Single-Gene Stroke Disorders

ABSTRACT

Monogenic causes of stroke are rare but should not be missed by the neurologist. The purpose of this review is to aid the reader in the evaluation of a patient with cryptogenic stroke with or without a family history suspicious for an inherited condition. The clinical findings, diagnosis, and management of monogenic causes of stroke and stroke look-alikes are discussed, including cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry's disease, vascular Ehlers-Danlos, Marfan syndrome, sickle cell disease, the thrombophilias, hereditary hemorrhagic telangiectasia, cerebral cavernous malformations, hereditary cerebral hemorrhage with amyloidosis, and mitochondrial encephalopathy, lactic acidosis, and strokelike episodes. A quick review of systems designed to screen for genetic stroke causes is presented. By correlating stroke subtype with phenotype, this review will familiarize the clinician with indications for focused genetic testing in appropriate patients.

Single gene - monogenic - stroke - cerebral infarction - cerebral hemorrhage

REFERENCES

• 1 Jerrard-Dunne P, Cloud G, Hassan A, Markus H S. Evaluating the genetic component of ischemic stroke subtypes: a family history study.  Stroke. 2003;  34 1364-1369
• 2 Joutel A, Corpechot C, Ducros A et al.. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.  Nature. 1996;  383 707-710
• 3 Joutel A, Vahedi K, Corpechot C et al.. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.  Lancet. 1997;  350 1511-1515
• 4 Kalimo H, Ruchoux M M, Viitanen M, Kalaria R N. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia.  Brain Pathol. 2002;  12 371-384
• 5 Desmond D W, Moroney J T, Lynch T, Chan S, Chin S S, Mohr J P. The natural history of CADASIL: a pooled analysis of previously published cases.  Stroke. 1999;  30 1230-1233
• 6 Chabriat H, Vahedi K, Iba-Zizen M T et al.. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.  Lancet. 1995;  346 934-939
• 7 Dichgans M, Mayer M, Uttner I et al.. The phenotypic spectrum of CADASIL: clinical findings in 102 cases.  Ann Neurol. 1998;  44 731-739
• 8 Markus H S, Martin R J, Simpson M A et al.. Diagnostic strategies in CADASIL.  Neurology. 2002;  59 1134-1138
• 9 Kalaria R N, Viitanen M, Kalimo H, Dichgans M, Tabira T. The pathogenesis of CADASIL: an update.  J Neurol Sci. 2004;  226 35-39
• 10 Joutel A, Dodick D D, Parisi J E, Cecillon M, Tournier-Lasserve E, Bousser M G. De novo mutation in the Notch3 gene causing CADASIL.  Ann Neurol. 2000;  47 388-391
• 11 Singhal S, Bevan S, Barrick T, Rich P, Markus H S. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype.  Brain. 2004;  127 2031-2038
• 12 Oberstein S A, Ferrari M D, Bakker E et al.. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group.  Neurology. 1999;  52 1913-1915
• 13 Ebke M, Dichgans M, Bergmann M et al.. CADASIL: skin biopsy allows diagnosis in early stages.  Acta Neurol Scand. 1997;  95 351-357
• 14 Mayer M, Straube A, Bruening R et al.. Muscle and skin biopsies are a sensitive diagnostic tool in the diagnosis of CADASIL.  J Neurol. 1999;  246 526-532
• 15 Joutel A, Favrole P, Labauge P et al.. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.  Lancet. 2001;  358 2049-2051
• 16 Lesnik Oberstein S A, van Duinen S G, van den Boom R et al.. Evaluation of diagnostic NOTCH3 immunostaining in CADASIL.  Acta Neuropathol (Berl). 2003;  106 107-111
• 17 Chabriat H, Levy C, Taillia H et al.. Patterns of MRI lesions in CADASIL.  Neurology. 1998;  51 452-457
• 18 O'Sullivan M, Jarosz J M, Martin R J, Deasy N, Powell J F, Markus H S. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL.  Neurology. 2001;  56 628-634
• 19 Coulthard A, Blank S C, Bushby K, Kalaria R N, Burn D J. Distribution of cranial MRI abnormalities in patients with symptomatic and subclinical CADASIL.  Br J Radiol. 2000;  73 256-265
• 20 Lesnik Oberstein S A, van den Boom R, van Buchem M A et al.. Cerebral microbleeds in CADASIL.  Neurology. 2001;  57 1066-1070
