CARASIL is a rare, genetic, autosomal recessive disorder characterized by non-hypertensive cerebral arteriopathy. It leads to subcortical infarcts, white matter changes, and alopecia.

CARASIL is caused by mutations in the HTRA1 gene, leading to abnormality in serine protease activity essential for vascular integrity.

ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY

CARASIL

(Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

David Goldemund M.D.
Updated on 18/06/2024, published on 12/05/2023

Definition

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)

→ Genetic cerebral small vessel diseases

Clinical presentation

CLASSIC CARASIL

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

HTRA1-CSVD

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 occurs at a young age

Neuroimaging

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

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

a skin biopsy is not useful for establishing a diagnosis

Differential diagnosis

Binswanger´s disease
- occurs in elderly individuals with multiple vascular risk factors
- absence of typical temporal lobe lesions
CADASIL
- 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
MELAS
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
RVCL-S

Management

no causal or disease-modifying treatment is available for CARASIL
therapy is similar to that of traditional small-vessel diseases
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, but memantine or donepezil may be helpful
physical therapy, walking aids, cognitive training
standard treatment of 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 disease