006508
extracellular matrix organization GO:0030198
transforming growth factor beta receptor signaling pathway GO:0007179 (direction contested)
smooth muscle cell differentiation GO:0051145
reactive oxygen species metabolic process GO:0072593 (emerging)
CL terms:
vascular associated smooth muscle cell CL:0000359
brain endothelial cell (verify the specific CL ID; generic endothelial cell CL:0000115)
brain pericyte CL:2000043
oligodendrocyte CL:0000128 (downstream white-matter injury)
Molecular profiling:
vessel proteomics (PMID:29725820)
patient iPSC line carrying p.R302Q, with differential HTRA1 and NOG expression (PMID:37009886)
no single-cell or spatial data specific to CADASIL2 were found

7. Anatomical structures affected

Organ level:
Brain. Primary sites are the cerebral white matter, basal ganglia, thalamus and pons/brainstem.
Spine: vertebrae and intervertebral discs.
Scalp hair, in a minority of patients.
Retinal involvement is reported mainly in CARASIL (e.g. macular oedema, PMID:38879362).
Tissue and cell level: the walls of small penetrating arteries and arterioles, specifically the tunica media (VSMCs), the intima and the internal elastic lamina.
Subcellular level: extracellular matrix (GO:0031012) and extracellular space (GO:0005615), where HTRA1 is secreted.
UBERON suggestions (verify): cerebral white matter, basal ganglion, pons, arteriole (UBERON:0001980), vertebral column.
Lateralization: bilateral and symmetric white-matter disease; lacunes are multifocal.

8. Temporal development

Onset: adult, usually after age 40. Onset is insidious: gait first, then mood and cognition. Occasional early onset with p.A252T or early alopecia (PMID:36530220, PMID:40499346).
Progression: slow and progressive. No formal staging exists. GeneReviews describes CARASIL as progressing slowly after symptom onset.
Remission: none.
Critical window for intervention: the presymptomatic carrier period, when vascular risk factors can still be controlled.

9. Inheritance and population

Inheritance: autosomal dominant (HP:0000006). Penetrance is incomplete and age-dependent, and is modified by vascular risk. Expressivity is variable, from MRI-only findings to severe disease.
UK Biobank: HTRA1 carriers were "at least 66% more likely to have had stroke" (PMID:36300346, pooled monogenic-SVD genes). In a separate 200,000-participant study, rare variants in five CSVD genes occurred in 0.5% of participants, with weak phenotype associations for HTRA1 (PMID:36035235).
Frequency among patients with familial or adult CSVD:
4.97% of NOTCH3-negative familial SVD probands; association statistics "P = 4.2 × 10(-6); odds ratio = 15.4" (PMID:26063658)
2.08% (7/337) in Taiwan (PMID:29895533)
11 HTRA1 cases in a Japanese monogenic-CSVD series in which NOTCH3, HTRA1 and ABCC6 together explained 94% (PMID:36261288)
0.8–6.5% of NOTCH3-negative CSVD worldwide (secondary review)
Prevalence: no population prevalence has been measured. Orphanet likely lists it as unknown (<1/1,000,000 class); check ORPHA:482077. Variant carrier frequency is about 1/450, but clinical disease is much rarer, so use measure_type: UNKNOWN or CASES_IN_LITERATURE until a source says otherwise.
Anticipation: none. Mosaicism: not described. Consanguinity: relevant to the biallelic form only.
Founder effects and geography: reported in Europe, Japan (R302Q recurrent), China (largest case series), Taiwan, India and Africa (PMID:32042911).
Sex ratio: no consistent sex bias reported.

