Case studies
Case 2: Familial ICH
Rare mutations in a number of genes are known to cause ICH. Mutations in KRIT1 and malcavernin, the proteins encoded by the genes at the CCM1 and CCM2 loci, respectively, are responsible for the majority of familial cerebral cavernous malfor- mations in which macroscopic malformed vessels develop and can cause ICH [52]. Familial disorders of the cerebral small vessels such as cerebral amyloid angiopathy (CAA) (Case 2), CADASIL, and COL4A1-related cerebrovascular disease share many manifestations in common with the common sporadic small-vessel pathologies that lead to spontaneous ICH.
Table 13.1 Single-gene disorders associated with stroke in young patients with family history
Disease Genetic basis Clinical spectrum Diagnostic tools
CADASIL NOTCH3 (AD) Small vessel and territorial strokes, depression, migraine headaches with aura, cognitive decline
MRI, skin biopsy (for granular osmophilic inclusions), mutation screen (NOTCH3)
MELAS Multiple mitochondrial
(maternal inheritance)
Mitochondrial myopathy, encephalopathy, lactic acidosis, strokes; developmental delay, sensorineural hearing loss, seizures
MRI and MR spectroscopy, muscle biopsy, CSF for lactate-to-pyruvate ratio; mutation screen of mtDNA Fabry’s disease GAL (X-linked) Cataracts, small fi ber neuropathy, stroke,
angiokeratomas, renal and cardiac failure
Alpha-galactosidase activity, mutation screen
Sickle-cell disease HBB (AR) Vaso-occlusive crisis, stroke, anemia, infection, pain crisis, seizure disorder
Complete blood count and smear, protein electrophoresis, mutation screen Homocystinuria CBS (AR) Premature atherosclerosis, lens
dislocation, Marfan-like features, stroke, mental retardation
Plasma and urine levels of homocysteine and methionine, mutation screen Marfan syndrome FBN1 (AD) Skeletal and soft tissue abnormalities,
cardioembolic stroke, aortic/cervical vessel dissection, ectopic lens
Morphometric and mutation screen
Ehlers–Danlos type IV syndrome
COL3A1 (AD) Excessive soft tissue fl exibility, spontaneous arterial dissection/rupture
Clinical and mutation screen
AD, autosomal dominant; AR, autosomal recessive; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy;
CSF, cerebrospinal fl uid; MR, magnetic resonance.
although the abnormal protein deposited in the cerebral small vessels will differ. Recently described mutations in COL4A1 have been found to underlie ICH-associated autosomal dominant familial ICH (Figure 13.2) with a pathology that differs from CAA [53,54], whereas CADASIL itself can also rarely cause ICH. Although there are differences among the various familial ICH syndromes that can allow the identifi cation of some general distinctions (Table 13.2), the overlap is suffi ciently broad to require genetic testing or histopathological tissue examination to confi rm any suspected diagnosis [55].
Diagnostic approach
In patients with familial ICH, a thorough pedigree evaluation must be undertaken including history of ICH/hemorrhagic stroke and cognitive changes/
dementia as well as considerations of other available phenotypic data (MRI characteristics including severity of leukoaraiosis, evidence of microhemor- rhages and chronic and/or subclinical macrohemor- rhages, and stroke), serial neuropsychological testing, and if available, results of neuropathological testing (biopsy vs. autopsy). Disease-specifi c genetic testing is recommended based on phenotypic considerations.
Role of genetic variation in disease risk, course, and biology
All APP mutations associated with CAA cluster within the Aβ-coding region of the gene (exons 16 and 17) [55]. In addition to point mutations within these exons, duplication of the locus on chromo- some 21 that contains APP has also been identifi ed in families with familial early-onset Alzheimer’s disease (AD) and CAA [56]. A striking observation is that clinical presentations can vary dramatically among different kindreds with the same mutation, suggesting that there are additional genetic factors that modify the strong effect of these mutations [57]. Multiple rare mutations have also been identi- fi ed in COL4A1-related cerebrovascular disease, as in the case of APP-related CAA and NOTCH3 in CADASIL.