• 21 Dichgans M, Holtmannspotter M, Herzog J, Peters N, Bergmann M, Yousry T A. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study.  Stroke. 2002;  33 67-71
• 22 Yanagawa S, Ito N, Arima K, Ikeda S. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.  Neurology. 2002;  58 817-820
• 23 Ophoff R A, DeYoung J, Service S K et al.. Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3  Am J Hum Genet. 2001;  69 447-453
• 24 Mascarenhas R, Santo G, Goncalo M, Ferro M A, Tellechea O, Figueiredo A. Familial Sneddon's syndrome.  Eur J Dermatol. 2003;  13 283-287
• 25 Szmyrka-Kaczmarek M, Daikeler T, Benz D, Koetter I. Familial inflammatory Sneddon's syndrome-case report and review of the literature.  Clin Rheumatol. 2005;  24 79-82
• 26 Ayoub N, Esposito G, Barete S, Soria C, Piette J C, Frances C. Protein Z deficiency in antiphospholipid-negative Sneddon's syndrome.  Stroke. 2004;  35 1329-1332
• 27 Frances C, Papo T, Wechsler B, Laporte J L, Biousse V, Piette J C. Sneddon syndrome with or without antiphospholipid antibodies. A comparative study in 46 patients.  Medicine (Baltimore). 1999;  78 209-219
• 28 Petty G W. Stroke: Pathophysiology, Diagnosis and Management. third ed. New York; Churchill Livingstone 1998
• 29 Aquino Gondim Fde A, Leacock R O, Subrammanian T A, Cruz-Flores S. Intracerebral hemorrhage associated with Sneddon's syndrome: is ischemia-related angiogenesis the cause? Case report and review of the literature.  Neuroradiology. 2003;  45 368-372
• 30 Boesch S M, Plorer A L, Auer A J et al.. The natural course of Sneddon syndrome: clinical and magnetic resonance imaging findings in a prospective six year observation study.  J Neurol Neurosurg Psychiatry. 2003;  74 542-544
• 31 Namjou B. Antiphospholipid syndrome: genetic review.  Curr Rheumatol Rep. 2003;  5 391-394
• 32 Khamashta M A, Cuadrado M J, Mujic F, Taub N A, Hunt B J, Hughes G R. The management of thrombosis in the antiphospholipid-antibody syndrome.  N Engl J Med. 1995;  332 993-997
• 33 Ashley-Koch A, Yang Q, Olney R S. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review.  Am J Epidemiol. 2000;  151 839-845
• 34 Adams R J, McKie V C, Hsu L et al.. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography.  N Engl J Med. 1998;  339 5-11
• 35 Rothman S M, Fulling K H, Nelson J S. Sickle cell anemia and central nervous system infarction: a neuropathological study.  Ann Neurol. 1986;  20 684-690
• 36 Russell M O, Goldberg H I, Hodson A et al.. Effect of transfusion therapy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease.  Blood. 1984;  63 162-169
• 37 Dobson S R, Holden K R, Nietert P J et al.. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events.  Blood. 2002;  99 3144-3150
• 38 Adams R, McKie V, Nichols F et al.. The use of transcranial ultrasonography to predict stroke in sickle cell disease.  N Engl J Med. 1992;  326 605-610
• 39 Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup R J. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK).  Am J Med Genet. 1998;  77 31-37
• 40 Cikrit D F, Miles J H, Silver D. Spontaneous arterial perforation: the Ehlers-Danlos specter.  J Vasc Surg. 1987;  5 248-255
• 41 Germain D P. Clinical and genetic features of vascular Ehlers-Danlos syndrome.  Ann Vasc Surg. 2002;  16 391-397
• 42 Pepin M, Schwarze U, Superti-Furga A, Byers P H. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.  N Engl J Med. 2000;  342 673-680
• 43 North K N, Whiteman D A, Pepin M G, Byers P H. Cerebrovascular complications in Ehlers-Danlos syndrome type IV.  Ann Neurol. 1995;  38 960-964
• 44 Schievink W I, Michels V V, Piepgras D G. Neurovascular manifestations of heritable connective tissue disorders. A review.  Stroke. 1994;  25 889-903
• 45 Schievink W I. Cerebrovascular involvement in Ehlers-Danlos syndrome.  Curr Treat Options Cardiovasc Med. 2004;  6 231-236
• 46 Scriver CRBA, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York; McGraw-Hill 2001
