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CADASIL in a North American family: clinical, pathologic, and radiologic findings
D W Desmond1, J T Moroney, T Lynch
1Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
Insights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presents with a wider range of symptoms than previously known. This genetic condition can manifest earlier in life, affecting cognitive function and causing neurological deficits.
Area of Science:
- Neurology
- Genetics
- Pathology
Background:
- The phenotypic spectrum of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is not fully understood despite existing patient data.
- Incomplete knowledge of CADASIL's varied clinical presentations hinders accurate diagnosis and management.
Purpose of the Study:
- To broaden the understanding of the phenotypic variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
- To document the clinical, pathological, and radiological features within a family affected by CADASIL.
Main Methods:
- Clinical, pathological, and radiological assessments were conducted on family members with CADASIL.
- Genetic testing confirmed a Notch3 mutation, while brain and skin biopsies provided pathological evidence.
- Neuropsychological testing and MRI scans were utilized to evaluate cognitive function and brain abnormalities.
Main Results:
- The proband exhibited subcortical infarcts, dementia with frontal lobe features, and hemiparesis, confirmed by biopsy showing small-vessel angiopathy and Notch3 mutation.
- Affected relatives presented with depression, seizures, learning disorders, executive dysfunction, and neurological signs, with skin biopsies showing pathognomonic granular osmiophilic material.
- MRI revealed diffuse white matter disease and lacunar infarcts in affected individuals, even in nonhypertensive patients.
Conclusions:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of vascular dementia.
- The manifestation of CADASIL may occur earlier in life than previously recognized, highlighting the need for broader diagnostic considerations.
Objective:
To expand the reported phenotypic range of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
Background:
Despite numerous patient reports, our knowledge of the phenotypic range of CADASIL remains incomplete.
Method:
We performed clinical, pathologic, and radiologic examinations on members of a family with CADASIL.
Results:
The proband is a 61-year-old man with a history of migraine and depression who has experienced multiple subcortical infarctions resulting in a stepwise decline. Neuropsychological testing documented a dementia syndrome with frontal lobe features and neurologic examination noted a left hemiparesis and a right-sided palmomental reflex. Brain biopsy with light microscopy revealed a nonatherosclerotic small-vessel angiopathy with periodic acid-Schiff positive granular changes in the media and white matter gliosis, with unremarkable cortex. Genetic testing confirmed a Notch3 mutation. The proband's first cousin has a history of depression, one seizure possibly resulting from an acute stroke, and a learning disorder. Neuropsychological testing demonstrated deficits in executive function and neurologic examination noted persistent extraneous adventitial movements, poor coordination, and primitive reflexes. Skin biopsy with electron microscopy demonstrated granular osmiophilic material within the basement membrane of vascular smooth muscle cells, which is considered to be pathognomonic of CADASIL. The proband's older son and younger son have histories of migraine and depression, respectively, and both also had learning disorders. MRI revealed diffuse white matter disease extending into the temporal lobes, and lacunar infarctions in these four nonhypertensive patients. Other family members have experienced migraine, recurrent stroke, dementia, and depression.
Conclusions:
CADASIL is a genetic basis for vascular dementia that may be manifest earlier in life than previously reported.