A four-generation Dutch family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), linked to chromosome 19p13

•

,

.

-?

Clinical Neurology and Neurosurgery ELSEVIER

Clinical Neurology and Neurosurgery 97 (1995) 307-313

A four-generation Dutch family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), linked to chromosome 19pl 3 R . W i e l a a r d a, M . B o r n e b r o e k b, R . A . O p h o f f b'c, H . A . O . W i n t e r - W a r n a r s d, P h . S c h e l t e n s e, R . R . F r a n t s c, M . D . F e r r a r i b, J. H a a n bs'* "Department of Neurology, Hofpoort Hospital, Woerden, Netherlands bDepartment of Neurology, University Hospital, Leiden, Netherlands" CMGC-Department of Human Genetics, Leiden, Netherlands" aDepartment of Radiology, Hofpoort Hospital, Woerden, Netherlands eDepartment of Neurology, Academic Hospital, Free University, Amsterdam, Netherlands fDepartment of Neurology, Rijnland Hospital, Leiderdorp, Netherlands Received 12 June 1995; revised 1 August 1995; accepted l August 1995

Abstract

We describe a four-generation Dutch family suffering from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Of twenty affected family members, ten are still alive. Age at onset of the strokes was between 29 and 52 years, with a mean of 41.8 years. This family has the typical clinical and radiological features of CADASIL (except for the occurrence of ischemic heart disease at a relatively young age in some subjects), and is linked to chromosome 19p13. This disease has so far been described in families from Finland, France, Germany, Italy, Japan, Spain and the United Kingdom, and there is a remarkable clinical and genetical homogeneity among all families reported, including this Dutch family.

Keywords: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); Chromosome 19p13; Linkage

1. Introduction

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been described in several European families [1-16]. Clinically, CADASIL is characterized by transient ischemic attacks and subcortical ischemic strokes, eventually leading to pseudobulbar palsy and dementia. Seizures and psychiatric symptoms (mainly depression) are mentioned as associated features, but probably are not

*Corresponding author. At: Department of Neurology, University Hospital, PO Box 9600, 2300 RC Leiden, The Netherlands. Fax: (31) (71)-24-8253. 0303-8467195l$9.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0303-8467(95)00068-2

a part of the syndrome [17]. The frequency of migraine with aura is reported to be much higher in CADASIL patients (approximately 40%) than in the general population [9,12,14]. Age at onset of the symptoms is mostly between 35 and 55 years, after which the disease tends to run a slowly progressive course over 10 or more years. The majority of the patients do not suffer from hypertension, which distinguishes CADASIL from Binswanger's disease as does the positive family history [14]. Cerebral CT scans show diffuse leukoencephalopathy and lacunar infarcts in the white matter. MRI more clearly shows the changes in the deep subcortical white matter, the basal ganglia, and, typically, in the external capsule. Usually, the corpus callosum is spared and the infratentorial region remains free of vascular changes. Histopathology shows white matter infarcts and diffuse loss of myeli-

infarction.

Fig. 1. D, o = unaffected; L

• = affected; ? = possibly affected; + = D N A

i n v e s t i g a t i o n . M R I = n e u r o l o g i c a l e x a m i n a t i o n a n d m a g n e t i c r e s o n a n c e i m a g i n g p e r f o r m e d ; MI = m y o c a r d i c

111-67 111-19 111-20 111-21 111-22 111-23 111-24 111-25 111-26 111-27 111-28 111-29 111-30 111-38 111-39 11t-40 111-41 111-42 111-43 111-44 111,.45 111-46 111-47 111.48 111-49 111-60 111-116 111-117 111-118 111-119 111-120 111-121 111-122 111-123 MRI MRI MRI MRI MRI MRi MRI MRI MRI MRI MRi MRI MRI MRI MRI M