• 47 van den Berg J S, Limburg M, Hennekam R C. Is Marfan syndrome associated with symptomatic intracranial aneurysms?.  Stroke. 1996;  27 10-12
• 48 Spittell P C, Spittell Jr J A, Joyce J W et al.. Clinical features and differential diagnosis of aortic dissection: experience with 236 cases (1980 through 1990).  Mayo Clin Proc. 1993;  68 642-651
• 49 Schievink W I, Parisi J E, Piepgras D G, Michels V V. Intracranial aneurysms in Marfan's syndrome: an autopsy study.  Neurosurgery. 1997;  41 866-870 discussion 871
• 50 Conway J E, Hutchins G M, Tamargo R J. Marfan syndrome is not associated with intracranial aneurysms.  Stroke. 1999;  30 1632-1636
• 51 van Soest S, Swart J, Tijmes N, Sandkuijl L A, Rommers J, Bergen A A. A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1  Genome Res. 1997;  7 830-834
• 52 van den Berg J S, Hennekam R C, Cruysberg J R et al.. Prevalence of symptomatic intracranial aneurysm and ischaemic stroke in pseudoxanthoma elasticum.  Cerebrovasc Dis. 2000;  10 315-319
• 53 Creange A, Zeller J, Rostaing-Rigattieri S et al.. Neurological complications of neurofibromatosis type 1 in adulthood.  Brain. 1999;  122 473-481
• 54 Conway J E, Hutchins G M, Tamargo R J. Lack of evidence for an association between neurofibromatosis type I and intracranial aneurysms: autopsy study and review of the literature.  Stroke. 2001;  32 2481-2485
• 55 Graf S, Schischma A, Eberhardt K E, Istel R, Stiasny B, Schulze B D. Intracranial aneurysms and dolichoectasia in autosomal dominant polycystic kidney disease.  Nephrol Dial Transplant. 2002;  17 819-823
• 56 ter Berg H W, Dippel D W, Limburg M, Schievink W I, van Gijn J. Familial intracranial aneurysms. A review.  Stroke. 1992;  23 1024-1030
• 57 Ryu S J. Intracranial hemorrhage in patients with polycystic kidney disease.  Stroke. 1990;  21 291-294
• 58 Schievink W I, Torres V E, Wiebers D O, Huston III J. Intracranial arterial dolichoectasia in autosomal dominant polycystic kidney disease.  J Am Soc Nephrol. 1997;  8 1298-1303
• 59 Yamauchi T, Tada M, Houkin K et al.. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25.  Stroke. 2000;  31 930-935
• 60 Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T. Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26.  Am J Hum Genet. 1999;  64 533-537
• 61 Edwards A, Bermudez C, Piwonka G et al.. Carney's syndrome: complex myxomas. Report of four cases and review of the literature.  Cardiovasc Surg. 2002;  10 264-275
• 62 Casey M, Vaughan C J, He J et al.. Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex.  J Clin Invest. 2000;  106 R31-R38
• 63 Stratakis C A, Kirschner L S, Carney J A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.  J Clin Endocrinol Metab. 2001;  86 4041-4046
• 64 Bayrak-Toydemir P, Mao R, Lewin S, McDonald J. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians.  Genet Med. 2004;  6 175-191
• 65 AAssar O S, Friedman C M, White Jr R I. The natural history of epistaxis in hereditary hemorrhagic telangiectasia.  Laryngoscope. 1991;  101 977-980
• 66 Dajani A S, Taubert K A, Wilson W et al.. Prevention of bacterial endocarditis. Recommendations by the American Heart Association.  Circulation. 1997;  96 358-366
• 67 Maher C O, Piepgras D G, Brown Jr R D, Friedman J A, Pollock B E. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia.  Stroke. 2001;  32 877-882
• 68 Moussouttas M, Fayad P, Rosenblatt M et al.. Pulmonary arteriovenous malformations: cerebral ischemia and neurologic manifestations.  Neurology. 2000;  55 959-964
• 69 Nanthakumar K, Graham A T, Robinson T I et al.. Contrast echocardiography for detection of pulmonary arteriovenous malformations.  Am Heart J. 2001;  141 243-246
• 70 Pugash R A. Pulmonary arteriovenous malformations: overview and transcatheter embolotherapy.  Can Assoc Radiol J. 2001;  52 92-102
• 71 Yap S, Naughten E. Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control.  J Inherit Metab Dis. 1998;  21 738-747
• 72 Mudd S H, Skovby F, Levy H L et al.. The natural history of homocystinuria due to cystathionine beta-synthase deficiency.  Am J Hum Genet. 1985;  37 1-31
