What are the types of familial small vessel diseases?

Familial Small Vessel Diseases of the Brain

The main familial small vessel diseases include CADASIL, CARASIL, COL4A1/2-related disorders, Fabry disease, RVCL/HERNS, deficiency of adenosine deaminase 2, and cerebral amyloid angiopathies, all of which can lead to stroke, cognitive impairment, and disability. 1

Major Types of Familial Small Vessel Diseases

1. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

• Genetics: Autosomal dominant; NOTCH3 gene mutations on chromosome 19
• Clinical features:
  • Lacunar strokes typically presenting in the 6th decade
  • Migraine with aura
  • Progressive dementia
  • Pseudobulbar affect
  • Cerebral microhemorrhages
• Prevalence: Classic phenotype in 1:20,000-1:50,000; cysteine-altering NOTCH3 mutations may occur in 1:300-1:450 people worldwide 1
• Diagnosis: MRI, skin biopsy, or genetic testing 2

2. CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

• Genetics: Autosomal recessive; HTRA1 gene mutations
• Clinical features:
  • Small-vessel strokes with onset around the 3rd decade
  • Premature alopecia
  • Dementia
  • Spondylosis
• Prevalence: Extremely rare 1

3. COL4A1/2-related disorders

• Genetics: Autosomal dominant (many de novo); COL4A1 or COL4A2 gene mutations
• Clinical features:
  • Small vessel disease
  • Intracranial hemorrhages
  • Microhemorrhages and aneurysms
  • Myopathy
  • Renal disease
  • Eye defects
  • Cardiac arrhythmias
• Prevalence: Extremely rare, likely underdiagnosed 1

4. Fabry Disease

• Genetics: X-linked; Alpha-galactosidase (GLA gene) deficiency
• Clinical features:
  • Young stroke (typically posterior circulation)
  • White matter abnormalities
  • Dolichoectatic vessels
  • Vertigo, hearing impairment, tinnitus
  • Cognitive disturbances
  • Small fiber peripheral neuropathy
  • Cardiomyopathy
  • Renal failure
  • Angiokeratomas
  • Corneal dystrophy
• Prevalence: Classic form 1:17,000-1:117,000 in males; higher prevalence of pathogenic mutations (1:3100-1:8454) 1
• Treatment: Enzyme replacement therapy with recombinant α-galactosidase A 1

5. Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL)/Hereditary Endotheliopathy with Retinopathy, Nephropathy, and Stroke (HERNS)

• Genetics: Autosomal dominant; TREX1 gene mutations
• Clinical features:
  • Small vessel disease
  • Retinopathy
  • Migraine
  • Seizures
  • Cognitive decline
  • Psychiatric disturbances
  • Renal and hepatic dysfunction
• Prevalence: Extremely rare 1

6. Deficiency of Adenosine Deaminase 2

• Genetics: Autosomal recessive; ADA2 gene mutations
• Clinical features:
  • Recurrent ischemic or hemorrhagic strokes
  • Recurrent fevers
  • Livedo racemosa
  • Bone marrow failure
  • Immunodeficiency
• Prevalence: Estimated at 1:222,000 individuals 1

7. Familial Cerebral Cavernous Malformations (CCMs)

• Genetics: Autosomal dominant; CCM1 (KRIT1), CCM2 (malcavernin), CCM3 (PDCD10) genes
• Clinical features:
  • CCM-related hemorrhage
  • Seizures
  • Focal neurologic deficits
• Prevalence: 1:3300-1:3800, symptomatic cases 1:5400-1:6200 1

8. Hereditary Cerebral Amyloid Angiopathies

• Genetics: Various genes including amyloid precursor protein gene, cystatin C, gelsolin, and BRI2
• Clinical features: Predisposition to lobar hemorrhages from rupture of affected small cortical vessels 2

9. Other Rare Familial Small Vessel Diseases

• Hereditary Infantile Hemiparesis, Retinal Arteriolar Tortuosity, and Leukoencephalopathy 3
• Hereditary Retinal Vasculopathy (HVR) 4
• Cerebroretinal Vasculopathy (CRV) 4
• Pseudoxanthoma Elasticum (PXE) - Autosomal recessive; ABCC6 gene mutations 1

Clinical Approach to Suspected Familial Small Vessel Disease

When to Suspect

• Early-onset stroke (before age 60)
• Family history of stroke, dementia, or migraine
• Stroke in the absence of traditional vascular risk factors
• Recurrent strokes
• Characteristic MRI findings (white matter hyperintensities, lacunar infarcts)
• Multi-system involvement (retina, kidney, skin, etc.)

Diagnostic Workup

1. Detailed family history: Focus on stroke, dementia, migraine, and early-onset neurological disorders
2. Brain MRI: Look for characteristic patterns of white matter hyperintensities, lacunar infarcts, microbleeds
3. Targeted examinations:
   • Ophthalmologic evaluation for retinal abnormalities
   • Skin examination for angiokeratomas (Fabry) or other lesions
   • Cardiac and renal function assessment
4. Genetic testing: Based on clinical suspicion and family history
   • NOTCH3 for CADASIL
   • HTRA1 for CARASIL
   • COL4A1/COL4A2 for collagen-related disorders
   • GLA for Fabry disease
   • TREX1 for RVCL/HERNS
   • ADA2 for ADA2 deficiency

Management Considerations

General Principles

• Most familial small vessel diseases lack specific treatments
• Management focuses on stroke prevention and symptom control
• Genetic counseling is important for affected families

Disease-Specific Treatments

• Fabry disease: Enzyme replacement therapy with recombinant α-galactosidase A has shown benefit in reducing microvascular endothelial deposits but has unclear impact on stroke risk 1
• ADA2 deficiency: Tumor necrosis factor inhibitors are being investigated 1

Clinical Pearls and Pitfalls

• Familial small vessel diseases are likely underdiagnosed due to variable expression and incomplete penetrance
• The absence of family history does not exclude these disorders due to de novo mutations or incomplete penetrance
• Extracerebral manifestations can provide important diagnostic clues (skin, eye, kidney involvement)
• Genetic testing should be guided by clinical features and family history
• These disorders often affect multiple organ systems, requiring multidisciplinary care

Familial small vessel diseases represent an important cause of stroke and vascular cognitive impairment, particularly in younger patients without traditional vascular risk factors. Recognition of these disorders is essential for appropriate genetic counseling and management.