~b

,3

oo

R. Wielaard et al. I Clinical Neurology and Neurosurgery 97 (1995) 307-313

nated axons [8,13,14,18,19]. The underlying vascular cause is a not well-defined arteriopathy, with granular electrondense osmophilic material in the media, affecting small penetrating arteries of the white matter and basal ganglia. Amyloid angiopathy, atherosclerosis, or other specific vascular abnormalities are absent. In several families associated features were reported: sensorineural hearing loss [9], hypercholesterolemia or hypertriglyceridemia [6,11], diabetes mellitus [6], monoclonal gammopathy [9], myocardial infarction [6], peripheral blood lymphocyte abnormalities [4], and gallstones [6]. It is not clear whether the familial youngadult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago, described in some Japanese families, has to be considered as CADASIL, or as another disease [20]. The differential diagnosis of CADASIL includes all hereditary causes of stroke, such as homocysteinuria, dyslipoproteinemias, Fabry's disease, hemoglobinopathies, polycythemia vera, coagulopathies, platelet disorders, neurocutaneous syndromes, fibromuscular dysplasia, connective tissue disorders, and amyloid angiopathy [21]. The disease locus has been linked to chromosome 19q12 in a number of unrelated French and Italian CADASIL families [12,16]. In the present human genome map the markers used are more exactly located on chromosome 19p13. Recently, evidence for genetic heterogeneity was found [15]. Here, we present a Dutch family with typical clinical and radiological features of CADASIL, linked to chromosome 19p13. Some members of the family also suffered from ischemic heart disease at a young age, which may be an argument that CADASIL has a systemic vascular pathophysiology.

2. Patients

The pedigree (Fig. 1) shows a four-generation family with 20 affected members (10 females, 10 males) in three successive generations. The couple in the first generation was reported to be healthy and both subjects died at the age of 76 years. The pedigree shows an autosomal dominant inheritance pattern. Medical data of generations I and II were obtained by oral history through generation III. Most members of generation III (9 clinically affected and 5 unaffected persons) were examined neurologically (by RW) and radiologically (CT or MRI). Age at onset of the strokes was between 29 and 52 years, with a mean of 41.8 years. Mean age at death (7 patients had died) was 51.7 years (range 44-59 years). Six subjects had suffered from a myocardial infarction (II-1, 11-2, 1I-7, 11-9, II-11, III-22), some of them at a young age (67, 54, 51, 58, 40, and 32 years respectively). Only patient 111-22 combined CADASIL with cardiac symp-

309

toms, whereas the other subjects with ischemic heartdisease showed no signs of CADASIL. Electrocardiography was normal in 3 patients with CADASIL (111-23, Ill-25, 111-49). Fourteen family members (8 affected, 6 not affected) were investigated for migraine symptoms using a standardized questionnaire based on the International Headache Society criteria [22]. Three of the 8 affected, and 3 of the 6 unaffected subjects appeared to suffer from migraine (3 with aura; 3 without aura). Onset of migraine was before the first stroke in the 3 CADASIL patients. Several patients (at least 7) showed signs of cognitive deterioration, occurring in a step-wise fashion or slowly progressive. Some patients did not show signs of cognitive decline, even after a long disease duration (e.g. 111-44, who remained cognitively normal for 16 years after the first stroke). The following laboratory investigations were performed in several patients of generation III, and found to be normal: hexosaminidases A and B, arylsulfatases A and B, ~-galactosidase, lupus anticoagulant, antitrombine III, protein C and S, apolipoprotein A-I, lipid metabolism (only cholesterol was slightly elevated in some patients), anticardiolipin, thyroid-function, TPHA, vitamins, lactate and pyruvate in CSF, anti-nuclear factor, long and very long chain fatty acids, amino acids, organic acids, lysosomal enzymes, neurotropic viruses, and total plasma homocystein level. Non-invasive investigation of cervical arteries was normal in 4 patients (II1-19, 111-25, Ill-44, III-49), and cerebral angiography proved normal in 3 patients (111-19, 111-23, 111-44).

3. Case report

Case III-22 suffered from a myocardic infarction at the age of 32 years. In 1984, at the age of 43, he developed word-finding difficulties, without headache. Except for aphasia, neurological examination was uneventful. Blood pressure was 115/85 mmHg. Blood analysis, was normal, except for a slightly elevated cholesterol (8.5 mmol/1; normal up to 6.5 mmol/l). A cerebral CT-scan showed hypodense lesions in the left hemisphere, and in the left white matter. CSF was normal, as was ultrasound examination of the carotid arteries. Neuropsychological examination revealed an above average intelligence quotient, and confirmed aphasia. The Wechsler Memory Scale revealed a memory quotient of 106. He was referred again at the age of 49 years, because of a decline in intellectual functioning. He still was slightly aphasic, but could no longer do simple mathematics. Neurological examination again showed no other abnormalities. Cholesterol was slightly elevated (7.1 mmol/1). Cerebral CT scan showed a number of small sharply delineated hypodense areas in the basal ganglia, thalamus, and white matter of both hemispheres. The white matter also was diffusely hypodense. MRI (Fig. 2) showed deeply

310

R. Wielaard et al./ Clinical Neurology and Neurosurgery 97 (1995) 30~313

located lacunar infarcts (thalamus, basal ganglia, cerebellum), and extensive white matter lesions. In april 1994 he suffered from a right-sided pure sensory ischemic cerebral infarct with discrete residual symptoms. In September 1994 he acutely could not walk straight forward, deviating towards the right, which improved after 2 days. During the last years, his intellectual functioning declined slowly. A recent examination revealed a decreased memory quotient of 86, reflecting cognitive decline. Intelligence quotient was not measured.