• 73 Kraus J P, Williamson C L, Firgaira F A et al.. Cloning and screening with nanogram amounts of immunopurified mRNAs: cDNA cloning and chromosomal mapping of cystathionine beta-synthase and the beta subunit of propionyl-CoA carboxylase.  Proc Natl Acad Sci USA. 1986;  83 2047-2051
• 74 Munke M, Kraus J P, Ohura T, Francke U. The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17.  Am J Hum Genet. 1988;  42 550-559
• 75 Kelly P J, Furie K L, Kistler J P et al.. Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency.  Neurology. 2003;  60 275-279
• 76 Fowler B. Disorders of homocysteine metabolism.  J Inherit Metab Dis. 1997;  20 270-285
• 77 Wilcken D E, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment.  J Inherit Metab Dis. 1997;  20 295-300
• 78 Yap S. Classical homocystinuria: vascular risk and its prevention.  J Inherit Metab Dis. 2003;  26 259-265
• 79 Yaghmai R, Kashani A H, Geraghty M T et al.. Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency.  Am J Med Genet. 2002;  108 57-63
• 80 Desnick R J, Brady R, Barranger J et al.. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy.  Ann Intern Med. 2003;  138 338-346
• 81 DeGraba T, Azhar S, Dignat-George F et al.. Profile of endothelial and leukocyte activation in Fabry patients.  Ann Neurol. 2000;  47 229-233
• 82 Brady R O, Schiffmann R. Clinical features of and recent advances in therapy for Fabry disease.  JAMA. 2000;  284 2771-2775
• 83 Giacomini P S, Shannon P T, Clarke J T, Jaigobin C. Fabry's disease presenting as stroke in a young female.  Can J Neurol Sci. 2004;  31 112-114
• 84 Grewal R P. Stroke in Fabry's disease.  J Neurol. 1994;  241 153-156
• 85 Eng C M, Guffon N, Wilcox W R et al.. Safety and efficacy of recombinant human alpha-galactosidase A-replacement therapy in Fabry's disease.  N Engl J Med. 2001;  345 9-16
• 86 Schiffmann R, Kopp J B, Austin III H A et al.. Enzyme replacement therapy in Fabry disease: a randomized controlled trial.  JAMA. 2001;  285 2743-2749
• 87 Mitsias P, Levine S R. Cerebrovascular complications of Fabry's disease.  Ann Neurol. 1996;  40 8-17
• 88 Moore D F, Altarescu G, Barker W C, Patronas N J, Herscovitch P, Schiffmann R. White matter lesions in Fabry disease occur in “prior” selectively hypometabolic and hyperperfused brain regions.  Brain Res Bull. 2003;  62 231-240
• 89 Hilz M J, Kolodny E H, Brys M, Stemper B, Haendl T, Marthol H. Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease.  J Neurol. 2004;  251 564-570
• 90 Crutchfield K E, Patronas N J, Dambrosia J M et al.. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease.  Neurology. 1998;  50 1746-1749
• 91 Moore D F, Herscovitch P, Schiffmann R. Selective arterial distribution of cerebral hyperperfusion in Fabry disease.  J Neuroimaging. 2001;  11 303-307
• 92 Moore D F, Ye F, Schiffmann R, Butman J A. Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry disease.  AJNR Am J Neuroradiol. 2003;  24 1096-1101
• 93 Kolodny E H, Pastores G M. Anderson-Fabry disease: extrarenal, neurologic manifestations.  J Am Soc Nephrol. 2002;  13(suppl 2) S150-S153
• 94 Rodgers G. Wintrobe's Clinical Hematology. Vol. 2. 10th ed. Baltimore; Williams and Wilkins 1999
• 95 Hankey G J, Eikelboom J W, van Bockxmeer F M, Lofthouse E, Staples N, Baker R I. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes.  Stroke. 2001;  32 1793-1799
• 96 Kim R J, Becker R C. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies.  Am Heart J. 2003;  146 948-957
• 97 Karttunen V, Hiltunen L, Rasi V, Vahtera E, Hillbom M. Factor V Leiden and prothrombin gene mutation may predispose to paradoxical embolism in subjects with patent foramen ovale.  Blood Coagul Fibrinolysis. 2003;  14 261-268
• 98 Aznar J, Mira Y, Vaya A et al.. Factor V Leiden and prothrombin G20210A mutations in young adults with cryptogenic ischemic stroke.  Thromb Haemost. 2004;  91 1031-1034
