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CADASIL)Characteristics in Japan: Variety of Clinical Features

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CADASIL)Characteristics in Japan: Variety of Clinical Features EDITORIAL Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)Characteristics in Japan: Variety of Clinical Features Key words: CADASIL,leukoencephalopathy, Notch3 tion (9). See also p 732. Cerebral autosomal dominant arteriopathy with subcortical Three patients from two unrelated families were found to infarcts and leukoencephalopathy (CADASIL)is a hereditary have the same Notch3 mutation, Argl33Cys. Unlike patients cerebrovascular disease with various clinical features includ- from Caucasian families, they had no migraine. The Argl 33Cys ing migraine, recurrent stroke episodes and dementia (1). In mutation has been reported in three French, one Dutch and 10 1996, Joutel and colleagues (2) found that mutations of the Finish families. The authors suggested that haplotype analysis Notch3gene on the short arm of chromosome19 were respon- be performed to investigate whether these families have a com- sible for this disease. monancestor or whether each mutation originated de novo. CADASILis characterized by protean signs and symptoms. The function of Notch3 is not well known. Joutel and col- Sometimes patients in the same family with the same Notch3 leagues (10) stated that Notch3 is known for its role in cell mutation have different phenotypes. Migraine occurs in the differentiation during drosophila development. No developmen- second decade of life and stroke in the forth decade. Some tal abnormality is known to be associated with CADASIL. patients have only stroke and no migraine-like headache. Some Almost all of the mutations lead to loss or gain of a cysteine. have mooddisorder or dementia. Dichgans and colleagues (3) The Notch3 gene has a repeated EGF-like domain. The muta- summarized findings from 1 10 patients in 29 families with bi- tion leads to an unpaired cysteine residue, which maycause opsy-proven CADASIL.Recurrent ischemic episodes, such as misfolding of the EGF-like domain. The abnormal protein struc- transient ischemic attack or stroke, were the most frequent pre- ture may be responsible for the GOMand cause degeneration sentation in 7 1%of the cases. Thirty-eight percent of the cases of the smooth muscle and arteriole media thickening leading had dementia. Twenty-eight percent of the cases had a history to lumen reduction. This could lead to multiple brain ischemia. of migraine, 87%of whomwere classified as migraine with We reported a Japanese CADASILfamily with a Notch3 aura. Ten percent had a history of epileptic seizures. Val237Met heterozygote ( 1 1). Twoaffected members of this MRIfindings of CADASILpatients include periventricular family had gait disturbance from their sixth decade. One of high intensity (T2-weighted images), multiple infarction of the them also had dementia and headache. MRIshowed basal ganglia, pons and subcortical white matter. A SPECT periventricular high intensity (T2-weighted image) and mul- study (4) indicated that cognitive impairment is linked to tiple small infarctions of the subcortical white matter and basal hypoperfusion in the basal ganglia. Demented patients with ganglia. This Val237Metmutation is not related to cysteine. CADASILexhibited a pattern of frontal, temporal and basal Nevertheless, we found degeneration of the smooth muscle and ganglia hypoperfusion. Skin or muscle biopsies are useful for GOMdeposits in arterioles of the skin biopsy specimen. diagnosis (5, 6). Eosinophilic granular deposits cause a thick- CADASILmay be underdiagnosed, especially in Japan. Fur- ening of the media of arterioles. Ultrastructural analysis re- ther studies of the Notch3 gene would lead to a better under- veals these deposits as granular osmiophilic material (GOM) standing of the genotype and phenotype of Japanese CADASIL. within the vascular smooth muscle basal lamina. In autopsy, the cerebral small arteries show a similar histopathology. This Yoshiki Adachi, MDand Kenji Nakashima, MD The Division of Neurology, Institute of Neurological Sciences, Faculty of small arteriopathy causes migraine, recurrent stroke episodes, Medicine, Tottori University, Nishimachi, mooddisorders and dementia without obvious atherosclerotic 36-1, Yonago 683-0826 risk factors. Over eighty unrelated families with CADASIL with Notch3 mutations have been reported. Manyfamilies were References Caucasian. Several Japanese families with CADASIL(7, 8) have been reported, but not all have been proved at the mo- 1) Tournier-Lasserve E, Joutel A, Melki J, et al. Cerebral autosomal domi- lecular level. In this issue, Uyamaet al reported the first fully nant arteriopathy with subcortical infarcts and leukoencephalopathy maps documented Japanese cases of CADASILwith Notch3 muta- to chromosome 19ql2. Nat Genet 3: 256-259, 1993. 681 Internal Medicine Vol. 39, No. 9 (September 2000) 2) Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, neuroimaging and genetic studies. J Neurol Sci 147: 55-62, 1997. a hereditary adult-onset condition causing stroke and dementia. Nature 8) Nishio T, Arima K, Eto K, Ogawa M, Sunohara N. Cerebral autosomal 383: 707-710, 1996. dominant arteriopathy with subcortical infarcts and leukoencephalopa- 3) Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of thy. -Report of an autopsied Japanese case-. Rinsho Shinkeigaku 37: CADASIL: Clinical findings in 102 cases. Ann Neurol 44: 731-739, 1998. 4) Mellies JK, Baumer T, Muller JA, et al. SPECT study of a German 9) Uyama910-916,E, Tokunaga M, SuenagaA, et al. Argl33Cys1997.mutation ofNotch3 CADASIL family. Neurology 50: 1715-1721, 1998. in two unrelated Japanese families with CADASIL.Intern Med 39: 732- 5) Ruchoux MM, Guerouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D. Systemic vascular smooth muscle cell impairment I cerebral au- 10) Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped tosomal dominant arteriopathy with subcortical infarcts and leukoencepha- nature of 737,Notch3 mutations in CADASILpatients.2000.Lancet 350: 1511- lopathy (CADASIL). Acta Neuropathol (Berl) 89: 500-5 12, 1995. 6) Ebke M, Dichgans M, Bergmann M, et al. CADASIL:skin biopsy allows 1 1) Adachi Y, Mori M, Nomura T, et al. One Japanese family with probable diagnosis in early stages. Acta Neurol Scand 95: 351-357, 1997. CADASIL(Notch31515,V237M). Clin Neurol (in 1997.press) (Abstract in Japa- 7) Utatsu Y, Takashima H, Michizono K, et al. Autosomal dominant early nese). onset dementia and leukoencephalopathy in a Japanese family: clinical, 682 Internal Medicine Vol. 39, No. 9 (September 2000).
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