Unusual clinical features and early brain MRI lesions in a family with cerebral autosomal dominant arteriopathy A. Malandrini, MD; P. Carrera, PhD; G. Ciacci, MD; S. Gonnelli, MD; M. Villanova, MD; S. Palmeri, MD; L. Vismara, MD; V. Brancolini, PhD; E. Signorini, MD; M. Ferrari, MD; and G.C. Guazzi, MD Article abstract-Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described inherited disorder. The pathologic gene maps on chromosome 19. The clinical spectrum of the disease consists of recurrent strokes, migraine, transient ischemic attacks, mood changes, and dementia. We report a genetically assessed CADASIL family with atypical clinical presentations of epileptic seizures. In two asymptomatic family members there were early brain abnormalities on MRI. Our report expands the clinical spectrum of CADASIL and suggests that it is possibly an undiagnosed disorder. NEUROLOGY 1997;48:1200-1203 The acronym CADASIL1s2(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) designates a recently described adult-onset inherited di~ease.l,~-ll The neuropathologic hallmark consists of thickening of the tunica media of the small cerebral arteries caused by deposition of granular electron-dense material and leading to subcortical ischemic l e ~ i o n s . ~ ~Brain * J ~ -MR ~~ images show bilateral confluent ischemic areas in the cerebral white matter.1,2,5-11 The pathologic gene has been mapped on chromosome 19.2J4The clinical picture, characterized by transient ischemic attacks, migraine, neuropsychiatric changes, strokes, and dementia is similar to that of ischemic cerebrovascular d i ~ 0 r d e r s . lApart ~ from dominant transmission, CADASIL should be suspected when there is a lack of vascular risk factors and confirmed by molecular genetic analysis. Here we describe a previously unreported Italian family with CADASIL in which affected members did not have the typical clinical manifestations of the disease. Seizures and leukoencephalopathy were the most salient features, and at least one of the patients had clinical stroke. Patients and methods. Family study (figure 1). W4, 76 years. At age 47 this woman developed grand ma1 seizures. Until the age of 65, the frequency was one every 1 to 2 months. At age 65, she was treated with phenobarbital and phenytoin, and the seizures reduced in frequency. At age 76, she had a sudden right hemiparesis with aphasia. The patient had no memory impairment or dementia. T,~ weighted images of brain MRI showed many bilateral confluent areas of altered signal in the white matter of the centrum semiovale and corona radiata (figure 2). 111/3, 56 years. This patient was healthy until age 49, when she developed absence-type seizures with a frequency of 5 to 7 per week. The seizures are characterized by detachment from the environment, a duration of 10 or 20 seconds, and motor automatisms (fumbling of the limbs or fingers). She is currently being treated with 400 mg/day carbamazepine. Neurologic and mental status examination are normal. She has occasional episodes of forgetfulness that do not limit her daily activities. T,-weighted brain MR images showed bilateral and partially confluent areas of altered signal in the white matter of the centrum semiovale (figure 3). Similar focal lesions were evident in the pons. TW6, 40 years. This man appears healthy, with normal neurologic examination. Brain MRI showed small sporadic bilateral ischemic lesions in the cerebral white matter (figure 4). 111/8, 38 years. This woman complains of occasional episodes of memory impairment that do not affect her daily activities. Neurologic and mental status examinations are normal. T,-weighted brain MR images showed many bilateral areas of altered signal with diameters of about 5 mm in the cerebral white matter (figure 5). Laboratory tests. Routine blood chemistry, apoproteins A and B, leukocyte lysosomal enzymes, partial thromboplastin time, platelet function, anti-phospholipid antibodies, immunologic and enzyme assays for protein C and S activity, plasminogen and protein C activators, heparin cofactor I1 and antithrombin 111 function were negative or normal in the four family members, with the exception of From the Istituto Scienze Neurologiche (Drs. Malandrini, Ciacci, Villanova, Palmeri, and Guazzi), Universita di Siena, Siena; Laboratorio di Genetica Molecolare (Drs. Carrera, Vismara, and Ferrari), IRCCS Ospedale S. Raffaele, Milano; Istituto di Patologia Medica (Dr. Gonnelli), Universita di Siena, Siena; and Istituto di Radiologia “A. Cesalpino” (Dr. Signorini), Terontola, Italy; and Department of Psychiatry (Dr. Brancolini), Columbia University, New York, NY. The financial support of Telethon-Italy (Grant E179) is gratefully acknowledged. V.B. and M.V. were also supported by Telethon-Italy. Received July 30, 1996. Accepted in final form November 1, 1996. Address correspondence and reprint requests to: Dr. Alessandro Malandrini, Institute of Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy. 1200 Copyright 0 1997 by the American Academy of Neurology Figure 1. Pedigree and segregation of haplotypes. Open bars represent the low-risk haplotype. Crosshatched bars represent