4. Linkage Blood of 8 patients (111-20 and III-67 did not participate) and 7 healthy family members was drawn and DNA was isolated according to Miller et al. [23]. In Table 1, clinical and neuroimaging data of all subjects used for the genetical analysis are summarized. Two polymorphic markers, assigned to chromosome 19p13, were analyzed in this family by polymerase chain reaction as described by Ophoff et al. [24]. The polymorphic markers used, D19S221 and D19S226, are reported to be linked to CADASIL [12]. Oligonucleotide sequences as well as allele frequencies are available through the Human Genome Data Base. Genetic linkage analysis was performed regarding CADASIL as an autosomal dominant disorder with penetrance of 0.90, a phenocopy of 0.001, and a gene frequency of 0.0001. Results of the two-point analysis are shown in Table 2. A maximum lod score of 3.78 was obtained at locus D19S226 without recombination.

5. Discussion

Fig. 2. (A and B) MRI (T 1- and T2-weighted images) of patient 111-22 showing multiple infarcts and diffuse leukoencephalopathy.

Recent studies have established that the diagnosis CADASIL can be based most reliably on the typical MRI picture, even in asymptomatic cases [14]. Indeed, in the family described here, one asymptomatic person (III-28) showed MRI abnormalities. Only very long-term followup can answer the question whether CADASIL can remain clinically asymptomatic even in old age (and thus, that the CADASIL gene can show non-penetrance). It is likely that one of the two eldest persons in the pedigree described here must have suffered from CADASIL and remained asymptomatic. An important consequence is that genetic linkage studies are only reliable when all asymptomatic family-members have been screened with cerebral MRI. Otherwise, they must be considered noninformative for linkage studies. Linkage studies in CADASIL have localized the gene in a 14 centimorgan interval bracketed by D19S221 and D19S222 on chromosome 19q12 [12,16]. Here, we con-

R. Wielaard et al./Clinical Neurology and Neurosurgery 97 (1995) 307 313

311

Table 1 Clinical and neuroimaging data of the subjects used for the genetical analysis Case

Sex

Status

Age (years)

Age at onset (years)

I1-9 II-115 1II-21 III-22

F M F M

Healthy Healthy Healthy Affected

68 74 56 53

1II-23

F

Affected

50

46

II1-25

F

Affected

48

42

Recurrent strokes, migraine with aura

III-28 III-43

F M

Affected Affected

41 48

42

Migraine with aura Recurrent strokes, cognitive deterioration

III-44

F

Affected

47

29

III-45

F

Affected

43

36

One transient ischemic attack, migraine with aura One transient ischemic attack

III-46 Ill-47 II1-48 111-49

F M F M

Healthy Healthy Healthy Affected

43 42 40 38

36

Ill-50

M

Healthy

35

43

Clinical features

MRI

Myocardic infarction -

Not performed Not performed No abnormalities Diffuse white matter hyperintensities, multiple lacunair infarcts Diffuse white matter hyperintensities, multiple lacunair infarcts, cortical and subcortical atrophia Diffuse white matter hyperintensities, lacunair infarcts in thalamus Diffuse white matter hyperintensities Diffuse white matter hyperintensities, multiple lacunair infarcts Diffuse white matter hyperintensities

Myocardic infarction, recurrent strokes, aphasia, cognitive deterioration Recurrent strokes, severe cognitive deterioration

Migraine without aura Migraine without aura Recurrent transient ischemic attacks

Diffuse white matter hyperintensities, multiple lacunair infarcts No abnormalities No abnormalities No abnormalities Diffuse white matter hyperintensities, multiple lacunair infarcts No abnormalities

MRI = magnetic resonance imaging.

firm linkage to chromosome 19 markers (D19S226 gave the highest lod score). Recently, these markers were more precisely located at 19p13. It seems that the clinical deterioration of CADASIL sufferers can progress in two ways: a stepwise deterioration due to successive strokes, or the gradual development of a pseudobulbar syndrome with spasticity, dysarthria, dysphagia, and dementia. In the early phase of the disease, the strokes often cause only mild disability and are more transient ischemic attack-like. Long asymptomatic periods can occur between strokes. Migraine with or without aura occurs in many patients in all CADASIL pedigrees reported [9,12,14]. Remarkably, CADASIL patients often develop migraine attacks shortly before or after their first stroke, suggesting a pathophysiological relationship between CADASIL and migraine. Recently, a family with autosomal dominant

