Aurora Semerano, MD
@semerano_aurora
Significant progress has been recently achieved in the field of cerebral small vessel disease (cSVD), and increasing efforts are ongoing to shed light on the underlying pathogenetic mechanisms. Whereas the vast majority of cases are multifactorial, a number of monogenic disorders with cSVD as dominant phenotype have been recognized, demonstrating that different molecular defects can ultimately result in similar brain involvement. A deeper knowledge of monogenic cSVD, and the identification of some unifying pathways, may also help in the comprehension of sporadic cSVD.
Since genes involved in cSVD are frequently expressed more broadly than in the brain, extracerebral manifestations are not surprising. The recent paper presented here by Rannikmäe et al. illustrates the results of a systematic literature review, aimed at summarizing the spectrum of extracerebral phenotypes of individuals with a pathogenic variant in a monogenic cSVD gene. Genes which have been taken into consideration are COL4A1, COL4A2, TREX1, HTRA1, ADA2, and CTSA. Information about extracerebral manifestations, as well as demographics, clinical characteristics, and stroke details, has been collected from any publication in literature reporting at least one patient carrying a pathogenic variant of the above-mentioned genes.
Extracerebral phenotypes were common, ranging from the 14% of individuals with a pathogenic variant in COL4A2 gene to the 100% of patients with CTSA gene involvement, and for 4 of the studied genes an extracerebral phenotype was reported even more frequently than stroke/TIA. Reported extracerebral phenotypes are summarized in this effective infographic, extracted from the paper, which reports the frequency of the manifestations for each gene and highlights the phenotypes which are shared by more than one monogenic cSVD (Figure 4). Interestingly, some of these manifestations, such as Raynaud phenomenon, retinal vasculopathy, and renal involvement, have a presumed vascular origin, suggesting an underlying systemic vasculopathy extending beyond the brain. However, also non-vascular phenotypes (including muscle involvement and hematologic features) were reported. Importantly, the authors also reported on novel potentially associated extracerebral phenotypes. Although the small sample numbers do not allow to establish true disease associations, recording and describing these relationships is important to provide novel insights as we achieve more and more knowledge on monogenic cSVD.
Beyond the pathogenetic insights, this study also has useful clinical implications, since extracerebral phenotypes may represent “flags” for the diagnosis on an individual patient basis (and in family members), assisting in the selection of patients for testing as well as in the selection of genes to be tested. By the way, the high proportion of private variants reported in this review by the authors highlights the importance of Next Generation Sequencing Technologies (NGST) in the clinical setting. These reflexions are even more relevant when considering that treatment options for some of these monogenic cSVD already exist or are in development in these last years.
Whereas the study is rigorous in methodology, the main limitations derive from the poor case characterization of some included reports and the intrinsic biases of case reports and series considered for the systematic literature review. In this regard, this article points out the importance of comprehensiveness and compliance with guidelines when reporting clinical cases in the literature. Moreover, the authors recommend the conduction of large-scale population-based longitudinal studies, for the unbiased collection of information and outcomes.
