We successfully diagnosed CADASIL in a Japanese case with peripheral neuropathy and the p.Arg75Pro mutation of the
NOTCH3 gene. The pathogenic mutation was previously reported as a cause of CADASIL in Japanese and Korean patients [
2,
3] and most frequently found in Japanese patients with CADASIL. None of Japanese cases had peripheral neuropathy [
4]. The pathophysiological mechanisms of brain lesions in CADASIL remain unclear. GOM accumulation in the small arterioles of the brain is a pathological feature of CADASIL [
1]. Notch3 is predominantly expressed in vascular smooth muscle cells in adults [
1,
5]. Previous immunoelectron microscopic examination revealed aggregated Notch3 protein in proximity to GOM deposits; however, it is unclear whether Notch3 protein is included in GOM [
6‐
8]. While peripheral neuropathy is usually not seen in the patients with CADASIL, a few previous studies reported the association between CADASIL and peripheral neuropathy [
5]. The study suggested axonal damage in peripheral nerve with clinical and electrophysiological findings. Our electron microscopic study revealed the deposition GOM in the wall of endoneurial small vessels in the peripheral nerve. Electrophysiological study showed multiple mononeuropathy, suggesting vascular dysfunction, while there was no inflammatory cell infiltration in the biopsied nerve. Novel protein–protein interactions caused by
NOTCH3 mutations has been suggested in vascular function. The dysfunction of blood vessels may induce hemodynamic abnormalities with low-grade chronic ischemia in peripheral nerves [
5,
9]. We excluded other causes of chronic progressive axonal neuropathy, including of diabetes mellitus neuropathy, alcoholic neuropathy, ANCA–associated vasculitis, and drug or toxin.
To investigate the frequency of CADASIL in the patients with peripheral neuropathy, we performed genetic analysis of 434 patients of clinically suspected hereditary neuropathy by whole exome sequencing. However,
NOTCH3 pathogenic mutation was not found among the patients. In the previous study of CADASIL cases with peripheral neuropathy, subcortical infarcts and/or leukoencephalopathy were detected by brain MRI [
5]. In other words, CADASIL cases presenting just with peripheral neuropathy have abnormal lesions in brain MRI. Although we didn’t detect
NOTCH3 mutation in the patients with hereditary neuropathy, the patients with neuropathy and brain lesions have better to be analyzed for the
NOTCH3 mutation.
In conclusion, CADASIL is to be included in the work-up of not classified peripheral neuropathies. Brain MRI and NOTCH3 gene analysis may provide a definite diagnosis for these neuropathies.