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CADASIL and white matter syndromes.

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3. van den Bosch H, Schutgens RBH, Wanders RJA, Tager JM. Biochemistry of peroxisomes. Annu Rev Biochem 1992;61:157-197
4. Lu J-F, Lawler A M , Watkins PA, et al. A mouse model for
X-linked adrenoleukodystrophy. Proc Natl Acad Sci USA 1997;
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5. Faust PL, Hatten ME. Targeted deletion of the PEXZ peroxisome assembly gene in mice provides a model for Zellweger
syndrome, a human neuronal migration disorder. J Cell Biol
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Refsum disease gene. Nat Genet 1997;17:185-189
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approach to inherited peroxisomal disorders: a series of 27 patients. Ann Neurol 1998;44:720-730
10. Theil AC, Schutgens RBH, Wanders RJA, Heymans HSA.
Clinical recognition of patients affected by a peroxisomal
disorder: a retrospective study in 40 patients. Eur J Pediatr
1992;151:117-120
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with peroxisomal disorders subdivided into 16 complernentation groups. J Pediatr 1995;127:13-22
12. Reuber BE, Germain-Lee E, Collins CS, et al. Mutations of
PEXl are the most common cause of peroxisome biogenesis
disorders. Nat Genet 1997;17:445-448
13. Braverman N, Steel G, Obie C, et al. Human PEX7 encodes
the peroxisomal PTS2 receptor and is responsible for rhizornelic
chondrodysplasia punctata. Nat Genet 1997;15:369 -376
14. Roels F, DeBie S, Schutgens RBH, Besley GTN. Diagnosis of
human peroxisomal disorders, a handbook. J Inherit Metab Dis
1995;18(Suppl 1):1-226
CADASIL and White Matter
Syndromes
Like an undersea volcano's eruption, the effects of
CADASIL (cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy) on
the shores of the ischemic stroke community may
prove more a tidal wave than a minor ripple. For starters, Binswanger's famous case, no less, may have been
CADASIL.' Although the heavy involvement of the
central cerebral white matter in CADASIL is well documented, how such a diffuse process exists in the vascular system is incompletely understood: its systemic
vascular effect is diagnosable by biopsy,' and the high
correlation with migraine and seizures suggests gray
matter vessels could also share in the disease, as some
cases with the histopathological findings have shown
involvement of cerebral surface a r t e r i e ~ .These
~
unset-
tled issues aside, CADASIL seems to show far more
central white matter vascular lesions than are typical
with hypertension-related lacunar disease.* Even given
a dominant inheritance and its differentially severe topography, CADASIL may join granulomatous arteritis
of the central nervous system5 to suggest that the brain
vasculature has biological properties somewhat different
from other vascular beds. There is more to brain ischemia than the easily trivialized classic concepts of
thrombosis and embolism.
The pathological process also spans a wide range of
abnormalities from thinning of myelin in some areas,
loss of axis cylinders in others, all the way to foci of
frank infarction, and has been associated with remarkably thickened walls of the small arteries. Classic concepts analogize energy failure causing infarction to that
of a fluorescent light tube (ie, threshold effects), but
some of the descriptions of CADASIL arouse again the
long-disputed"' notion of a process of chronic ishernia,',^ which might be analogous to an incandescent light, that is, a range between full function and
full-thickness tissue death.
O n the clinical side, the case material is only slowly
accumulating. Further changes are to be expected before the final distinctive clinical pictures are clarified.
From smaller cases series and from some meta-analyses,
migraine has been cited as a distinctive feature of the
syndrome, an observation of interest to the natureover-nurture crowd, considering the proximity of gene
loci.l0 The present case series supports an association
but calls into question whether migraine as an initiating symptom predicts CADASIL. Given its high frequency, migraine alone may not any better predict
CADASIL than it did aneurysm or arteriovenous malformation. The cumulative evidence of brain dysfunction in CADASIL cases is relentless, but less well delineated are the data that support the widely used and
nonsynonymous terms stepwise and progressive. The
former points to distinctive events that seem best recognized when they have the motor or sensory components from classic lacunar syndromes. The latter suggests something far more insidious and applies mainly
to behavioral disturbances, not so easily correlated with
specific lesions. Progress in the taxonomy of white matter lesions has been painfully slow. Still unanswered are
how ischemic centrum semiovale white matter diseases
achieve their syndromic effects; too few examples exist
of focal infarcts confined to major ipsihemispheral or
transcallosal pathways to substantiate the hopes of classic connectionists, this despite the secular catechisms
found in most neurology textbooks. Some examples
have appeared of injury to specific thalamocortical
pathways that interfere with cerebrovascular reactivity," effects that far exceed the inference made from
the small size of the deep infarct and that might well
be part of the effects of the more diffuse lesions. The
Copyright 0 1998 by the American Neurological Association
715
cerebral site of ischemic lesions has so far not been emphasized enough,12 and may explain the continued
frustration in attempts to correlate simple brain lesion
volume with clinical indices of dementia.13 Former
concepts of dementia from white matter infarction
continue to undergo radical redefinition. l 4
Modern neurological cartographers face far more
daunting tasks than those who mapped the cerebrum
and its gross anatomical pathways. Watching the remarkable resiliency of the brain to the effects of lesions,
ours will be the more complex endeavor, determining
which, where, how many, and how large must be the
lesions that eventually blunt the brain’s capacities to
rewrite its software, yielding the clinical picture we currently crudely call dementia. Further detailed studies of
the clinical course and lesion correlates in CADASIL
cases could help illuminate this process. The sufferers
and their families have an equally keen interest in the
outcomes.
