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CARASIL

Synonyms: Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, Maeda Syndrome

, MD, PhD, , MD, PhD, and , MD, PhD.

Author Information
, MD, PhD
Department of Molecular Neuroscience
Resource Branch for Brain Disease
Brain Research Institute
Niigata University
Niigata, Japan
, MD, PhD
Department of Medical Technology
School of Health Sciences Faculty of Medicine
Niigata University
Niigata, Japan
, MD, PhD
Department of Neurology
Kameda Medical Center
Kamogawa, Japan

Initial Posting: ; Last Update: September 11, 2014.

Summary

Clinical characteristics.

CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by early-onset changes in the deep white matter of the brain observed on MRI and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 30 years. Twenty-three percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly over the five to 20 years following the onset of neurologic symptoms. Scalp alopecia before age 30 years and acute mid- to lower-back pain (lumbago) with onset between ages ten and 40 years are characteristic.

Diagnosis/testing.

Diagnosis relies on brain MRI findings and molecular genetic testing of HTRA1, the only gene in which pathogenic variants are known to be associated with CARASIL.

Management.

Treatment of manifestations: supportive care including emotional support and counseling for affected individuals and their families; walking aids for gait disturbance and/or medication for spasticity; anxiolytic medication for character change as needed; routine care for dementia.

Surveillance: Follow-up intervals are based on the severity and type of symptoms and the needs of the individuals and their care givers.

Genetic counseling.

CARASIL is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies is possible if the pathogenic variants in the family have been identified.

Diagnosis

Suggestive Findings

CARASIL should be suspected in individuals presenting before age 55 years with:

  • Slowly progressive dementia
    • Mood changes such as apathy and irritability
  • Gait disturbance
  • Extended white matter lesions and external capsule lesions on brain imaging
    • Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms [Fukutake & Hirayama 1995, Fukutake 2011, Nozaki et al 2014].
    • Brain MRI resembling that of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Findings in symptomatic individuals:
      • White matter hyperintensities are symmetrically distributed and located in the periventricular and deep white matter [Fukutake & Hirayama 1995, Fukutake 2011, Nozaki et al 2014], suggesting that the white matter changes precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
      • T2-signal abnormalities in the white matter of the anterior part of the temporal lobe, the cerebellum, brain stem, middle cerebellar peduncle, and in the external capsule, characteristic of CARASIL, are sometimes observed [Fukutake 2011, Nozaki et al 2014].
      • Relative preservation of U-fibers is observed.
      • Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) are sometimes found in basal ganglia and subcortical white matter.
    • Note: The progression of MRI changes is not well documented in CARASIL; thus, it is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
  • Additional young adult-onset findings:
    • Spondylosis deformans. Acute mid- to lower-back pain (lumbago) associated with spondylosis and disk degeneration with osteophyte formation in the lumbar spine
    • Alopecia. Typically seen in teen years
      Note: Alopecia is variable: probands carrying HTRA1 mutations without alopecia have been reported [Yanagawa et al 2002, Nishimoto et al 2011, Bianchi et al 2014].
  • Family history consistent with autosomal recessive inheritance

Establishing the Diagnosis

The diagnosis of CARASIL is established in a proband with detection of biallelic pathogenic variants of HTRA1 (Table 1).

An alternative genetic testing strategy is use of a multi-gene panel that includes HTRA1 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1.

Summary of Molecular Genetic Testing Used in CARASIL

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
HTRA1Sequence analysis 2Unknown 3
Deletion/duplication analysis 4Unknown
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.
4.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Clinical Characteristics

Clinical Description

Neurologic symptoms begin between ages 20 and 50 years.

The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 30 years.

Mood change (depression and irritability) and cognitive dysfunction begin between ages 20 and 50 years. Pseudobulbar palsy also begins between ages 30 and 50 years. Twenty-three percent of affected individuals have a lacunar stroke-like episode (e.g., hemiparesis or hemisensory impairment) before age 40 years.

The disease progresses slowly over five to 20 years following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop.

