Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

A hereditary autosomal recessive nonhypertensive cerebral small vessel arteriopathy characterized by alopecia, SPONDYLOSIS, and progressive motor dysfunction and DEMENTIA with onset typically in the second or third decade of life. Mutations in the HTRA1 gene have been identified. OMIM: 600142

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Networked: 58 relevant articles (1 outcomes, 0 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
2.	CADASIL
3.	Cerebral Small Vessel Diseases
4.	Fabry Disease (Fabry's Disease)
5.	Leukoencephalopathies

Experts

1.	Onodera, Osamu: 14 articles (11/2021 - 04/2009)
2.	Nozaki, Hiroaki: 13 articles (11/2021 - 04/2009)
3.	Nishizawa, Masatoyo: 7 articles (11/2021 - 04/2009)
4.	Koyama, Akihide: 6 articles (11/2021 - 04/2009)
5.	Kato, Taisuke: 5 articles (11/2021 - 05/2011)
6.	Uemura, Masahiro: 5 articles (11/2021 - 01/2016)
7.	Shiga, Atsushi: 5 articles (01/2016 - 04/2009)
8.	Ando, Shoichiro: 3 articles (11/2021 - 01/2019)
9.	Kanazawa, Masato: 3 articles (11/2021 - 01/2019)
10.	Kawata, Hirotoshi: 3 articles (11/2021 - 04/2009)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy:

