(Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

David Goldemund M.D.
Updated on 04/02/2024, published on 12/05/2023


  • CARASIL is a very rare (probably underdiagnosed) hereditary disease affecting the small cerebral vessels, spine, and hair follicles
  • caused by a mutation in the HTRA1 gene on chromosome 10q (10q25.3-q26.2)
    • high-temperature requirement protein A1, a highly conserved serine protease (Clausen, 2002)
  • there are 2 forms (Onodera, 2010)
    • classic CARASIL – associated with biallelic pathogenic variants  (AR inheritance)
    • HTRA1-CSVD – associated with heterozygous HTRA1 pathogenic variant (AD inheritance)
  • classic CARASIL is characterized by early-onset white matter changes and associated neurologic symptoms (early-onset gait disturbance, cognitive impairment) and scalp alopecia
  • HTRA1-CSVD may be oligosymptomatic or asymptomatic (with positive neuroimaging only)

Clinical presentation


  • premature alopecia (starting in the teenage years; one of the initial symptoms)
  • musculoskeletal symptoms (before the age of 30)

    • deforming spondylosis (cervical spine and/or thoracolumbar spine), disc herniation
    • knee or elbow osteoarthritis
  • spastic gait (between 20 and 40 years of age)
  • recurrent ischemic stroke-like episodes (typically before age 40) with gradually progressive vascular dementia and mood changes (apathy)
  • symptomatic poststroke epilepsy
  • unlike CADASIL, migraine is not a feature of classic CARASIL


  • slowly progressive gait disturbance and stroke-like episodes (typically occur after the age of 40)
  • may be followed by mood changes and cognitive dysfunction
  • spondylosis and alopecia are less common

Diagnostic evaluation

CARASIL should be suspected if the combination of diffuse vascular leukoencephalopathy, alopecia, and disk herniations occur at a young age


  • CT shows nonspecific hypodensities in the white matter (leukoaraiosis)
  • MRI detects hypointensities on T1 and hyperintensities on T2
    • white matter lesions (WML)
      • U-fibers are relatively preserved
      • it is not clear whether the anterior temporal pole and external capsule lesions are observed in the early stages of CARASIL
    • lacunar infarcts in the basal ganglia, thalamus, and pons
    • arc sign – increased T2 signal across the pons at the level of middle cerebellar peduncles  (Röben, 2016)
    • cerebral microbleeds (CMBs) → see here
CARASIL - arc sign (Roeben, 2016)

Laboratory tests

  • genetic testing – considered the gold standard for a definitive diagnosis
    • mutation affects the HTRA1 gene located on chromosome 10q (10q25.3-q26.2
    • once HTRA1 pathogenic variant(s) have been identified in family members, prenatal and preimplantation testing is possible
  • skin biopsy does not help establish the diagnosis

Differential diagnosis

  • Binswanger´s disease
    • occurs in elderly individuals with multiple vascular risk factors
    • absence of typical temporal lobe lesions
    • symptoms appear 10-15 years earlier in patients with classic CARASIL
    • migraine and depression are not present in CARASIL
  • Susac syndrome
    • no temporal lobe involvement
    • prominent retinopathy and hearing impairment
  • primary angiitis of the CNS (PACNS)
    • an inflammatory disorder affecting the cerebral blood vessels
  • progressive multiple sclerosis
  • COL4A1 cerebral small-vessel disease
    • COL4A1 refers to a gene that encodes one of the collagen proteins, specifically collagen type IV alpha 1
    • mutations in the COL4A1 gene have been associated with various medical conditions, particularly those related to abnormalities in the blood vessels, kidneys, and the nervous system
    • the effects of COL4A1 mutations can vary widely among individuals, and the severity of symptoms can differ
  • CARASAL (cathepsin A-related arteriopathy with strokes and leukoencephalopathy) – an extremely rare condition
    • mutations in the CTSA gene, which encodes the enzyme cathepsin A; these mutations lead to abnormal blood vessel development and function in the brain
    • individuals with CARASAL typically experience recurrent strokes or stroke-like episodes + leukoencephalopathy on MRI
    • CARASAL usually becomes apparent in adulthood, typically during the third to fifth decades of life


  • no causal or disease-modifying treatment is available for CARASIL
  • therapy is similar to that of traditional small vessel disease
  • management of modifiable vascular risk factors
  • antiplatelets in secondary stroke prevention
    • no data on primary prevention
  • risk/benefit ratio of tPA and anticoagulation is uncertain
  • symptomatic treatment of psychiatric disorders and spasticity
    • there is no specific treatment for cognitive decline in CARASIL, but memantine or donepezil may be helpful
  • physical therapy, walking aids, cognitive training
  • standard treatment of spinal spondylosis and mood disorders
  • genetic counseling is recommended for individuals and families affected by CARASIL to provide guidance and support regarding the genetic aspects of the condition

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