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Mar 12, 2002 - reflecting leukoaraiosis. Cardiac echography and. Doppler echographic examination of the arterial trunks at the cervical level did not reveal ...
Copyright C Blackwell Munksgaard 2002

J Cutan Pathol 2002: 29: 498–501 Blackwell Munksgaard . Printed in Denmark

Journal of

Cutaneous Pathology ISSN 0303-6987

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): a neurovascular disease diagnosed by ultrastructural examination of the skin Background: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a recently recognized neurovascular disease due to mutations of the Notch3 gene, manifesting with strokes or stroke-like episodes, major psychiatric symptoms and dementia. The diagnosis can be confirmed either by molecular analysis or by ultrastructural examination of the brain or more simply the skin. Methods: The skin of a patient with a suspected diagnosis of CADASIL was studied by electron microscopy. Results: Characteristic granular osmiophilic material within the basement membrane surrounding pericytes and smooth muscle cells of small and medium-sized vessels of the skin were found, confirming the diagnosis of CADASIL. Conclusions: CADASIL is an additional example of a neurologic disease that can be diagnosed thanks to electron microscopic examination of the skin. Dermatopathologists should be aware of these ultrastructural findings, all the more so since the disease could be more common than originally thought. Kanitakis J, Thobois S, Claudy A, Broussolle E. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): a neurovascular disease diagnosed by ultrastructural examination of the skin. J Cutan Pathol 2002; 29: 498–501. C Blackwell Munksgaard 2002.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), also known as hereditary multi-infarct-type dementia (MIM 600276), is a vascular disorder affecting mainly the central nervous system. It is a progressive, familial disease due to mutations in the Notch3 gene (19p13.2-p13.1) that manifests in young and middleaged adults with migraine (with or without aura), strokes or stroke-like episodes, major psychiatric symptoms and finally dementia.1–4 Patients suffering from this disease were first reported in 1977,5 but the 498

Jean Kanitakis1, Ste´phane Thobois2, Alain Claudy1 and Emmanuel Broussolle2 1

Department of Dermatology, Hoˆpital Ed. Herriot, and 2Department of Neurology (U401402), Hoˆpital Neurologique Pierre Wertheimer, Lyon, France

Jean Kanitakis, Hoˆpital Ed. Herriot (Pav. R), 69437 Lyon cx 03, France Tel: π33 472110301 Fax: π33 472110323 e-mail: kanitak/lyon151.inserm.fr Accepted March 12, 2002

disease became better known in the 1990s after the discovery of the diagnostic pathologic findings in various tissues, including the brain and skin, and the discovery of the responsible gene.6 More than 400 affected families have been identified primarily in Europe, but also in North America, Asia and Africa.4,7 Most of these cases have been published in neurology journals; very few reports on this disease have appeared in the dermatological literature,8–10 even though the diagnosis can be made by pathological examination of the skin. We present herein our

CADASIL and skin ultrastructure

Fig. 1. Granular osmiophilic material (arrows) abutting the basal membrane of pericytes surrounding a dermal vessel. Some osmiophilic inclusions are seen in the cytoplasm of an endothelial cell (E). L, vascular lumen; R, red-blood cell (magnification ¿4700).

diagnostic ultrastructural findings in the skin of a new patient with CADASIL, and briefly review the relevant literature. Case report A 46-year-old male French patient with an unremarkable family history was admitted to the neurology department for a regressive left hemiplegia of vascular origin, predominating on the upper limb and the face. No somatosensory deficits were found. Routine laboratory work-up was normal. Cerebral CT scan showed cortical atrophy, multiple small infarcts within the central nuclei of the gray matter, and hypodensities of the white matter in both cerebral hemispheres, reflecting leukoaraiosis. Cardiac echography and Doppler echographic examination of the arterial trunks at the cervical level did not reveal significant abnormalities. On the basis of these findings, the diagnosis of CADASIL was suspected, and the patient was referred to our dermatology department for confirmation of the diagnosis through ultrastructural examination of the skin.

A punch biopsy was taken under local anaesthesia from clinically normal-looking skin of the arm and processed for transmission electron microscopy (fixation in glutaraldehyde, post-fixation in osmium tetroxide, embedding in epon). Semithin sections showed some vessels with a wide lumen in the mid-dermis, which looked otherwise normal. Ultrathin sections stained with uranyl-acetate and lead citrate disclosed some large capillaries and arterioles in the deep dermis. Within these vessels, the plasma membrane of several pericytes showed shallow infoldings, where deposits of granular osmiophilic material (GOM) were seen; they formed electron-dense ovoid or rounded aggregates measuring 0.5–1 mm, abutting the cell membrane and becoming gradually less dense towards the surrounding dermis (Figs. 1 and 2). Some granular material of medium density was found in the immediately adjacent dermis, forming loose aggregates merging with collagen fibres. In areas facing the GOM, the plasma membrane of pericytes showed clustered pinocytotic vesicles (Fig. 3); occasionally, an electron-dense material was found within the cytoplasm of the cells, coming in contact with the inner face of the plasma membrane. Some endothelial cells also contained round, deeply osmiophilic inclusions (Fig. 1) or membrane-bound inclusions with an electron-lucent core, suggestive of lipidic material. Several capillaries were observed in the upper and mid-dermis; they did not contain characteristic GOMs, but their basal lamina was frequently multilayered. Epidermal cells (Langerhans cells, keratinocytes and melanocytes), the dermoepidermal junction, the basement membrane of an eccrine sweat gland and smooth muscle cells of an erector pili muscle did not show obvious changes. Discussion Although cases of hereditary multi-infarct dementia were first published in 1977,5 the disease known as

