Cerebral Arteriopathy, Autosomal Dominant, with Subcortical Infarcts and Leukoencephalopathy

Alternative Names

  • CADASIL
  • Dementia, Hereditary Multi-Infarct Type
  • CASIL
  • Chronic Familial Vascular Encephalopathy
  • Familial Disorder with Subcortical Ischemic Strokes
  • Agnogenic Medial Arteriopathy
  • Familial Binswanger's Disease

Associated Genes

Notch Receptor 3
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WHO-ICD-10 version:2010

Diseases of the circulatory system

Cerebrovascular diseases

OMIM Number

125310

Mode of Inheritance

Autosomal dominant

Gene Map Locus

19p13.2

Description

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited adult-onset leukodystrophy, characterized by migraine headaches, recurrent transient ischemic attacks (TIA), cognitive impairment, and psychiatric dysfunction. The pathophysiology of this condition is related to abnormalities in blood flow of small vessels, especially those of the brain. CADASIL is an adult-onset disease, with the first signs typically presenting in the fourth decade of life. Symptoms initially start off with migraine with aura, transient ischemic attacks or strokes, and/or mood disorders, such as depression. The recurrence of multiple strokes leads to cognitive defects, progressive memory loss, dementia, and hemiparesis. Affected patients may also rarely present with epileptic seizures.

The standard test for diagnosis of CADASIL uses electron micrographic analysis of skin biopsies, which reveal electron-dense granules in the media of arterioles. MRI studies show lesions around the basal ganglia, periventricular white matter and the pons. Interestingly, these lesions can be seen in individuals even before the first symptoms appear. However, definitive diagnosis requires genetic identification of mutations in the NOTCH3 gene. There is no specific treatment for the condition. Since patients are very likely to be affected with cerebrovascular complications, the use of anti-platelet agents is recommended as a preventive measure. Other risk factors for stroke, such as smoking, and the use of contraceptive pills, should also be avoided. Patients are advised to manage the disease by adopting a healthy lifestyle. CADASIL is a disease with a slow progression. By the seventh decade of their life, most patients suffer from severe cognitive impairment and dementia, and may become completely dependent.

The NOTCH3 gene is the only gene known to be implicated in the pathogenesis of CADSIL. The NOTCH genes are known to encode for membrane bound proteins that interact with ligands and play a key role in neural development in drosophila. The exact function of the human homologues of this gene is not known. However, it is likely that the gene is involved in influencing the transcription of certain genes implicated in the function and survival of vascular smooth muscle cells. Mutations in this gene may, therefore, cause these cells to die, resulting in a destruction of the arterial walls, and loss of blood supply. In addition, the abnormal NOTCH3 protein tends to aggregate in the cranial blood vessels.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
125310.1LebanonUnknownNo NM_000435.3:c.1369T>CHeterozygousAutosomal, DominantJalkh et al. 2019
125310.2United Arab EmiratesFemaleNoYes Global development delay; Hypotonia; Abn... NM_000435.2:c.3691C>THeterozygousSaleh et al. 2021 De novo mutation
125310.3United Arab EmiratesMaleYesYes Global developmental delay; Recurrent ce... NM_000435.3:c.4581_4594delHomozygousAutosomal, RecessiveSaleh et al. 2021 Similarly affected c...

Other Reports

Iraq

Mignarri et al. (2011) reported a 54-year-old Iraqi Kurdish male with CADASIL. The patient had a 6-month history of progressive cognitive decline, gait disturbances and urinary incontinence. The patient's mother died suddenly at 63 years of age, a brother died at 60 after a 10-year history of progressive motor and cognitive decline. Two other siblings, a 58-year-old brother and a 62-year-old sister have histories of psychiatric disturbances with major depression. On admission, neurological examination showed unsteady gait and hypoactive deep tendon reflexes. Brain MRI showed severe, confluent periventricular white matter lesions with bilateral involvement of the external capsule, temporal lobe and lacunar infarcts in the basal ganglia and pons. Mutational analysis of NOTCH3 gene uncovered the c.3691C>T (p.Arg1231Cys) mutation in exon 22.

