Genetic Vasculopathies Research Articles

Whole-exome sequencing for the identification of genetic vasculopathies among a cohort of primary CNS vasculitis

Whole-exome sequencing for the identification of genetic vasculopathies among a cohort of primary CNS vasculitis

Smooth Muscle Cell – Extracellular Matrix Alterations in Genetic Vasculopathies

Pathogenic variants in 11 genes predispose individuals to aneurysms and dissections of the thoracic aorta and in some cases, vascular complications throughout the arterial tree, termed heritable thoracic aortic disease (HTAD) (Renard M et al. JACC, 2018;72:605–615). These genes are involved in vascular smooth muscle cell (SMC) contraction and metabolism, extracellular matrix (ECM) integrity and transforming growth factor β (TGF β) signaling. A unifying hypothesis is that the mutated gene products contribute to altered mechano‐transduction leading to vasculopathy (Humphrey JD et al. Circ Res 2015;116:1448–1461; Pinard A, Jones GT, Milewicz DM. Circ Res 2019;124:588–606). The objective of this study was to employ light (LM) and electron (EM) microscopy to evaluate the thoracic aortic and other arterial tissue from individuals harboring pathogenic variants in the 11 established predisposition genes who underwent surgical aneurysm or dissection repair. These individuals (n) harbored pathogenic variants in the following genes: FBN1 (13), ACTA2 (6), TGFBR1 (7), TGFBR2 (3), TGFβ2 (3), SMAD3 (3), LOX (1), MYLK (1), PRKG1 (1), and COL3A1 (4); total 42. Arterial specimens were evaluated using LM consensus criteria (Halushka MK et al. Cardiovasc Pathol 2016;25:247–257). EM was performed on selected cases (Davis EC. Lab Invest 1993;68:89–99). By LM, specimens were graded (0 – 3+) for mucoid extracellular matrix accumulation (MEMA), elastic fiber fragmentation and/or loss (EFFL), SMC nuclear loss/laminar medial collapse (SMCNL/LMC), and overall medial degeneration (A 1–2, B 3–4, C 5–6, D 7–9); intimal lesions (0–3+) and medial dissection (+/−) also were noted. The 42 specimens included 17 with medial dissection and 25 non‐dissected aneurysms. By LM, cases showed a spectrum of extent and severity of medial degenerative changes: A mild 8 cases, B moderate 18 cases, C moderately severe 14 cases, and D severe 2 cases. By EM, COL3A1 specimens showed reduction of collagen fibrils and shape variations of residual collagen fibrils; elastin fiber connections to SMCs were intact. In contrast, specimens with mutations in the TGF β pathway exhibited multiple foci with deficiency of elastic fibers and loss of elastic fiber connections to SMC but had normal collagen ultrastructure. These results support the hypothesis that the pathogenesis of genetic vasculopathies involves structural defects in the interaction of ECM components and SMCs, including impairment of the elastin‐contractile unit directly or through loss of structural support provided by collagen.Support or Funding InformationLocal funds

Incomplete Circle of Willis and Migraine: Role for Shear‐Induced Platelet Aggregation?

Incomplete Circle of Willis and Migraine: Role for Shear‐Induced Platelet Aggregation?

Migraine and Neurogenetic Disorders

In the current classification of headache disorders, headache attributable to genetic disorders is not classified separately, rather as headache attributed to cranial or cervical vascular disorder. The classification thus implies that a vascular pathology causes headache in these genetic disorders. Unquestionably, migraine is one of the prominent presenting features of several genetic cerebral small vessel diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty. Shared genetic features, increased susceptibility, and/or vascular endothelial dysfunction may play a role in pathogenesis of migraine. Common or overlapping pathways involving the responsible genes may provide insight regarding the pathophysiological mechanisms that can explain their comorbidity with migraine. This review focuses on clinical features of genetic vasculopathies. An independent category-migraine related to genetic disorders-should be considered to classify these disorders.

EVER‐Acta lecture: Telomere maintenance and retinal vascularisation

AbstractAbnormal development of the retinal vasculature is an important cause of vision loss in infancy, childhood and, occasionally, in adult life. In addition to retinopathy of prematurity from exposure to oxygen after preterm birth, several genetic defects affecting retinal vascularization have recently been discovered, affecting either Wnt signaling or telomere maintenance. The canonical norrin–beta‐catenin pathway of Wnt signaling is deranged by mutations in frizzeld‐4 (FZD4), low density lipoprotein receptor‐related protein 5 (LRP5), norrin (NDP) and other genes. These lead to vascular leakage, vitreoretinal traction or both in Coats’ disease, familial exudative vitreoretinopathy (FEVR), Norrie’s disease and osteoporosis‐pseudoglioma syndrome. Mutations in telomeric repeat‐binding factor 1‐interacting nuclear factor 2 (TINF2) and CTS telomere maintenance complex component 1 (CTC1) in Revesz syndrome and cerebroretinal microangiopathy with calcifications and cysts (CRMCC) can even cause retinal angiomas. Wnt signaling initially was the suspect for them as well, because all six diseases share more or less widespread retinal avascularity as a hallmark. Indeed, a link between the two pathways is still possible. The manifestations of the telomere‐related syndromes are more protean than those of Wnt‐related ones, which have no other significant systemic findings than osteoporosis if LRP5 is mutated. The former may lead to a cerebral and intestinal vasculopathy or hepatopathy, all of which can be fatal, and to skin and hair abnormalities. Milder forms can escape diagnosis until adulthood. It is useful to recognize these genetic vasculopathies. Genes for cases which still go unexplained remain to be discovered.

