Update on the Genetics of Stroke and Cerebrovascular Disease 2004

Stroke. February 2005; Vol. 36, No. 2, 179

Key Words: Advances in Stroke • intracranial aneurysm • subarachnoid hemorrhage

Intracranial aneurysms (IA): A Finnish study of 222 affected relative pairs with IAs found evidence for linkage near locus D19S246. Several promising candidate genes are located around this locus. Another study involving families from Japan and Utah found evidence for linkage at locus D7S2421, which is near the elastin gene. Some previous studies have failed to confirm linkage of IA to elastin. Perhaps this reflects ascertainment issues to indicate genetic heterogeneity of the IA trait. A recent linkage study using a very large family with apparent autosomal dominant IAs identified a locus on chromosome 1p34–36. A recent study investigated the collagen 2 gene in Japanese patients with IAs. A significant association between an exonic single nucleotide polymorphism and familial IA was found. This single nucleotide polymorphism causes an amino acid change from alanine to proline with a change in thermal stability for the collagen triple-helical domain.

Cerebral cavernous malformations (CCMs): Three loci for CCM have been identified: CCM1 (chromosome 7q), CCM2 (7p), and CCM3 (3q). The genes responsible for all 3 types of CCM have now been identified. CCM1 is caused by KRIT1, CCM2 is caused by MGC4607 (also known as malcavernin), and CCM3 is caused by programmed cell death protein 10.

Ischemic Stroke:
CADASIL:Remains the prototypical inherited type of inherited ischemic stroke. The exact pathogenesis of CADASIL remains a mystery, although mutations in Notch3 are known to cause this autosomal dominant disorder. Several studies have suggested that a gain-of-function process is responsible for the disease phenotype, whereas others have suggested an abnormality in a signaling pathway for some patients.

New information about genetic aspects of ischemic stroke has emerged in several areas. The DeCode group published another study showing that a 4-marker single nucleotide polymorphism in the 5-lipoxygenase activating protein was associated with almost a 2-fold increased risk of stroke. As with the discovery of the association between stroke and the phosphodiesterase 4D gene last year, these advances await confirmation by other research groups and validation in animal models of stroke.

Polymorphisms in a host of other genes have been reported to be associated with ischemic stroke, including the low-density lipoprotein receptor, endothelial nitric oxide synthase, tissue plasminogen activator, serum paraoxonase, and glycoprotein IIIa (a platelet membrane receptor for fibrinogen and von Willebrand factor). In many cases, these associations are only for specific subtypes of ischemic stroke, or the polymorphisms are intronic with no known functional significance for gene expression or protein function.

The ongoing POLARIS study will hopefully address some of these concerns with its large number of patients and careful study design. Perhaps one of the most intriguing new studies report an association between a polymorphism in the COX-2 gene and ischemic events. The polymorphism is at position –765 and causes a G-to-C change. This polymorphism had a protective effect, reducing the risk of myocardial infarction and ischemic stroke, and reducing C-reactive protein and MMP2 and MMP 9 expression. These findings may be relevant in light of recent reports of an increased risk of ischemic events caused by some COX-2 inhibitors.

Studies Link Gene Mutation to Parkinson's Disease

Lancet 2005: 365(9455), 15 January 2005

Three teams of scientists have identified a genetic mutation that is linked to about 5 percent of inherited cases of Parkinson's disease.
The fault on the recently discovered LRRK2 gene is one of five genetic defects linked to the progressive nervous system disorder and could lead to improved diagnosis and the development of a genetic test.
"Our results suggest that the mutation we have studied is the most common cause of Parkinson's disease identified to date," said Dr Tatiana Foroud, an associate professor at Indiana University School of Medicine in Indianapolis.
"We found there is a novel mutation which is common in these families," Bonifati said in an interview. "The other groups in the UK and the US found the same mutation independently."
"The main challenge is now to try and understand how this and other Parkinson disease-associated LRRK2 mutations lead to neurodegenerative disease, in order to design novel therapeutic and preventive strategies," he added. (Reuters)

Summary
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause some forms of autosomal dominant Parkinson's disease. We measured the frequency of a novel mutation (Gly2019Ser) in familial Parkinson's disease by screening genomic DNA of patients and controls. Of 767 affected individuals from 358 multiplex families, 35 (5%) individuals were either heterozygous (34) or homozygous (one) for the mutation, and had typical clinical findings of idiopathic Parkinson's disease. Thus, our results suggest that a single LRRK2 mutation causes Parkinson's disease in 5% of individuals with familial disease. Screening for this mutation should be a component of genetic testing for Parkinson's disease.

New tool to detect Alzheimer's early

Doctors have long known that smell is one of the first senses to fail as Alzheimer's begins its slow and incurable progression. Tracking the process whereby a person loses their ability to smell could play a pivotal role in early detection and treatment of Alzheimer's. And now researchers at Columbia have developed a tool that will aid early detection.

