Beyond the Brain

Abstract

Background and Purpose: An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature. Methods: We performed a systematic review following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), searching Medline/Embase for publications describing individuals with pathogenic variants in COL4A1/2 , TREX1 , HTRA1 , ADA2, and CTSA genes (PROSPERO 74804). We included any publication reporting on ≥1 individual with a pathogenic variant and their clinically relevant phenotype. We extracted individuals’ characteristics and information about associated extracerebral phenotypes and stroke/transient ischemic attack. We noted any novel extracerebral phenotypes and looked for shared phenotypes between monogenic cSVDs. Results: After screening 6048 publications, we included 96 COL4A1 (350 individuals), 32 TREX1 (115 individuals), 43 HTRA1 (38 homozygous/61 heterozygous individuals), 16 COL4A2 (37 individuals), 119 ADA2 (209 individuals), and 3 CTSA (14 individuals) publications. The majority of individuals originated from Europe/North America, except for HTRA1 , where most were from Asia. Age varied widely, ADA2 individuals being youngest and heterozygous HTRA1/CTSA individuals oldest. Sex distribution appeared equal. Extracerebral phenotypes were common: 14% to 100% of individuals with a pathogenic variant manifested at least one extracerebral phenotype (14% COL4A2 , 43% HTRA1 heterozygotes, 47% COL4A1 , 57% TREX1 , 91% ADA2 , 94% HTRA1 homozygotes, and 100% CTSA individuals). Indeed, for 4 of 7 genes, an extracerebral phenotype was observed more frequently than stroke/transient ischemic attack. Ocular, renal, hepatic, muscle, and hematologic systems were each involved in more than one monogenic cSVD. Conclusions: Extracerebral phenotypes are common in monogenic cSVD with extracerebral system involvement shared between genes. However, inherent biases in the existing literature mean that further data from large-scale population-based longitudinal studies collecting health outcomes in a systematic unbiased way is warranted. The emerging knowledge will help to select patients for testing, inform clinical management, and provide further insights into the underlying mechanisms of cSVD.

A novel COL4A1 variant associated with recurrent epistaxis and glioblastoma

“…Mutated COL4A1 disrupts the basic structure of cerebral small vessels via a dominant-negative effect or haploinsufficiency, which results in autosomal-dominant cerebral small-vessel disease 1 , 2 . Approximately 60% of patients with COL4A1 -related disorders present with diffuse white matter lesions, 50% with microbleeds, and 10–30% with hemorrhagic stroke 3 , 4 . The high incidence of intracerebral hemorrhage illustrates the clinical differences from other hereditary cerebral small-vessel diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS) 3 .…”

“…To date, more than 350 patients and 70 pathogenic and likely pathogenic variants have been reported 5 . The phenotypic spectrum of COL4A1 -related disorders has been expanding, and accumulating data have shown that extracerebral hemorrhages may also occur 4 . Moreover, the coexistence of neural tumors has been observed 6 .…”

“…Broad phenotypes have been linked to COL4A1 -related disorders, ranging from catastrophic hemorrhage in the uterus to adult-onset hemorrhagic/ischemic stroke, epilepsy, and even clinically asymptomatic patients 4 , 5 . A wide intrafamilial variation in clinical symptoms has also been confirmed 11 .…”

“…Cerebral hemorrhage is an important feature in COL4A1 -related disorders. Perinatal cerebral hemorrhage may lead to porencephaly 1 , 14 , which has been observed in approximately 20% of patients 4 . Of note, the index patient presented with unilateral cerebellar hypoplasia and a cleft, which were attributable to perinatal cerebellar hemorrhage 15 , in addition to a porencephalic enlargement of the left ventricle.…”

“…Published data have indicated that hemorrhage may be observed in extracerebral organs. To date, six patients with retinal hemorrhages have been reported 4 . Moreover, a 30-week-old fetus was affected by hemorrhages in the thymus, liver, and adrenal glands 16 , and a 9-year-old boy developed diffuse pulmonary hemorrhage 17 .…”