Spondylosis (disk degeneration with osteophyte formation) results in acute lower- and mid-back pain (lumbago) and lower-limb pain beginning between ages ten and 30 years. MRI may show disc herniations, degeneration of vertebral bodies, and nodular thickening of the posterior longitudinal ligament [Zheng et al 2009]. Also reported on radiography are severe spondylitis deformans with osteoporosis in the cervical and lumbar spine [Nozaki et al 2014] and deformity and formation of osseous specula in the knee joints [Yanagawa et al 2002].

Alopecia is frequently (not always) seen in the teen years. Scalp alopecia is diffuse, not confined to the frontal or parietal regions. There is no obvious body hair loss.

Pathology. From the autopsy findings, arteriosclerosis associated with intimal thickening and dense collagen fibers, loss of vascular smooth muscle cells, and hyaline degeneration of the media have been observed in cerebral small arteries. These pathologic findings resemble those observed in persons with non-hereditary ischemic cerebral small-vessel disease [Maeda et al 1976, Zhang & Olsson 1997, Tanoi et al 2000, Yanagawa et al 2002, Okeda et al 2004, Oide et al 2008]. These changes are predominant in cerebral small arteries; therefore, skin biopsy is not useful for diagnosis.

Note: Granular osmiophilic material within the vascular media close to smooth muscle cells, a pathologic hallmark for CADASIL, is never observed in CARASIL.

Genotype-Phenotype Correlations

No strong genotype-phenotype correlations exist in CARASIL.

Individuals homozygous for the p.Arg370Ter pathogenic variant who make no protein as a result of nonsense-mediated mRNA decay cannot be clinically distinguished from individuals homozygous for the missense mutation who have some residual enzyme activity [Hara et al 2009].

Siblings who share the same genotype may have a variable clinical course.

Nomenclature

Other names for CARASIL include the following:

  • Familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
  • Nemoto disease

Prevalence

CARASIL has been reported in individuals from Japan, China, Spain, Turkey, and Italy. However, no founder haplotype has been identified; thus, the authors suspect that the disease will be found more widely.

Differential Diagnosis

Inherited disorders that cause leukoaraiosis in adulthood are summarized in Table 2. They can be distinguished from CARASIL by clinical signs, MRI findings, mode of inheritance, and appropriate laboratory investigations.

Table 2.

Inherited Disorders that Cause Leukoaraiosis in Adulthood

DiseaseInheritanceGeneUnique Clinical FeaturesSelected OMIM Links
CADASIL 1AD NOTCH3Isolated T2 hyperintensities involving the temporal poles; skin biopsy can be evaluated for NOTCH3 protein expression and granular osmophilic material by EM
HERNS (hereditary endotheliopathy with retinopathy, nephropathy, and stroke) 2AD TREX1 Retinal artery abnormalities (macular capillary dropout, tortuous telangiectasia); progressive visual loss; Raynaud phenomenon, migraine, contrast-enhancing lesion, mimicking tumor; proteinuria and hematuria
HANAC (hereditary angiopathy with nephropathy, aneurysms and muscle cramps) 3AD COL4A1 Renal abnormalities (hematuria, cystic kidney), intracranial aneurysm, muscle cramps, retinal arteriolar tortuosity (retinal hemorrhages)
Fabry diseaseXRGLAPeriodic severe pain in the extremities, angiokeratoma, renal insufficiency, hypohidrosis, left ventricular hypertrophy, corneal opacities
Familial cerebral amyloid angiopathy AD APP Lobar hemorrhage, multiple microbleeds
Familial British dementia 4AD ITM2BAtaxia and spasticity
Familial SVD, Portuguese-French type 5AD Unknown NA
Swedish hereditary multi-infarct dementia 6AD Unknown NA

The differential diagnosis of CARASIL comprises sporadic small vessel diseases including Binswanger disease, hereditary small vessel diseases (SVDs), and primary angiitis of the nervous system. The clinical characteristics and MRI abnormalities in these conditions may resemble those of CARASIL. Binswanger disease can be distinguished from CARASIL by the presence of hypertension.

