Rare Neurovascular Diseases in Korea: Classification and Related Genetic Variants

Abstract

Rare neurovascular diseases (RNVDs) have not been well-recognized in Korea. They involve the central nervous system and greatly affect the patients' lives. However, these diseases are difficult to diagnose and treat due to their rarity and incurability. We established a list of RNVDs by referring to the previous literature and databases worldwide to better understand the diseases and their current management status. We categorized 68 RNVDs based on their pathophysiology and clinical manifestations and estimated the prevalence of each disease in Korea. Recent advances in genetic, molecular, and developmental research have enabled further understanding of these RNVDs. Herein, we review each disease, while considering its classification based on updated pathologic mechanisms, and discuss the management status of RNVD in Korea.

Keywords: Classification; Diagnosis; Genetics; Neurovascular; Rare diseases.

Fig. 1. Schematic representation of rare neurovascular diseases from the rare disease databases worldwide.

CADASIL = cerebral autosomal dominant arteriopathy with subcortical ischemic strokes and leukoencephalopathy, CARASAL = cathepsin A–related arteriopathy with strokes and leukoencephalopathy, CARASIL = cerebral autosomal recessive arteriopathy with subcortical ischemic strokes and leukoencephalopathy, CLOVES = congenital lipomatous overgrowth, vascular malformations, epidermal nevis, spinal/skeletal anomalies/scoliosis, MELAS = mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, NORD = national organization for rare disorders, OMIM = online mendelian inheritance in man, PHACE = posterior fossa malformations, large facial hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities syndrome

Fig. 2. Registered rare neurovascular diseases in Korea (from the Health Insurance Review and Assessment database).

CADASIL = cerebral autosomal dominant arteriopathy with subcortical ischemic strokes and leukoencephalopathy, CARASIL = cerebral autosomal recessive arteriopathy with subcortical ischemic strokes and leukoencephalopathy, MELAS = mitochondrial encephalopathy with lactic acidosis and stroke-like episodes

Fig. 3. Main signaling pathways involved in rare neurovascular diseases.

ALK = Activin-Like Kinase Receptor, BMP = bone morphogenetic protein, BMPR = BMP receptor, CM-AVM = capillary malformation-arteriovenous malformation, CLOVES = congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi and spinal/skeletal anomalies and/or scoliosis, MARK = mitogen-activated protein kinases, PDGFR = platelet-derived growth factor receptor, PI3K = phosphoinositide 3-kinase, RASA1 = Ras p21 protein activator 1, TGF-β = transforming growth factor beta, VEGFR = vascular endothelial growth factor receptors

Fig. 4. Imaging evaluation of the family with hereditary hemorrhagic telangiectasia.

A. A pedigree chart for the family. Clinical manifestation and genetic variation status are marked. Positive sign (+) indicates the presence of the ENG c.808C>T hetero variant; negative sign (−) indicates its absence; An arrow in the pedigree chart indicates a proband. B. Two pial arteriovenous fistulas were visualized on the right vertebral arteriography in the proband. C. Arterial spin labeling perfusion imaging represents arteriovenous shunting (arrow) as red color in the right parieto-occipital lesion. D. Four-dimensional MRA showed early filing of the nidus (long arrow) and draining veins (short arrows) on arterial phase in the proband's sister. E. A fusion image of three-dimensional rotational angiography in both internal carotid arteries demonstrated multiple arteriovenous malformations (short arrows) and fistula (long arrow). F, G. A pulmonary arteriovenous fistula (arrows) was demonstrated on the chest CT (F) and confirmed on the pulmonary arteriography (G) in the proband's father. The pedigree (A) is adapted from Kim et al. Neurointervention 2019;14:91–98 [25]. AVF = arteriovenous fistula, AVM = arteriovenous malformation, DM = diabetes mellitus, ICH = intracranial hemorrhage

Fig. 5. A patient diagnosed with Klippel-Trénaunay syndrome by advanced MR imaging and genetic test (PIK3CA positive).

A. Four-dimensional MR angiography showed arteriovenous shunt in the skull base draining to the frontal diploic veins and superior sagittal sinus. B. Arterial spin labeling imaging demonstrated shunted blood within the sphenoid body and the left greater wing (arrows). C–F. In digital subtraction angiography (C) and susceptibility-weighted imaging (D), cortical venous reflux (black arrow) and consequent hemosiderin deposition (white arrow) were observed in the right frontal lobe. Extensive skull base involvement of the vascular lesion (asterisks) is well visualized on the enhanced time-of-flight images (E) and three-dimensional rotational angiography (F). G. Whole body MRI with T2-weighted short-tau inversion recovery imaging showed asymmetric soft tissue hypertrophy of the left lower extremity. Multiple subcutaneous high signal intensity lesions in both legs suggest varicose veins and venous malformations.