Table 2 Two-point lod scores Locus

D19S221 D19S226

Recombination fraction (O) 0.00

0 . 0 5 0.10

0.20

1.17 3.78

1 . 0 6 0.94 0.69 3 . 4 6 3 . 1 2 2.40

0.30

Zn,.x

Omax

1.17 3.78

0.00 0.00

0.40

0.42 0.14 1 . 6 0 0.72

migraine with MRI white matter abnormalities was described with some evidence for linkage to the CADASIL locus (maximum lod-score 2.044, without recombination) [25]. In this study, migraine occurred in approximately 50% of affected and unaffected persons, suggesting that the combination of CADASIL and migraine in this family probably is coincidental. Inspired by the association of CADASIL and migraine, Joutel et al. [26] searched linkage of familial hemiplegic migraine (FHM) with chromosome 19 markers, and indeed found linkage of F H M to chromosome 19. The F H M and CADASIL region most likely are different [24,26,27], showing the serendipity of this finding. This point will, however, only be solved when the genes for CADASIL and FIlM will be identified. In the pedigree described here, 6 individuals suffered from a heart attack, some of them at a relatively young age. In only one of them, however, CADASIL was also proven. Intensive search did not reveal a cause for the heart attacks, except for a slight elevation of cholesterol in several patients. It is possible that the cerebral and the cardiac ischemic problems are caused by the same (genetically determined) pathological mechanism. The vascular changes which are characteristic for CADASIL have also be found in a sural nerve biopsy of a CADASIL patient [28], in the heart [13], in striated muscle, skin, retina and all along the arterial tree [29,30]. These find-

312

R. Wielaard et al./Clinical Neurology and Neurosurgery 97 (1995) 307-313

ings probably reflect that CADASIL has a systemic vascular pathophysiology. Immunological abnormalities have been described by Tournier-Lasserve in two CADASIL patients [9]. One patient had monoclonal gammopathy of undetermined significance (IgG-lambda), and improved after plasmapheresis. The brother of that patient died of myeloma (IgG-kappa). One CADASIL patient without gammopathy, however, did not benefit from plasmapheresis. One of the present cases had IgG-kappa gammopathy. The combination of CADASIL and gammopathy probably is coincidence, but must be evaluated carefully, because an immunologic pathophysiology is possible. This is supported by the finding of oligoclonal bands in CSF of a CADASIL patient [19]. In addition, weak staining with antibodies to IgA, IgG, IgM, Clq, C3 was found in arterioles of CADASIL patients [18,28], next to staining with antibodies against lambda and kappa light chain [28]. In summary, CADASIL has so far been described in families from Finland, France, Germany, Italy, Japan, Spain and the United Kingdom, with a remarkable clinical and genetical homogeneity. Here, we confirm this homogeneity in a Dutch pedigree, which shows the typical clinical and radiological features of CADASIL. Besides, our study confirms a possible relation between CADASIL and the immune system, and confirms linkage to chromosome 19p13.

References [1] Stevens DL, Hewlett RH, Brownell B (1977) Chronic familial vascular encephalopathy. Lancet I: 1364-1365. [2] Sourander P, Walinder J (1977) Hereditary multi-infarct dementia. Lancet 1: 1015. [3] Sourander P, Walinder J (1977) Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol 9: 247-254. [4] Behan PO, Kennedy PGE (1981) Chronic familial cerebral vasculopathy with peripheral blood lymphocyte abnormalities. Ann Neurol 10: 74. [5] Bomhof MAM (1985) Hereditary Binswanger's disease. J Neurol 32 (suppl):S 122. [6] Sonninen V, Savontaus ML (1987) Hereditary multi-infarct dementia. Eur Neurol 27: 209-215. [7] Bousser MG, Tournier-Lasserve E, Aylward R, Tourbah A, Dormont D, Romero N, Cabanis E (1988) Recurrent strokes in a family with diffuse white matter abnormalities and muscular lipidosis. A new mitochondrial cytopathy? J Neurol 235 (Suppl): $4$5. [8] Davous P, Fallet-Bianco C (1991) Demence sous-corticale familiale avec leucoencephalopathie arteriopathique: observation clinicopathologique. Rev Neurol 5: 376-384. [9] Tournier-Lasserve E, Iba-Zizen MT, Romero N, Bousser MG (1991) Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy. Stroke 22:1297 1302. [10] Salvi F, Michelucci R, Plasmati R, Parmeggiani L, Zonari P, Mascalchi M, Tassinari CA (1992) Slowly progressive familial

