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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
HTRA1	Sequence analysis	Sequence variants 2	Unknown 3	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in HTRA1.

A SNP (rs11200638: -512G>A) at the promoter region of HTRA1 for which homozygosity for the AA genotype increased risk of wet age-related macular degeneration has been identified as age-related macular degeneration 7 (ARMD7) (OMIM 610149).

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.

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.

Testing 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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. See for a list of laboratories offering DNA banking.

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 have been 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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Revision History

• 17 February 2011 (cd) Revision: prenatal testing available clinically

• 27 April 2010 (me) Review posted live

• 5 January 2010 (oo) Original submission