1.	Peptide Hydrolases (Proteases)FDA Link 05/01/2015 - "A novel HTRA1 exon 2 mutation causes loss of protease activity in a Pakistani CARASIL patient." 01/01/2012 - "CARASIL-associated mutant HTRA1s have decreased protease activity and fail to repress the TGF-β signaling, raising the possibility that chronic upregulation in the signaling pathways are involved in the pathogenesis of CARASIL. " 11/01/2011 - "The CARASIL-associated mutant HTRA1s lost their protease activity and increase the TGF-β family signaling. " 05/01/2011 - "We demonstrated that CARASIL-associated mutant HTRA1s decrease protease activity and fail to decrease TGF-β family signaling. " 01/01/2016 - "These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. "
2.	Serine (L-Serine)FDA Link 09/10/2013 - "The efficacy of SMG-8 knockdown to improve the mutant phenotype was confirmed using another cell line, from a cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy patient who carries a PTC-containing mutation in HtrA serine peptidase 1. Our results suggest that SMG-8 is an appropriate target for inhibiting NMD to improve NMD-exacerbated mutant phenotypes. " 09/30/2019 - "Results show that Mut-high-temperature requirement serine peptidase A1 geneL364P mice present similar pathological characteristics to patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, suggesting that the Mut-high-temperature requirement serine peptidase A1 geneL364P mouse model was generated successfully. " 09/30/2019 - "To further explore the molecular pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a recombination mouse model expressed human high-temperature requirement serine peptidase A1 gene mutant identified by our group was generated using the Donor & Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 system and termed the Mut-high-temperature requirement serine peptidase A1 geneL364P mouse model. " 01/01/2018 - "Homozygous and compound heterozygous mutations in the high temperature requirement serine peptidase A1 gene (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. " 10/26/2020 - "Homozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1 (HTRA1) gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). "
3.	High-Temperature Requirement A Serine Peptidase 1IBA 01/01/2020 - "CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). " 02/01/2011 - "Mutations in the serine protease HTRA1 gene are associated with CARASIL. " 11/15/2021 - "Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. " 01/01/2019 - "Background: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). " 10/01/2013 - "Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene were studied in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). "
4.	Serine Proteases (Serine Protease)IBA 01/01/2022 - "We previously reported the first family with CARASIL in China, which involves a high-temperature requirement serine protease gene mutation (HtrA1L364P ). " 11/01/2018 - "HtrA1 is a serine protease that has been linked to cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a small blood vessel disease in humans. " 08/01/2015 - "The HtrA serine protease 1 (HTRA1) gene has been identified as the causative gene of CARASIL. " 01/01/2022 - "Homozygous or compound heterozygous mutations in the high-temperature requirement A serine protease 1 gene (HTRA1) elicits cerebral autosomal recessive arteriopathy with subcortical infarcts and white matter lesions (CARASIL). " 05/15/2020 - "Homozygous or compound heterozygous mutations in the high-temperature requirement A serine protease 1 gene (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a very rare hereditary cerebral small-vessel disease (SVD). "
5.	Retinaldehyde (Retinal)IBA 04/01/2009 - "Clinical manifestations such as optic neuritis and retinal vascular change might be caused by the pathological changes of CARASIL. " 01/01/2015 - "These include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1-related cerebral SVD, autosomal dominant retinal vasculopathy with cerebral leukodystrophy, and Fabry disease. " 03/01/2013 - "To understand the molecular pathogenesis for CSVD, here, we review the clinical spectrum, pathological findings and the molecular pathogenesis of CSVD caused by single gene defect: including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COLAA1-related disorders, retinal vasculopathy with cerebral leukodystrophy, Fabry disease, and hereditary cerebral amyloid angiopathy." 01/01/2014 - "The most common forms are related to vascular pathology, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy (RVCL), and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). " 11/15/2012 - "Clinical features and diagnostic clues of these conditions, [cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related cerebral small vessel diseases, autosomal dominant retinal vasculopathy with cerebral leukodystrophy (AD-RVLC), and Fabry's disease] are here reviewed. "
6.	Fibronectins (Fibronectin)IBA 01/01/2012 - "Here we show that increased expression of LAP and ED-A fibronectin are limited to affected small arteries in patients with CARASIL. " 05/01/2011 - "Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. " 11/18/2014 - "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. " 04/01/2008 - "Arterial adventitia in CARASIL was conspicuously thin and immunoreactivities for type I, III, and VI collagens and fibronectin were appreciably weak in this region, indicating a reduction in the mural extracellular matrix (ECM). " 04/01/2015 - "The mutation in HTAR1 related to CARASIL fails to repress TGF-beta signaling and induces the accumulation of extracellular matrix, including the extra domain-A region of fibronectin and versican. "
7.	Transforming Growth Factor beta (TGF-beta)IBA 06/01/2010 - "Thus, we have concluded that the increased TGF-Beta signaling causes arteriopathy in CARASIL." 01/01/2018 - "Transforming growth factor beta 1 (TGFB1) is dysregulated in the hereditary SVD, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). " 08/10/2011 - "[Dementia: progress in diagnosis and treatment; Topics, V. Recent topics; 4. Detection of novel dementia-related genes; 2) Dysregulation of TGF-beta family signaling and hereditary cerebral small vessel disease: insight into molecular pathogenesis of CARASIL]." 06/01/2010 - "We found that CARASIL-associated mutant HTRA1s exhibited decreased protease activity and failed to repress TGF-Beta family signaling. " 04/23/2009 - "We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL. "
8.	Collagen Type IV (Type IV Collagen)IBA 12/01/2015 - "Several other inherited forms of SVD include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, collagen type IV α1 and α2 gene-related arteriopathy and FOXC1 deletion related arteriopathy. " 04/01/2017 - "CADASIL, CARASIL, collagen type IV mutations (including PADMAL), retinal vasculopathy with cerebral leukodystrophy, Fabry disease, hereditary cerebral hemorrhage with amyloidosis, and forkhead box C1 mutations are described in terms of genetics, pathology, clinical manifestation, imaging, and diagnosis. " 02/01/2011 - "With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. " 01/01/2020 - "cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and type IV collagen (COL4)A1/2. We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management. "
9.	Transforming Growth Factors (Transforming Growth Factor)IBA 01/01/2017 - "The loss of HTRA1 protease activity increases signaling via transforming growth factor (TGF)β, thereby resulting in CARASIL. " 03/01/2011 - "CARASIL-associated mutant HTRA1 exhibited decreased protease activity and failed to repress transforming growth factor-β family signaling, indicating that the increased signaling causes arteriopathy in CARASIL. " 02/01/2011 - "CARASIL-associated mutant HTRA1s exhibited decreased protease activity and failed to repress transforming growth factor-β (TGF-β) family signaling, indicating that the increased TGF-β signaling causes arteriopathy in CARASIL. " 04/01/2015 - "CARASIL is caused by a mutation in HTAR1, a serine protease that regulates transforming growth factor (TGF)-beta signaling. "
10.	Proteins (Proteins, Gene)FDA Link 11/15/2021 - "Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL." 08/01/2015 - "A frameshift mutation in the HTRA1 gene detected in a CARASIL pedigree resulted in reduced HTRA1 protein and increased TGF-β1 expression, which may cause severe CARASIL and peripheral small arterial disease." 08/01/2015 - "Subcutaneous tissue biopsy and HTRA1 gene analysis were performed in a CARASIL patient, and HTRA1 and TGF-β1 protein expression in subcutaneous tissue and cultured fibroblasts from the proband were detected by immunohistochemistry and western blotting. " 08/01/2015 - "Here, we report a novel mutation in the HTRA1 gene in a CARASIL pedigree and explore its pathogenesis at the protein level. " 01/01/2018 - "Intriguingly, high-temperature requirement protein A1 (HTRA1), the extracellular protease mutated in CARASIL, was found to be strongly enriched (4.9-fold, p = 1.6 × 10-3) and to colocalize with Notch3ECD deposits in patient vessels suggesting a sequestration process. "