Fig. 2. Granular osmiophilic material (arrows) around a pericyte of a dermal vessel. N, nucleus (magnification ¿5300).

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Fig. 3. Granular osmiophilic material (g) in close contact with the basal membrane of a pericyte. v, pinocytotic vesicles (magnification ¿20000).

CADASIL became more widely known in the early 1990s, when the acronym was coined.11 It is an increasingly recognized disorder, manifesting with gait disturbance (90%), recurrent ischemic episodes (71%), cognitive defects (48%), migraine (38% – of which 87% are associated with aura), pseudobulbar palsy (52%), dementia (28%), urinary incontinence (86%) and epileptic seizures (10%).12 The disease is due to mutations in the Notch3 gene (19p13.2-p13.1), which consists of 33 exons encoding for a transmembrane receptor with a large extracellular domain that contains 34 tandem EGF-like repeats. The pathogenic mutations are located within the 23 exons encoding these repeat sequences, and result in the gain or loss of cysteine residues.6 Genes of the Notch family are highly expressed in embryonic tissues, where they play a fundamental role in cell fate determination; however, the function of these genes in adult tissues is still unknown. The symptoms and signs of CADASIL are presumably related to the progressive occlusion of the small perforating vessels of the white matter.2 Products of the Notch genes are specifically expressed by arterial vessels,13 but the mechanism whereby 500

Notch3 mutations lead to the various phenotypic expressions of the disease remains unknown. From a molecular point of view, CADASIL is analogous to the Drosophila lethal-abruptex condition, a model that could facilitate future research into the pathogenesis of the disease.14 CADASIL is inherited as an autosomal dominant trait, but sporadic cases exist (as in the case of our patient), due to de novo mutations.7 The pathognomonic ultrastructural findings of CADASIL consist in specific granular osmiophilic material (GOM) deposited around smooth muscle cells and pericytes of small and medium-sized arterioles. These are found within the brain but also in other tissues, including peripheral nerves, skeletal muscles, spinal cord, myocardium, intestine, liver, kidney and skin.4,15,16 Other ultrastructural alterations have also been observed, including reduplication of the basal lamina of dermal capillaries, attenuation of endothelial cells17 and abnormal elastic fibres,18 but these changes are not pathognomonic. Skin biopsy is an ideal test for confirmation of the diagnosis of CADASIL and the differential diagnosis from other vascular dementias,19 since it is much easier to obtain than a brain, muscle or nerve biopsy; it also has a high sensitivity, at least equal to that of muscle biopsies,20,21 and can detect the carrier status.22 Rare CADASIL cases have been reported with negative electron microscopic findings;23,24 these are likely due to the fact that the changes in the skin may be focal, necessitating multiple sections to be examined.25 Compared with molecular analysis, electron microscopy is easier, less expensive and probably equally sensitive;26 it has even proved positive in cases where genetic testing did not reveal mutations in the cluster regions of the Notch gene.8 Very recently, a mouse monoclonal antibody (1E4) against the Notch3 protein has become available and has been used successfully for the diagnosis in skin specimens, with a sensitivity comparable to that of molecular analysis.27 The chemical nature of the GOM remains unknown. The material usually stains with PAS, consistent with acid polysaccharide. Other histochemical stains have shown that the material does not contain amyloid, elastin, chromatin, calcium or iron (see Lapoint et al.4 for a review); an electron energy loss spectrometry analysis also showed no metal or mineral material within the GOM.28 Immunoenzymatic and immunofluorescence studies have also shown absence of immunoglobulins or complement proteins, as well as HSP 70, cystatin C, transthyretin, gelsolin, fibrinogen, ubiquitin, cathepsin D and a1-antichymotrypsin.4 One study has shown possible reactivity of the GOM with aB crystallin, found also intracellularly in myocytes, suggesting possible deposition from degenerating myocytes.24 Our ultrastructural findings, showing the presence of electron-dense, granular material and of osmiophilic, membrane-bound inclusions

CADASIL and skin ultrastructure within the cytoplasm of pericytes, is consistent with this contention. Along with molecular analysis (detection of Notch3 mutations), electron microscopy is the definitive diagnostic technique in CADASIL,4 confirming a probable diagnosis based on clinical and MRI findings.2 Dermatopathologists should be aware of the characteristic ultrastructural findings in CADASIL, all the more so since the disease could be more common than originally thought. Next to other neurometabolic diseases such as lipofucsinosis,29 CADASIL further extends the spectrum of the diagnostic applications of cutaneous biopsy in general medicine.