Migraine and small vessel diseases

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies affecting small cerebral vessels, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy and hereditary infantile hemiparesis, retinal arteriolar tortuosity and leucoencephalopathy. Moreover, several studies have reported an association between migraine and white matter lesions or clinically silent infarct-like abnormalities in the posterior circulation. In this review, we focus on genetic vasculopathies associated with migraine and speculate about the pathophysiological mechanism that can explain this comorbidity.

Mendelian and complex causes of migraine: Bridging the gap

Migraine, and particularly migraine with aura (MA), has a strong genetic component. The best evidence for this are the significantly increased familial risk of migraine, the significantly higher concordance rate of migraine in monozygotic than in dizygotic twin pairs (1,2) and the three identified genes, CACNA1A, ATP1A2 and SCNA1, that can cause familial hemiplegic migraine (FHM), a rare monogenic subtype of migraine associated with hemiparesis during aura (3). Migraine is also a prominent part of the phenotype of several mendelian diseases, including Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and other genetic vasculopathies (4). CADASIL is a monogenic form of small-vessel disease of the brain, characterized by recurrent ischemic stroke in 60–85% of patients and cognitive decline in nearly all patients after the age of 50 years. MA is the third cardinal manifestation of the disease, present in up to 40% of patients and often the first clinical manifestation, presenting some 10 years ahead of the other symptoms (5). CADASIL is caused by dominant mutations in the NOTCH3 gene, which encodes a transmembrane receptor primarily expressed in the vasculature and important for the structural and functional integrity of small arteries (6). NOTCH3 has 33 exons but all CADASIL mutations occur in the exons 2–24 encoding the 34 epidermal growth factor–like repeats, with strong clustering in exons 3 and 4, and, lead to an odd number of cysteine residues causing the NOTCH3 protein to abnormally accumulate in the vessel. The dominant view is that the primary determinant of the CADASIL disease involves novel pathogenic roles for mutant Notch3 receptor rather than compromised NOTCH3 function (5). Genetically modified mice that recapitulate the pre-symptomatic stage of the CADASIL disease have been recently obtained. Of interest, recent work showed that transgenic mice expressing a Notch3 protein with an archetypal CADASIL mutation (Arg90Cys) in smooth muscle cells have a lower threshold for evoking cortical spreading depression (CSD) than wild-type mice, consistent with a MA phenotype (7). Menon et al. (8) analyzed the NOTCH3 gene for its involvement with common migraine. They conducted an association study, which tests for significant differences in allele frequencies between case and controls, with two common polymorphisms located in exons 3 and 4 of NOTCH3, in a community-based setting. They elegantly demonstrate that rs1043994 (684A>G), located in exon 4 of the gene, is associated with an increased risk of developing MA. As is now a requirement for publication of genetic association studies, in order to distinguish true findings from spurious associations, Menon et al. have used a pre-planned replication sample to confirm or refute findings in the discovery cohort. While the association with rs1043994 was replicated, the second polymorphism (rs3815188, [381C>T], in exon 3) that was associated with migraine in the discovery cohort could not be confirmed in the second sample. Interestingly, rs1043994 increased the risk of MA but not of migraine without aura (MO), similarly to the CADASIL mutation in NOTCH3 (5). This is in line with heritability studies suggesting that MA and MO may have at least partly distinct genetic backgrounds (3). Of note, however, both the discovery and the replication cohort had a limited sample size, with 260 cases or less, and the power to detect an association with both polymorphisms, which have a minor allele frequency between 8% and 12%, was relatively low. Indeed, as for other complex genetic diseases, the odds ratio (OR) of developing migraine associated with

Migraine and Genetic and Acquired Vasculopathies

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty (HIHRATL). The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. Common genetic susceptibility, increased susceptibility to cortical spreading depression (CSD) and vascular endothelial dysfunction are among the possible explanations. The relation between migraine and acquired vasculopathies such as ischaemic stroke and coronary heart disease has long been established, further supporting a role of the (cerebral) blood vessels in migraine. This review focuses on genetic and acquired vasculopathies associated with migraine. We speculate how genetic and acquired vascular mechanisms might be involved in migraine.

Multiple coagulation defects and the Cohen syndrome

A 13-year-old male presented with new onset seizures, sagittal sinus thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs. Laboratory investigation demonstrated combined deficiency of protein C, protein S, and antithrombin III. He and his 17-year-old sister had a mental retardation-multiple anomaly syndrome associated with microcephaly, unusual facies, and lax connective tissue. Their dysmorphology included elongated faces with narrow forehead, arched eyebrows, large mouth with down-turned corners, malformed teeth, and furrowed tongue. Both had Marfanoid habitus with lax joints, pectus excavatum, kyphoscoliosis, and flat narrow feet. The most likely diagnosis for these siblings is the autosomal recessive Cohen syndrome of mental retardation, congenital hypotonia with Marfanoid habitus, microcephaly, pleasant affect, micrognathia, and open mouth with prominent incisors. The sagittal sinus thrombosis, left frontal intracranial hemorrhage, carotid aneurysm, tortuous descending aorta, and deep venous thrombosis suffered by the male sibling adds the Cohen syndrome to genetic vasculopathies that may be associated with stroke.