Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease

Abstract

Background Cerebral small‐vessel disease (cSVD) is an important cause of stroke and vascular dementia. Most cases are multifactorial, but an emerging minority have a monogenic cause. While NOTCH3 is the best‐known gene, several others have been reported. We aimed to summarize the cerebral phenotypes associated with these more recent cSVD genes. Methods and Results We performed a systematic review (PROSPERO [International Prospective Register of Systematic Reviews]: CRD42020196720), searching Medline/Embase (conception to July 2020) for any language publications describing COL4A1/2 , TREX1 , HTRA1 , ADA2 , or CTSA pathogenic variant carriers. We extracted data about individuals’ characteristics and clinical and vascular radiological cerebral phenotypes. We summarized phenotype frequencies per gene, comparing patterns across genes. We screened 6485 publications including 402, and extracted data on 390 individuals with COL4A1 , 123 with TREX1 , 44 with HTRA1 homozygous, 41 with COL4A2 , 346 with ADA2 , 82 with HTRA1 heterozygous, and 14 with CTSA . Mean age ranged from 15 ( ADA2 ) to 59 years ( HTRA1 heterozygotes). Clinical phenotype frequencies varied widely: stroke, 9% ( TREX1 ) to 52% ( HTRA1 heterozygotes); cognitive features, 0% ( ADA2 ) to 64% ( HTRA1 homozygotes); and psychiatric features, 0% ( COL4A2 ; ADA2 ) to 57% ( CTSA ). Among individuals with neuroimaging, vascular radiological phenotypes appeared common, ranging from 62% ( ADA2 ) to 100% ( HTRA1 homozygotes; CTSA ). White matter lesions were the most common pathology, except in ADA2 and COL4A2 cases, where ischemic and hemorrhagic lesions dominated, respectively. Conclusions There appear to be differences in cerebral manifestations across cSVD genes. Vascular radiological changes were more common than clinical neurological phenotypes, and present in the majority of individuals with reported neuroimaging. However, these results may be affected by age and biases inherent to case reports. In the future, better characterization of associated phenotypes, as well as insights from population‐based studies, should improve our understanding of monogenic cSVD to inform genetic testing, guide clinical management, and help unravel underlying disease mechanisms.

Case report: Two unique nonsense mutations in HTRA1-related cerebral small vessel disease in a Chinese population and literature review

“…Radiologic hallmarks of CARASIL include high-signal-intensity lesions in the periventricular and deep white matter and multiple lacunar infarcts in the basal ganglia and the thalamus, but the superficial white matter is generally spared ( 11 ). Whittaker et al ( 12 ) have also reported that microbleeds are mostly found in the deep white matter of the brain in patients with heterozygous HTRA1 mutations. Our findings are consistent with the results of the above studies, in that both of these patients had diffuse WMLs and chronic microbleeds in the deep white matter and lacunar infarcts in the basal ganglia and the corona radiata.…”

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

“…Pathway analyses highlight ECM structure and function, known to play an important role in cSVD 5 , 20 , 21 , and several loci include genes involved in the matrisome (ECM and associated proteins), perturbations of which were proposed as a convergent pathologic pathway in cSVD ( LAMC1 , EFEMP1 , COL4A2 , SH3PXD2A , VWA2 ) 5 , 21 . Several PVS risk loci (at FOXF2 , EFEMP1 , KCNK2 and NBEAL1-ICA1L ) are known risk loci for other cSVD features (WMH, SVS) 5 , 22 , 23 , and mutations in two MTAG genes cause monogenic SVD (at COL4A1-COL4A2 and STN1 ) 24 , 25 .…”

Genetic Causes of Cerebral Small Vessel Diseases

“…51 In a subset of patients, brain calcifications, schizencephaly, and cerebellar atrophy have been found. 49 Patients with all the subtypes of HCHWA develop a neuroimaging picture which resembles that of the sporadic forms of CAA. Besides periventricular and/or subcortical WMHs, hemorrhages in different stages of evolution are commonly found.…”

“…19,48 Unlike patients with COL4A2 mutations, a variable degree of brain atrophy is described in those affected by COL4A1 -related CSVD, with rare involvement of corpus callosum. 48,49 In subjects with the HANAC syndrome, WMHs can be periventricular, subcortical, and/or subtentorial, involving the centrum semiovale, internal and external capsules, frontal and parietal lobes, and, rarely, the pons, but sparing the posterior cerebral regions. 50 A specific additional MRI element of COL4A1 -related CSVD and HANAC syndrome is represented by intracranial aneurysms, which are often asymptomatic, multiple in up to 50% of patients and mainly involve intracranial carotid (as in HANAC) and middle cerebral and basilar arteries.…”

“…51 In a subset of patients, brain calcifications, schizencephaly, and cerebellar atrophy have been found. 49…”