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Table 1 Monogenic disorders associated with cerebral small vessel disease (modified from Bersano et al. [7])

From: Genetics of vascular dementia – review from the ICVD working group

Disease

CADASIL

Fabry disease

RVCL

COL4A1

CARASIL

OMIM

#125310

#301500

#192315

#120130

#60142

Pattern of inheritance

Autosomal dominant

X-linked recessive

Autosomal dominant

Autosomal dominant

Autosomal recessive

Gene

NOTCH3

α-GAL A gene (GLA)

TREX1

COL4A1

HTRA1

Locus

19p13

Xq22

3p21.3-p21.2

13q34

10q25

Gene product

Notch 3 receptor

Alpha galactosidase A enzyme

DNA specific 3’-5’ exonuclease DNase III

Type IV collagen α1

HTRA1 serine peptidase/protease 1

Clinical manifestations

 Stroke

  Age at onset, years

20–70

33–46 (M)/40–52 (F)

40–50

14–49

20–40

 Stroke subtype

  Small vessel disease

+

+

+

+

+

  Large vessel disease

+

  Cardioembolic

+

  Hemorrhagic

Rare

Rare

+

 Other neurological manifestations

  Psychiatric disturbance

+

+

+

+

+

  Migraine with/without aura

+

+

+

  Seizures

+

 

+

+

 

  Cognitive impairment

+

±

+

+

+

 Extra-neurological manifestations

  Neuropathy

+ (80%)

±

+

  Myopathy

+

+

+

  Renal disease

+

+

+

  Skin involvement

+

  Ocular involvement

±

Retinal arteriolar narrowing

+

Cornea verticillata

+

Retinopathy

+

Cataracts, retinopathy

+

Retinopathy

  Gastrointestinal involvement

+

±

+

  Cardiac involvement

+

+

  Others

 

Acroparhestesia, hypoacusia

Raynaud phenomena (80%), hepatopathy

Poroencephaly, prenatal bleeding, infantile hemiparesis

Alopecia, spondylosis deformans, acute lumbago

Radiological findings

 White matter lesions

+

+

+

+

+

 Lacunar lesions

+

+

+

+

+

 Cortical-subcortical lesions

+

±

 Intracerebral hemorrhage (ICH)

+

+

+

+

 Aneurysms

+

+

 Peculiar findings

Temporal lobe hyperintensities, external capsule involvement

Pulvinar hyperintensities on T1-wheighted images

Subcortical contrast-enhancing lesions with surrounding edema

Porencephaly, ICH

Pathological findings

Granular osmiophilic material surrounding vascular smooth muscle cells

Cytoplasmatic Gb3 inclusions in vascular endothelial cells and smooth muscle cells

Multilaminated vascular basement membranes

Interruption and thickening

of basement membrane

Degeneration in vascular smooth muscle cells

  1. CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CARASIL cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, RVCL retinal vasculopathy with cerebral leukodystrophy