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Short Communications
Autosomal Dominant Syndrome With
Strokelike Episodes and Leukoencephalopathy
Elizabeth Tournier-Lasserve, MD; Marie-Th6rese Iba-Zizen, MD;
Norma Romero, MD; and Marie-Germaine Bousser, MD
Background and Purpose: We conducted a prospective survey of a family presenting a new
syndrome characterized mainly by recurrent strokelike episodes and neuroimaging evidence of
leukoencephalopathy.
Summary of Report: Forty-five members of a single family were studied clinically and with
magnetic resonance imaging. Nine had strokelike episodes, including transient ischemic
attacks, and minor or major strokes starting between the fourth and sixth decades, with
neuroimaging evidence of small, deep infarcts and a widespread white matter disorder. Other
symptoms included migraine (three), dementia (two), epilepsy (one), and hearing loss (one). In
some patients, we found various immunologic anomalies and muscular lipidosis without
ragged-red fibers. Eight other family members were clinically normal, but had identical
neuroimaging signs of leukoencephalopathy. No abnormality was detected in the 28 other
members of the family examined. Extensive investigations failed to reveal any known cause of
cerebral ischemia.
Conclusions: There appears to be a new syndrome in this family that is characterized by recurrent
subcortical strokelike episodes, leukoencephalopathy, immunologic anomalies, muscular lipidosis,
and an autosomal dominant pattern of transmission. {Stroke 1991^2:1297-1302)
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S

troke in association with the finding of leukoencephalopathy on neuroimaging has been
reported in a number of nonfamilial conditions, such as Binswanger's disease, and in some rare
genetic and metabolic disorders, such as metabolic
encephalopathy, lactic acidosis, and stroke (MELAS)
and homocystinuria.1'2 We report here an autosomal
dominant syndrome observed in a French family that
is characterized mainly by subcortical strokelike episodes starting in midadulthood and by neuroimaging
evidence of a widespread white matter disorder. The
condition is associated with muscular lipidosis without ragged-red fibers and with various immunologic
abnormalities of uncertain significance.
Case Reports

Forty-five members of a family originating from the
Loire-Atlantique region of France underwent extensive clinical, biological, and radiological investigation. Figure 1 shows the pedigree of this family. The
From Unit* de Pathologie de PImmunit6, Faculty de Midecine
Necker (E.T-L.), Service de Neuro-radiologie, Hdpital des
Quinze-vingts (M-T.I-Z.), Unit6 INSERM 075 and 153 (N.R.),
Service de Neurologje, Hdpital Saint-Antoine (M-G.B.), Paris,
France.
Address for reprints: Pr. M.G. Bousser, Service de Neurologie,
H6pital Saint-Antoine 75571-PARIS Ce"dex 12, France.
Received February 20, 1991; accepted June 5, 1991.

45 subjects examined belonged to generations III (18
subjects) and FV (27 subjects). All gave informed
consent. Nine (six males, three females) had suffered
recurrent strokelike episodes (focal cerebral deficits
of sudden onset with varying degrees of recovery),
which had started between 30 and 60 years of age
(Table 1). These led to pseudobulbar palsy in three
and dementia in two. The second most frequent
symptom, present in three patients, was episodic
headache suggestive of migraine. One patient developed significant psychiatric disturbance and another
had sensorineural deafness. No optic nerve, spinal
cord, peripheral nerve, muscle, or other organ involvement was detected. There was no ophthalmoplegia, proximal weakness, ataxia, growth failure,
or symptoms during childhood. Table 1 summarizes
the clinical presentation of these nine patients; only
one case will be fully reported (family member III-5).
Four members of generations I and II had suffered of
recurrent strokes.
A 50-year-old previously healthy male was first examined in 1976 after the sudden onset of expressive
dysphasia with buccofacial apraxia, from which he
recovered completely within 2 months. Two other episodes of sudden onset occurred: one in 1977, again with
dysphasia, and the other in 1983, with left-sided numbness involving the cheek, tongue, andfirstthree fingers.
From 1977 on the patient complained of recurrent

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Vol 22, No 10

October 1991

FIGURE 1. Family pedigree. Filled symbols, patients; half-filled symbols, asymptomatic subjects with abnormal magnetic
resonance imaging (MRI); empty symbols,
healthy individuals; bordered symbols, subjects examined clinically and with MRI;
squares, male subjects; circles, female subjects; oblique slash, deceased.