• 99 Salobir B, Sabovic M, Peternel P, Stegnar M, Grad A. Classic risk factors, hypercoagulability and migraine in young women with cerebral lacunar infarctions.  Acta Neurol Scand. 2002;  105 189-195
• 100 Vasse M, Guegan-Massardier E, Borg J Y, Woimant F, Soria C. Frequency of protein Z deficiency in patients with ischaemic stroke.  Lancet. 2001;  357 933-934
• 101 Pezzini A, Del Zotto E, Archetti S et al.. Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.  Stroke. 2002;  33 664-669
• 102 Azuma H, Uno Y, Shigekiyo T, Saito S. Congenital plasminogen deficiency caused by a Ser572 to Pro mutation.  Blood. 1993;  82 475-480
• 103 Santamaria A, Mateo J, Tirado I et al.. Homozygosity of the T allele of the 46 C-> T polymorphism in the F12 gene is a risk factor for ischemic stroke in the Spanish population.  Stroke. 2004;  35 1795-1799
• 104 Hsieh K, Funk M, Schillinger M et al.. Vienna Stroke Registry. Impact of the platelet glycoprotein Ib alpha Kozak polymorphism on the risk of ischemic cerebrovascular events: a case-control study.  Blood Coagul Fibrinolysis. 2004;  15 469-473
• 105 Voetsch B, Loscalzo J. Genetic determinants of arterial thrombosis.  Arterioscler Thromb Vasc Biol. 2004;  24 216-229
• 106 Austin H, Chimowitz M I, Hill H A et al.. Cryptogenic stroke in relation to genetic variation in clotting factors and other genetic polymorphisms among young men and women.  Stroke. 2002;  33 2762-2768
• 107 Alberts M J. Stroke genetics update.  Stroke. 2003;  34 342-344
• 108 Sykes T C, Fegan C, Mosquera D. Thrombophilia, polymorphisms, and vascular disease.  Mol Pathol. 2000;  53 300-306
• 109 Revesz T, Holton J L, Lashley T et al.. Sporadic and familial cerebral amyloid angiopathies.  Brain Pathol. 2002;  12 343-357
• 110 Miller J H, Wardlaw J M, Lammie G A. Intracerebral haemorrhage and cerebral amyloid angiopathy: CT features with pathological correlation.  Clin Radiol. 1999;  54 422-429
• 111 Greenberg S M. Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment.  Neurology. 1998;  51 690-694
• 112 Greenberg S M, O'Donnell H C, Schaefer P W, Kraft E. MRI detection of new hemorrhages: potential marker of progression in cerebral amyloid angiopathy.  Neurology. 1999;  53 1135-1138
• 113 Greenberg S M, Eng J A, Ning M, Smith E E, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage.  Stroke. 2004;  35 1415-1420
• 114 Bornebroek M, Haan J, Roos R A. Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D): a review of the variety in phenotypic expression.  Amyloid. 1999;  6 215-224
• 115 Fernandez-Madrid I, Levy E, Marder K, Frangione B. Codon 618 variant of Alzheimer amyloid gene associated with inherited cerebral hemorrhage.  Ann Neurol. 1991;  30 730-733
• 116 Levy E, Carman M D, Fernandez-Madrid I J et al.. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.  Science. 1990;  248 1124-1126
• 117 Levy E, Lopez-Otin C, Ghiso J, Geltner D, Frangione B. Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases.  J Exp Med. 1989;  169 1771-1778
• 118 Graffagnino C, Herbstreith M H, Schmechel D E, Levy E, Roses A D, Alberts M J. Cystatin C mutation in an elderly man with sporadic amyloid angiopathy and intracerebral hemorrhage.  Stroke. 1995;  26 2190-2193
• 119 Haan J, Roos R A. Comparison between the Icelandic and Dutch forms of hereditary cerebral amyloid angiopathy.  Clin Neurol Neurosurg. 1992;  94(suppl) S82-S83
• 120 Olafsson I, Grubb A. Hereditary cystatin C amyloid angiopathy.  Amyloid. 2000;  7 70-79
• 121 Passero S, Burgalassi L, D'Andrea P, Battistini N. Recurrence of bleeding in patients with primary intracerebral hemorrhage.  Stroke. 1995;  26 1189-1192
• 122 Clatterbuck R E, Eberhart C G, Crain B J, Rigamonti D. Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations.  J Neurol Neurosurg Psychiatry. 2001;  71 188-192
• 123 Wong J H, Awad I A, Kim J H. Ultrastructural pathological features of cerebrovascular malformations: a preliminary report.  Neurosurgery. 2000;  46 1454-1459
• 124 Labauge P, Brunereau L, Laberge S, Houtteville J P. Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations.  Neurology. 2001;  57 1825-1828
