EDITORIAL 1229 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.036202 on 16 August 2004. Downloaded from Stroke genes its sensitivity vary from 50% to over ....................................................................................... 90%.17 The identification of magnetic reso- nance imaging (MRI) features, highly Genes for stroke suggestive of CADASIL, has greatly increased recognition of the disease.19 20 H Markus Confluent involvement of the anterior temporal pole (fig 1) is rare in sporadic ................................................................................... cerebral small vessel disease, but is Identifying the genes involved in multifactorial stroke present in over 90% of patients with CADASIL.17 19 20 Involvement of the external capsule is also common but alf the risk of ischaemic stroke of prevalence are difficult because of less specific. In contrast to sporadic remains unexplained by conven- significant under reporting, but a mini- small vessel disease,17 corpus callosum Htional risk factors1 and genetic mum prevalence of 1 in 100 000 has involvement may occur.21 This can lead predisposition has been widely specu- been estimated in south east England to misdiagnosis as multiple sclerosis. lated to account for some of this (unpublished data). However, despite The combination of improved MRI unexplained risk.2 Although significant its relative frequency, recent studies diagnosis and wider availability of progress has been made unravelling the have shown that CADASIL accounts genetic testing has led to both increased basis of single gene stroke disorders, for only a minority of patients with diagnosis of CADASIL and the apprecia- identifying the underlying genes for small vessel disease stroke on a popula- tion that the phenotype is much more common or multifactorial stroke, for tion basis.11 diverse than originally described. Cases which there is no obvious Mendelian Mutations in the notch 3 gene are presenting with stroke in the eighth or pattern of inheritance, has proved diffi- associated with a systemic arteriopathy even ninth decade have been reported. cult. Has this situation changed with the with particularly severe involvement of The phenotype may vary markedly recent publication of the first indepen- the cerebral small vessels.12 A combina- within families, and no consistent gen- dent risk gene for common stroke?3 tion of small lacunar infarcts affecting otype–phenotype correlations have been the white matter and deep grey matter identified.14 ARE GENETIC FACTORS nuclei and more diffuse chronic ischae- mic changes, seen on imaging as leuko- IMPORTANT IN STROKE RISK? IDENTIFYING GENES FOR What is the evidence that genetic risk araiosis, occur. Clinical manifestations MULTIFACTORIAL STROKE factors are important in stroke risk? are confined to the central nervous Identifying the genetic predisposition to Twin studies suggest a modest genetic system; the most frequent are recurrent copyright. multifactorial stroke has proved a component, more important in younger lacunar strokes most commonly occur- harder task. It is usually assumed that individuals.45Many studies have deter- ring in the fourth or fifth decade, such influences are polygenic although mined whether a family history of migraine usually accompanied by aura, the number of responsible genes is stroke is more common in stroke cases which frequently begins in the third or unknown. Such genes could act by compared with normal controls.26Most fourth decade, and a subcortical demen- predisposing to conventional risk fac- report an association, which is stronger tia in the sixth and seventh decade.13 14 tors, by modulating the effect of con- both in younger individuals and with Depression is frequent and may precede ventional risk factors, or as independent certain stroke subtypes, particularly the onset of strokes. Less common risk factors for stroke. Almost all studies small vessel disease (lacunar) and large features include an acute reversible of polygenic stroke to date have vessel atherosclerotic stroke.78 Animal encephalopathy15 and epilepsy. All employed a candidate gene methodol- studies have implicated the existence of mutations reported to date result in ogy. The frequencies of polymorphisms independent stroke genes. The sponta- the gain or loss of a cysteine residue http://jnnp.bmj.com/ (DNA sequence variants) in already neously hypertensive stroke prone rat forming part of paired disulphide bonds identified genes are compared between suffers both early onset stroke and in epidermal growth like factor repeats stroke cases and controls. A large larger infarcts in response to experi- in the