10. Diagnostics

Genetic testing: diagnosis rests on finding a heterozygous P/LP HTRA1 variant (GeneReviews). Recommended routes are a CSVD gene panel (NOTCH3, HTRA1, COL4A1/2, ABCC6, TREX1, GLA, CTSA) or exome sequencing. Verdura: "screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology." mRNA analysis can confirm NMD for stop variants (PMID:34270682).
Imaging (MRI):
confluent WMH, lacunes, microbleeds, dilated perivascular spaces
brainstem/pontine "chocolate chip sign" on SWI as a candidate biomarker (PMID:40017561, PMID:40866829, PMID:40632435)
anterior temporal pole WMH is less common than in CADASIL1 (PMID:40607620)
7T caveat: sulcal vessels can mimic microbleeds (PMID:39569513)
Biopsy and pathology: no skin-biopsy marker equivalent to GOM. Autopsy shows arteriosclerosis of small arteries with loss of medial smooth muscle and intimal thickening (PMID:29797751, PMID:36524103).
Laboratory: no specific biomarker. Routine vascular risk work-up applies.
Differential diagnosis: CADASIL1 (NOTCH3; GOM on skin biopsy, temporal pole and external capsule WMH), CARASIL (biallelic, earlier onset), COL4A1/2 disease, Fabry disease, CARASAL (CTSA), RVCL-S (TREX1), sporadic hypertensive arteriolosclerosis, multiple sclerosis and CNS vasculitis (misdiagnoses reported, PMID:36334553, PMID:40997360), and adult-onset leukodystrophies.
Screening: cascade testing of relatives after genetic counselling. No newborn or population screening.

11. Outcome and prognosis

Survival: no survival or life-expectancy data exist. Progressive disability and dementia accumulate over years to decades.
Complications: recurrent stroke, vascular dementia, gait failure leading to falls and dependence, depression.
Prognostic factors: variant domain (exon 4) and CADD score (PMID:33963955), plus vascular risk burden (PMID:36300346).
Recovery: none. Management is supportive.

12. Treatment

No disease-modifying therapy exists. GeneReviews management (PMID:20437615) with suggested NCIT bindings (verify each):

Intervention	Suggested NCIT term	Notes
Antiplatelet therapy, used cautiously when microbleeds are present	Pharmacotherapy NCIT:C15986, plus `therapeutic_agent` (e.g. aspirin, CHEBI)	GeneReviews: "Consideration of anti-platelet therapy and anti-hypertensive therapy"
Antihypertensive therapy and vascular risk control	NCIT:C15986, plus an agent class	Supported by penetrance data (PMID:36300346, PMID:36530220)
Spasticity drugs (baclofen, tizanidine)	NCIT:C15986, plus CHEBI baclofen / tizanidine	GeneReviews
Physical therapy, walking aids, home adaptation	Physical Therapy NCIT:C15302; Rehabilitation NCIT:C15315	`therapeutic_modality: BEHAVIORAL`
Wig for alopecia; standard care for spondylosis and mood disorder	Supportive Care NCIT:C15747	—
Genetic counselling	Genetic Counseling NCIT:C15240	—

Experimental and preclinical: - Candesartan (AT1 receptor blocker) prevented arteriopathy progression in Htra1-/- mice (PMID:34779414). This is preclinical only, in a CARASIL model. - The NOX4 inhibitor GLX351322 rescued BBB and cognitive deficits in mice (PMID:42169653). - No registered ClinicalTrials.gov trial specific to HTRA1-CSVD was found in this search.

Pharmacogenomics: none.

13. Prevention

Primary: no primary prevention for the variant itself. Preimplantation and prenatal testing are possible once the familial variant is known (GeneReviews).
Secondary and tertiary: strict control of vascular risk factors, smoking cessation, and limiting salt intake (GeneReviews; PMID:36530220).
Counselling: each offspring has a 50% risk. For the semidominant spectrum, offer counselling to all family members (PMID:34303089).

14. Other species and natural disease

Naturally occurring disease: none found in OMIA for HTRA1-related cerebral arteriopathy.
Orthologs: mouse Htra1 (MGI). The protease is highly conserved; bacterial DegP/HtrA is the ancestral family.

15. Model organisms

Model	Recapitulation	Key reference
Htra1-/- mouse	CARASIL-like arteriopathy: intimal thickening, abnormal elastic lamina, vasodilation, matrisome (FN, LTBP-4) accumulation, reduced distensibility and CBF. Used to test candesartan. Models the biallelic state, so it shows only partial fidelity for heterozygous disease	PMID:34779414
Htra1-/- mouse, aortic VSMCs	Synthetic VSMC switch, MMP9, cell death	PMID:29768431
Htra1-/- mouse, placenta	Intrauterine growth restriction and placental defects (off-target phenotype)	PMID:25446274
Htra1 R274Q knock-in mouse	Vessel accumulation of FN, LTBP4, FBLN5 and EGFL8. Closer to a missense allele	LMU dissertation 2022 (not peer-reviewed)
Htra1 L364P mouse	Reported CARASIL-like features; VSMC apoptosis	PMID:31601092
HTRA1-deficient VSMCs	Impaired contractile maturation; increased JAG1/NOTCH3	PMID:31796853
Patient iPSC line (heterozygous p.R302Q)	Cell resource; HTRA1 and NOG dysregulation	PMID:37009886
Lentiviral missense HtrA1 in mouse brain endothelial cells	TGF-β/SMAD activation, ROS, apoptosis	PMID:39613464

