23/06/2025
Uncommon Genetic Causes of Stroke
A number of heritable conditions may include cerebral
ischemia among the clinical manifestations.
🧠Cerebral Autosomal Dominant Arteriopathy
With Subcortical Infarcts and Leukoencephalopathy Syndrome (CADASIL)
CADASIL syndrome is an AD condition characterized
clinically by
1. ,
2. ,
3. mood disturbances, and
4. .
The defect is on chromosome 19 at 19q13.1 (a missense mutation in the Notch3 gene). The Notch3 gene encodes a transmembrane protein thought to be involved in cell signaling during embryonic development and is critical for vascular smooth muscle cell differentiation, vascular development, and vascular remodeling following injury. The mutation results in accumulation of the Notch3 protein in the cytoplasmic membrane of vascular smooth muscle cells, pathologically resulting in widespread myelin pallor of the white matter and multiple small infarcts in the WM and BG.
Clinically, patients with CADASIL syndrome regularly
have with aura in their youth, recurrent stroke or strokelike episodes in their 40s to 60s (often in the absence of conventional risk factors), and often a progressive dementia. Psychiatric disturbances, especially mood disturbances, are also relatively common. Other clinical symptoms may include pseudobulbar affect, urinary incontinence, gait disturbance, and upper motor neuron signs.
The diagnosis can be made by
1. pedigree analysis (family history),
2. typical MRI findings,
3. skin biopsy, or
4. genetic testing.
MRI of the brain generally shows confluent deep white matter changes often involving the anterior temporal lobes.
Skin biopsy may show granular osmophilic material with electron microscopy.
No current treatment is known to delay progression of
the disease. Antithrombotics, as , are typically used to prevent ischemic .
🧠Cerebral Autosomal Recessive Arteriopathy With
Subcortical Infarcts and
Syndrome (CARASIL).
CARASIL syndrome is an AR. It syndrome results from mutations in the HTRA1 gene and differs from CADASIL syndrome in its inheritance pattern. Patients with CARASIL syndrome often have an associated
1. ,
2. lumbar , and
3. episodes of acute low back .
🧠Marfan Syndrome
It is an AD condition that may also predispose a patient to stroke and cerebrovascular disease. The defect is in the FBN1 gene that encodes the connective protein fibrillin 1. Patients may have ischemic stroke related to mitral or aortic valve disease, aortic , and a predisposition to cerebral formation.
🧠Pseudoxanthoma Elasticum
Pseudoxanthoma elasticum is an AR disease of connective tissue characterized by progressive dystrophic mineralization of elastic fibers within the skin, retina, and arterial walls. Clinically, patients have
1. skin lesions (yellow or orange papules),
2. increased laxity,LP
3. redundancy of skin,
4. loss of visual acuity,
5. cardiovascular and cerebrovascular complications,
6. ischemic stroke,
7. a syndrome resembling Binswanger disease, and
8. a predisposition to aneurysm formation.
🧠Vascular Type of Ehlers-Danlos Syndrome (formerly type IV)
it is an AD disorder due to a mutation of the gene that encodes type III procollagen. Patients with this disorder are predisposed to rupture of arteries, the bowel, and the uterus. Cerebrovascular complications include:
1. a predisposition to intracranial aneurysm formation,
2. arterial dissection, and
3. possible carotid-cavernous fistula.
🧠Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome ( MELAS)
MELAS syndrome is caused by a rare disorder of mitochondrial DNA. Most cases result from a point mutation, from A to G, in the
loop of the transfer RNA gene at mt3243. Clinically,
patients may present variably with a combination of:
1. progressive encephalopathy,
2. seizures,
3. ischemic stroke,
4. , and
5. .
The diagnosis of MELAS syndrome is made through
several investigations. MRI of the head often shows ischemic areas crossing arterial boundaries. In
addition, patients may have basal ganglia calcification.
They may have an elevated level of blood lactic acid and an increased lactate to pyruvate ratio. Similarly, in the CSF, the lactate level may be elevated.
Muscle biopsy may show ragged red fibers in skeletal muscle. Molecular genetic analysis and magnetic resonance spectroscopy of the brain can also be performed to secure the diagnosis.
Treatment of MELAS syndrome is supportive, and the
disease is progressive. l-arginine and coenzyme Q10 are often used. acid should be avoided in patients with mitochondrial disorders, should seizures occur, because of interference with the respiratory chain function.
🧠Fabry Disease
It is an X-linked lysosomal storage disorder
secondary to a mutation in the GLA gene resulting in a deficiency of α-galactosidase. Male persons are hemizygous for the mutation and therefore often present clinically with the classic signs and symptoms of cutaneous angiokeratomas, corneal and lenticular opacities, deafness, and often painful paresthesias. Female persons, who are heterozygous for the mutation, present with a range of phenotypes from asymptomatic carriers, which is most common, to a more severe syndrome similar to male persons, thought to be related to a process known as X chromosome inactivation. Ischemic stroke can occur, more often involving the posterior circulation, and patients are also prone to coronary and renal artery disease.
Neurovascular imaging may show dilatation or of the vertebrobasilar arteries, and .
Patients with Fabry disease should receive #α-galactosidase replacement therapy.
🧠Inflammatory and Noninflammatory Arteriopathies
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