dementia with recurrent strokes and white matter hypodensities on CT scan. Ital J Neurol Sci 13: 135-140. [111 Mas JL, Dilouya A, De Recondo J (1992) A familial disorder with subcortical ischemic strokes, dementia and leukoencephalopathy. Neurology 42:1015 1019. [12] Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J, Bach MA, Bousser MG (1993) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps on chromosome 19. Nature Genetics 3: 256259. [13] Baudrimont M, Dubas F, Joutel A, Tournier-Lasserve E, Bousser MG (1993) Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy: a clinicopathological study. Stroke 4: 122-125. [14] Bousser MG, Tournier-Lasserve E (1994) Summary of the proceedings of the first international workshop on CADASIL. Stroke 5: 704-707. [15] St Clair D, Bolt J, Morris S, Doyle D (1995) Hereditary multiinfarct dementia unlinked to chromosome 19q12 in a large Scottish pedigree: Evidence of probable locus heterogeneity. J Med Genet 32:57 60. [16] Sabbadini G, Francia A, Calandriello L, Di Biasi C, Trasimeni G, Gualdi GF, Palladini G, Manfredi M, Frontali M (1995) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL): clinical, neuroimaging, pathological, and genetic study of a large Italian family. Brain 18: 207 215. [17] Bowler JV, Hachinski V (1994) Progress in the genetics of cerebrovascular disease: Inherited subcortical arteriopathies. Stroke 5: 16961698. [18] Gray F, Robert F, Labrecque R, Chretien F, Baudrimont M, Fallet-Bianco C, Mikol J, Vinters HV (1994) Autosomal dominant arteriopathic leuko-encephalopathy and Alzheimer's disease. Neuropathol Appl Neurobiol 20:22 30. [19] Zhang WW, Ma KC, Andersen O, Sourander P, Tollesson PO, Olsson Y (1994) The microvascular changes in cases of hereditary multi-infarct disease of the brain. Acta Neuropathol 7: 317324. [20] Fukutake T, Hirayama K (1995) Familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension. Eur Neurol 5:69 79. [21] Natowicz M, Kelley RI (1987) Mendelian etiologies of stroke. Ann Neurol 22:175 192. [22] Headache classification committee of the international headache society (1988) classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Cephalagia (Suppl 7). [23] Miller A, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from nucleated cells. Nucleic Acids Res 6: 1215. [24] Ophoff RA, Eijk van R, Sandkuijl LA, Terwindt GM, Grubben CPM, Haan J, Lindthout D, Ferrari MD, Frants RR (1994) Genetic heterogeneity of familial hemiplegic migraine. Genomics 2: 21-26. [25] Chabriat H, Tournier-Lasserve E, Vahedi K, Leys D, Joutel A, Nibbio A, Escaillas JP, Iba-Zizen MT, Bracard S, Tehindrazanarivelo, Gastaut JL, Bousser MG (1995) Autsomal dominant migraine with MRI white-matter abnormalities mapping to the CADASIL locus. Neurology 45: 10861091. [26] Joutel A, Bousser MG, Biousse V, Labauge P, Chabriat H, Nibbio A, Maciazek J, Meyer B, Bach MA, Weissenbach J, Lathrop M, Tournier-Lasserve E (1993) A gene for familial hemiplegic migraine maps to chromosome 19. Nature Genet 5: 4(L45. [27] Haan J, Terwindt GM, Bos PLJM, Ophoff RA, Frants RR, Ferrari MD (1994) Familial hemiplegic migraine in the Netherlands. Clin Neurol Neurosurg 96: 244-249.

R. Wielaard et al./Clinical Neurology and Neurosurgerv 97 (1995) 307 313

[28] Schroder JM, Sellhaus B, Jorg J (1995) Identification of the characteristic vascular changes in a sural nerve biopsy of a case with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Acta Neuropathol 9: 116-121. [29] Ruchoux MM, Chabriat H, Bousser MG, Baudrimont M, Tournier-Lasserve E (1994) Presence of ultrastructural arterial

313

lesions in muscle and skin vessels of patients with CADASIL. Stroke 5: 2291-2292. [30] Ruchoux MM, Guerouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D (1995) Systematic vascular smooth muscle impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Acta Neuropathol 9: 500-512.