Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) is a very rare monogenic autosomal dominant cerebral small vessel disease.

Epidemiology

CARASAL is considered extremely rare, with less than thirty cases reported in the literature ^1-5. The condition tends to clinically manifest in the third to fifth decades of life ².

Clinical presentation

The potential clinical manifestations are varied and may be mild for the degree of radiographic changes ^1-5:

• focal neurological deficits from stroke

• migraine-like headache

• cognitive impairment and dementia

• movement disorders, e.g. gait disorder, dystonia

• vestibulocochlear symptoms

Extracranial clinical manifestations may also be seen, although, given the rarity of the condition, it is unclear if these are due to CARASAL or are simply seen in association ^1-5:

• sicca symptoms

• atypical facial pain

• muscle cramps

• systemic hypertension

• diabetes mellitus

Pathology

CARASAL is caused by a point mutation (c.973C>T) in the CTSA gene, located within chromosome 20q13.12, which encodes for cathepsin A ^1-4. This mutation is inherited in an autosomal dominant pattern ^1-5. It is yet to be fully elucidated how this mutation leads to the clinicoradiological syndrome that is observed in CARASAL ^1,5.

Notably, this is condition is very distinct from autosomal recessive mutations in CTSA implicated in the lysosomal storage disorder galactosialidosis ².

Radiographic features

MRI is the imaging modality of choice and demonstrates the following features ^1-5:

• leukoencephalopathy and lacunar infarcts

  • extensive subcortical white matter involvement sparing subcortical U-fibers, typically in frontoparietal regions and sparing temporal white matter

  • deeper structures such as in the basal ganglia, thalamus, pons, and dentate nuclei

• deep cerebral microhemorrhages

  • uncommon feature

  • deep intracerebral (macro)hemorrhage is very rare

Treatment and prognosis

No specific disease-modifying treatment is available and symptomatic management and specialist screening is recommended ¹. It is thought that life expectancy is similar to that of an unaffected individual ⁴.

Differential diagnosis

• cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

• ​cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

• COL4A1 brain small-vessel disease

• heterozygous HTRA1-related cerebral small vessel disease

• hypertensive microangiopathy