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attacks of severe headache with nausea, photophobia,
and phonophobia. He gradually developed a typical
pseudobulbar palsy, and by 1986 he was severely dysarthric and almost unable to walk. He was apathetic,
depressed, and moderately demented (Mini-Mental
State Examination [MMSE] score of 23/30). In view of
his steady deterioration, the absence of apparent cause
(infra), and the discovery of a monoclonal gammopathy
without evidence of plasma cell malignancy, he underwent plasmapheresis in October 1986. After five sessions he began to improve, and after 10 sessions he was
able to walk long distances without assistance and his
speech had improved. The MMSE score was 27/30, and
the Barthel Activities of Daily Living index had risen
from 65 to 85. Since then, plasmapheresis has been
performed every 1-2 months. The patient's clinical
condition has remained stable, without any new further
episodes. Blood pressure (130/80 mm Hg) and general
examination have been normal at all times.
Methods
Computed tomography (CT) of the brain (CE
12 000 from CGR or Elscint 2400) was performed in
the nine clinically affected subjects, using the orbitomeatal plane as reference. Brain magnetic resonance
imaging (MRI) studies were performed in all 45
subjects, the first 32 at 0.15 or 0.5 T (Magniscan GE
CGR) and the remainder at 1.5 T (Sigma GE-CGR).
Tl- and T2-weighted sequences were used in all
subjects, with contiguous slices (5-9 mm thick), in
sagittal and axial planes using the neuro-ocular plane
as reference. Computed tomography showed small

areas of well-delineated hypodensity, without contrast enhancement, scattered throughout the basal
ganglia and adjacent white matter, with a preponderance for the external capsule. Furthermore, diffuse
and confluent areas of hypodensity were observed in
the hemispheric white matter (leukoaraiosis). These
two types of lesions were confirmed by MRI which
showed, first, small, deep, and well-delineated areas
of abnormal signal (decreased on Tl-weighted imaging and increased on T2-weighted imaging), and
secondly, on T2-weighted imaging, extensive areas of
hypersignal in the white matter of the cerebral hemispheres. The small, deep, well-delineated lesions
were present in all nine patients and were strikingly
similar in all of them, whereas increased white matter
signal, present in eight patients, was also found in
eight totally asymptomatic subjects, to a variable
extent (Figure 2).
The following investigations were performed in all
affected individuals, except where otherwise stated,
and were normal: duplex scanning of cervical arteries,
four-vessel angiography (performed in four patients),
electrocardiography, two-dimensional echocardiography, Holter monitoring, chest x-ray, nerve-conduction
velocities (performed in three patients), lipid metabolism [total, LDL, and HDL cholesterol; triglycerides;
apolipoprotein A-I; Lp(a)], detailed coagulation and
hemostasis studies, serum creatine kinase enzymes,
hexosaminidases A and B, arylsulfatases A and B, and
a-galactosidase. Free and total serum camitine levels,
blood lactates, and pyruvates at rest and after exercise
were normal except in patient 111-23, where, twice,

Toumier-Lassavc et al
TABLE 1.

Autosomal Dominant Strokelike Episodes

Clinical Presentation of the Nine Patients in Generations III and IV

Propositus
(age of onset)

Vascular risk factors

Main clinical features

ni-5 (50)

Hypertension
Myocardial infarction
None

m-17 (54)

None

IU-19 (40)

Increased cholesterol

111-23 (47)

None

111-24 (42)

None

IV-2 (39)

Cigarette smoker

IV-21 (34)
rV-22 (33)

None
Cigarette smoker

Two sudden episodes of left hemiplegia (1980, 1988) with poor recovery.
Pseudobulbar palsy and subcortical dementia.
Two sudden episodes of dysphasia (1976, 1977) and one (1983) of left
face and and arm numbness. Severe pseudobulbar palsy. Migraine
without aura. IgG-A benign monoclonal gammopathy. Improvement with
plasmapheresis.
Three episodes of sudden onset with good recovery in 1 week to 1
month (1983, pure left hemiplegia; 1984, dysphasia; 1985, left
hemiplegia and loss of balance).
From 1971 on, grand mal seizures and status epilepticus. Three sudden
and poorly regressive episodes (1983, right sensory motor deficit and
dysarthria; 1986, pure left sensory deficit; 1988, severe right hemiplegia),
pseudobulbar palsy, subcortical dementia, psychiatric disturbance
(depressions 1984, 1988), manic episode (1985). No response to
plasmapheresis.
Multiple 5- to 15-minute episodes of paresthesia in left hand and face
followed by left-sided headache lasting <1 hour (migraine with aura or
transient ischemic attacks).
Multiple transient episodes (30-60 minutes) of two types: left arm and
face weakness and paresthesia, and bilateral blurring of vision without
headache.
One sudden episode of dysarthria and left-sided facial weakness lasting
1 month.
One sudden episode of expressive dysphasia lasting 5 days.
Multiple episodes (3-24 hours) of dysphasia with or without visual field
defects. One sudden episode of pure hemiplegia lasting 1 month.
Migraine with and without aura. Bilateral sensorineural hearing loss.