References 1. Chabriat H, Joutel A, Vahedi K et al. CADASIL. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Rev Neurol (Paris) 1997; 153: 376. 2. Davous P, Cadasil: a review with proposed diagnostic criteria. Eur J Neurol 1998; 5: 219. 3. Kalimo H, Viitanen M, Amberla K et al. CADASIL: hereditary disease of arteries causing brain infarcts and dementia. Neuropath Appl Neurobiol 1999; 25: 257. 4. Lapoint SF, Patel U, Rubio A. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Adv Anat Pathol 2000; 7: 307. 5. Sourander P, Walinder J. Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol (Berl) 1977; 39: 247. 6. Joutel A, Corpechot C, Ducros A et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383: 707. 7. Joutel A, Dodick DD, Parisi JE et al. De novo mutation in the Notch3 gene causing CADASIL. Ann Neurol 2000; 47: 388. 8. Hausser I, Spranger M, Steegmans-Schwarz I et al. Diagnostic value of ultrastructural skin vessel examination in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Abstract). SCUR Annual Meeting, Köln, May 5, 1998. 9. Rumbaugh JA, La Duca JR, Shan Y et al. CADASIL: the dermatologic diagnosis of a neurologic disease. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Am Acad Dermatol 2000; 43: 1128. 10. Walsh J, Perniciaro C, Meschia J. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): diagnostic skin biopsy changes determined by electron microscopy. J Am Acad Dermatol 2000; 43: 1125. 11. Tournier-Lasserve E, Joutel J, Mekli J et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nature Genet 1993; 3: 256. 12. Dichgans M, Mayer M, Uttner I et al. The phenotypic spec-

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18.

19. 20.

21.

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24.

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trum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998; 44: 731. Villa N, Walker L, Lindsell C et al. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 2001; 108: 161. Fryxell K, Soderlund M, Jordan T. An animal model for the molecular genetics of CADASIL. Stroke 2001; 32: 6. Ruchoux MM, Guerouaou D, Vandenhaute B et al. Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Acta Neuropathol (Berl) 1995; 89: 500. Ruchoux MM, Chabriat H, Bousser M et al. Presence of ultrastructural arterial lesions in muscle and skin vessels of patients with CADASIL. Stroke 1994; 25: 2291. Ruchoux MM, Maurage CA. Endothelial changes in muscle and skin biopsies in patients with CADASIL. Neuropathol Appl Neurobiol 1998; 24: 60. Caronti B, Calandriello L, Francia A et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Neuropathological and in vitro studies of abnormal elastogenesis. Acta Neurol Scand 1998; 98: 259. Ruchoux MM, Brulin P, Leteurtre E et al. Skin biopsy value and leukoaraiosis. Ann NY Acad Sci 2000; 903: 285. Goebel H, Meyermann R, Rosin R et al. Characteristic morphologic manifestation of CADASIL, cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy, in skeletal muscle and skin. Muscle Nerve 1997; 20: 625. Mayer M, Straube A, Bruening R et al. Muscle and skin biopsies are a sensitive diagnostic tool in the diagnosis of CADASIL. J Neurol 1999; 246: 526. Ebke M, Dichgans M, Bergmann M et al. CADASIL: skin biopsy allows diagnosis in early stages. Acta Neurol Scand 1997; 95: 351. De Freitas G, Miklossy J, Christen-Zach S et al. A CADASIL case with normal skin biopsy and without mutations in exons 3 and 4 of the Notch3 gene. J Neurol Sci 2001; 193: 43. Rubio A, Rifkin D, Powers J et al. Phenotypic variability of CADASIL and novel morphologic findings. Acta Neuropathol (Berl) 1997; 94: 247. Schultz A, Santoianni R, Hewan-Lowe K. Vasculopathic changes of CADASIL can be focal in skin biopsies. Ultrastruct Pathol 1999; 23: 241. Furby A, Vahedi K, Force M et al. Differential diagnosis of a vascular leukoencephalopathy within a CADASIL family: use of skin biopsy electron microscopy study and direct genotypic screening. J Neurol 1998; 245: 734. Joutel A, Favrole P, Labauge P et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 2001; 358: 2049. Schröder J, Seybold V, Isenberg C et al. Eels-analysis revealed negative metal and mineral evidence in GOM-deposits in a Cadasil patient (Abstract). J Invest Dermatol 2000; 115: 929. Manca V, Kanitakis J, Zambruno G et al. Ultrastructural study of the skin in a case of juvenile ceroid-lipofuscinosis. Am J Dermatopathol 1990; 12: 412.

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