Department of Psychiatry
Medical Subject Headings
CADASIL; Receptors, Notch; Mutation; Case Reports
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular dementia1,2. The mutations implicated in CADASIL are located on Chromosome 19 within the NOTCH3 gene, which encodes a transmembrane receptor that is primarily expressed in vascular smooth muscle cells. Over one hundred distinct mutations have been described which alter the number of cysteine residues in the extracellular region and result in a CADASIL phenotype. Cysteine-sparing mutations with CADASIL phenotype have been reported four times. Two German kindreds were recently described with a CADASIL-like phenotype associated with a cysteine-sparing NOTCH3 mutation. We present another such case in a third family, with the same point mutation described in the German families. The patient is a 55-year-old Caucasian woman with five years of progressive cognitive impairment, chronic headaches, and gait instability. Prior to presenting at our clinic, she had been diagnosed with Alzheimer disease. Her neuropsychological testing (Table One) and MRI studies (Figure One), however, were more consistent with a subcortical vascular dementia. Her genetic CADASIL screen was “negative” although a missense mutation in NOTCH3 was identified. At the time of that test, no cysteine-sparing mutations causing CADASIL had been reported. Workup of other family members is ongoing. Elucidation of this case will provide corroboration of a cysteine-sparing CADASIL mutation, and will inform the discussion of whether this represents a distinct entity or a CADASIL subtype. With the field of neurogenetics rapidly evolving, interpretation of standard genetic tests may need to include literature review to ascertain the correct diagnosis.
Sullivan J, Benjamin S, Case Report: CADASIL with Cysteine-Sparing Notch-3 Mutation, American Neuropsychiatric Association (poster), American Neuropsychiatric Association, February 2009.
Sullivan J, Benjamin S, Case Report: CADASIL with Cysteine-Sparing Notch-3 Mutation, American Neuropsychiatric Association, abstract, Journal of Neuropsychiatry and Clinical Neuroscience 21(2):221, 2009. DOI 10.1176/appi.neuropsych.21.2.221.
Sullivan, John F. and Benjamin, Sheldon, "CADASIL with Cysteine-Sparing Notch-3 Mutation" (2009). Psychiatry Publications and Presentations. Paper 476.