extracellular portion of the number of candidate genes have been mental middle cerebral artery occlusion. transmembrane notch 3 protein.16 This studied, but until recently no robust Chromosomal loci have been identified results in an epidermal growth like replicable associations had been for both of these traits, although the factor repeat with an unpaired cysteine 2 910 reported. This is common in the genet- responsible genes remain elusive. By residue, but whether this results in ics of many other complex diseases. It is on September 30, 2021 by guest. Protected crossing this animal with the sponta- disease through a loss of function, or possible that genetic influences are so neously hypertensive rat, it has been through deposition or toxicity of the small that they cannot be detected, but demonstrated that these influences act notch 3 extracellular domain, is uncer- many previous studies have had serious independently of hypertension. tain. Their stereotyped nature allows methodological limitations. Sample their easy identification. Genetic screen- sizes have been small with most well ing is now available in many labora- SINGLE GENE DISORDERS, below those recently estimated as neces- tories worldwide. Mutations may occur STROKE, AND CADASIL sary to detect even moderate genetic risk in any one of the exons 2 to 23 encoding A large number of single gene disorders factors for stroke.822 Multiple hypo- the extracellular portion of the protein can cause stroke (table 1) but most of thesis testing and publication bias are 2 but tend to cluster at the N-terminal these are extremely rare. It is now both likely to have contributed to end, allowing 90% to be detected by the apparent that CADASIL (cerebral auto- spurious associations. These biases can somal dominant arteriopathy with limited screening offered by most subcortical infarcts and leucoencephalo- laboratories.16 17 Skin biopsy may also pathy) is the most common single gene be useful for diagnosis; electron micro- Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts disorder leading to ischaemic stroke, scopy shows typical granular osmiophi- and leucoencephalopathy; IMT, intima media and is much more frequent than was lic inclusions adjacent to smooth muscle thickness; MRI, magnetic imaging resonance; previously appreciated. True estimates cells of small arteries, but estimates of PDE, phosphodiesterase www.jnnp.com 1230 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.036202 on 16 August 2004. Downloaded from Table 1 Monogenic causes of ischaemic stroke Disorders Gene/chromosomal location reponsible Small vessel disease CADASIL notch 3 gene CARASIL Unknown Cerebroretinal vasculopathy and HERNS 3p21.1–21.3 Large artery disease Dyslipidaemias Various Moyamoya disease 3p24.2–26 and 17q25 Pseudoxanthoma elasticum ABCC6 gene Neurofibromatosis type I NFI gene Disorders affecting both small and large arteries Fabry disease a-galactosidase A gene Homocystinuria cystathione b synthase gene MTHFR Sickle cell disease Haemoglobin S and SC Cardioembolic Cardiomyopathies: primary/secondary Various Familial dysrythmias Various Prothrombotic disorders Protein C, S Protein S and C genes Antithrombin III deficiency Antithrombin III gene Familial anticardiolipin syndrome Unknown Activated protein C resistance Factor V Leiden mutation Arterial dissection Ehlers-Danlos syndrome type IV collagen type III gene Fibromuscular dysplasia Unknown Marfan syndrome fibrillin-1 gene Mitochondrial disorders MELAS Mitochondrial DNA mutations Disorders are listed according to postulated disease mechanisms and examples of each disease mechanism are given. Single gene disorders causing conventional risk factors for stroke, such as hypertension, will also result in stroke but are not included. Details of specific diseases are available in reviews.218 CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leucoencephalopathy; HERNS, hereditary endotheliopathy with retinopathy, nephropathy, and stroke; MELAS; mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes; MTHFR, copyright. methylene tetrahydrofolate reductase. be limited by replication of positive made it is vital that future studies take associations in a second independent these considerations into account. population, but this has been rarely Identifying large numbers of younger performed in stroke studies. patients with specific subtypes is likely An important consideration, ignored to require collaborative national, and in many studies, is the heterogeneity of even multinational, efforts. stroke. Stroke describes a syndrome of different pathophysiological processes THE USE OF INTERMEDIATE Figure 1 T2 weighted MRI scans