the high-risk haplotype. The generations are indicated by Roman numerals. Filled symbols represent subjects with abnormal MRI and neurologic symptoms. Half-filled symbols represent asymptomatic subjects with abnormal MRI, Empty symbols represent unaffected subjects older than age 35 without neurologic symptoms. Hatched symbols indicate unaffected subjects younger than age 35 without neurologic symptoms and with normal MRI results. elevated serum levels of cholesterol (347 mg%) in patient IU4. ECGs and echocardiograms were normal. None of the four patients had hypertension. Doppler ultrasonography of the carotid vessels (normal in patients 11113 and IIU6) showed bilateral calcified plaque at the origin of the internal carotid arteries in patient 1114. EEG was normal in patients 11U3 and 11116; patient IU4 showed diffuse theta activity. Other family members, Subject U 1 died at age 78 years of unknown causes. He suffered from frequent grand maltype epileptic seizures from the age of about 50 years. Subjects IIU4, IVll, and IVl2 were apparently healthy; neurologic examinations were normal. Brain MRI was normal in subjects IV11 and IV12 and was not performed in subject IIU4. Subjects IIU1 and IIU4 died in the perinatal period of unknown causes. Doppler ultrasonography of the carotid vessels and EEG were normal in subject 11115. Subjects IU1 (aged 84 years), IU2 (81 years), IV13 (10 years), and IV14 (7 years) were reported to be healthy, but were not available for examination. Molecular genetic analysis. Microsatellite analysis. A linkage study was performed in order to see whether CADASIL was linked to chromosome 19 in this family. Seven polymorphic microsatellite markers from the GBnBthon linkage map16 (D19S221, D19S226, D19S841, D19S411, D19S199, D19S215, D19S222) within the previously mapped region on chromosome 19 were analyzed.2 The analyzed region spans a 14-cM interval between D19S221 and D19S222. In particular, markers D19S226, 841, 411, and 199 span a 2-cM interval on 19~13.1,where gene location was recently refined.14 Genomic DNA was extracted from peripheral blood lymphocytes by standard techniques.17 Microsatellite genomic sequences were amplified by polymerase chain reaction and analyzed by 6% polyacrylamide gel electrophoresis as previously described." Microsatellite analysis was performed in the following subjects, including two with CADASIL and two asymptomatic carriers: IU4, IIU2, IIIl3, 11115, 11116, IIII8, IVll, IVl2. Linkage analysis. Linkage analysis was performed using the Linkage package, version 5.l.lS Lod scores were calculated for each marker for various recombination fractions. Marker allele frequencies and number of alleles of the Genome Data Bank were used. Disease status was based on brain MRI results as described by TournierLasserve et a1.2 Asymptomatic subjects IV/1 and IV12, under the age of 35 years, with normal brain MRIs, were regarded as being of unknown status. Subjects IIU6 and IIU8 with abnormal brain MRIs were considered to be asymptomatic carriers. Haplotypes were inferred by minimizing the number of crossovers. Results. Figure 1 shows the haplotyping of the family. Crossovers were observed in subjects IVl1 and IV12; in particular, the affected chromosome inherited from the mother was recombined proximal to D19S221 and distal to D19S199, respectively. These two individuals (IVll, aged 32 years, and IV12, aged 28 years) were asymptomatic, May 1997 NEUROLOGY 48 1201 Figure 2. (Patient 1114) Brain MRI showing bilateral confluent areas of altered signal in the white matter of the centrum semiouale. Figure 3. (Patient 11113) T,-weighted brain MRI showing focal and partially confluent bilateral areas of hyperdensity in the cerebral white matter. with a normal MRI; thus, according to Tournier-Lasserve et a1.,2 who mapped the gene within D19S226 and D19S199, they should not develop the disease. This point is supported by Chabriat et al.,I5 who reported positive neuroimaging signs between ages 30 and 40 years. The pairwise linkage analysis gave positive but not sig- nificant lod score values with markers D19S199 and D19S222 (0.6 at 0 = 0) (table). The low values (Z = 0.0 at 0 = 0) with markers D19S221, D19S226, D19S841, and D19S411 can be explained by the low informativity of this family. Figure 4. (Patient IIIIS) T,-weighted brain MRI showing small focal areas of hyperdensity in the white matter of the cerebral hemispheres. Figure 5. (Patient IIIl8) T,-weighted brain MRI showing bilateral focal areas of hyperdensity in the cerebral white matter. 