Kuwait

Pandey and Abubacker (2006) were the first to report on CADASIL from Kuwait. They studied two patients, both Kuwaiti women in their 30s, who had both been erroneously diagnosed with multiple sclerosis based on their clinical history and MRI findings. The first patient had a history of headache and numbness. She had a mild sensory loss to light touch in the right hand. There was no involvement of the spinal cord. A repeat MRI showed extensive white matter abnormalities in the shape of focal lesions that spared the cortex, and other large coalescent lesions in the frontal, temporal and insular regions. No oligoclonal bands were seen in the CSF. Interestingly, the patient's mother and brother had also been diagnosed with MS in light of similar symptoms. Skin biopsy and genetic tests confirmed the diagnosis of CADASIL in this family. The second patient presented with right sided numbness of the face and body, sensory loss in the face, and brisk deep tendon reflexes more on the right side. Repeat MRI in her case also showed lesions similar to the previous case. No oligoclonal bands were visible in the CSF. Her mother and sister had also been diagnosed with MS. However, genetic testing confirmed the diagnosis of CADASIL. Pandey and Abubacker (2006) warned that the clinical and brain imaging features of CADASIL could be easily misinterpreted as that arising from MS, and that a thorough clinical evaluation and imaging analysis may be required, especially due to the lack of awareness of CADASIL among physicians.

[Pandey T, Abubacker S. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: an imaging mimic of multiple sclerosis. A report of two cases. Med Princ Pract. 2006; 15(5):391-5.]

Bohlega et al. (2007) reported on CADASIL among native Arabs, including a Kuwaiti affected family. The proband had an early onset of the disease, starting with migraine by the age of 20 and multiple strokes by the age of 28 years. Six of the eight siblings were also affected; three of whom died. The transmission of the disease was through the affected mother. One of the proband's siblings had two affected daughters. The most common symptom was migraine, followed by stroke and dementia. Bohlega et al. (2007) also detected the same known pathogenic heterozygous mutation in the NOTCH3 gene in this as well as another affected family from Saudi Arabia. The third pedigree in this study came from Yemen. Bohlega et al. (2007) concluded that CADASIL was probably under-diagnosed in Arabs.In 2008, Abu-Amero et al. expanded on this study and included another Saudi and a Sudanese affected family to the original three pedigrees. In order to study the reported association of CADASIL with mitochondrial abnormalities, Abu-Amero et al. (2008) sequenced the entire mitochondrial genomes in patients from these families as well as 159 healthy Arab controls. Although a number of mitochondrial polymorphisms were identified in the patients, this was statistically insignificant when taking the polymorphisms in the controls into account. Of the polymorphisms detected in the patients, only five were found to be non-symonymous, and even these five were predicted to be non-pathogenic. This result was at odds against an earlier study that showed pathogenic mtDNA mutations in CADASIL patients. Abu-Amero et al. (2008) also tried to assign the index patients into their respective mitochondrial haplogroups. Each patient was found to fall into a unique haplogroup.

[See also: Saudi Arabia, Yemen > Bohlega et al., 2007].

Saudi Arabia

Bohlega et al. (2007) described a Saudi Arabian family with CADASIL. The proband in this family was a 40-year old male who presented with sudden left-sided weakness, and a history of multiple transient ischemic attacks (TIAs). His father was reported to have had frequent migraine attacks, and died at age 58. His paternal aunt had also died following recurrent strokes. Of his siblings, one brother and sister were affected. Brain MRI of these three siblings showed multiple bilateral ischemic lesions. The father had additionally marked brain atrophy. Two cousins of the proband were also affected.

[See also: Kuwait, Yemen > Bohlega et al., 2007; Kuwait > Abu-Amero et al., 2008].

Sudan

[See: Kuwait > Abu-Amero et al., 2008].

Yemen

Bohlega et al. (2007) reported a Yemeni family with CADASIL. The proband, a 48-year old male, presented with history of repeated attacks of numbness on the right side. Of his three sisters, one had a history of migraine, and another of multiple strokes. Their father died of dementia at 58 years. A paternal uncle and a paternal aunt also died following multiple strokes. Multiple ischemic white matter lesions were seen on brain MRI scans of the proband and his affected sisters. Bohlega et al. (2007) were able to detect a known pathogenic heterozygous mutation in the NOTCH3 gene in this family. Two sons of the proband were also found to harbor the mutation, though they were asymptomatic at the time of the report.

[See also: Kuwait > Bohlega et al., 2007; Abu-Amero et al., 2008].

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