Heterozygous HTRA1-related cerebral small vessel disease, also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 2 (CADASIL2), is a very rare monogenic cerebral small vessel disease.
Heterozygous HTRA1-related cerebral small vessel disease is an HTRA1-related cerebral small vessel disease, and thus is closely related to, but distinct from, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
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Epidemiology
Heterozygous HTRA1-related cerebral small vessel disease is likely very rare, although its true incidence and prevalence are not known. The condition tends to clinically manifest between the third and sixth decades of life 1-3.
Clinical presentation
The clinical presentation of heterozygous HTRA1-related cerebral small vessel disease may be asymptomatic, but when symptomatic, is similar to CARASIL, albeit milder 1,2.
Neurological clinical features in symptomatic patients 1-3:
cognitive impairment
gait disturbance, occurs less commonly than in CARASIL
stroke, ischemic stroke occurring more commonly than intracerebral hemorrhage
Non-neurological clinical features in symptomatic patients 1,2:
alopecia, occurs much less commonly than in CARASIL
lumbago due to deforming spondylosis, occurs less commonly than in CARASIL
Pathology
Heterozygous HTRA1-related cerebral small vessel disease, as its name suggests, is caused by a monoallelic mutation in HTRA1, the same gene implicated in CARASIL 1-4. The mechanisms by which a mutation in a single allele causes cerebral small vessel disease is not fully elucidated, but is thought to be due to either haploinsufficiency or dominant-negative effects 1,2. In some instances, the monoallelic mutation may demonstrate an autosomal dominant pattern of inheritance through a pedigree, however, the penetrance is low 1-3.
Radiographic features
MRI
MRI is the imaging modality of choice and demonstrates the following features 1-4:
leukoencephalopathy: diffuse subcortical white matter involvement sparing the subcortical U-fibers, most commonly involving the periventricular regions and centrum semiovale
lacunar infarcts: located in the basal ganglia, brainstem, and subcortical white matter
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cerebral microhemorrhages: located in both deep and lobar regions, although often most prominent in the basal ganglia
one study found microhemorrhages surrounding the midbrain, described as the 'chocolate chip sign', may be a characteristic radiographic feature 5
intracerebral hemorrhage is uncommon (~15% of patients)
Treatment and prognosis
No specific disease-modifying treatment is available and thus, management is supportive and symptomatic.
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