The system that governs our sense of smell is centered in the same area of the brain that is first attacked, then damaged, during the original stages of Alzheimer's. But for researchers such as Davangere Devanand, professor of psychiatry and neurology at Columbia University Medical Center, the perplexing issue was, exactly which smells people lose the ability to recognize. Could memory loss be detected soon enough to allow for early treatment, and once isolated, what might findings about smell loss suggest for developing detection and treatment methods for Alzheimer's?

To discover possible connections, Deavand and his team assembled a test group of 150 people, from 43 to 85 years old, and with varied degrees of memory loss. To establish a baseline, this group was initially tested then re-tested every six months in order to measure overall ability to identify 10 separate smells: lemon, leather, clove, lilac, menthol, pineapple, natural gas, soap, strawberry and lavender. The results were compared to a control group of 63 healthy volunteer with no memory impairment. Volunteers were given scented cards and asked to identify a series of smells. The results, gathered over nine years, indicated that volunteers who preformed poorly at identifying the smells over time went on to develop Alzheimer's. None of the non-afflicted subjects developed the disease.

Devanand says, "Early diagnosis of Alzheimer's disease is critical for patients and their families to receive the most beneficial treatment and medications." He added that tests such as these may very soon go a long way toward helping detect Alzheimer's far sooner than is currently possible. He recently presented his findings at a meeting of the American College of Neuropsychopharmacology.

The trial conducted by Devanand and his team also lays important groundwork for future advances. In future, medical investigators will be able to build on the work of Devanand and his researchers to perhaps find a cure for Alzheimer's

HRT Linked to Raised Stroke Risk

BMJ, doi:10.1136/bmj.38331.655347.8F (published online 7 January 2005)

Association between hormone replacement therapy and subsequent stroke: a meta-analysis

Design Systematic review of randomised controlled trials identified from the Cochrane Library, Embase, and Medline; reviews; and reference lists of relevant papers.
Studies reviewed 28 trials, with 39 769 subjects, were identified.
Review measures Rates for cerebrovascular events analysed with a random effects model. Sensitivity analyses for heterogeneity included phase of prevention (primary or secondary), type of hormone replacement therapy (oestrogen alone or combined with progesterone), type of oestrogen (estradiol or conjugated equine oestrogen), size of trial (<5000>5000 patients), length of follow up (3 years or >3 years), sex (women only or men only), and trial quality (high or low).
Results Hormone replacement therapy was associated with significant increases in total stroke (odds ratio 1.29 (95% confidence interval 1.13 to 1.47), n=28), non-fatal stroke (1.23 (1.06 to 1.44), n=21), stroke leading to death or disability (1.56 (1.11 to 2.20), n=14), ischaemic stroke (1.29 (1.06 to 1.56), n=16), and a trend to more fatal stroke (1.28 (0.87 to 1.88), n=22). It was not associated with haemorrhagic stroke (1.07 (0.65 to 1.75), n=17) or transient ischaemic attack (1.02 (0.78 to 1.34), n=22). Statistical heterogeneity was not present in any analysis.
Conclusions Hormone replacement therapy was associated with an increased risk of stroke, particularly of ischaemic type. Among subjects who had a stroke, those taking hormone replacement therapy seemed to have a worse outcome. Hormone replacement therapy cannot be recommended for the primary or secondary prevention of stroke.

Month of Birth Linked to Risk of Multiple Sclerosis

BMJ 2005;330:120 (15 January)

Design Population based study with population and family based controls and a retrospective cohort identified from death certificates. A post hoc pooled analysis was carried out for large northern datasets including Sweden and Denmark.
Setting 19 MS clinics in major cities across Canada (Canadian collaborative project on the genetic susceptibility to multiple sclerosis); incident cases of MS from a population based study in the Lothian and Border regions of Scotland; and death records from the UK Registrar General.
Populations 17 874 Canadian patients and 11 502 British patients with multiple sclerosis.
Results In Canada (n = 17 874) significantly fewer patients with MS were born in November compared with controls from the population census and unaffected siblings. These observations were confirmed in a dataset of British patients (n = 11 502), in which there was also an increase in the number of births in May. A pooled analysis of datasets from Canada, Great Britain, Denmark, and Sweden (n = 42 045) showed that significantly fewer (8.5%) people with MS were born in November and significantly more (9.1%) were born in May. For recent incident data, the effect of month of birth was most evident in Scotland, where MS prevalence is the highest.
Conclusions Month of birth and risk of MS are associated, more so in familial cases, implying interactions between genes and environment that are related to climate. Such interactions may act during gestation or shortly after birth in individuals born in the northern countries studied.