J. P. Mohr, MD
Dtprtment of Neurology
Neurological Institute
Columbia-Presbyterian Medical Center
New York, NY
References
1. Mast H, Tatemichi TK, Mohr JP. Chronic brain ischemia: the
contributions of Otto Binswanger and Alois Alzheimer to the
mechanisms of vascular dementia. J Neurol Sci 1995;132:4-10
2. Ruchoux MM, Chabriat H, Bousser MG, et al. Presence of
ultrastructural arterial lesions in muscle and skin vessels of patients with CADASIL. Stroke 1994;25:2291-2292 (Letter)
3. Rubio A, Rifkin D, Powers JL, et al. Phenotypic variability of
CADASIL and novel morphologic findings. Acta Neuropathol
1997;94:247-254
4. Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol 1969;12:1-15
5. Kolodny EK, Rebeiz JJ, Caviness VS, Richardson EP. Granulomatous angiitis of the central nervous system. Arch Neurol
1968;19:510-524
6. Fisher CM. Dementia in cerebrovascular disease. In: Took JF,
Siekert RG, Whisnant JP, eds. Cerebral vascular disease. Transactions of the sixth Princeton conference. New York: Grune
and Stratton, 1968;6:232-235
7. Tomlinson BE, Blessed G, Roth M. Observations on the brains
of demented old people. J Neurol Sci 1970;11:205-242
8. Ferszt R, Cervos-Navarro J. Cerebrovascular pathology: aging
and brain failure. In: Cervos-Navarro J, Sarkander HI, eds.
Brain aging and neuropharmacology, vol 21. New York: Raven
Press, 1983:133-1 51
9. Meguro K, Hatazawa J, Yamaguchi T. Cerebral circulation and
oxygen metabolism associated with subclinical periventricular
hyperintensity as shown by magnetic resonance imaging. Ann
Neurol 1990;28:378-383
10. Joutel A, Bousser M-G, Biousse V, et al. A gene for familial
hemiplegic migraine maps to chromosome 19. Nat Genet 1993;
5:40-45
11. Tatemichi TK, Desmond DW, Prohovnik I, et al. Confusion
and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome? Neurology 1992;42:1966-1979
716
12. Tatemichi TK, Sacktor N, Mayeux R. Dementia associated
with cerebrovascular disease, other degenerative diseases, and
metabolic disorders. In: Terry RD, Katzman R, Bick IU,eds.
Alzheimer disease. New York: Raven Press, 1994:123-166
13. Crystal HA, Dickson DW, Sliwinski MJ, et al. Pathological
markers associated with normal aging and dementia in the elderly. Ann Neurol 1993;34:566-573
14. Hachinski V. Vascular dementia. Neurology 1993;43:21592160
Alzheimer’s Disease Genetics:
Home Runs and Strikeouts
Yogi Berra once said that “90% of baseball is half mental.” Most think he meant that home runs are great,
but strikeouts are more frequent. Winning games in
baseball relies on not only slull but strategy and a lot of
patience. Investigating the genetics of Alzheimer’s disease must certainly be at least as complicated as winning baseball games. This disease has been discussed as
one of several examples of “complex” genetic disorders
because it may have multiple genetic and some nongenetic causes, which may interact with each other. Rare
mutations in the amyloid precursor protein (APP) or
in one of the two presenilins (PSENI and PSENII)
genes result in autosomal dominant forms of this disorder with onset in middle age, while a relatively common polymorphism in the apolipoprotein-E gene increases susceptibility to the disease in later life.
Additional mutations or polymorphisms in other predisposing genes can be expected.
The discovery of disease-causing mutations in genes
for early-onset disease was facilitated by the availability
of living affected (and unaffected) family members in
more than one generation. The more difficult task was
the identification of a gene related to Alzheimer’s disease beginning late in life, for which large multigenerational families with this disease are rare. Pericak-Vance
and colleagues2 identified the chromosomal location of
the first susceptibility locus for late-onset Alzheimer’s
disease on chromosome 19q13.2 by linkage analysis in
a genome scan of affected relatives pooled from a large
number of families. This seminal observation eventually led to the observation that the ~4 polymorphism of
the apolipoprotein E (APOE) gene significantly increases susceptibility to Alzheimer’s d i ~ e a s e Although
.~
association does not prove causation, several aspects of
the APOE ~4 allele suggest that it is an Alzheimer’s
disease susceptibility locus. In Caucasians, there appears
to be a dose effect of the APOE ~4 allele on disease
risk4 and a protective effect of the less frequent ~2 al-
Copyright 0 1998 by the American NeuroIogical Association
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