ISCHEMIC STROKE

Genetic Cerebral Small Vessel Diseases

David Goldemund M.D.
Updated on 30/12/2023, published on 28/12/2023

• cerebral small vessel diseases (SVDs) encompass a group of disorders that primarily affect the small blood vessels in the brain (small arteries, arterioles, capillaries, and venules)
• typical SAVD features include leukoencephalopathy, lacunar strokes, and microbleeds
• the underlying causes of SVDs may differ:
  • sporadic forms
    • common in older populations, affecting approximately 80% of individuals aged 65 and nearly all aged 90, making it a prevalent age-related condition → Binswanger´s disease
    • strongly associated with hypertension
  • monogenic forms are rare
    • responsible for 1%-5% of all strokes and several other disturbances  (Manini, 2023)
    • genetic discoveries have enabled a new etiology-based classification of SVDs
• both forms result in impaired blood flow, vessel wall damage, and leakage of blood components into brain tissues; these changes lead to significant morbidity and mortality due to stroke and dementia
• this article provides an overview of genetic SVDs, focusing on their etiology, clinical manifestations, neuroimaging features, diagnostic approaches, and management strategies

• the exact mechanisms underlying genetic small vessel diseases are diverse and depend on the specific genetic mutation
  • mutations in genes encoding proteins involved in the structural integrity and function of cerebral small vessels
  • commonly implicated genes include NOTCH3, HTRA1, COL4A1, and COL4A2
• these mechanisms may involve abnormal protein aggregation, inflammation, and damage to vascular smooth muscle cells and extracellular matrix, which collectively contribute to small vessel dysfunction and cerebral damage (ischemia or hemorrhage)

• despite many genes being involved, the phenotypes of monogenic cerebral SVDs partly overlap
  • recurrent ischemic or hemorrhagic strokes, cognitive impairment, gait disturbances, and mood disorders
  • lacunar infarcts and microbleeds and extensive white matter lesions (WMLs) are characteristic findings on neuroimaging
• the specific additional clinical features can vary depending on the underlying genetic mutation
• the severity and progression of symptoms vary depending on the specific genetic mutation and individual factors

• combination of clinical evaluation, neuroimaging (MRI and CT scans), genetic testing to identify causative mutations
• MRI is crucial in identifying typical imaging features like white matter hyperintensities, microbleeds, and lacunar infarcts
• genetic testing confirms the diagnosis by identifying pathogenic mutations.
  • genetic testing can be challenging and time-consuming – neurologists should be adequately informed of the genetic background of SVD and should be able to select patients to undergo genetic assessment and the genes to be analyzed

• currently, there is no specific cure for most genetic small vessel diseases
• symptomatic therapy
  • antiseizure medications (ASMs) for seizures, treatment of cognitive impairment and mood disorders
    
  • renal monitoring with regular assessment of kidney function and treatment of kidney disease
  • neurorehabilitation to improve mobility and cognitive function
• risk factors modification – antihypertensive therapy, statins, and antiplatelet agents are commonly used to manage vascular risk factors
• preventing complications and providing supportive care
• family members may benefit from genetic counseling and screening

• CARASIL is a rare AR disorder associated with mutations in the HTRA1 gene
• it leads to similar symptoms as CADASIL, including strokes and cognitive impairment
• specific features include: (Fukutake, 2011)
  • the recessive mode of inheritance
  • early age of onset (20 to 30 years)
  • the frequent occurrence of spondylosis and alopecia as associated non-neurologic manifestations
  • typically an absence of migraine and depression

→ CARASIL

• caused by mutations in the α-galactosidase A (α-Gal-A) gene located on the X chromosome
• phenotype varies depending on the specific gene defect and residual enzyme activity; the severe form may be seen in both males and heterozygous females

→ Fabry disease

• caused by mutations in the APP, CST3, or ITM2B genes inherited in an AD pattern (one copy of the mutated gene is sufficient to cause the disease)
  • the Dutch type (the APP gene mutation) is the most common, with stroke often presenting as the initial symptom
• characterized by the accumulation of amyloid protein in the blood vessel walls of the brain, leading to bleeding and cognitive deficits
• individuals with hereditary CAA experience progressive deterioration of cognitive functions (dementia), stroke, and other neurological complications beginning in mid-adulthood

→ Cerebral amyloid angiopathy (CAA)

• a rare AD disorder resulting from mutations in the TREX1 gene
  • disrupts the normal function of the encoded enzyme, leading to an accumulation of single-stranded DNA
• the dysfunction of TREX1 leads to a complex pathology primarily affecting small blood vessels in the brain and retina (cerebroretinal vasculopathy)
• RVCL refers to a group of cerebroretinal syndromes originally described as separate disorders:
  • cerebroretinal vasculopathy (CRV)
  • hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS)
  • hereditary vascular retinopathy (HVR)
• it can lead to strokes and cognitive decline, vision loss (due to retinopathy), and other systemic manifestations (renal impairment, liver dysfunction, and Raynaud’s phenomenon)
  • the mean age of retinopathy onset ∼45 years
• diagnosis
  • MRI detects typical cerebral changes
  • fundoscopy for assessing retinal vessel abnormalities
  • genetic testing

• ultra-rare monogenic autosomal dominant (AD) condition caused by point mutations in the CTSA gene (chromosome 20q13.12), which encodes the enzyme cathepsin A; these mutations lead to abnormal blood vessel development and function in the brain (particularly affecting the white matter and deep brain structures)
  • cathepsin-A is a carboxypeptidase that associates with the lysosomal enzymes b-galactosidase and neuraminidase, promoting their stabilization
• CARASAL usually becomes apparent in adulthood, typically during the third to fifth decades of life
• clinical presentation:  (Finsterer, 2019)
  • stroke
  • migraine-like headache
  • cognitive impairment and behavioral disinhibition
  • depression
  • movement disorders, e.g. gait disorder, dystonia
  • facial pain
  • muscle cramps
  • therapy-resistant hypertension (Bugiani, 2017)
    
• MRI scans typically show evidence of small subcortical infarcts (basal ganglia, thalamus) and diffuse extensive white matter changes, sparing temporal white matter
  • microbleeds are rare

• COL4A disorders refer to a spectrum of genetic conditions resulting from mutations in the COL4A1 and COL4A2 genes
• these genes encode one of the collagen proteins, specifically collagen type IV, a critical component of basement membranes in various tissues, including blood vessels, kidneys, and the brain
• mutations in these genes lead to multisystemic manifestations, predominantly affecting the cerebrovascular system, eyes, and kidneys
  • Pontine Autosomal Dominant MicroAngiopathy with Leukoencephalopathy (PADMAL) is an autosomal dominant monogenic belonging to COL4A1-related disorders  (Roos, 2023)
    
  • HANAC syndrome (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) (Alamowitch, 2009)
• the effects of COL4A1 mutations can vary widely among individuals, and the severity of symptoms can differ