CARASIL should also be considered in any young person who has alopecia in conjunction with multiple white matter lesions on MRI.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CARASIL, the following evaluations are recommended:

  • T2* gradient echo imaging to check cerebral microbleeds
  • Spine MRI to check the degenerative change in lumbar or cervical spine
  • Medical genetics consultation

Treatment of Manifestations

Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families.

Gait disturbance from spasticity and pyramidal signs in the lower extremities may require walking aids or medication such as baclofen or tizanidine.

Personality change may require antipsychotic medication.

If spinal spondylosis is severe and patients show some neurologic deficit due to spinal compression, orthopedic treatment may be helpful to relieve symptoms.

A wig or hairpiece may be helpful for alopecia.

Prevention of Secondary Complications

Anti-platelet therapy and anti-hypertension therapy may be recommended; however, there is no evidence for their effectiveness.

Surveillance

The interval at which a person with CARASIL are followed depends on the severity and type of symptoms and the needs of the affected individual and care givers.

Agents/Circumstances to Avoid

Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis, should be avoided.

Evaluation of Relatives at Risk

It has been speculated that hypertension or smoking may influence the age of onset and frequency of stroke episodes in individuals with CARASIL; smoking may result in earlier disease onset [Singhal et al 2004] and smoking or hypertension may increase the frequency of stroke episodes in individuals with CADASIL [Samii et al 2010]. Therefore, it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures such as oral administration of anti-hypertensive drugs and abstinence from smoking.

  • If the HTRA1 pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known, brain MRI can be used to clarify the genetic status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No special management is necessary in pregnancy for individual with CARASIL.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There is no clinical trial for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CARASIL is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one HTRA1 pathogenic variant).
  • It is not clear whether carriers are asymptomatic. Some reports suggest a mild phenotype in heterozygous individuals [Mendioroz et al 2010, Chen et al 2013, Bianchi et al 2014]. However, it is difficult to distinguish their symptoms from the small vessel disease in elderly. Thus, further study is necessary to clarify this issue.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of one HTRA1 pathogenic variant is 2/3.
  • It is not clear whether carriers are asymptomatic (see Parents of a proband, second bullet).

Offspring of a proband. The offspring of an individual with CARASIL are obligate heterozygotes (carriers) for one HTRA1 pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic adult relatives of individuals with CARASIL is possible after molecular genetic testing has identified the specific pathogenic variants in the family. Such testing should be performed in the context of formal genetic counseling, and is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Testing is always appropriate to consider in symptomatic individuals in a family with an established diagnosis of CARASIL regardless of age.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the HTRA1 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the HTRA1 pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for CARASIL have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CARASIL: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
HTRA110q26​.13Serine protease HTRA1HTRA1 databaseHTRA1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for CARASIL (View All in OMIM)

600142CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY; CARASIL
602194HTRA SERINE PEPTIDASE 1; HTRA1

Gene structure. HTRA1 has nine exons and a transcript 2138 bp in length. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Six missense mutations in exons 3 and 4, two nonsense mutations, and one deletion have been reported. See Table 3 (pdf).

Normal gene product. HTRA1, a 480-amino acid protein, belongs to the HTRA protein family, the members of which have dual roles as chaperones and serine proteases [Clausen et al 2002]. Members of the HTRA family serve as stress sensors for unfolded proteins and repress transforming growth factor-beta (TGF-β) family signaling [Clausen et al 2002, Oka et al 2004]. HTRA1 is a serine protease; its protease domain is encoded in exons 3-6 [Hara et al 2009].

Abnormal gene product. Biochemical and functional studies of mutant HTRA1 with CARASIL revealed the loss of protease activity and consequent dysinhibition of TGF-β family signaling of mutant HTRA1 [Hara et al 2009].

References

Published Guidelines/Consensus Statements

  1. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-18-15. [PubMed: 23428972]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 9-8-14.

Literature Cited

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Chapter Notes

Revision History

  • 11 September 2014 (me) Comprehensive update posted live
  • 17 February 2011 (cd) Revision: prenatal testing available clinically
  • 27 April 2010 (me) Review posted live
  • 5 January 2010 (oo) Original submission
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