Limitations and suggested KB encoding - No heterozygous mouse model reproduces human CSVD. - Mice lack the decades of vascular-risk exposure that drive penetrance. - Candidate HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussions: heterozygous mice, and the direction of TGF-β signalling.

Key references (PMIDs)

Clinical, genetic and population - 20437615: GeneReviews, HTRA1 Disorder - 26063658: Verdura 2015, Brain - 19387015: Hara 2009, NEJM - 27164673: Nozaki 2016, Neurology - 31316458: Uemura 2019, Front Neurol - 34270682: stop-codon haploinsufficiency, Brain 2021 - 32719647: review, Front Neurol 2020 - 33963955: genotype–phenotype systematic review, 2021 - 40607620: HTRA1 vs NOTCH3 comparison, Int J Stroke - 36047879: Chinese series compared with CADASIL - 36261288: Japanese monogenic CSVD frequency - 29895533: Taiwanese series - 36530220: uniallelic p.A252T - 34303089: semidominant family - 36300346: UK Biobank penetrance - 36035235: UK Biobank five-gene study - 39196222: genetically proxied HTRA1 activity and stroke - 30859180: rs2293871 and CSVD MRI extremes

Imaging and pathology - 40017561, 39270409: chocolate chip sign and brainstem microbleeds - 29797751: autopsy of a heterozygote

Mechanism and models - 29725820: CADASIL vessels show an HTRA1 loss-of-function profile - 25369932: HTRA1 processes LTBP-1 - 32017060: HTRA1 expression and TGF-β in carriers - 31796853: HTRA1 and VSMC maturation - 29768431: synthetic VSMC switch in Htra1-/- - 34779414: candesartan in Htra1-/- mice - 42169653: endothelial NOX4 - 37009886: patient iPSC line

Web sources consulted: PMC7284040; OMIM 616779 mirror; Verdura 2015 (HAL); Frontiers Neurol 2019 (Uemura); QxMD 19387015; PMC10659557; Cambridge UKB penetrance; medRxiv 2021 WMH preprint; JCI 140555; LMU dissertation; MedGen 895965; GenCC HTRA1; NCBI E-utilities.

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	49
Resolved	49
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	0
Quoted claims not found in source	1
References weighed for topical relevance	49
On topic	39
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:27164673 (abstract only): "symptomatic/manifesting heterozygotes of CARASIL"
Text part not found as substring: 'symptomatic/manifesting heterozygotes of CARASIL' (note: only abstract available for PMID:27164673, full text may contain this excerpt)

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	41
Resolved	35
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	5
Terms whose name was checked	8
Terms named correctly	2
Terms named as a different term	4
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

GO:0004252 (1 mention) - the report calls it "molecular function; decreased"; GO calls it serine-type endopeptidase activity
GO:0007179 (1 mention) - the report calls it "direction contested"; GO calls it transforming growth factor beta receptor signaling pathway
GO:0072593 (1 mention) - the report calls it "emerging"; GO calls it reactive oxygen species metabolic process
CL:0000128 (1 mention) - the report calls it "downstream white-matter injury"; CL calls it oligodendrocyte

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0000020 (1 mention) - the report calls it "Urinary incontinence / urgency"; HP calls it Urinary incontinence
GO:0031012 (1 mention) - the report calls it "Subcellular level: extracellular matrix"; GO calls it extracellular matrix**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, ORPHA, Orphanet.

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CADASIL Type 2 (HTRA1-related autosomal dominant cerebral small vessel disease): research report

0. Note on the existing KB stub (kb/disorders/CADASIL_Type_2.yaml)

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Key references (PMIDs)

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

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0. Note on the existing KB stub (`kb/disorders/CADASIL_Type_2.yaml`)