COL4A1 and COL4A2, the most abundant uni- versal type IV collagens of basement membrane (BM), contribute to microscopic BM changes consistent with structural disruption in mice har- Case 2
A 47-year-old engineer presented with an 18- month history of progressive unsteadiness and a 6-month history of slurred speech. His family history was signifi cant for Alzheimer dementia in his paternal grandfather and cognitive changes in his 51-year-old brother who subsequently died of intracerebral hemorrhage (ICH). The patient complained of vertigo, headache, and inability to concentrate at work. On examination, he was found to have gait ataxia, a cerebellar type of dysarthria, gaze-evoked nystagmus on horizontal versions gaze, and impaired (saccadic) pursuit eye movements but no signs of upper-motor neuron signs. He had no evidence of hypertension or generalized vascular disease, and his
neuropsychological testing revealed a mild degree of intellectual deterioration with weak verbal memory for his age. A CT scan showed extensive white-matter hypodensities with white-matter ischemic change. Spinal fl uid was normal. Six months later, he was readmitted for new intermittent diplopia, choking, and overall deterioration in the mentioned problems. MRI few years later showed marked white-matter ischemic change and some evidence of cortical atrophy. By age 52, he was wheelchair-bound due to marked cerebellar signs, increased tone in all extremities, blurred vision, and profound memory impairment. In the last year of his life, he was incontinent of urine, unable to speak, and totally dependent. At the age of 54, he died suddenly of a massive cerebral hemorrhage.
Differential diagnosis
CAA-related ICH may occur both as spontaneous ICH in the elderly or a rare familial syndrome in which manifestations generally develop earlier in life as a result of mutations within the gene for
the β-amyloid precursor protein (APP) and accu-
mulation of β-amyloid peptide (Aβ) within the vessels. In addition to APP, mutations in other genes (cystatin C, BRI, transthyretin) can cause familial ICH with autosomal dominant transmission identi- cal to what is seen in APP-related familial ICH,
(a)
(b) (c) (d)
(e)
Fig. 13.2 COL4A1 mutation in a family with retinal arteriolar tortuosity, white-matter abnormalities, and cerebral hemorrhage. (Reprinted with permission from Gould D, et al. NEJM. 2006;354:1489–1496. Copyright © 2006 Massachusetts Medical Society. All rights reserved.) Panel (a) shows the pedigree of a French family with small-vessel disease. All affected members of the family (solid symbols) had retinal vascular tortuosity and leukoencephalopathy. The genotype (normal [G/G] or mutant [G/A]) is indicated for each family member. Patients II-2 and II-3 died of cerebral hemorrhage after anticlotting therapy at 40 years of age and head trauma at 33 years of age, respectively. The square symbols represent males, the circles females, and the symbols with a slash a deceased person. Panel (b), a red-free photograph of the right eye of patient III-2 (at 20 years of age), shows marked tortuosity of the medium and small arterioles, particularly in the macula. No changes were apparent in the veins or capillaries, and no microaneurysms were observed. Cerebral magnetic resonance imaging (MRI) in patient II-1 (at 40 years of age) revealed diffuse periventricular white-matter abnormalities on fl uid-attenuated inversion recovery (panel (c), bright signal) and silent microbleeding in the deep cerebellum on gradient echo-weighted imaging (panel (d), arrow). No MRI or retinal abnormalities were detected in the absence of a mutant genotype. As shown in panel (e), genomic-sequence analysis of COL4A1 revealed a G1769A transition in exon 25, leading to a change from glycine to glutamic acid at position 562 (G562E) in affected family members; this change was not observed in the chromosomes of unaffected family members or in 196 population-matched control chromosomes. The asterisk indicates heterozygosity for the mutant nucleotide.
boring COL4A1 mutations [53,58,59]. The majority of the COL4A1 protein forms a triple helical domain, consisting of Gly-X-Y residue repeats, which is essential for its association with other proteins in the formation of extracellular BMs. All of the mutations identifi ed thus far in humans are either missense mutations involving one of the Gly residues or result in the deletion of an exon within the triple helical domain [54]. Mutations in COL4A1 have been linked to a spectrum of cerebrovascular disease in humans, consistent with a fundamental role for COL4A1 in the strength of basement membranes.
These include perinatal ICH with consequent porencephaly, adult-onset ICH, microhemorrhages, lacunar strokes, and leukoaraiosis (Table 13.2) [58,60–63].
Genetic counseling and prognosis
Once again, professional genetic counseling is advis- able prior to obtaining any genetic testing. Although discouraging neurological outcomes is the general rule for Mendelian ICH syndromes, relative unpre- dictability of each individual presentation (varying degrees of age of onset, development of cognitive decline, for example) is likely related to environ- mental and genetic modifi ers. The apparent role of COL4A1 in cerebral vessels’ tolerance of minor head trauma in humans raises the possibility that the rec-
ognition of COL4A1 familial syndromes may offer immediate benefi t to affected individuals. Pregnant mothers with carriers of a culprit COL4A1 mutation might benefi t from surgical delivery, while affected individuals may benefi t from advice against contact sports and other activities that carry high risk of minor head injury.
Case 3: Young patient with stroke and