1202 NEUROLOGY 48 May 1997 Table Two-point lod scores between CADASZL and chromosome 19 markers Recombination fractions (6) Locus 0.00 0.001 0.05 D19S199 0.60 0.59 0.54 0.47 0.32 0.17 0.05 -0.07 -0.03 -0.01 0.32 0.17 0.05 0.10 D19S215 -0.24 -0.23 -0.18 - 0.14 D19S222 0.60 0.59 0.54 0.47 0.20 0.30 0.40 CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 3. van Bogaert L. Encephalopathie sous corticale progressive Discussion. In the present family, two-point link(Binswanger) a evolution rapide chez deux soeurs. La Meage analysis confirmed association of the disease decine Hellenique 1955;24:961-972. with anomalies of chromosome 19. Our report ex4. Sourander P, Walinder J. Hereditary multi-infarct dementia. Acta Neuropathol (Berl) 1977;39:247-254. pands the clinical spectrum and understanding of 5. Davous P, Fallet-Bianco C. Demence sous-corticale familiale CADASIL. Seizures occurred in three members beavec leucoencephalopathie arteriopathique: observation longing to three generations and were the main, ofclinico-pathologique. Rev Neurol (Pans) 1991;147:376-384. ten the only, clinical presentation. Apart from the 6. Mas JL, Dilouya A, de Recondo J . A familial disorder with subcortical ischemic strokes, dementia and leukoencephalopahemiparesis in patient II/4 at age 76 years, none of thy. Neurology 1992;42:1015-1019. the usual cardinal manifestations was present in the 7. Salvi F, Michelucci R, Plasmati R, e t al. Slowly progressive affected members. The small cortical microinfarcts familial dementia with recurrent strokes and white matter could have been responsible for seizures in our pahypodensities on CT scan. Ital J Neurol Sci 1992;13:135-140. 8. Baudrimont M, Dubas F, Joutel A, Tournier-Lasserve E, tients. Excluding seizures caused by dysmetabolic Bousser MG. Autosomal dominant leukoencephalopathy and encephalopathies, the genetic epileptic syndromes subcortical ischemic stroke: a clinicopathological study. Stroke are limited to a few special forms, such as benign 1993;24:122-125. familiar convulsions or juvenile myoclonic epi1ep~y.I~ 9. Ragno M, Tournier-Lasserve E, Fiori MG, et al. An Italian kindred with cerebral autosomal dominant arteriopathy with Genetic epilepsies usually have infantile onset, a subcortical infarcts and leukoencephalopathy (CADASIL). typical familial EEG pattern, and clinical homogeneAnn Neurol 1995;38:231-236. ity in a single family. The present patients did not 10. Sabbadini G, Francia A, Calandriello L, e t al. Cerebral automeet these diagnostic criteria; the EEG abnormalisoma1 dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): clinical, neuroimaging, ties in patient II/4 were nonspecific. pathological and genetic study of a large Italian family. Brain Chabriat et al.15 recommended that the MRI find1995;118:207-215. ing of small focal ischemic areas in the cerebral 11. Malandrini A, Carrera P, Palmeri S, e t al. Clinicopathological white matter of young or adult subjects, in the aband genetic studies of two further Italian families with cerebral autosomal dominant arteriopathy. Acta Neuropathol sence of any known risk factors for vascular disease, (Berl) 1996;92:115-122. should prompt investigation of family members for 12. Zhang WW, Ma KC, Andersen 0, Sourander P, Tollesson PO, CADASIL. On the basis of the present report, the Olsson Y. The microvascular changes in cases of hereditary association of familial epilepsy and brain MRI abnormulti-infarct disease of the brain. Acta Neuropathol (Berl) 1993;87:317-324. malities should also suggest CADASIL. Because two 13. Gray F, Robert F, Labrecque R, e t al. Autosomal dominant asymptomatic family members had slight white matarteriopathic leukoencephalopathy and Alzheimer’s disease. ter abnormalities, brain MRI is confirmed as the best Neuropathol Appl Neurobiol 1994;20:22-30. diagnostic tool, prior to molecular genetic analysis. 14. Ducros A, Nagy T, Alamowitch S, e t al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoenOur family suggests that CADASIL is possibly an cephalopathy, genetic homogeneity, and mapping of the locus underestimated disorder. within a 2-cM interval. Am J Hum Genet 1996;58:171-181. Acknowledgment We are grateful to Ms. A. Cabras for skillful technical assistance. References 1. Tournier-Lasserve E, Iba-Zizen M-T, Bousser MG. Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy. Stroke 1991;22:1297-1302. 2. Tournier-Lasserve E, Joutel A, Melki J , e t al. Cerebral autosoma1 dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps t o chromosome 19q12. Nat Genet 1993;3:256-259. 15. Chabriat H, Vahedi K, Iba-Zizen MT, et al. Clinical spectrum of CADASIL: a study of 7 families. Lancet 1995;346:934-939. 16. Dib C, Faure S, Samson D, et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 1996;380:152-154. 17. Maniatis TM, Fritdch EF, Sambrook J , eds. Molecular cloning. A laboratory manual. New York: Cold Spring Harbor Lab, 1990. 18. Lathrop GM, Laiouel JM, Julier C, Ott J . Strategies for multilocus linkage analysis in humans. Proc Nat Acad Sci USA 1984;81:3443-3446. 19. Shorvon SD. Epidemiology, classification, natural history and genetics of epilepsy. Lancet 1990;336:93-96. May 1997 NEUROLOGY 48 1203 Unusual clinical features and early brain MRI lesions in a family with cerebral autosomal dominant arteriopathy A. Malandrini, P. Carrera, G. Ciacci, et al. Neurology 1997;48;1200-1203 DOI 10.1212/WNL.48.5.1200 This information is current as of May 1, 1997 Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/48/5/1200.full.html Citations This article has been cited by 4 HighWire-hosted articles: http://www.neurology.org/content/48/5/1200.full.html##otherarticles Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1997 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.