Charles S.
Yanofsky, M.D.
Jon L. Vickery, M.D
Albert D. Heck, M.D.
Francis J. Janton, III, M.D.
Liana Laza, M.D.
Neurological Occasional Notes (NON)
Genetic Conditions Predisposing to
Stroke:
From time to time I intend to encapsulate useful information for neurologists. Here is my first offering.
Today I saw a 58 year old non-diabetic, non-hypertensive woman, total cholesterol 159, 109 pounds, who still smokes some cigarettes having had multiple stents and bypasses, lower extremity claudication. She has no blood pressure in the left arm, falsely low bp on the right, a thready left radial pulse, a cranial MRI showing white matter abnormalities (“leukoaraiosis”), and loud bruits in her carotids, infra-clavicular areas and both femoral arteries. There’s a very positive family history of heart disease and stroke. These severe atherosclerotic vasculopaths may have no other traditional risk factors and there are a lot of them. They have some predisposition yet to be defined.
Then at the hospital a 39 year old formerly smoking diabetic woman of Native American extraction had a right hemisphere stroke. She was 200 pounds, her family history was riddled with NIDDM, atherosclerotic disease and obesity. That interests me. One theory: descendents recently hunter-gatherer populations possess endocrine systems more suited to situations where food supplies are intermittent and at short supply. Fat persons are predisposed to excessive caloric intake where food is plentiful, make efficient use of calories in catch as catch can situations, binging or feasting. Obesity runs in families. Obese families are adapted to situations where food is in short supply and are actually fitter than slim lineages under adverse conditions. But they don’t do well in our society with endless supplies of food. Americans have so much food, we are picking off stocks in the middling range of metabolism. Obesity, adult onset diabetes are epidemic. So thin folks ought to be aware, far from casting aspersions on their fat brethren, that under different conditions prevailing until very recently, the thin died off.
Enough idle speculation. Stroke is less a disease than an endpoint with a varied pathogenesis. There are myriad genetic predispositions. The very best examples are mild inherited hypercoagulable states, that will end in stroke under certain conditions, if you are have protein S deficiency and use oral contraceptives for instance. This defines just one possible synergy. Oral contraceptives, even smoking are stroke safe for perhaps the vast majority of the population. As far as genetic predispositions for stroke, we have barely scratched the surface. But it is extremely fascinating to anybody who is interested in stroke or any disease. We know that for infectious diseases only a small fraction of exposures will cause infection. You have to have the right combination of circumstances, a synergy, which consists firstoff of a genetic predisposition, then some combination of unfortunate circumstances leading to the expression of disease. Every disease tends to occur in a more susceptible host. It behooves us as physicians, if we are ever going to get to the point of preventing disease, to define these predispositions. Elevated total cholesterol and certain patterns of composition HDL, LDL, triglycerides run in families. Apolipoprotein types are inherited. These will have to be better defined.
The following are some genetic conditions related to stroke. Many have been culled from The Journal of Stroke and Cerebrovascular Diseases Vol 11(5): Aug-Oct 2002, especially p252-264 “Mendelian and Mitochondrial Disorders Associated with Stroke” by Scott Silliman but also from other sources. I felt this would be useful and instructive for neurologists and others.
Key: AD=Autosomal Dominant, X=x-linked recessive, ME=Maternal inheritance as in mitochondrial disorders, AR=autosomal recessive.
I. Genetic Syndromes Causing Stroke:
a. Ischemic
i. Hereditary Cerebroretinal Vasculopathy(HCRV) and Hereditary Endotheliopathy with Retinopathy, Nephropathy and Stroke (HERNS): AD. Retinal capillary telangiectases, perimacular microaneurysms, capillary obliteration, retinal infarctions. “Supertentorial Brain Masses” fibrinoid necrosis vasculopathy spares cortex. 3p21?
ii. Fabry Disease: X. (Xq22): lysosomal α-galactosidase. Painful neuropathy with burning dysesthesia, cardiac arrhyth, renal disease, anhidrosis and fever, corneal deposits, dark cutaneous vascular angioectases. Ischemic>hemorrhagic strokes esp. vertebro-basilar. Intracellular sphingolipid accum.
iii. CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. AD (“notch 3 gene” on Chr. 19): Cerebral ischemia, Abn MRI, headaches, TIA’s, lacunes, vascular dementia, extensive WM vasc disease. Over 400 families. Skin biopsy for osmophilic deposits, blood test.
iv. MELAS Mitochondrial Encephalopathy with Lactic Acidosis and Stroke. ME. Epilepsy, Headache, strokes, hearing loss. Teenage onset.
v. Sickle Cell Disease: AR. Painful crises, anemia, large vessel stroke in young patients.
vi. Factor V Leiden: hypercoagulable. Heterozygotes increase risk of thrombosis 5-8 fold, homozygotes 30-140 fold. Gene present in 5% Caucasian, 1.2% African-American. DVT and PE, Cerebral Sinus Thrombosis, miscarriage, toxemia, Budd-Chiari etc.
vii.
Other: Prothrombin 20210, Protein S, Protein C
deficiencies, Antithrombin III deficiencies. Beware of synergism with othe
i.
Homocysteinuria: AR. Disables cystathionine synthetase.
Rare disease but instructive as far as synergies with smoking and othe
b. Hemorrhagic
i.
Cerebral Amyloid Angiopathy (CAA): ? ApoE, Alzheime
ii. Von-Hippel-Lindau Disease (VHL): Familial Cerebro-retinal angiomatosis. AD- short arm of chr 3 (3p). Classic example of disabling mutation of tumor suppressing gene and “two-hit theory” Manifestations: angiomas-angioblastomas, brain, cord, pheos, islet cell tumors, incr erythropoietin, others.
iii. Osler-Weber-Rendu: Hereditary Hemorrhagic Telangiectasis (HHT): AD. Different genes in endoglin-Transforming Growth Factor β cascade. Cerebral AVM’s, nosebleeds, GI bleeds.
iv. Cavernous Malformations: (CM’s): Heterogeneous Mostly AD. Hispanic families described. CCM and KRIT1 (Krev interaction trapped 1) genes. Neurological, ocular other organ systems.
Charles Yanofsky December 7, 2002