Vitamin E intake and risk of amyotrophic lateral sclerosis

Annals of Neurology, 2005 Volume 57, Issue 1, Pages 104-110

Abstract
Oxidative stress may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). We therefore examined prospectively whether individuals who regularly use supplements of the antioxidant vitamins E and C have a lower risk of ALS than nonusers. The study population comprised 957,740 individuals 30 years of age or older participating in the American Cancer Society's Cancer Prevention Study II. Information on vitamin use was collected at time of recruitment in 1982; participants then were followed up for ALS deaths from 1989 through 1998 via linkage with the National Death Index. During the follow-up, we documented 525 deaths from ALS. Regular use of vitamin E supplements was associated with a lower risk of dying of ALS. The age- and smoking-adjusted relative risk was 0.99 (95% confidence interval [CI], 0.69-1.41) among occasional users, 0.59 (95% CI, 0.36-0.96) in regular users for less than 10 years, and 0.38 (95% CI, 0.16-0.92) in regular users for 10 years or more as compared with nonusers of vitamin E (p for trend = 0.004). In contrast, no significant associations were found for use of vitamin C or multivitamins. These results suggest that vitamin E supplementation could have a role in ALS prevention.

The "Eye of the Tiger" Sign

The "Eye of the Tiger" Sign
Picture from CMAJ • January 4, 2005; 172 (1)

A 13-year-old boy presented to a pediatric clinic with progressive decreased movements. His vision had been decreasing for 8 years, and he had been unable to walk for 3 years.

The patient was born to a healthy nonconsanguineous couple. His mother's pregnancy and his natal history were unremarkable. During infancy his ability to hold his neck and to sit with and without support was delayed. Motor and speech delay were noticed at 2 years, and at 4 years his night vision began to deteriorate, and he had frequent falls with subsequent injuries. An ophthalmologist diagnosed retinitis pigmentosa (RP). At school, his behaviour and academic ability were normal.
At the age of 10, the patient developed spasticity, decreased movements of his lower limbs and dystonic postural abnormalities. The spasticity and dystonia were progressive and disabling enough to restrict him to a wheelchair. His speech deteriorated, and he gradually stopped talking. His parents also observed an intellectual decline. The patient was seen by a number of physicians, none of whom was able to establish a satisfactory diagnosis, until he presented to the pediatric clinic. Funduscopy confirmed the finding of RP, and an MRI showed marked bilateral high-signal intensities surrounding the globus pallidus — the "eye of the tiger" sign that is characteristic of pantothenate kinase-associated neurodegeneration (PKAN) (Fig. 1left; the right image shows an age-matched normal MRI).1

PKAN, formerly known as Hallervorden–Spatz disease, was first described in 1922.2 It is an autosomal recessive neurodegenerative disorder associated with accumulation of iron in the basal ganglia,1 and it has 2 major forms: early onset and late onset.2 Early-onset PKAN is rapidly progressive and characterized by gait impairment, as seen in our patient. Dystonia develops, leading to loss of ambulation and restriction of activities by mid-adolescence. Intellectual impairment, RP and optic atrophy are also associated with the disease.2 Late-onset PKAN presents by 20 years, manifesting a progressive picture of dementia, parkinsonism, dystonia, anarthria, aphonia and incontinence.2 The pathognomonic "eye of the tiger" sign is seen in both forms of the disease. No prevalence studies have yet been done on this disease or its different forms.
PKAN has been mapped to chromosome 20p12.3-p13.3 Mutations in PANK2, the gene encoding the enzyme pantothenate kinase 2, have been demonstrated in the majority of patients with PKAN.1,3 The presence of mutation in PANK2 leads to a genetic diagnosis and makes presymptomatic testing of family members possible, but an MRI can still be considered the "gold standard" in diagnosing early-onset PKAN.1

The differential diagnosis for progressive dystonia in children includes idiopathic generalized dystonia, dopa-responsive dystonia, myoclonic dystonia, metachromatic leukodystrophy, Niemann–Pick disease type C and Lesch–Nyhan syndrome.4
There is no specific treatment. Some patients show residual activity of the enzyme, but the benefit of pantothenate supplementation in ameliorating symptoms has not yet been proven. However, levodopa, anticholinergics and intrathecal baclofen have been shown to improve the patient's quality of life.2

References
1. Hayflick SJ, Westaway SK, Barbara L, Zhou B, Johnson M, Ching K, et al. Genetic, clinical, and radiographic delineation of Hallervorden–Spatz syndrome. N Engl J Med 2003;348:33-40[Abstract/Free Full Text]
2. Neil Gordon. Pantothenate kinase-associated neurodegeneration (Hallervorden–Spatz syndrome). Eur J Pediatr Neurol 2002;6:243-7.[CrossRef][Medline]
3. Zhou B, Westaway SK, Levinson B, Johnson M, Gitshier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden–Spatz syndrome. Nat Genet 2001;28: 345-9.[CrossRef][Medline]
4. Assmann B, Surtees R, Hoffmann GF. Approach to the diagnosis of neurotransmitter diseases exemplified by the differential diagnosis of childhood-onset dystonia. Ann Neurol 2003;54(Suppl 6):S18-24.

1st Unvaccinated Rabies Survivor

1st Rabies Survivor (AP picture)
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