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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
Niigata University
Niigata, Japan
, MD, PhD
Department of Neurology, Clinical Neuroscience Branch
Brain Research Institute
Niigata University
Niigata, Japan
, MD, PhD
Department of Neurology
Kameda Medical Center
Kamogawa, Japan

Initial Posting: ; Last Revision: February 17, 2011.

Summary

Disease 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. About 50% of affected individuals have a lacunar stroke-like episode before age 40 years. Mood changes (depression and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 30 and 50 years. The disease progresses slowly over the five to 20 years following the onset of neurologic symptoms. Scalp alopecia in the teens and acute mid to lower back pain (lumbago) with onset between ages 20 and 40 years are characteristic.

Diagnosis/testing. Diagnosis relies on brain MRI findings and molecular genetic testing of HTRA1, the only gene in which mutation is 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 an asymptomatic 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 disease-causing mutations in the family have been identified.

Diagnosis

Clinical Diagnosis

CARASIL should be suspected in persons with the following [Fukutake & Hirayama 1995, Hara et al 2009]:

  • Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms. The neurologic finding is usually slowly progressive gait disturbance with spasticity in the lower extremities [Fukutake & Hirayama 1995, Hara et al 2009].
  • Alopecia in the teens

    Note: Alopecia is variable: a sib with leukoaraiosis without alopecia has been reported [Yanagawa et al 2002, Hara et al 2009].
  • Acute mid to lower back pain (lumbago) between the ages 20 and 40 years. MRI and/or X-rays show spondylosis and disk degeneration with osteophyte formation in the cervical and/or lumbar spine.
  • A family history consistent with autosomal recessive inheritance

Brain imaging. Brain magnetic resonance imaging (MRI) resembles that of CADASIL (cerebral autosomal dominant ateriopathy 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], suggesting that the white matter changes precede the onset of neurologic symptoms, including gait disturbance, character change, and cognitive decline.
  • T2-signal abnormalities in the white matter of the cerebellum, brain stem, middle cerebellar peduncle and in the external capsule, characteristics of CARASIL, are sometimes observed.
  • 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.

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 early signs in CADASIL, are also observed in early stages of CARASIL.

Pathology. Arteriosclerosis associated with intimal thickening and dense collagen fibers, loss of vascular smooth muscle cells, and hyaline degeneration of the media were 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 relatively limited 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.

Molecular Genetic Testing

Gene. HTRA1 is the only gene in which mutation is known to be associated with CARASIL.

Clinical testing

  • Sequence analysis of entire coding and flanking intronic regions. HTRA1 is a serine protease; its protease domain exists in exons 3-6 [Hara et al 2009]. Of the four causative mutations in HTRA1 identified to date, two are nonsense mutations and two are missense mutations in exon 3 and 4.

Table 1. Summary of Molecular Genetic Testing Used in CARASIL

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
HTRA1Sequence analysisSequence variants 2Unknown 3

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Hara et al [2009]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • The diagnosis is suggested by: young-adult onset of spasticity, emotional lability, alopecia, white changes on MRI, and pedigree compatible with autosomal recessive inheritance.
  • The diagnosis is confirmed by HTRA1 molecular genetic testing, which should begin with exons 3-6, followed by complete sequencing of HTRA1.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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

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 30 and 50 years. Pseudobulbar palsy also begins between ages 30 and 50 years. About 50% of affected individuals have a lacunar stroke-like episode 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 20 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 lumbar spine and deformity and formation of osseous specula in the knee joints [Yanagawa et al 2002].

Genotype-Phenotype Correlations

No strong genotype-phenotype correlations exist in CARASIL.

Individuals homozygous for the p.Arg370X mutation 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 variable clinical course.

Nomenclature

Other names for CARASIL include:

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

Prevalence

CARASIL has been reported in individuals from Japan and China. 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 Features
CADASIL 1AD NOTCH3Isolated T2 hyperintensities involving the temporal poles; skin biopsy can be evaluated for NOTCH3 protein expression and granular osmophilic material (GOM) 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) 3 AD COL4A1 Renal abnormalities (hematuria, cystic kidney), intracranial aneurysm, muscle cramp, 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 4 AD ITM2BAtaxia and spasticity
Familial SVD-Portuguese-French type 5 AD Unknown
Swedish hereditary multi-infarct dementia 6 AD Unknown

The differential diagnosis of CARASIL includes 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 in an individual diagnosed with CARASIL, the following evaluations are recommended:

  • Neurologic evaluation
  • Standard brain MRI (FLAIR sequence) to check the involvement of cerebral white matter.
  • Spine MRI to check the degenerative change in lumbar or cervical spine

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.

Character change may require anxiolytic medication.

Dementia has no specific treatment

Prevention of Secondary Complications

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

Surveillance

The interval at which persons with CARASIL are followed depends on the severity and type of symptoms and the needs of the individuals and their 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

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials 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 mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic 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 is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CARASIL are obligate heterozygotes (carriers) for an HTRA1 disease-causing mutation.

