Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a systemic genetic disorder affecting the cerebral small vessels, spine and hair follicles. 

It should not be confused with its autosomal dominant counterpart, CADASIL. Autosomal recessive inherited diseases are usually more severe than autosomal dominant genetic disorders and CARASIL is no exception to this general rule.

Epidemiology

CARASIL is a very rare disease with roughly 50 cases reported, mostly from inside Asia until recently, when the disease was also documented in a European family ^1,2,2.

The true prevalence is unknown, and CARASIL is probably under-recognised since no founder haplotype has been identified, and the recently encountered European disease carriers support the theory of a wider distribution ^1,2,4.

Clinical presentation

Typically patients present in young adulthood (twenties and thirties) with:

• premature alopecia (as early as teenage years; most common initial symptom)

• relapsing ischaemic stroke-like episodes (typically in the 3rd decade) with gradually progressive vascular dementia

• not infrequently, symptomatic epilepsy (secondary to infarctions)

• relapsing severe low back pain and deforming spondylosis (present in roughly 80% of patients, notably early onset)

Pathology

Macroscopic appearance

Shows cerebral arteriosclerotic changes, most intense in white matter and basal ganglia.

Microscopic appearance

Intense arteriosclerosis is seen predominantly in the small penetrating arteries. Aids in differentiation from other entities are the lack of amyloid deposition and absence of the granular appearance characteristics of CADASIL.

Extraneural changes are less severe and although they include the cutis, skin biopsies are not helpful in establishing the diagnosis.

Genetics

CARASIL is, after CADASIL, the second known genetic form of ischaemic CNS disease caused by non-hypertensive microangiopathy in which the causative gene defect has been identified.

Mutations in HTRA1 gene on chromosome 10q (10q25.3-q26.2) are responsible for CARASIL. It codes for the ubiquitous HTRA1 enzyme, which regulates signalling by proteins in the transforming growth factor-beta (TGF-β) family, which again is essential for multiple critical cell functions including angiogenesis. The pivotal role of TGF-β in CARASIL is hypothesised, but not totally clarified.

Radiographic features

CNS manifestations

CT

• diffuse homogeneous leukoaraiosis 

• ex-vacuo ventriculomegaly, predominantly affecting the lateral ventricles

• in ~25% of patients, small hypodense areas may be seen located in the pontine base (possibly presenting Wallerian degeneration of the corticospinal tract)

MRI

• diffuse leukoencephalopathy

• multiple lacunar infarctions in the deep nuclei, most often

  • basal ganglia

  • thalamus

• high T2 signal connecting the middle cerebellar peduncles across the pons; arc sign ⁸

• cerebral microhaemorrhages may be seen ⁸

Musculoskeletal manifestations

Changes may be appreciated by plain radiograph, CT or MRI, and are those of:

• deforming spondylosis with or without intervertebral space narrowing, located in the cervical and/or thoracolumbar spine

  • typical location upper lumbar regions (which is in some contradiction to the sporadic spondylosis) 

  • kyphosis

• elbow or knee osteoarthritis 

Treatment and prognosis

As there are no causative treatment options, treatment focuses on the prevention of ischaemic strokes. Interestingly, treatment with known antiplatelet agents and anticoagulant lacks evidence. 

Another goal of management is to prevent the onset of dementia symptoms. Genetic counselling is also an important part of primary care.

History and etymology

It was first described by S Nemoto, a Japanese physician, in 1960 where it was initially described as part of the Binswanger spectrum ^5,6. Nemoto went on to publish a seminal case series with S Maeda et al. in 1976 ⁷. The disease is sometimes known as Nemoto disease or Maeda syndrome in recognition of their contributions.

Differential diagnosis

• sporadic cerebral small vessel diseases (SVD)

• encephalitis subcorticalis chronica progressiva (Binswanger disease)

• primary angiitis of the CNS

• progressive multiple sclerosis 

  • involvement of subcortical U-fibres is less pronounced in CARASIL

• CADASIL

  • symptom onset in CARASIL is 10-15 years earlier

  • migraine and depression are not seen in CARASIL

  • early white matter changes in CARASIL are homogenous rather than punctuate as seen in CADASIL

• COL4A1 brain small-vessel disease

• cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)