Di Lorenzo Cherubino. Cefalea e vasculopatie genetiche. ASMaD 2011Presentation Transcript
Migraine and genetic vasculopathies.
migraine is associated with vascular disorders, meanly due to endothelial abnormal activation, and dysfunction.
migraine is a main symptom of several genetic vasculopathies: CADASIL, MELAS, RVCL, CRV, and HIHRATL.
The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear.
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.
The most common clinical manifestations are migraine, TIAs or strokes.
Pathophysiology : progressive degeneration of the smooth muscle cells in blood vessels.
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.
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.
The disease progresses to subcortical dementia associated with pseudobulbar palsy and urinary incontinence .
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 ).
Diagnosis: MRIs show multiple confluent white matter lesions , also in asymptomatic carriers
These lesions, similar to those due to Binswanger disease, are concentrated around the basal ganglia , periventricular white matter and pons
By skin biopsy is possible to show the arteriopathy, but the definitive test is sequencing the whole gene .
Treatment: No specific treatments are available
Primary and secondary prevention of stroke are recommend, but anticoagulation and tPA are not indicated for the propensity for microhemorrhages
Some patients assumed folic acid and L-arginine.
M itochondrial e ncephalomyopathy, l actic a cidosis, and s troke-like episodes is a member of the family of mitochondrial cytopathies.
A feature of these diseases is that they are caused by defects in the mitochondrial genome (mtDNA) which is maternally inherited.
The disease can manifest in both sexes.
Presentation : affects mainly nervous system and muscles, but also kidney and hormonal dysfunctions are reported.
Muscle weakness and pain , recurrent headaches , loss of appetite , vomiting , and seizures appear in childhood .
Stroke-like episodes with hemiparesis , vision , cognitive and consciousness alterations , seizures , and severe migraine-like headaches beginning before age 40 .
Repeated stroke-like episodes can progressively damage irreversibly the brain.
Diagnosis/testing: is based on clinical findings and molecular genetic testing.
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.
Mutations can usually be detected in mtDNA, however, the occurrence of "heteroplasmy" can result in varying tissue distribution of mutated mtDNA, making necessary to search in other tissues (muscle).
Treatment : No specific treatment exists.
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.
Coenzyme Q10 and its analog, idebenone, have been beneficial in some individuals, to prevent primary manifestations.
Other genetic vasculopathies
R etinal v asculopathy with c erebral l eukodystrophy (RVCL)
H ereditary i nfantile h emiparessis, r etinal a rteriolar t ortuosity and l eukoencephalopahty (HIHRATL)
C erebro r etinal v asculopathy (CRV)
H ereditary v ascular r etinopathy (HVR )
H ereditary s ystemic a ngiopathy (HSA)
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
Migraine and Stroke (Cause or Case?)
Does shared biological phenomenon (genetically determinate) independently accounts for the comorbidity, or is one clinical feature the consequence of the other?
All the genetic vasculopathies are also leukodystrophic demyelinizating disorders, independently from strokes
Migraine is not present in CARASIL (recessive form of CADASIL) and Binswanger, although symptoms and anatomo- pathologic features were similar
PFO gene mutations were not find in PFO migraineurs, but PFO was found in more members of a large CADASIL families
Almost all mitochondriopathies could be comorbid to migrain, also in lack of vasculopathies