Wednesday, March 3, 2010
An unusual case of CADASIL? Or something else?
I recently did a brain autopsy on a 70-year-old woman who died from an intraparenchymal brain hemorrhage after a seven-year history of progressive dementia. The gross photograph (provided by Chad Jeffers, Memorial Medical Center, Springfield, IL) follows:
I know what you're thinking: an amyloid angiopathic bleed, or perhaps a hypertensive bleed, in a patient with Alzheimer disease. That's what I was thinking until I saw in the chart that abnormal white matter changes on MRI prompted the neurologist to order Notch3 genetic testing on the patient, which surprisingly came back positive for a mutation. The patient therefore carried a clinical diagnosis of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), despite the fact that she had no clear family history indicative of this disease and despite the advanced age of symptom onset. At autopsy, there was no evidence of amyloid angiopathy on Congo red stain. She did appear to have the PAS-positive vessel wall deposits that would be consistent with a diagnosis of CADASIL (see photomicrographs below). Plus, it is hard to refute a positive genetic test. The Notch3 test has excellent specificity, from what I hear. Although one does not typically think of intracranial hemorrhage in the context of CADASIL, a series out of Korea (Choi JC et al. Neurology 67(11), 12 December 2006, pp 2042-2044) found that 25% of their symptomatic patients with CADASIL had intracranial hemorrhage (ICH). If anyone has any other ideas about what might be the diagnosis in this case, I would love to hear from you.
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11 comments:
This is Dr Sathe from NYU. I would be interested in findig out what the mutation was. Was it a cysteine involving sequence change?
I'll query the clinician and the specific mutation and post what I find out when I get the info. Thanks!
Dr. Sathe:
I obtained the mutation report on this case (the analysis was done on a whole blood sample by Athena Diagnostics). The patient did indeed have a mutation involving cysteine -- loss of a cysteine residue and replacement with a tyrosine. It was a G to A nucleotide transition at position 3260, codon position 1061. As you know, 90% of CADASIL mutations involve gain or loss of a cysteine residue located within the 23 exons encoding for the 34 epidermal growth factor (EGF)-like repeat domains of the Notch3 receptor. Thanks for your query.
Brian
I have a diagnosis of cadasil but have not yet had the notch-3 test. is it absolutely necessary for the diagnosis? It costs 800 dollars and i dont have that kind of money. should i get the skin biopsy instead? i do not think that my insurance covers either of them.
I'm not sure about the insurance converage on this issue. Perhaps another reader will see your post and contribute a response. Best of luck to you..
Hi, my fiance recently found out that his biological father was diagnosed with CADASIL in 2000, the problem is we haven't been successful in getting in contact with his dad, we actually have 1 medical record he had sent my fiance's mother when he was first diagnosed. Jeff is 28 and I believe he has already shown some signs of the disease, we have a son and for his sake Jeff wants to be tested. Jeff's dad was diagnosed at the The Carbondale Clinic in IL is there anyway to get his father's records without his consent?
To Anonymous:
Help me understand why you need the father's medical record? You can get the genetic test on your fiance and on his son. I'm not sure I understand why its is necessary to get the father's genetic status.
To Anonymous: If you have decided you want to know whether or not your diagnosis is CADASIL or not, I would suggest the genetic test over the skin biopsy which is non definitive. You would need a the genetic test to qualify for any clinical trials, not that there are any in the US, there is just 1 currently being conducted by Dr. Sathe who posted here. My question is how do you "have a diagnosis" without this test? Do you have a family history? Given the family history, almost all insurance companies cover the test in full. Mine was $4,000 covered in full by my insurance.
Well I know from experience, as I also have a genetic autosomal dominate disease, Charcot Marie Tooth type 1A, they generally will not test children for an adult onset disorder. And getting someone to order a genetic test on Jeff who can only say his dad has CADASIL, with nothing to prove it, is not going to be easy. So yeah that is our issue.....
Is there a physician in PIttsburgh that tests and treats this disorder? I have been to many doctors with these symptoms and have a mother that has suffered with them for years. I would like to know the name of a doctor to have this testing done.
To Leticia: I personally don't know of a physician in Pittsburgh who might have experience with CADASIL patients, but I imaging the neurology department at the University of Pittsburgh could point you in the right direction if you call them.
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