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 disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations 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 homepage - Mendelian genesHTRA1

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

Normal allelic variants. HTRA1 has nine exons and a transcript 2138 bp in length.

Pathologic allelic variants. Two missense mutations in exons 3 and 4 and two nonsense mutations have been reported (Table 3).

Table 3. HTRA1 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Normalc.102C>T
(230C>T)
p.Ala34AlaNM_002775​.4
NP_002766​.1
c.108G>C
(236G>C)
p.Gly36Gly
c.108G>T
(236G>T)
p.Gly36Gly
Pathologicc. 754G>Ap.Ala252Thr
c. 889G>Ap.Val297Met
c. 904C>Tp.Arg302X
c.1108C>Tp.Arg370X

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. HTRA1, a 480-amino acid protein, belongs to the HTRA protein family, the members of which have dual activities 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

Literature Cited

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  2. Clausen T, Southan C, Ehrmann M. The HtrA family of proteases: implications for protein composition and cell fate. Mol Cell. 2002;10:443–55. [PubMed: 12408815]
  3. Fukutake T, Hirayama K. Familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension. Eur Neurol. 1995;35:69–79. [PubMed: 7796840]
  4. Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, Kawata H, Koyama A, Arima K, Takahashi T, Ikeda M, Shiota H, Tamura M, Shimoe Y, Hirayama M, Arisato T, Yanagawa S, Tanaka A, Nakano I, Ikeda S, Yoshida Y, Yamamoto T, Ikeuchi T, Kuwano R, Nishizawa M, Tsuji S, Onodera O. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med. 2009;360:1729–39. [PubMed: 19387015]
  5. Jen J, Cohen AH, Yue Q, Stout JT, Vinters HV, Nelson S, Baloh RW. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology. 1997;49:1322–30. [PubMed: 9371916]
  6. Low WC, Junna M, Borjesson-Hanson A, Morris CM, Moss TH, Stevens DL, St Clair D, Mizuno T, Zhang WW, Mykkanen K, Wahlstrom J, Andersen O, Kalimo H, Viitanen M, Kalaria RN. Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL. Brain. 2007;130:357–67. [PubMed: 17235124]
  7. Maeda S, Nakayama H, Isaka K, Aihara Y, Nemoto S. Familial unusual encephalopathy of Binswanger's type without hypertension. Folia Psychiatr Neurol Jpn. 1976;30:165–77. [PubMed: 971885]
  8. Mead S, James-Galton M, Revesz T, Doshi RB, Harwood G, Pan EL, Ghiso J, Frangione B, Plant G. Familial British dementia with amyloid angiopathy: early clinical, neuropsychological and imaging findings. Brain. 2000;123:975–91. [PubMed: 10775542]
  9. Oide T, Nakayama H, Yanagawa S, Ito N, Ikeda S, Arima K. Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Neuropathology. 2008;28:132–42. [PubMed: 18021191]
  10. Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M, Tsuchiya A, Ueta Y, Soma A, Kanda H, Matsumoto M, Kawaichi M. HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins. Development. 2004;131:1041–53. [PubMed: 14973287]
  11. Okeda R, Murayama S, Sawabe M, Kuroiwa T. Pathology of the cerebral artery in Binswanger's disease in the aged: observation by serial sections and morphometry of the cerebral arteries. Neuropathology. 2004;24:21–29. [PubMed: 15068169]
  12. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E. et al. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med. 2007;357:2687–95. [PubMed: 18160688]
  13. Tanoi Y, Okeda R, Budka H. Binswanger's encephalopathy: serial sections and morphometry of the cerebral arteries. Acta Neuropathol. 2000;100:347–55. [PubMed: 10985691]
  14. Terwindt GM, Haan J, Ophoff RA, Groenen SM, Storimans CW, Lanser JB, Roos RA, Bleeker-Wagemakers EM, Frants RR, Ferrari MD. Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon. Brain. 1998;121:303–16. [PubMed: 9549508]
  15. Verreault S, Joutel A, Riant F, Neves G, Rui Silva M, Maciazek J, Tournier-Lasserve E, Bousser MG, Chabriat H. A novel hereditary small vessel disease of the brain. Ann Neurol. 2006;59:353–7. [PubMed: 16404745]
  16. Yanagawa S, Ito N, Arima K, Ikeda S. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Neurology. 2002;58:817–20. [PubMed: 11889251]
  17. Zhang WW, Olsson Y. The angiopathy of subcortical arteriosclerotic encephalopathy (Binswanger's disease): immunohistochemical studies using markers for components of extracellular matrix, smooth muscle actin and endothelial cells. Acta Neuropathol. 1997;93:219–24. [PubMed: 9083552]
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Chapter Notes

Revision History

  • 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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