Di Lorenzo Cherubino. Cefalea e vasculopatie genetiche. ASMaD 2011


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Di Lorenzo Cherubino. Cefalea e vasculopatie genetiche. ASMaD 2011

  1. 2. Migraine and genetic vasculopathies. <ul><li>migraine is associated with vascular disorders, meanly due to endothelial abnormal activation, and dysfunction. </li></ul><ul><li>migraine is a main symptom of several genetic vasculopathies: CADASIL, MELAS, RVCL, CRV, and HIHRATL. </li></ul><ul><li>The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. </li></ul>
  2. 3. CADASIL <ul><li>C erebral a utosomal d ominant a rteriopathy with s ubcortical i nfarcts and l eukoencephalopathy is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3; it is part of the family of the Leukodistrophies. </li></ul><ul><li>The most common clinical manifestations are migraine, TIAs or strokes. </li></ul>
  3. 4. <ul><li>Pathophysiology : progressive degeneration of the smooth muscle cells in blood vessels. </li></ul><ul><li>Mutations in the Notch 3 gene (on the short arm of chromosome 19, in the same locus of FHM) cause an abnormal accumulation of Notch 3 at the cytoplasmic membrane of vascular smooth-muscle cells both in cerebral and extracerebral vessels. </li></ul>CADASIL
  4. 5. <ul><li>Clinical features: CADASIL may start with attacks of migraine with aura or subcortical transient ischemic attacks or strokes , or mood disorders between 35 to 55 years of age. </li></ul><ul><li>The disease progresses to subcortical dementia associated with pseudobulbar palsy and urinary incontinence . </li></ul>CADASIL
  5. 7. Axial FLAIR ( A – C ) and T2*-weighted gradient ( D ) MR images of CADASIL patients. Complete MR imaging spectrum of CADASIL: confluent hyperintensities ( A – C ), lacunar infarcts ( A, arrow ), subcortical lacunar lesions ( B, arrow ), and microbleeds ( D, arrow ).
  6. 8. <ul><li>Diagnosis: MRIs show multiple confluent white matter lesions , also in asymptomatic carriers </li></ul><ul><li>These lesions, similar to those due to Binswanger disease, are concentrated around the basal ganglia , periventricular white matter and pons </li></ul><ul><li>By skin biopsy is possible to show the arteriopathy, but the definitive test is sequencing the whole gene . </li></ul>CADASIL
  7. 9. <ul><li>Treatment: No specific treatments are available </li></ul><ul><li>Primary and secondary prevention of stroke are recommend, but anticoagulation and tPA are not indicated for the propensity for microhemorrhages </li></ul><ul><li>Some patients assumed folic acid and L-arginine. </li></ul>CADASIL
  8. 10. MELAS
  9. 11. <ul><li>M itochondrial e ncephalomyopathy, l actic a cidosis, and s troke-like episodes is a member of the family of mitochondrial cytopathies. </li></ul><ul><li>A feature of these diseases is that they are caused by defects in the mitochondrial genome (mtDNA) which is maternally inherited. </li></ul><ul><li>The disease can manifest in both sexes. </li></ul>MELAS
  10. 12. <ul><li>Presentation : affects mainly nervous system and muscles, but also kidney and hormonal dysfunctions are reported. </li></ul><ul><li>Muscle weakness and pain , recurrent headaches , loss of appetite , vomiting , and seizures appear in childhood . </li></ul><ul><li>Stroke-like episodes with hemiparesis , vision , cognitive and consciousness alterations , seizures , and severe migraine-like headaches beginning before age 40 . </li></ul><ul><li>Repeated stroke-like episodes can progressively damage irreversibly the brain. </li></ul>MELAS
  11. 13. <ul><li>Diagnosis/testing: is based on clinical findings and molecular genetic testing. </li></ul><ul><li>Mutations in the mtDNA are causative. About 80% of individuals with typical clinical findings, presents an A-to-G transition at nucleotide 3243 (m.3243A>G) of gene MT-TL1, but also other genes, could account for MELAS. </li></ul><ul><li>Mutations can usually be detected in mtDNA, however, the occurrence of &quot;heteroplasmy&quot; can result in varying tissue distribution of mutated mtDNA, making necessary to search in other tissues (muscle). </li></ul>MELAS
  12. 15. <ul><li>Treatment : No specific treatment exists. </li></ul><ul><li>AED are adopted for seizures (no valproate), insulin, or hypoglycemic agents for diabetes, L-arginine for stroke-like episode, and cochlear implantation for sensorineural hearing loss. </li></ul><ul><li>Coenzyme Q10 and its analog, idebenone, have been beneficial in some individuals, to prevent primary manifestations. </li></ul>MELAS
  13. 16. Other genetic vasculopathies <ul><li>R etinal v asculopathy with c erebral l eukodystrophy (RVCL) </li></ul><ul><li>H ereditary i nfantile h emiparessis, r etinal a rteriolar t ortuosity and l eukoencephalopahty (HIHRATL) </li></ul><ul><li>C erebro r etinal v asculopathy (CRV) </li></ul><ul><li>H ereditary v ascular r etinopathy (HVR ) </li></ul><ul><li>H ereditary s ystemic a ngiopathy (HSA) </li></ul><ul><li>COL4A1-related disorder </li></ul>
  14. 17. MTHFR and Migraine with Aura Vit B12 Vit B12 NADPH NADP + MTHFR methylenetetrahydrofolate reductase DHF dihydrofolate THF tetrahydrofolate 5,10-methylene-THF 5,10-methylenetetrahydrofolate 5-methyl-THF 5-methyltetrahydrofolate MTR methionine synthase SAH S-adenosylhomocysteine NADPH reduced form of Nicotinamide adenine dinucleotide phosphate NADP+ oxidized form of Nicotinamide adenine dinucleotide phosphate SAM S-Adenosyl methionine
  15. 19. Migraine and Stroke (Cause or Case?) <ul><li>Does shared biological phenomenon (genetically determinate) independently accounts for the comorbidity, or is one clinical feature the consequence of the other? </li></ul><ul><li>All the genetic vasculopathies are also leukodystrophic demyelinizating disorders, independently from strokes </li></ul><ul><li>Migraine is not present in CARASIL (recessive form of CADASIL) and Binswanger, although symptoms and anatomo- pathologic features were similar </li></ul><ul><li>PFO gene mutations were not find in PFO migraineurs, but PFO was found in more members of a large CADASIL families </li></ul><ul><li>Almost all mitochondriopathies could be comorbid to migrain, also in lack of vasculopathies </li></ul>