Therapies and Procedures

1.

Therapeutics 02/01/2011 - "Also reviewed is recent progress in understanding single-gene disorders in which stroke is a major feature of the phenotype, including CADASIL, CARASIL, hereditary angiopathy with nephropathy, aneurysm and muscle cramps, and Fabry disease and progress in pharmacogenomics as it relates to response to antiplatelet therapy." 01/01/2020 - ": 4H: Hypomyelination, hypogonadotropic hypogonadism and hypodontia; AAV: Adeno-associated virus; AD: autosomal dominant; AGS: Aicardi-Goutieres syndrome; ALSP: Axonal spheroids and pigmented glia; APGBD: Adult polyglucosan body disease; AR: autosomal recessive; ASO: Antisense oligonucleotide therapy; AxD: Alexander disease; BAEP: Brainstem auditory evoked potentials; CAA: Cerebral amyloid angiopathy; CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy; CARASIL: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CGH: Comparative genomic hybridization; ClC2: Chloride Ion Channel 2; CMTX: Charcot-Marie-Tooth disease, X-linked; CMV: Cytomegalovirus; CNS: central nervous system; CRISP/Cas9: Clustered regularly interspaced short palindromic repeat/CRISPR-associated 9; gRNA: Guide RNA; CTX: Cerebrotendinous xanthomatosis; DNA: Deoxyribonucleic acid; DSB: Double strand breaks; DTI: Diffusion tensor imaging; FLAIR: Fluid attenuated inversion recovery; GAN: Giant axonal neuropathy; H-ABC: Hypomyelination with atrophy of basal ganglia and cerebellum; HBSL: Hypomyelination with brainstem and spinal cord involvement and leg spasticity; HCC: Hypomyelination with congenital cataracts; HEMS: Hypomyelination of early myelinated structures; HMG CoA: Hydroxy methylglutaryl CoA; HSCT: Hematopoietic stem cell transplant; iPSC: Induced pluripotent stem cells; KSS: Kearns-Sayre syndrome; L-2-HGA: L-2-hydroxy glutaric aciduria; LBSL: Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate; LCC: Leukoencephalopathy with calcifications and cysts; LTBL: Leukoencephalopathy with thalamus and brainstem involvement and high lactate; MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; MERRF: Myoclonic epilepsy with ragged red fibers; MLC: Megalencephalic leukoencephalopathy with subcortical cysts; MLD: metachromatic leukodystrophy; MRI: magnetic resonance imaging; NCL: Neuronal ceroid lipofuscinosis; NGS: Next generation sequencing; ODDD: Oculodentodigital dysplasia; PCWH: Peripheral demyelinating neuropathy-central-dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschprung disease; PMD: Pelizaeus-Merzbacher disease; PMDL: Pelizaeus-Merzbacher-like disease; RNA: Ribonucleic acid; TW: T-weighted; VWM: Vanishing white matter; WES: whole exome sequencing; WGS: whole genome sequencing; X-ALD: X-linked adrenoleukodystrophy; XLD: X-linked dominant; XLR: X-linked recessive."