HI-4 (56)

1299

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lactate levels at rest were observed to be > 2 mM/1
(i.e., 3 mM/1 and 3.2 mM/1). Total plasma homocysteine level was measured in three cases and found to
be increased in one (patient IV-22, 21 jimol/1).
The cerebrospinal fluid was analyzed in five patients: it was normal in two (111-17, 19), showed an
increase in protein (0.94 g/1) with an IgG monoclonal
A peak in one (III-5), a mild pleocytosis (8 cells/mm3)
in one (FV-2), and oligoclonal bands in two (IV-2,
22).
Extensive immunologic investigations (screening
for antibodies to DNA, nuclear soluble proteins,
mitochondria, striated muscle, smooth muscle, thyroid, and skin; blood lymphocyte subpopulation analysis using monoclonal antibodies directed toward
CD3, CD4, CD8, T-cell antigens, and B-cell and
natural killer cell antigens) were performed because
patient III-6 had died of myeloma (IgG-»c) and his
brother, III-5, had a benign monoclonal gammopathy. Antibodies were detected in the serum of some
patients: antinuclear antibodies (immunofluorescence, titers 1/100-1/400) in three (III-5, 19, IV-22)
and antibodies directed toward skin or striated muscle in two (111-17, 21).
Biopsies were obtained from the left deltoid of
four patients (IV-4,5,19, IV-22) and one asymptomatic subject (111-21) with leukoencephalopathy for
histochemical and electron microscopic studies.3 In
two patients (III-5, 19), mitochondria were isolated
from 1 g fresh muscle and the analysis of their
functions performed.4 Whereas muscle biopsy was

normal in the asymptomatic subject, a similar abnormal histochemical pattern was observed in the patients: type I fiber predominance (51-65%), type II
fiber atrophy, and accumulation of sudanophilic lipids within muscle fibers (Figure 3). Neither glycogen
accumulation nor ragged-red fibers were seen. Electron microscopy revealed numerous large lipid droplets in the intermyofibrillary spaces. The morphology
and number of mitochondria were normal. Free
muscle carnitine values were normal in three cases,
but the esterified/total carnitine ratio was increased
in two subjects: (III-5,46.5%; 111-21,54.4%; controls,
<33%). Muscle mitochondria displayed normal electron transport and energy coupling. The respiratory
chain, as well as /3-oxidation, Krebs cycle, pyruvate
dehydrogenase, and transmembrane transport of
ADP, phosphate, and ATP, was functionally intact.
Discussion
The genealogical study of this family shows that six
males and three females were clinically affected and
that five males and three females were clinically
asymptomatic, but had MRI white matter hyperintensity signals on T2-weighted imaging. The disease
is transmitted either paternally or maternally and
affects approximately 50% of offspring. The offspring
of unaffected parents are also unaffected. This pattern is consistent with an autosomal dominant pattern of inheritance.
All clinically affected subjects presented with episodes of focal brain deficits of sudden onset. The

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Stroke Vol 22, No 10 October 1991

FIGURE 2. Panels IA and B: Magnetic
resonance imaging (MRI) scan of patient
111-5. Tl-weighted imaging: numerous lowsignal subcortical lesions (left and right thaiami, posterior limb of left internal capsule,
right external capsule, and left temporo-occipital white matter). T2-weighted imaging: corresponding areas of high signal with a more
diffuse white matter increased signal Panels
HA and B: MRI scan of family member
111-21. Tl-weighted imaging: Signal return
from white matter is abnormal but no focal
areas are seen. T2-weighted imaging: Diffuse
high-signal intensity of the subcortical white
matter.