• 125 Zabramski J M, Wascher T M, Spetzler R F et al.. The natural history of familial cavernous malformations: results of an ongoing study.  J Neurosurg. 1994;  80 422-432
• 126 Rigamonti D, Hadley M N, Drayer B P et al.. Cerebral cavernous malformations. Incidence and familial occurrence.  N Engl J Med. 1988;  319 343-347
• 127 Brunereau L, Labauge P, Tournier-Lasserve E, Laberge S, Levy C, Houtteville J P. Familial form of intracranial cavernous angioma: MR imaging findings in 51 families. French Society of Neurosurgery.  Radiology. 2000;  214 209-216
• 128 Gunel M, Awad I A, Anson J, Lifton R P. Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21.  Proc Natl Acad Sci USA. 1995;  92 6620-6624
• 129 Notelet L, Chapon F, Khoury S et al.. Familial cavernous malformations in a large French kindred: mapping of the gene to the CCM1 locus on chromosome 7q.  J Neurol Neurosurg Psychiatry. 1997;  63 40-45
• 130 Polymeropoulos M H, Hurko O, Hsu F et al.. Linkage of the locus for cerebral cavernous hemangiomas to human chromosome 7q in four families of Mexican-American descent.  Neurology. 1997;  48 752-757
• 131 Craig H D, Gunel M, Cepeda O et al.. Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27.  Hum Mol Genet. 1998;  7 1851-1858
• 132 Labauge P, Laberge S, Brunereau L, Levy C, Tournier-Lasserve E. Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Societe Francaise de Neurochirurgie.  Lancet. 1998;  352 1892-1897
• 133 Ghiso J, Frangione B. Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia.  J Alzheimers Dis. 2001;  3 65-73
• 134 Nicoll J A, Burnett C, Love S et al.. High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy.  Ann Neurol. 1997;  41 716-721
• 135 O'Donnell H C, Rosand J, Knudsen K A et al.. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage.  N Engl J Med. 2000;  342 240-245
• 136 Pavlakis S G, Phillips P C, DiMauro S, De Vivo D C, Rowland L P. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome.  Ann Neurol. 1984;  16 481-488
• 137 Deschauer M, Muller T, Wieser T, Schulte-Mattler W, Kornhuber M, Zierz S. Hearing impairment is common in various phenotypes of the mitochondrial DNA A3243G mutation.  Arch Neurol. 2001;  58 1885-1888
• 138 Majamaa K, Moilanen J S, Uimonen S et al.. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population.  Am J Hum Genet. 1998;  63 447-454
• 139 Ohshita T, Oka M, Imon Y et al.. Serial diffusion-weighted imaging in MELAS.  Neuroradiology. 2000;  42 651-656
• 140 Sue C M, Crimmins D S, Soo Y S et al.. Neuroradiological features of six kindreds with MELAS tRNA(Leu) A2343G point mutation: implications for pathogenesis.  J Neurol Neurosurg Psychiatry. 1998;  65 233-240
• 141 Hirano M, Pavlakis S G. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts.  J Child Neurol. 1994;  9 4-13
• 142 Pronicki M, Sykut-Cegielska J, Mierzewska H et al.. Diversity of clinical symptoms in A3243G mitochondrial DNA mutation (MELAS syndrome mutation).  Med Sci Monit. 2002;  8 CR767-CR773
• 143 Klopstock T, Jaksch M, Gasser T. Age and cause of death in mitochondrial diseases.  Neurology. 1999;  53 855-857
• 144 Mori M, Yamagata T, Goto T, Saito S, Momoi M Y. Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS.  Brain Dev. 2004;  26 453-458
• 145 Saitoh S, Momoi M Y, Yamagata T, Mori Y, Imai M. Effects of dichloroacetate in three patients with MELAS.  Neurology. 1998;  50 531-534
• 146 Spruijt L, Naviaux R K, McGowan K A et al.. Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate.  Muscle Nerve. 2001;  24 916-924
• 147 Berbel-Garcia A, Barbera-Farre J R, Etessam J P et al.. Coenzyme Q 10 improves lactic acidosis, strokelike episodes, and epilepsy in a patient with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes).  Clin Neuropharmacol. 2004;  27 187-191
• 148 Kubota M, Sakakihara Y, Mori M, Yamagata T, Momoi-Yoshida M. Beneficial effect of L-arginine for stroke-like episode in MELAS.  Brain Dev. 2004;  26 481-483 discussion 480