Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)

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

Extra-cranialExtracranial 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 clinicoradiolgoicalclinicoradiological 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-fibres, typically in frontoparietal regions and sparing temporal white matter

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

• deep cerebral microhaemorrhages

  • uncommon feature

  • deep intracerebral (macro)haemorrhage is very rare

Treatment and prognosis

No specific disease-modifying treatment is currently 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

• hypertensive microangiopathy