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time course was highly variable, being that of complete resolution within a few minutes to minimal
recovery with various degrees of sequelae. In all but
two patients recurrences occurred over the years,
leading to pseudobulbar palsy in three and to severe
dementia of the subcortical type in two. Such a
clinical profile is highly suggestive of an ischemic
process, but, in the absence of pathologic data, the
term "strokelike episodes" has been used in the
present description. Computed tomography and
MRI showed small, well-delineated lesions compatible with, though not diagnostic of, small, deep infarcts, which seem, remarkably, to spare the cortex.
The other principal feature of the condition is a
white matter disorder, as shown by leukoaraiosis on
CT scan and increased signal return on T2-weighted
imaging on MRI. Such a leukoencephalopathy has
been described in numerous disorders and its significance is still debated; its frequency increases with
age, systemic hypertension, other vascular risk factors, and in patients presenting with stroke or dementia.3 In the present family, it is remarkable in that it
is also observed in some young, symptom-free family

members having either an affected parent or a parent
with the same subclinical white matter disorder.
Extensive cardiovascular investigations helped to
rule out the majority of classic causes of cerebral
ischemia such as atheroma, cardiac emboli, or hematologic disorders. The association of multiple subcortical strokes and white matter disease is suggestive of
Binswanger's disease6 and can also be observed in
lacunar syndromes.7 However, the present disorder
differs from these in its earlier onset, low rate of
hypertension (1 of 9), and autosomal dominant pattern of inheritance. Among the familial conditions
that can cause stroke, hereditary dyslipoproteinemias,8 thrombotic disorders,9 homocystinuria,10 and
Fabry's disease11 have distinct clinical presentations
and were ruled out by appropriate investigations.
Familial cerebral amyloid angiopathy12 cannot be
formally excluded without brain histology, but the
absence of cerebral hemorrhage in this family made
it unlikely. Strokelike episodes, white-matter disease,
and muscular lipidosis are features of MELAS syndrome.2 However, the absence of ragged-red fibers,
the normality of muscular mitochondrial respiratory

Toumier-Lasserve et al

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Autosomal Dominant Strokelike Episodes

\V

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A3**

FIGURE 3. Muscle biopsy from patient 111-19 showing marked accumulation of lipids in type I muscle fibers. Sudan red stain.

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chain and /3-oxidation investigations, and the absence
of a number of the usual clinical features of MELAS
(onset during childhood, mental retardation, cortical
infarcts)13do
not favor this diagnosis. Three other
families -15 with autosomal dominant recurrent
strokes have been reported, but in the absence of
MRI and muscle biopsies, it is impossible to know
whether they suffer from the same condition.
Thus, in the present family, there appears to be a
new autosomal dominant syndrome characterized by
recurrent subcortical strokelike episodes, leukoencephalopathy, and muscular lipidosis. It is interesting
to note that the familial nature of this condition was
long ignored, mainly because of the relatively late age
of onset of symptoms. It might well be that its real
frequency is presently underestimated. The cause of
this disease, the responsible genetic defect, the role
of the abnormal immune status, and the pathogenesis
of the strokelike episodes remain to be elucidated.
Note added in proof. Patient 111-19 died on December 12, 1990. Macroscopic examination of the brain
showed a recent massive striate hemorrhage on the
left side. The remaining white matter on both sides
looked greyish and granular with multiple small
lacunes. Detailed neuropathologic data will be presented in a second paper to be submitted for publication in this journal.
Acknowledgments

We are greatly indebted to Association pour la
Recherche sur la Scl6rose en Plaques (ARSEP) for
making the MRI studies possible.

We are grateful to all the residents and physicians
who helped us, particularly to Drs. A. Abanou, R.
Aylward, M.A. Bach, N. Baumann, J. Breton-Gorius,
M. Chaussain, F. Danon, D. Dormont, M. Jouas, C.
Marsac, J. Tamraz, and A. Tourbah, and to Prs. J.R.
Feve, J.C. Homberg, A. Munich, J. Pouget, S. Richard, and M. Samama. We are indebted to Mrs.
Jocelyne Ruffie and Nadia Kneisky for their assistance in the preparation of the manuscript and to Dr.
B. Youl for helping with the English. We would also
like to thank most warmly all the members of the
family for their remarkable collaborative support.
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Ncurol 1987;22:175-192
2. Pavlakis SG, Philipps PC, Di Mauro S, De vivo DC, Rowland
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3. Dubowitz V: Muscle Biopsy: A Practical Approach. London,
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4. Morgan-Hughes JA, Darveniza P, Kanh SN, Landon DN,
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lacunes (editorial). Stroke 1988; 19:1071-1073
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lipoprotein metabolism, in Harris H, Hirschhorn K (eds):

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Stroke Vol 22, No 10 October 1991

Advances in Human Genetics, Volume 14. New York, Plenum
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9. Rodgers GM, Shuman MA: Congenital thrombotic disorders.
AmJ Hematol 1986;21:419-430
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12. Haan J, Roos RAC, Algra PR, Lanser JBK, Bots GTAM,
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Ada Neuwpathol (Berl) 1977^9:247-254
KEY WORDS • dementia, vascular • leukoencephalopathy •
migraine

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